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Sample records for allergic lung inflammation

  1. Iron supplementation decreases severity of allergic inflammation in murine lung.

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    Laura P Hale

    Full Text Available The incidence and severity of allergic asthma have increased over the last century, particularly in the United States and other developed countries. This time frame was characterized by marked environmental changes, including enhanced hygiene, decreased pathogen exposure, increased exposure to inhaled pollutants, and changes in diet. Although iron is well-known to participate in critical biologic processes such as oxygen transport, energy generation, and host defense, iron deficiency remains common in the United States and world-wide. The purpose of these studies was to determine how dietary iron supplementation affected the severity of allergic inflammation in the lungs, using a classic model of IgE-mediated allergy in mice. Results showed that mice fed an iron-supplemented diet had markedly decreased allergen-induced airway hyperreactivity, eosinophil infiltration, and production of pro-inflammatory cytokines, compared with control mice on an unsupplemented diet that generated mild iron deficiency but not anemia. In vitro, iron supplementation decreased mast cell granule content, IgE-triggered degranulation, and production of pro-inflammatory cytokines post-degranulation. Taken together, these studies show that iron supplementation can decrease the severity of allergic inflammation in the lung, potentially via multiple mechanisms that affect mast cell activity. Further studies are indicated to determine the potential of iron supplementation to modulate the clinical severity of allergic diseases in humans.

  2. The Coordinated Action of CC Chemokines in the Lung Orchestrates Allergic Inflammation and Airway Hyperresponsiveness

    OpenAIRE

    Gonzalo, Jose-Angel; Lloyd, Clare M.; Wen, Danyi; Albar, Juan P.; Wells, Timothy N.C.; Proudfoot, Amanda; Martinez-A, C.; Dorf, Martin; Bjerke, Torbjörn; Coyle, Anthony J.; Gutierrez-Ramos, Jose-Carlos

    1998-01-01

    The complex pathophysiology of lung allergic inflammation and bronchial hyperresponsiveness (BHR) that characterize asthma is achieved by the regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes correlate with the coordinated production of chemokines. Here, we have assessed the role that different chemokines play in lung allergic inflammation and BHR by blocking their activities in vivo. Our results show that bloc...

  3. Bystander suppression of allergic airway inflammation by lung resident memory CD8+ T cells

    Science.gov (United States)

    Marsland, Benjamin J.; Harris, Nicola L.; Camberis, Mali; Kopf, Manfred; Hook, Sarah M.; Le Gros, Graham

    2004-04-01

    CD8+ memory T cells have recently been recognized as playing a key role in natural immunity against unrelated viral infections, a phenomenon referred to as "heterologous antiviral immunity." We now provide data that the cellular immunological interactions that underlie such heterologous immunity can play an equally important role in regulating T helper 2 immune responses and protecting mucosal surfaces from allergen-induced inflammation. Our data show that CD8+ T cells, either retained in the lung after infection with influenza virus, or adoptively transferred via the intranasal route can suppress allergic airway inflammation. The suppression is mediated by IFN-, which acts to reduce the activation level, T helper 2 cytokine production, airways hyperresponsiveness, and migration of allergen-specific CD4+ T cells into the lung, whereas the systemic and draining lymph node responses remain unchanged. Of note, adoptive transfer of previously activated transgenic CD8+ T cells conferred protection against allergic airway inflammation, even in the absence of specific-antigen. Airway resident CD8+ T cells produced IFN- when directly exposed to conditioned media from activated dendritic cells or the proinflammatory cytokines IL-12 and IL-18. Taken together these data indicate that effector/memory CD8+ T cells present in the airways produce IFN- after inflammatory stimuli, independent of specific-antigen, and as a consequence play a key role in modifying the degree and frequency of allergic responses in the lung.

  4. Allergic lung inflammation alters neither susceptibility to Streptococcus pneumoniae infection nor inducibility of innate resistance in mice

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    Evans Christopher M

    2009-07-01

    Full Text Available Abstract Background Protective host responses to respiratory pathogens are typically characterized by inflammation. However, lung inflammation is not always protective and it may even become deleterious to the host. We have recently reported substantial protection against Streptococcus pneumoniae (pneumococcal pneumonia by induction of a robust inflammatory innate immune response to an inhaled bacterial lysate. Conversely, the allergic inflammation associated with asthma has been proposed to promote susceptibility to pneumococcal disease. This study sought to determine whether preexisting allergic lung inflammation influences the progression of pneumococcal pneumonia or reduces the inducibilty of protective innate immunity against bacteria. Methods To compare the effect of different inflammatory and secretory stimuli on defense against pneumonia, intraperitoneally ovalbumin-sensitized mice were challenged with inhaled pneumococci following exposure to various inhaled combinations of ovalbumin, ATP, and/or a bacterial lysate. Thus, allergic inflammation, mucin degranulation and/or stimulated innate resistance were induced prior to the infectious challenge. Pathogen killing was evaluated by assessing bacterial CFUs of lung homogenates immediately after infection, the inflammatory response to the different conditions was evaluated by measurement of cell counts of bronchoalveolar lavage fluid 18 hours after challenge, and mouse survival was assessed after seven days. Results We found no differences in survival of mice with and without allergic inflammation, nor did the induction of mucin degranulation alter survival. As we have found previously, mice treated with the bacterial lysate demonstrated substantially increased survival at seven days, and this was not altered by the presence of allergic inflammation or mucin degranulation. Allergic inflammation was associated with predominantly eosinophilic infiltration, whereas the lysate-induced response

  5. VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice.

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    Jesse M Damsker

    Full Text Available Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation--NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone--but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases.

  6. VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice.

    Science.gov (United States)

    Damsker, Jesse M; Dillingham, Blythe C; Rose, Mary C; Balsley, Molly A; Heier, Christopher R; Watson, Alan M; Stemmy, Erik J; Jurjus, Roslyn A; Huynh, Tony; Tatem, Kathleen; Uaesoontrachoon, Kitipong; Berry, Dana M; Benton, Angela S; Freishtat, Robert J; Hoffman, Eric P; McCall, John M; Gordish-Dressman, Heather; Constant, Stephanie L; Reeves, Erica K M; Nagaraju, Kanneboyina

    2013-01-01

    Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation--NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone--but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases. PMID:23667681

  7. Eosinophilic inflammation in allergic asthma

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    Samantha Souza Possa

    2013-04-01

    Full Text Available Eosinophils are circulating granulocytes involved in pathogenesis of asthma. A cascade of processes directed by Th2 cytokine producing T-cells influence the recruitment of eosinophils into the lungs. Furthermore, multiple elements including interleukin (IL-5, IL-13, chemoattractants such as eotaxin, Clara cells, and CC chemokine receptor (CCR3 are already directly involved in recruiting eosinophils to the lung during allergic inflammation. Once recruited, eosinophils participate in the modulation of immune response, induction of airway hyperresponsiveness and remodeling, characteristic features of asthma. Various types of promising treatments for reducing asthmatic response are related to reduction in eosinophil counts both in human and experimental models of pulmonary allergic inflammation, showing that the recruitment of these cells really plays an important role in the pathophysiology of allergic diseases such asthma.

  8. Eosinophilic inflammation in allergic asthma

    OpenAIRE

    IolandaFátima Lopes CalvoTibério; CarlaMáximoPrado

    2013-01-01

    Eosinophils are circulating granulocytes involved in pathogenesis of asthma. A cascade of processes directed by Th2 cytokine producing T-cells influence the recruitment of eosinophils into the lungs. Furthermore, multiple elements including interleukin (IL)-5, IL-13, chemoattractants such as eotaxin, Clara cells, and CC chemokine receptor (CCR)3 are already directly involved in recruiting eosinophils to the lung during allergic inflammation. Once recruited, eosinophils participate in the modu...

  9. Eosinophilic Inflammation in Allergic Asthma

    OpenAIRE

    Possa, Samantha S.; Leick, Edna A; Carla M. Prado; Martins, Mílton A.; Tibério, Iolanda F. L. C.

    2013-01-01

    Eosinophils are circulating granulocytes involved in pathogenesis of asthma. A cascade of processes directed by Th2 cytokine producing T-cells influence the recruitment of eosinophils into the lungs. Furthermore, multiple elements including interleukin (IL)-5, IL-13, chemoattractants such as eotaxin, Clara cells, and CC chemokine receptor (CCR)3 are already directly involved in recruiting eosinophils to the lung during allergic inflammation. Once recruited, eosinophils participate in the modu...

  10. IL-12 can alleviate Th17-mediated allergic lung inflammation through induction of pulmonary IL-10 expression

    OpenAIRE

    Durrant, DM; Metzger, DW

    2010-01-01

    Interleukin (IL)-12 has been shown to suppress T helper type 2 (Th2)-induced pathogenesis that is associated with allergic asthma, largely through interferon (IFN)-γ production. We have recently shown that in the absence of T-bet, the major regulator of IFN-γ expression, allergic lung inflammation is primarily associated with IL-17-associated recruitment of neutrophils into the pulmonary tract of mice. In the absence of T-bet, exogenous IL-12 was still able to suppress neutrophilic infiltrati...

  11. Periostin in Allergic Inflammation

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    Kenji Izuhara

    2014-01-01

    Full Text Available Periostin, an extracellular matrix protein belonging to the fasciclin family, has been shown to play a critical role in the process of remodeling during tissue/organ development or repair. Periostin functions as a matricellular protein in cell activation by binding to their receptors on cell surface, thereby exerting its biological activities. After we found that periostin is a downstream molecule of interleukin (IL-4 and IL-13, signature cytokines of type 2 immune responses, we showed that periostin is a component of subepithelial fibrosis in bronchial asthma, the first formal proof that periostin is involved in allergic inflammation. Subsequently, a great deal of evidence has accumulated demonstrating the significance of periostin in allergic inflammation. It is of note that in skin tissues, periostin is critical for amplification and persistence of allergic inflammation by communicating between fibroblasts and keratinocytes. Furthermore, periostin has been applied to development of novel diagnostics or therapeutic agents for allergic diseases. Serum periostin can reflect local production of periostin in inflamed lesions induced by Th2-type immune responses and also can predict the efficacy of Th2 antagonists against bronchial asthma. Blocking the interaction between periostin and its receptor, αv integrin, or down-regulating the periostin expression shows improvement of periostin-induced inflammation in mouse models or in in vitro systems. It is hoped that diagnostics or therapeutic agents targeting periostin will be of practical use in the near future.

  12. The sickle cell mouse lung: proinflammatory and primed for allergic inflammation.

    Science.gov (United States)

    Andemariam, Biree; Adami, Alexander J; Singh, Anurag; McNamara, Jeffrey T; Secor, Eric R; Guernsey, Linda A; Thrall, Roger S

    2015-09-01

    Comorbid asthma in sickle cell disease (SCD) confers higher rates of vaso-occlusive pain and mortality, yet the physiological link between these two distinct diseases remains puzzling. We used a mouse model of SCD to study pulmonary immunology and physiology before and after the induction of allergic airway disease (AAD). SCD mice were sensitized with ovalbumin (OVA) and aluminum hydroxide by the intraperitoneal route followed by daily, nose-only OVA-aerosol challenge to induce AAD. The lungs of naive SCD mice showed signs of inflammatory and immune processes: (1) histologic and cytochemical evidence of airway inflammation compared with naive wild-type mice; (2) bronchoalveolar lavage (BAL) fluid contained increased total lymphocytes, %CD8+ T cells, granulocyte-colony stimulating factor, interleukin 5 (IL-5), IL-7, and chemokine (C-X-C motif) ligand (CXCL)1; and (3) lung tissue and hilar lymph node (HLN) had increased CD4+, CD8+, and regulatory T (Treg) cells. Furthermore, SCD mice at AAD demonstrated significant changes compared with the naive state: (1) BAL fluid with increased %CD4+ T cells and Treg cells, lower %CD8+ T cells, and decreased interferon gamma, CXCL10, chemokine (C-C motif) ligand 2, and IL-17; (2) serum with increased OVA-specific immunoglobulin E, IL-6, and IL-13, and decreased IL-1α and CXCL10; (3) no increase in Treg cells in the lung tissue or HLN; and (4) hyporesponsiveness to methacholine challenge. In conclusion, SCD mice have an altered immunologic pulmonary milieu and physiological responsiveness. These findings suggest that the clinical phenotype of AAD in SCD mice differs from that of wild-type mice and that individuals with SCD may also have a unique, divergent phenotype perhaps amenable to a different therapeutic approach. PMID:25843670

  13. Effects of bone marrow mononuclear cells from healthy or ovalbumin-induced lung inflammation donors on recipient allergic asthma mice

    OpenAIRE

    Abreu, Soraia C.; Antunes, Mariana A.; Mendonça, Lucas; Branco, Vivian C; de Melo, Elga Bandeira; Olsen, Priscilla C.; Diaz, Bruno L.; Weiss, Daniel J; Paredes, Bruno D; Xisto, Debora G.; Morales, Marcelo M; Rocco, Patricia RM

    2014-01-01

    Introduction Asthma is characterized by a chronic inflammatory process which may lead to several changes in bone marrow cell composition. We hypothesized that bone marrow mononuclear cells (BMMCs) obtained from ovalbumin (OVA)-induced lung inflammation mice may promote different effects compared to BMMCs from healthy donors in a model of allergic asthma. Methods C57BL/6 mice were randomly assigned to two groups. In the OVA group, mice were sensitized and challenged with ovalbumin, while healt...

  14. Preventing carbon nanoparticle-induced lung inflammation reduces antigen-specific sensitization and subsequent allergic reactions in a mouse model

    OpenAIRE

    Kroker, Matthias; Sydlik, Ulrich; Autengruber, Andrea; Cavelius, Christian; Weighardt, Heike; Kraegeloh, Annette; Unfried, Klaus

    2015-01-01

    Background Exposure of the airways to carbonaceous nanoparticles can contribute to the development of immune diseases both via the aggravation of the allergic immune response in sensitized individuals and by adjuvant mechanisms during the sensitization against allergens. The cellular and molecular mechanisms involved in these adverse pathways are not completely understood. We recently described that the reduction of carbon nanoparticle-induced lung inflammation by the application of the compa...

  15. Adoptive transfer of IL-4Rα+ macrophages is sufficient to enhance eosinophilic inflammation in a mouse model of allergic lung inflammation

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    Ford Andrew Q

    2012-01-01

    Full Text Available Abstract Background The IL-4 receptor α (IL-4Rα chain has a broad expression pattern and participates in IL-4 and IL-13 signaling, allowing it to influence several pathological components of allergic lung inflammation. We previously reported that IL-4Rα expression on both bone marrow-derived and non-bone marrow-derived cells contributed to the severity of allergic lung inflammation. There was a correlation between the number of macrophages expressing the IL-4Rα, CD11b, and IAd, and the degree of eosinophilia in ovalbumin challenged mice. The engagement of the IL-4Rα by IL-4 or IL-13 is able to stimulate the alternative activation of macrophages (AAM. The presence of AAM has been correlated with inflammatory responses to parasites and allergens. Therefore, we hypothesized that IL-4Rα+ AAM play an active role in allergic lung inflammation. To directly determine the role of AAM in allergic lung inflammation, M-CSF-dependent macrophages (BMM were prepared from the bone-marrow of IL-4Rα positive and negative mice and transferred to IL-4RαxRAG2-/- mice. Wild type TH2 cells were provided exogenously. Results Mice receiving IL-4Rα+/+ BMM showed a marked increase in the recruitment of eosinophils to the lung after challenge with ovalbumin as compared to mice receiving IL-4Rα-/- BMM. As expected, the eosinophilic inflammation was dependent on the presence of TH2 cells. Furthermore, we observed an increase in cells expressing F4/80 and Mac3, and the AAM marker YM1/2 in the lungs of mice receiving IL-4Rα+/+ BMM. The BAL fluid from these mice contained elevated levels of eotaxin-1, RANTES, and CCL2. Conclusions These results demonstrate that transfer of IL-4Rα + macrophages is sufficient to enhance TH2-driven, allergic inflammation. They further show that stimulation of macrophages through IL-4Rα leads to their alternative activation and positive contribution to the TH2-driven allergic inflammatory response in the lung. Since an increase in AAM

  16. Induction and effector phase of allergic lung inflammation is independent of CCL21/CCL19 and LT-beta

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    Corinne Ploix, Riaz I. Zuberi, Fu-Tong Liu, Monica J. Carson, David D. Lo

    2009-01-01

    Full Text Available The chemokines CCL21 and CCL19, and cell bound TNF family ligand lymphotoxin beta (LTβ, have been associated with numerous chronic inflammatory diseases. A general role in chronic inflammatory diseases cannot be assumed however; in the case of allergic inflammatory disease, CCL21/CCL19 and LTβ have not been associated with the induction, recruitment, or effector function of Th2 cells nor dendritic cells to the lung. We have examined the induction of allergic inflammatory lung disease in mice deficient in CCL21/CCL19 or LTβ and found that both kinds of mice can develop allergic lung inflammation. To control for effects of priming differences in knockout mice, adoptive transfers of Th2 cells were also performed, and they showed that such effector cells had equivalent effects on airway hyper-responsiveness in both knockout background recipients. Moreover, class II positive antigen presenting cells (B cells and CD11c+ dendritic cells showed normal recruitment to the peribronchial spaces along with CD4 T cells. Thus, the induction of allergic responses and recruitment of both effector Th2 cells and antigen presenting cells to lung peribronchial spaces can develop independently of CCL21/CCL19 and LTβ.

  17. Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

    OpenAIRE

    Dulek, Daniel E.; Newcomb, Dawn C.; Goleniewska, Kasia; Cephus, Jaqueline; Zhou, Weisong; Reiss, Sara; Toki, Shinji; Ye, Fei; Zaynagetdinov, Rinat; Sherrill, Taylor P.; Timothy S. Blackwell; Moore, Martin L.; Boyd, Kelli L.; Kolls, Jay K.; Peebles, R. Stokes

    2014-01-01

    The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infect...

  18. Allergen-Experienced Group 2 Innate Lymphoid Cells Acquire Memory-like Properties and Enhance Allergic Lung Inflammation.

    Science.gov (United States)

    Martinez-Gonzalez, Itziar; Mathä, Laura; Steer, Catherine A; Ghaedi, Maryam; Poon, Grace F T; Takei, Fumio

    2016-07-19

    Group 2 innate lymphoid cells (ILC2s) in the lung are stimulated by inhaled allergens. ILC2s do not directly recognize allergens but they are stimulated by cytokines including interleukin (IL)-33 released by damaged epithelium. In response to allergens, lung ILC2s produce T helper 2 cell type cytokines inducing T cell-independent allergic lung inflammation. Here we examined the fate of lung ILC2s upon allergen challenges. ILC2s proliferated and secreted cytokines upon initial stimulation with allergen or IL-33, and this phase was followed by a contraction phase as cytokine production ceased. Some ILC2s persisted long after the resolution of the inflammation as allergen-experienced ILC2s and responded to unrelated allergens more potently than naive ILC2s, mediating severe allergic inflammation. The allergen-experienced ILC2s exhibited a gene expression profile similar to that of memory T cells. The memory-like properties of allergen-experienced ILC2s may explain why asthma patients are often sensitized to multiple allergens. PMID:27421705

  19. Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring

    International Nuclear Information System (INIS)

    Formaldehyde (FA) is an environmental and occupational pollutant, and its toxic effects on the immune system have been shown. Nevertheless, no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring. In this study, our objective was to investigate the effects of low-dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring. Pregnant Wistar rats were assigned in 3 groups: P (rats exposed to FA (0.75 ppm, 1 h/day, 5 days/week, for 21 days)), C (rats exposed to vehicle of FA (distillated water)) and B (rats non-manipulated). After 30 days of age, the offspring was sensitised with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge the parameters were evaluated. Our data showed that low-dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis, IL-6 and TNF-alpha secretion. Elevated levels of IL-10 were found. Any systemic alteration was detected in the exposed pregnant rats, although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated COX-1 expression and reduced cNOS and SOD-2 in the uterus. Therefore, we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment. - Highlights: • Formaldehyde exposure does not cause lung inflammation in pregnant rats. • Formaldehyde exposure suppresses allergic lung inflammation in the offspring. • Formaldehyde exposure induces oxidative stress in uterine environment

  20. Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring

    Energy Technology Data Exchange (ETDEWEB)

    Maiellaro, Marília [Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo (Brazil); Correa-Costa, Matheus [Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo (Brazil); Vitoretti, Luana Beatriz; Gimenes Júnior, João Antônio [Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo (Brazil); Câmara, Niels Olsen Saraiva [Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo (Brazil); Tavares-de-Lima, Wothan [Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo (Brazil); Farsky, Sandra Helena Poliselli [Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo (Brazil); Lino-dos-Santos-Franco, Adriana, E-mail: adrilino@usp.br [Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo (Brazil)

    2014-08-01

    Formaldehyde (FA) is an environmental and occupational pollutant, and its toxic effects on the immune system have been shown. Nevertheless, no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring. In this study, our objective was to investigate the effects of low-dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring. Pregnant Wistar rats were assigned in 3 groups: P (rats exposed to FA (0.75 ppm, 1 h/day, 5 days/week, for 21 days)), C (rats exposed to vehicle of FA (distillated water)) and B (rats non-manipulated). After 30 days of age, the offspring was sensitised with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge the parameters were evaluated. Our data showed that low-dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis, IL-6 and TNF-alpha secretion. Elevated levels of IL-10 were found. Any systemic alteration was detected in the exposed pregnant rats, although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated COX-1 expression and reduced cNOS and SOD-2 in the uterus. Therefore, we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment. - Highlights: • Formaldehyde exposure does not cause lung inflammation in pregnant rats. • Formaldehyde exposure suppresses allergic lung inflammation in the offspring. • Formaldehyde exposure induces oxidative stress in uterine environment.

  1. Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice

    DEFF Research Database (Denmark)

    Hansen, Jitka S; Nørgaard, Asger W; Koponen, Ismo K;

    2016-01-01

    and pulmonary irritation was investigated in addition to ovalbumin-specific antibodies, inflammatory cells, total protein and surfactant protein D in bronchoalveolar lavage fluid and hemeoxygenase-1 and cytokines in lung tissue. Overall, airway allergy was not exacerbated by any of the exposures. In contrast...... showed that irritation responses might be modulated by airway allergy. However, aggravation of allergic symptoms was observed by neither exposure to ozone nor exposure to ozone-initiated limonene reaction products. In contrast, anti-inflammatory properties of the tested limonene-containing pollutants...... might attenuate airway allergy....

  2. Neuroimmune semaphorin 4D is necessary for optimal lung allergic inflammation.

    Science.gov (United States)

    Shanks, K; Nkyimbeng-Takwi, E H; Smith, E; Lipsky, M M; DeTolla, L J; Scott, D W; Keegan, A D; Chapoval, S P

    2013-12-01

    Neuroimmune semaphorin 4D (Sema4D) was found to be expressed and function in the nervous and immune systems. In the immune system, Sema4D is constitutively expressed on T cells and regulates T cell priming. In addition, it displays a stimulatory function on macrophages, DC, NK cells, and neutrophils. As all these cells are deeply involved in asthma pathology, we hypothesized that Sema4D plays a critical non-redundant regulatory role in allergic airway response. To test our hypothesis, we exposed Sema4D(-/-) and WT mice to OVA injections and challenges in the well-defined mouse model of OVA-induced experimental asthma. We observed a significant decrease in eosinophilic airway infiltration in allergen-treated Sema4D(-/-) mice relative to WT mice. This reduced allergic inflammatory response was associated with decreased BAL IL-5, IL-13, TGFβ1, IL-6, and IL-17A levels. In addition, T cell proliferation in OVA₃₂₃₋₃₃₉-restimulated Sema4D(-/-) cell cultures was downregulated. We also found increased Treg numbers in spleens of Sema4D(-/-) mice. However, airway hyperreactivity (AHR) to methacholine challenges was not affected by Sema4D deficiency in either acute or chronic experimental disease setting. Surprisingly, lung DC number and activation were not affected by Sema4D deficiency. These data provide a new insight into Sema4D biology and define Sema4D as an important regulator of Th2-driven lung pathophysiology and as a potential target for a combinatory disease immunotherapy. PMID:23911404

  3. Silibinin attenuates allergic airway inflammation in mice

    International Nuclear Information System (INIS)

    Highlights: ► Silibinin diminishes ovalbumin-induced inflammatory reactions in the mouse lung. ► Silibinin reduces the levels of various cytokines into the lung of allergic mice. ► Silibinin prevents the development of airway hyperresponsiveness in allergic mice. ► Silibinin suppresses NF-κB transcriptional activity. -- Abstract: Allergic asthma is a chronic inflammatory disease regulated by coordination of T-helper2 (Th2) type cytokines and inflammatory signal molecules. Silibinin is one of the main flavonoids produced by milk thistle, which is reported to inhibit the inflammatory response by suppressing the nuclear factor-kappa B (NF-κB) pathway. Because NF-κB activation plays a pivotal role in the pathogenesis of allergic inflammation, we have investigated the effect of silibinin on a mouse ovalbumin (OVA)-induced asthma model. Airway hyperresponsiveness, cytokines levels, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. Pretreatment of silibinin significantly inhibited airway inflammatory cell recruitment and peribronchiolar inflammation and reduced the production of various cytokines in bronchoalveolar fluid. In addition, silibinin prevented the development of airway hyperresponsiveness and attenuated the OVA challenge-induced NF-κB activation. These findings indicate that silibinin protects against OVA-induced airway inflammation, at least in part via downregulation of NF-κB activity. Our data support the utility of silibinin as a potential medicine for the treatment of asthma.

  4. Silibinin attenuates allergic airway inflammation in mice

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Yun Ho [Department of Anatomy, Medical School, Institute for Medical Sciences, Chonbuk National University, Jeonju, Jeonbuk 561-756 (Korea, Republic of); Jin, Guang Yu [Department of Radiology, Yanbian University Hospital, YanJi 133002 (China); Guo, Hui Shu [Centralab, The First Affiliated Hospital of Dalian Medical University, Dalian 116011 (China); Piao, Hong Mei [Department of Respiratory Medicine, Yanbian University Hospital, YanJi 133000 (China); Li, Liang chang; Li, Guang Zhao [Department of Anatomy and Histology and Embryology, Yanbian University School of Basic Medical Sciences, 977 Gongyuan Road, YanJi 133002, Jilin (China); Lin, Zhen Hua [Department of Pathology, Yanbian University School of Basic Medical Sciences, YanJi 133000 (China); Yan, Guang Hai, E-mail: ghyan@ybu.edu.cn [Department of Anatomy and Histology and Embryology, Yanbian University School of Basic Medical Sciences, 977 Gongyuan Road, YanJi 133002, Jilin (China)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer Silibinin diminishes ovalbumin-induced inflammatory reactions in the mouse lung. Black-Right-Pointing-Pointer Silibinin reduces the levels of various cytokines into the lung of allergic mice. Black-Right-Pointing-Pointer Silibinin prevents the development of airway hyperresponsiveness in allergic mice. Black-Right-Pointing-Pointer Silibinin suppresses NF-{kappa}B transcriptional activity. -- Abstract: Allergic asthma is a chronic inflammatory disease regulated by coordination of T-helper2 (Th2) type cytokines and inflammatory signal molecules. Silibinin is one of the main flavonoids produced by milk thistle, which is reported to inhibit the inflammatory response by suppressing the nuclear factor-kappa B (NF-{kappa}B) pathway. Because NF-{kappa}B activation plays a pivotal role in the pathogenesis of allergic inflammation, we have investigated the effect of silibinin on a mouse ovalbumin (OVA)-induced asthma model. Airway hyperresponsiveness, cytokines levels, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. Pretreatment of silibinin significantly inhibited airway inflammatory cell recruitment and peribronchiolar inflammation and reduced the production of various cytokines in bronchoalveolar fluid. In addition, silibinin prevented the development of airway hyperresponsiveness and attenuated the OVA challenge-induced NF-{kappa}B activation. These findings indicate that silibinin protects against OVA-induced airway inflammation, at least in part via downregulation of NF-{kappa}B activity. Our data support the utility of silibinin as a potential medicine for the treatment of asthma.

  5. Neuroimmune semaphorin 4D is necessary for optimal lung allergic inflammation

    OpenAIRE

    Shanks, K; Nkyimbeng-Takwi, EH; Smith, E.; Lipsky, MM; DeTolla, LJ; Scott, DW; Keegan, AD; Chapoval, SP

    2013-01-01

    Neuroimmune semaphorin 4D (Sema4D) was found to be expressed and function in the nervous and immune systems. In the immune system, Sema4D is constitutively expressed on T cells and regulates T cell priming. In addition, it displays a stimulatory function on macrophages, DC, NK cells, and neutrophils. As all these cells are deeply involved in asthma pathology, we hypothesized that Sema4D plays a critical non-redundant regulatory role in allergic airway response. To test our hypothesis, we expo...

  6. Budesonide suppresses pulmonary antibacterial host defense by down-regulating cathelicidin-related antimicrobial peptide in allergic inflammation mice and in lung epithelial cells

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    Wang Peng

    2013-02-01

    Full Text Available Abstract Background Glucocorticoids are widely regarded as the most effective treatment for asthma. However, the direct impact of glucocorticoids on the innate immune system and antibacterial host defense during asthma remain unclear. Understanding the mechanisms underlying this process is critical to the clinical application of glucocorticoids for asthma therapy. After sensitization and challenge with ovalbumin (OVA, BALB/c mice were treated with inhaled budesonide and infected with Pseudomonas aeruginosa (P. aeruginosa. The number of viable bacteria in enflamed lungs was evaluated, and levels of interleukin-4 (IL-4 and interferon-γ (IFN-γ in serum were measured. A lung epithelial cell line was pretreated with budesonide. Levels of cathelicidin-related antimicrobial peptide (CRAMP were measured by immunohistochemistry and western blot analysis. Intracellular bacteria were observed in lung epithelial cells. Results Inhaled budesonide enhanced lung infection in allergic mice exposed to P. aeruginosa and increased the number of viable bacteria in lung tissue. Higher levels of IL-4 and lower levels of IFN-γ were observed in the serum. Budesonide decreased the expression of CRAMP, increased the number of internalized P. aeruginosa in OVA-challenged mice and in lung epithelial cell lines. These data indicate that inhaled budesonide can suppress pulmonary antibacterial host defense by down-regulating CRAMP in allergic inflammation mice and in cells in vitro. Conclusions Inhaled budesonide suppressed pulmonary antibacterial host defense in an asthmatic mouse model and in lung epithelium cells in vitro. This effect was dependent on the down-regulation of CRAMP.

  7. Surfactant and allergic airway inflammation.

    Science.gov (United States)

    Winkler, Carla; Hohlfeld, Jens M

    2013-01-01

    Pulmonary surfactant is a complex mixture of unique proteins and lipids that covers the airway lumen. Surfactant prevents alveolar collapse and maintains airway patency by reducing surface tension at the air-liquid interface. Furthermore, it provides a defence against antigen uptake by binding foreign particles and enhancing cellular immune responses. Allergic asthma is associated with chronic airway inflammation and presents with episodes of airway narrowing. The pulmonary inflammation and bronchoconstriction can be triggered by exposure to allergens or pathogens present in the inhaled air. Pulmonary surfactant has the potential to interact with various immune cells which orchestrate allergen- or pathogen-driven episodes of airway inflammation. The complex nature of surfactant allows multiple sites of interaction, but also makes it susceptible to external alterations, which potentially impair its function. This duality of modulating airway physiology and immunology during inflammatory conditions, while at the same time being prone to alterations accompanied by restricted function, has stimulated numerous studies in recent decades, which are reviewed in this article. PMID:23896983

  8. Neutrophil Inhibitory Factor Selectively Inhibits the Endothelium-Driven Transmigration of Eosinophils In Vitro and Airway Eosinophilia in OVA-Induced Allergic Lung Inflammation

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    Silvia Schnyder-Candrian

    2012-01-01

    Full Text Available Leukocyte adhesion molecules are involved in cell recruitment in an allergic airway response and therefore provide a target for pharmaceutical intervention. Neutrophil inhibitory factor (NIF, derived from canine hookworm (Ancylostoma caninum, binds selectively and competes with the A-domain of CD11b for binding to ICAM-1. The effect of recombinant NIF was investigated. Intranasal administration of rNIF reduced pulmonary eosinophilic infiltration, goblet cell hyperplasia, and Th2 cytokine production in OVA-sensitized mice. In vitro, transendothelial migration of human blood eosinophils across IL-4-activated umbilical vein endothelial cell (HUVEC monolayers was inhibited by rNIF (IC50: 4.6±2.6 nM; mean ± SEM, but not across TNF or IL-1-activated HUVEC monolayers. Treatment of eosinophils with rNIF together with mAb 60.1 directed against CD11b or mAb 107 directed against the metal ion-dependent adhesion site (MIDAS of the CD11b A-domain resulted in no further inhibition of transendothelial migration suggesting shared functional epitopes. In contrast, rNIF increased the inhibitory effect of blocking mAbs against CD18, CD11a, and VLA-4. Together, we show that rNIF, a selective antagonist of the A-domain of CD11b, has a prominent inhibitory effect on eosinophil transendothelial migration in vitro, which is congruent to the in vivo inhibition of OVA-induced allergic lung inflammation.

  9. Mucosal exposure to cockroach extract induces allergic sensitization and allergic airway inflammation

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    Arizmendi Narcy G

    2011-12-01

    Full Text Available Abstract Background Allergic sensitization to aeroallergens develops in response to mucosal exposure to these allergens. Allergic sensitization may lead to the development of asthma, which is characterized by chronic airway inflammation. The objective of this study is to describe in detail a model of mucosal exposure to cockroach allergens in the absence of an exogenous adjuvant. Methods Cockroach extract (CE was administered to mice intranasally (i.n. daily for 5 days, and 5 days later mice were challenged with CE for 4 consecutive days. A second group received CE i.n. for 3 weeks. Airway hyperresponsiveness (AHR was assessed 24 h after the last allergen exposure. Allergic airway inflammation was assessed by BAL and lung histology 48 h after the last allergen exposure. Antigen-specific antibodies were assessed in serum. Lungs were excised from mice from measurement of cytokines and chemokines in whole lung lysate. Results Mucosal exposure of Balb/c mice to cockroach extract induced airway eosinophilic inflammation, AHR and cockroach-specific IgG1; however, AHR to methacholine was absent in the long term group. Lung histology showed patchy, multicentric damage with inflammatory infiltrates at the airways in both groups. Lungs from mice from the short term group showed increased IL-4, CCL11, CXCL1 and CCL2 protein levels. IL4 and CXCL1 were also increased in the BAL of cockroach-sensitized mice in the short-term protocol. Conclusions Mucosal exposure to cockroach extract in the absence of adjuvant induces allergic airway sensitization characterized by AHR, the presence of Th2 cytokines in the lung and eosinophils in the airways.

  10. Role of platelets in allergic airway inflammation.

    Science.gov (United States)

    Idzko, Marco; Pitchford, Simon; Page, Clive

    2015-06-01

    Increasing evidence suggests an important role for platelets and their products (e.g., platelet factor 4, β-thromboglobulin, RANTES, thromboxane, or serotonin) in the pathogenesis of allergic diseases. A variety of changes in platelet function have been observed in patients with asthma, such as alterations in platelet secretion, expression of surface molecules, aggregation, and adhesion. Moreover, platelets have been found to actively contribute to most of the characteristic features of asthma, including bronchial hyperresponsiveness, bronchoconstriction, airway inflammation, and airway remodeling. This review brings together the current available data from both experimental and clinical studies that have investigated the role of platelets in allergic airway inflammation and asthma. It is anticipated that a better understanding of the role of platelets in the pathogenesis of asthma might lead to novel promising therapeutic approaches in the treatment of allergic airway diseases. PMID:26051948

  11. Intelectin is required for IL-13-induced monocyte chemotactic protein-1 and -3 expression in lung epithelial cells and promotes allergic airway inflammation

    OpenAIRE

    Gu, Naibing; Kang, Guannan; Jin, Chang'E; Xu, Yongjian; ZHANG, ZHENXIANG; Erle, David J.; Zhen, Guohua

    2009-01-01

    Asthma is characterized by airway inflammation, mucus overproduction, airway hyperreactivity, and peribronchial fibrosis. Intelectin has been shown to be increased in airway epithelium of asthmatics. However, the role of intelectin in the pathogenesis of asthma is unknown. Airway epithelial cells can secrete chemokines such as monocyte chemotactic protein (MCP)-1 and -3 that play crucial roles in asthmatic airway inflammation. We hypothesized that intelectin plays a role in allergic airway in...

  12. Roles of IL-22 in Allergic Airway Inflammation

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    Koichi Hirose

    2013-01-01

    Full Text Available IL-23- and IL-17A-producing CD4+ T cell (Th17 cell axis plays a crucial role in the development of chronic inflammatory diseases. In addition, it has been demonstrated that Th17 cells and their cytokines such as IL-17A and IL-17F are involved in the pathogenesis of severe asthma. Recently, IL-22, an IL-10 family cytokine that is produced by Th17 cells, has been shown to be expressed at the site of allergic airway inflammation and to inhibit allergic inflammation in mice. In addition to Th17 cells, innate lymphoid cells also produce IL-22 in response to allergen challenge. Functional IL-22 receptor complex is expressed on lung epithelial cells, and IL-22 inhibits cytokine and chemokine production from lung epithelial cells. In this paper, we summarize the recent progress on the roles of IL-22 in the regulation of allergic airway inflammation and discuss its therapeutic potential in asthma.

  13. Nasal hyperreactivity and inflammation in allergic rhinitis

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    I. M. Garrelds

    1996-01-01

    Full Text Available The history of allergic disease goes back to 1819, when Bostock described his own ‘periodical affection of the eyes and chest’, which he called ‘summer catarrh’. Since they thought it was produced by the effluvium of new hay, this condition was also called hay fever. Later, in 1873, Blackley established that pollen played an important role in the causation of hay fever. Nowadays, the definition of allergy is ‘An untoward physiologic event mediated by a variety of different immunologic reactions’. In this review, the term allergy will be restricted to the IgE-dependent reactions. The most important clinical manifestations of IgE-dependent reactions are allergic conjunctivitis, allergic rhinitis, allergic asthma and atopic dermatitis. However, this review will be restricted to allergic rhinitis. The histopathological features of allergic inflammation involve an increase in blood flow and vascular permeability, leading to plasma exudation and the formation of oedema. In addition, a cascade of events occurs which involves a variety of inflammatory cells. These inflammatory cells migrate under the influence of chemotactic agents to the site of injury and induce the process of repair. Several types of inflammatory cells have been implicated in the pathogenesis of allergic rhinitis. After specific or nonspecific stimuli, inflammatory mediators are generated from cells normally found in the nose, such as mast cells, antigen-presenting cells and epithelial cells (primary effector cells and from cells recruited into the nose, such as basophils, eosinophils, lymphocytes, platelets and neutrophils (secondary effector cells. This review describes the identification of each of the inflammatory cells and their mediators which play a role in the perennial allergic processes in the nose of rhinitis patients.

  14. Transfer of in vivo primed transgenic T cells supports allergic lung inflammation and FIZZ1 and Ym1 production in an IL-4Rα and STAT6 dependent manner

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    Keegan Achsah D

    2011-10-01

    Full Text Available Abstract Background CD4+ T helper type 2 (TH2 cells, their cytokines IL-4, IL-5 and IL-13 and the transcription factor STAT6 are known to regulate various features of asthma including lung inflammation, mucus production and airway hyperreactivity and also drive alternative activation of macrophages (AAM. However, the precise roles played by the IL-4/IL-13 receptors and STAT6 in inducing AAM protein expression and modulating specific features of airway inflammation are still unclear. Since TH2 differentiation and activation plays a pivotal role in this disease, we explored the possibility of developing an asthma model in mice using T cells that were differentiated in vivo. Results In this study, we monitored the activation and proliferation status of adoptively transferred allergen-specific naïve or in vivo primed CD4+ T cells. We found that both the naïve and in vivo primed T cells expressed similar levels of CD44 and IL-4. However, in vivo primed T cells underwent reduced proliferation in a lymphopenic environment when compared to naïve T cells. We then used these in vivo generated effector T cells in an asthma model. Although there was reduced inflammation in mice lacking IL-4Rα or STAT6, significant amounts of eosinophils were still present in the BAL and lung tissue. Moreover, specific AAM proteins YM1 and FIZZ1 were expressed by epithelial cells, while macrophages expressed only YM1 in RAG2-/- mice. We further show that FIZZ1 and YM1 protein expression in the lung was completely dependent on signaling through the IL-4Rα and STAT6. Consistent with the enhanced inflammation and AAM protein expression, there was a significant increase in collagen deposition and smooth muscle thickening in RAG2-/- mice compared to mice deficient in IL-4Rα or STAT6. Conclusions These results establish that transfer of in vivo primed CD4+ T cells can induce allergic lung inflammation. Furthermore, while IL-4/IL-13 signaling through IL-4Rα and STAT6 is

  15. Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice.

    Science.gov (United States)

    Goodwin, Meagan; Sueblinvong, Viranuj; Eisenhauer, Philip; Ziats, Nicholas P; LeClair, Laurie; Poynter, Matthew E; Steele, Chad; Rincon, Mercedes; Weiss, Daniel J

    2011-07-01

    Bone marrow-derived mesenchymal stromal cells (BMSCs) mitigate inflammation in mouse models of acute lung injury. However, specific mechanisms of BMSC actions on CD4 T lymphocyte-mediated inflammation in vivo remain poorly understood. Limited data suggests promotion of Th2 phenotype in models of Th1-mediated diseases. However, whether this might alleviate or worsen Th2-mediated diseases such as allergic asthma is unknown. To ascertain the effects of systemic administration of BMSCs in a mouse model of Th2-mediated allergic airways inflammation, ovalbumin (OVA)-induced allergic airways inflammation was induced in wild-type C57BL/6 and BALB/c mice as well as in interferon-γ (IFNγ) receptor null mice. Effects of systemic administration during antigen sensitization of either syngeneic or allogeneic BMSC on airways hyperreactivity, lung inflammation, antigen-specific CD4 T lymphocytes, and serum immunoglobulins were assessed. Both syngeneic and allogeneic BMSCs inhibited airways hyperreactivity and lung inflammation through a mechanism partly dependent on IFNγ. However, contrary to existing data, BMSCs did not affect antigen-specific CD4 T lymphocyte proliferation but rather promoted Th1 phenotype in vivo as assessed by both OVA-specific CD4 T lymphocyte cytokine production and OVA-specific circulating immunoglobulins. BMSCs treated to prevent release of soluble mediators and a control cell population of primary dermal skin fibroblasts only partly mimicked the BMSC effects and in some cases worsened inflammation. In conclusion, BMSCs inhibit Th2-mediated allergic airways inflammation by influencing antigen-specific CD4 T lymphocyte differentiation. Promotion of a Th1 phenotype in antigen-specific CD4 T lymphocytes by BMSCs is sufficient to inhibit Th2-mediated allergic airways inflammation through an IFNγ-dependent process. PMID:21544902

  16. Protective effect of soybean oil- or fish oil-rich diets on allergic airway inflammation

    Science.gov (United States)

    Navarro-Xavier, Roberta Araujo; de Barros, Karina Vieira; de Andrade, Iracema Senna; Palomino, Zaira; Casarini, Dulce Elena; Flor Silveira, Vera Lucia

    2016-01-01

    Background The increased prevalence of asthma and allergic diseases in westernized societies has been associated with increased intake of diets rich in n-6 fatty acids (FAs) and poor in n-3 FAs. This study aimed to analyze the prophylactic effects of treatment with a soybean oil-rich diet (rich in n-6) or fish oil (rich in n-3) in an allergic airway inflammation model on lung inflammation score, leukocyte migration, T-helper cell (Th)-2 (interleukin [IL]-4, IL-5) and Th1 (interferon [IFN]-γ, tumor necrosis factor-α) cytokines, lipoxin A4, nitric oxide, bradykinin, and corticosterone levels in bronchoalveolar lavage (BAL) or lungs. Methods Male Wistar rats fed with soybean oil- or fish oil-rich diet or standard rat chow were sensitized twice with ovalbumin–alumen and challenged twice with ovalbumin aerosol. The BAL and lungs were examined 24 hours later. Results Both diets, rich in n-6 or n-3 FAs, impaired the allergic lung inflammation and reduced leukocyte migration, eosinophil and neutrophil percentages, and IL-4/IL-5/bradykinin levels in BAL and/or lungs, as well as increased the nitric oxide levels in BAL. The soybean oil-rich diet additionally increased the levels of lipoxin A4 and corticosterone in the lungs. Conclusion Data presented demonstrated that the n-6 FA-rich diet had protective effect upon allergic airway inflammation and was as anti-inflammatory as the n-3 FA-rich diet, although through different mechanisms, suggesting that both diets could be considered as complementary therapy or a prophylactic alternative for allergic airway inflammation. PMID:27274303

  17. Protective effect of soybean oil- or fish oil-rich diets on allergic airway inflammation

    OpenAIRE

    Navarro-Xavier, Roberta Araujo; Barros, Karina Vieira de; de Andrade, Iracema Senna; Palomino, Zaira; Casarini, Dulce Elena; Flor Silveira, Vera Lucia

    2016-01-01

    Background The increased prevalence of asthma and allergic diseases in westernized societies has been associated with increased intake of diets rich in n-6 fatty acids (FAs) and poor in n-3 FAs. This study aimed to analyze the prophylactic effects of treatment with a soybean oil-rich diet (rich in n-6) or fish oil (rich in n-3) in an allergic airway inflammation model on lung inflammation score, leukocyte migration, T-helper cell (Th)-2 (interleukin [IL]-4, IL-5) and Th1 (interferon [IFN]-γ, ...

  18. Selective depletion of Foxp3+ Treg during sensitization phase aggravates experimental allergic airway inflammation.

    Science.gov (United States)

    Baru, Abdul Mannan; Hartl, Andrea; Lahl, Katharina; Krishnaswamy, Jayendra Kumar; Fehrenbach, Heinz; Yildirim, Ali O; Garn, Holger; Renz, Harald; Behrens, Georg M N; Sparwasser, Tim

    2010-08-01

    Recent studies highlight the role of Treg in preventing unnecessary responses to allergens and maintaining functional immune tolerance in the lung. We investigated the role of Treg during the sensitization phase in a murine model of experimental allergic airway inflammation by selectively depleting the Treg population in vivo. DEpletion of REGulatory T cells (DEREG) mice were depleted of Treg by diphtheria toxin injection. Allergic airway inflammation was induced using OVA as a model allergen. Pathology was assessed by scoring for differential cellular infiltration in bronchoalveolar lavage, IgE and IgG1 levels in serum, cytokine secretion analysis of lymphocytes from lung draining lymph nodes and lung histology. Use of DEREG mice allowed us for the first time to track and specifically deplete both CD25(+) and CD25(-) Foxp3(+) Treg, and to analyze their significance in limiting pathology in allergic airway inflammation. We observed that depletion of Treg during the priming phase of an active immune response led to a dramatic exacerbation of allergic airway inflammation in mice, suggesting an essential role played by Treg in regulating immune responses against allergens as early as the sensitization phase via maintenance of functional tolerance. PMID:20544727

  19. Selective suppression of leukocyte recruitment in allergic inflammation

    Directory of Open Access Journals (Sweden)

    CL Weller

    2005-03-01

    Full Text Available Allergic diseases result in a considerable socioeconomic burden. The incidence of allergic diseases, notably allergic asthma, has risen to high levels for reasons that are not entirely understood. With an increasing knowledge of underlying mechanisms, there is now more potential to target the inflammatory process rather than the overt symptoms. This focuses attention on the role of leukocytes especially Th2 lymphocytes that regulate allergic inflammation and effector cells where eosinophils have received much attention. Eosinophils are thought to be important based on the high numbers that are recruited to sites of allergic inflammation and the potential of these cells to effect both tissue injury and remodelling. It is hoped that future therapy will be directed towards specific leukocyte types, without overtly compromising essential host defence responses. One obvious target is leukocyte recruitment. This necessitates a detailed understanding of underlying mechanisms, particularly those involving soluble che-moattractants signals and cell-cell adhesion molecules.

  20. Expansion of CD4(+ CD25(+ and CD25(- T-Bet, GATA-3, Foxp3 and RORγt cells in allergic inflammation, local lung distribution and chemokine gene expression.

    Directory of Open Access Journals (Sweden)

    You Lu

    Full Text Available Allergic asthma is associated with airway eosinophilia, which is regulated by different T-effector cells. T cells express transcription factors T-bet, GATA-3, RORγt and Foxp3, representing Th1, Th2, Th17 and Treg cells respectively. No study has directly determined the relative presence of each of these T cell subsets concomitantly in a model of allergic airway inflammation. In this study we determined the degree of expansion of these T cell subsets, in the lungs of allergen challenged mice. Cell proliferation was determined by incorporation of 5-bromo-2'-deoxyuridine (BrdU together with 7-aminoactnomycin (7-AAD. The immunohistochemical localisation of T cells in the lung microenvironments was also quantified. Local expression of cytokines, chemokines and receptor genes was measured using real-time RT-PCR array analysis in tissue sections isolated by laser microdissection and pressure catapulting technology. Allergen exposure increased the numbers of T-bet(+, GATA-3(+, RORγt(+ and Foxp3(+ cells in CD4(+CD25(+ and CD4(+CD25(- T cells, with the greatest expansion of GATA-3(+ cells. The majority of CD4(+CD25(+ T-bet(+, GATA-3(+, RORγt(+ and Foxp3(+ cells had incorporated BrdU and underwent proliferation during allergen exposure. Allergen exposure led to the accumulation of T-bet(+, GATA-3(+ and Foxp3(+ cells in peribronchial and alveolar tissue, GATA-3(+ and Foxp3(+ cells in perivascular tissue, and RORγt(+ cells in alveolar tissue. A total of 28 cytokines, chemokines and receptor genes were altered more than 3 fold upon allergen exposure, with expression of half of the genes claimed in all three microenvironments. Our study shows that allergen exposure affects all T effector cells in lung, with a dominant of Th2 cells, but with different local cell distribution, probably due to a distinguished local inflammatory milieu.

  1. Vitamin E Isoforms as Modulators of Lung Inflammation

    Directory of Open Access Journals (Sweden)

    Hiam Abdala-Valencia

    2013-10-01

    Full Text Available Asthma and allergic diseases are complex conditions caused by a combination of genetic and environmental factors. Clinical studies suggest a number of protective dietary factors for asthma, including vitamin E. However, studies of vitamin E in allergy commonly result in seemingly conflicting outcomes. Recent work indicates that allergic inflammation is inhibited by supplementation with the purified natural vitamin E isoform α-tocopherol but elevated by the isoform γ-tocopherol when administered at physiological tissue concentrations. In this review, we discuss opposing regulatory effects of α-tocopherol and γ-tocopherol on allergic lung inflammation in clinical trials and in animal studies. A better understanding of the differential regulation of inflammation by isoforms of vitamin E provides a basis towards the design of clinical studies and diets that would effectively modulate inflammatory pathways in lung disease.

  2. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease

    OpenAIRE

    Taube, C; Tertilt, C; Gyülveszi, G; Dehzad, N; Kreymborg, K; Schneeweiss, K; E. Michel; Reuter, S; Renauld, J C; Arnold-Schild, D; Schild, H; Buhl, R; Becher, B. (Bertram)

    2011-01-01

    Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-defi...

  3. IL-22 Is Produced by Innate Lymphoid Cells and Limits Inflammation in Allergic Airway Disease.

    OpenAIRE

    Taube, Christian; Tertilt, Christine; Gyülveszi, Gabor; Dehzad, Nina; Kreymborg, Katharina; Schneeweiss, Kristin; Michel, Erich; Reuter, Sebastian; Renauld, Jean-Christophe; Arnold-Schild, Danielle; Schild, Hansjörg; Buhl, Roland; Becher, Burkhard

    2011-01-01

    Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-defi...

  4. Volatile organic compounds enhance allergic airway inflammation in an experimental mouse model.

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    Ulrike Bönisch

    Full Text Available BACKGROUND: Epidemiological studies suggest an association between exposure to volatile organic compounds (VOCs and adverse allergic and respiratory symptoms. However, whether VOCs exhibit a causal role as adjuvants in asthma development remains unclear. METHODS: To investigate the effect of VOC exposure on the development of allergic airway inflammation Balb/c mice were exposed to VOCs emitted by new polyvinylchloride (PVC flooring, sensitized with ovalbumin (OVA and characterized in acute and chronic murine asthma models. Furthermore, prevalent evaporated VOCs were analyzed and mice were exposed to selected single VOCs. RESULTS: Exposure of mice to PVC flooring increased eosinophilic lung inflammation and OVA-specific IgE serum levels compared to un-exposed control mice. The increased inflammation was associated with elevated levels of Th2-cytokines. Long-term exposure to PVC flooring exacerbated chronic airway inflammation. VOCs with the highest concentrations emitted by new PVC flooring were N-methyl-2-pyrrolidone (NMP and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB. Exposure to NMP or TXIB also increased the allergic immune response in OVA-sensitized mice. In vitro or in vivo exposure to NMP or TXIB reduced IL-12 production in maturing dendritic cells (DCs and enhanced airway inflammation after adoptive DC transfer into Balb/c mice. At higher concentrations both VOCs induced oxidative stress demonstrated by increased isoprostane and glutathione-S-transferase-pi1 protein levels in the lung of non-sensitized mice. Treatment of PVC flooring-exposed mice with N-acetylcysteine prevented the VOC-induced increase of airway inflammation. CONCLUSIONS: Our results demonstrate that exposure to VOCs may increase the allergic immune response by interfering with DC function and by inducing oxidative stress and has therefore to be considerate as risk factor for the development of allergic diseases.

  5. Therapeutic Effects of DNA Vaccine on Allergen-Induced Allergic Airway Inflammation in Mouse Model

    Institute of Scientific and Technical Information of China (English)

    Guoping Li; Zhigang Liu; Nanshan Zhong; Bin Liao1; Ying Xiong

    2006-01-01

    Vaccination with DNA encoding Dermatophagoides pteronyssinus group 2 (Der p 2) allergen previously showed its effects of immunologic protection on Der p 2 allergen-induced allergic airway inflammation in mice. In present study, we investigated whether DNA vaccine encoding Der p 2 could exert therapeutic role on allergen-induced allergic airway inflammation in mouse model and explored the mechanism of DNA vaccination in asthma specific-allergen immunotherapy. After sensitized and challenged by Der p 2, the BALB/c mice were immunized with DNA vaccine. The degrees of cellular infiltration were scored. IgE levels in serum and IL-4/lL-13 levels in BALF were determined by ELISA. The lung tissues were assessed by histological examinations. Expressions of STAT6 and NF-κB in lung were determined by immunohistochemistry staining. Vaccination of mice with DNA vaccine inhibited the development of airway inflammation and the production of mucin induced by allergen, and reduced the level of Der p 2-specific IgE level. Significant reductions of eosinophii infiltration and levels of IL-4and IL-13 in BALF were observed after vaccination. Further more, DNA vaccination inhibited STAT6 and NF-κBexpression in lung tissue in Der p 2-immunized mice. These results indicated that DNA vaccine encoding Der p 2allergen could be used for therapy of allergen-induced allergic airway inflammation in our mouse model.

  6. Allergic Lung Inflammation Reduces Tissue Invasion and Enhances Survival from Pulmonary Pneumococcal Infection in Mice, Which Correlates with Increased Expression of Transforming Growth Factor β1 and SiglecF(low) Alveolar Macrophages.

    Science.gov (United States)

    Sanfilippo, Alan M; Furuya, Yoichi; Roberts, Sean; Salmon, Sharon L; Metzger, Dennis W

    2015-07-01

    Asthma is generally thought to confer an increased risk for invasive pneumococcal disease (IPD) in humans. However, recent reports suggest that mortality rates from IPD are unaffected in patients with asthma and that chronic obstructive pulmonary disease (COPD), a condition similar to asthma, protects against the development of complicated pneumonia. To clarify the effects of asthma on the subsequent susceptibility to pneumococcal infection, ovalbumin (OVA)-induced allergic lung inflammation (ALI) was induced in mice followed by intranasal infection with A66.1 serotype 3 Streptococcus pneumoniae. Surprisingly, mice with ALI were significantly more resistant to lethal infection than non-ALI mice. The heightened resistance observed following ALI correlated with enhanced early clearance of pneumococci from the lung, decreased bacterial invasion from the airway into the lung tissue, a blunted inflammatory cytokine and neutrophil response to infection, and enhanced expression of transforming growth factor β1 (TGF-β1). Neutrophil depletion prior to infection had no effect on enhanced early bacterial clearance or resistance to IPD in mice with ALI. Although eosinophils recruited into the lung during ALI appeared to be capable of phagocytizing bacteria, neutralization of interleukin-5 (IL-5) to inhibit eosinophil recruitment likewise had no effect on early clearance or survival following infection. However, enhanced resistance was associated with an increase in levels of clodronate-sensitive, phagocytic SiglecF(low) alveolar macrophages within the airways following ALI. These findings suggest that, while the risk of developing IPD may actually be decreased in patients with acute asthma, additional clinical data are needed to better understand the risk of IPD in patients with different asthma phenotypes. PMID:25964474

  7. Effects of sublingual immunotherapy on allergic inflammation: an update.

    Science.gov (United States)

    Yacoub, Mona-Rita; Colombo, Giselda; Marcucci, Francesco; Caminati, Marco; Sensi, Laura; Di Cara, Giuseppe; Frati, Franco; Incorvaia, Cristoforo

    2012-08-01

    The most common allergic diseases, and especially the respiratory disorders such as rhinitis and asthma, are closely related to the allergic inflammation elicited by the causative allergen. This makes inflammation the main target of anti-allergic therapies. Among the available treatments, allergen specific immunotherapy (AIT) has a patent effect on allergic inflammation, which persists also after its discontinuation, and is the only therapy able to modify the natural history of allergy. The traditional, subcutaneous route of administration was demonstrated to modify the allergen presentation by dendritic cells (DCs) that in turn correct the phenotype of allergen-specific T cells, switching from the Th2-type response, typical of allergic inflammation and characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy of Th2 or to tolerance, the latter being related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual AIT with high allergen doses proved to be similar to subcutaneous immunotherapy. Data obtained from biopsies clearly indicate that the pathophysiology of the oral mucosa, with particular importance for mucosal DCs, plays a crucial role in inducing tolerance to the administered allergen. PMID:22506880

  8. Sphingolipids: A Potential Molecular Approach to Treat Allergic Inflammation

    Directory of Open Access Journals (Sweden)

    Wai Y. Sun

    2012-01-01

    Full Text Available Allergic inflammation is an immune response to foreign antigens, which begins within minutes of exposure to the allergen followed by a late phase leading to chronic inflammation. Prolonged allergic inflammation manifests in diseases such as urticaria and rhino-conjunctivitis, as well as chronic asthma and life-threatening anaphylaxis. The prevalence of allergic diseases is profound with 25% of the worldwide population affected and a rising trend across all ages, gender, and racial groups. The identification and avoidance of allergens can manage this disease, but this is not always possible with triggers being common foods, prevalent air-borne particles and only extremely low levels of allergen exposure required for sensitization. Patients who are sensitive to multiple allergens require prophylactic and symptomatic treatments. Current treatments are often suboptimal and associated with adverse effects, such as the interruption of cognition, sleep cycles, and endocrine homeostasis, all of which affect quality of life and are a financial burden to society. Clearly, a better therapeutic approach for allergic diseases is required. Herein, we review the current knowledge of allergic inflammation and discuss the role of sphingolipids as potential targets to regulate inflammatory development in vivo and in humans. We also discuss the benefits and risks of using sphingolipid inhibitors.

  9. Nasal and bronchial airway reactivity in allergic and non allergic airway inflammation

    OpenAIRE

    Kölbeck, Karl-Gustav

    2003-01-01

    In allergic or asthmatic airways disease, upper and lower airways show a uniform eosinophilic inflammation of the mucosa, and bronchial hyperreactivity is a common finding. To study the co- variation of mucosal reactivity in upper and lower airways, histamine challenges of both sites were performed in a group of patients with allergic rhinitis during non-season. Upper airways were monitored during challenge by the use of rhinostereometry, an optical technique that non-invasi...

  10. Estrogen Signaling Modulates Allergic Inflammation and Contributes to Sex Differences in Asthma

    Science.gov (United States)

    Keselman, Aleksander; Heller, Nicola

    2015-01-01

    Asthma is a chronic airway inflammatory disease that affects ~300 million people worldwide. It is characterized by airway constriction that leads to wheezing, coughing, and shortness of breath. The most common treatments are corticosteroids and β2-adrenergic receptor antagonists, which target inflammation and airway smooth muscle constriction, respectively. The incidence and severity of asthma is greater in women than in men, and women are more prone to develop corticosteroid-resistant or “hard-to-treat” asthma. Puberty, menstruation, pregnancy, menopause, and oral contraceptives are known to contribute to disease outcome in women, suggesting a role for estrogen and other hormones impacting allergic inflammation. Currently, the mechanisms underlying these sex differences are poorly understood, although the effect of sex hormones, such as estrogen, on allergic inflammation is gaining interest. Asthma presents as a heterogeneous disease. In typical Th2-type allergic asthma, interleukin (IL)-4 and IL-13 predominate, driving IgE production and recruitment of eosinophils into the lungs. Chronic Th2-inflammation in the lung results in structural changes and activation of multiple immune cell types, leading to a deterioration of lung function over time. Most immune cells express estrogen receptors (ERα, ERβ, or the membrane-bound G-protein-coupled ER) to varying degrees and can respond to the hormone. Together these receptors have demonstrated the capacity to regulate a spectrum of immune functions, including adhesion, migration, survival, wound healing, and antibody and cytokine production. This review will cover the current understanding of estrogen signaling in allergic inflammation and discuss how this signaling may contribute to sex differences in asthma and allergy. PMID:26635789

  11. Inhibition of allergic airway inflammation by antisense-induced blockade of STAT6 expression

    Institute of Scientific and Technical Information of China (English)

    TIAN Xin-rui; TIAN Xin-li; BO Jian-ping; LI Shao-gang; LIU Zhuo-la; NIU Bo

    2011-01-01

    Background The signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a pivotal role in asthma pathogenesis. Activation of STAT6 expression results in T helper cell type 2 (Th2) cell differentiation leading to Th2-mediated IgE production, development of allergic airway inflammation and hyperreactivity. Therefore,antagonizing the expression and/or the function of STAT6 could be used as a mode of therapy for allergic airway inflammation.Methods In this study, we synthesized a 20-mer phosphorothioate antisense oligonucleotide (ASODN) overlapping the translation starting site of STAT6 and constructed STAT6 antisense RNA (pANTI-STAT6), then transfected them into murine spleen lymphocytes and analyzed the effects of antagonizing STAT6 function in vitro and in a murine model of asthma.Results In vitro, we showed suppression of STAT6 expression and interleukin (IL)-4 production of lymphocytes by STAT6 ASODN. This effect was more prominent when cells were cultured with pANTI-STAT6. In a murine model of asthma associated with allergic pulmonary inflammation in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate (FITC)-labeled STAT6 ASODN to DNA uptake in lung cells was accompanied by a reduction of intracellular STAT6 expression. Such intrapulmonary blockade of STAT6 expression abrogated signs of lung inflammation, infiltration of eosinophils and Th2 cytokine production.Conclusion These data suggest a critical role of STAT6 in the pathogenesis of asthma and the use of local delivery of STAT6 ASODN as a novel approach for the treatment of allergic airway inflammation such as in asthma.

  12. Allergic rhinitis and asthma: inflammation in a one-airway condition

    OpenAIRE

    Haahtela Tari; Jeffery Peter K

    2006-01-01

    Abstract Background Allergic rhinitis and asthma are conditions of airway inflammation that often coexist. Discussion In susceptible individuals, exposure of the nose and lungs to allergen elicits early phase and late phase responses. Contact with antigen by mast cells results in their degranulation, the release of selected mediators, and the subsequent recruitment of other inflammatory cell phenotypes. Additional proinflammatory mediators are released, including histamine, prostaglandins, cy...

  13. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease.

    Directory of Open Access Journals (Sweden)

    Christian Taube

    Full Text Available Interleukin (IL-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-deficient mice and found that they suffer from significantly higher airway hyperreactivity upon airway challenge. IL-22-deficiency led to increased eosinophil infiltration lymphocyte invasion and production of CCL17 (TARC, IL-5 and IL-13 in the lung. Mice treated with IL-22 before antigen challenge displayed reduced expression of CCL17 and IL-13 and significant amelioration of airway constriction and inflammation. We conclude that innate IL-22 limits airway inflammation, tissue damage and clinical decline in allergic lung disease.

  14. Endocrine disruptors found in food contaminants enhance allergic sensitization through an oxidative stress that promotes the development of allergic airway inflammation

    International Nuclear Information System (INIS)

    In the past few decades, there has been a significant increase in incidence of allergic diseases. The hygiene hypothesis may provide some clues to explain this rising trend, but it may also be attributable to other environmental factors that exert a proallergic adjuvant effects. However, there is limited information on the risks of developing allergic asthma and related diseases through the ingestion of environmental chemicals found in food contaminants. In the present study, we have shown that oral administration of tributyltin, used as a model environmental chemical, induced oxidative-stress status in the bronchial lymph node, mesenteric lymph node and spleen, but not in the lung, where the initial step of allergic asthma pathogenesis takes place. Mice exposed to tributyltin exhibited heightened Th2 immunity to the allergen with more severe airway inflammation. Tributyltin also induced Treg cells apoptosis preferentially over non-Treg cells. All these effects of tributyltin exposure were canceled by the administration of glutathione monoethyl ester. Meanwhile, tributyltin did not affect airway inflammation of mice transferred with allergen-specific Th2 cells. Collectively, these results suggest that tributyltin exerts its pathological effect during the sensitization phase through oxidative stress that enhances the development of allergic diseases. The current study dissects the pathogenic role of oxidative stress induced by oral exposure to an environmental chemical during the sensitization phase of allergic airway inflammation and would be important for developing therapeutics for prevention of allergic diseases. - Highlights: • Oral exposure to TBT exacerbates airway inflammation. • TBT induces oxidative stress in secondary lymphoid organs, but not in the lung. • TBT preferentially induces regulatory T cell apoptosis over non-Treg cells. • TBT does not enhance pre-existing airway inflammation in sensitized mice. • Chemicals in food contaminants

  15. Endocrine disruptors found in food contaminants enhance allergic sensitization through an oxidative stress that promotes the development of allergic airway inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Takuma, E-mail: katotaku@doc.medic.mie-u.ac.jp [Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine (Japan); Tada-Oikawa, Saeko [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine (Japan); Wang, Linan [Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine (Japan); Murata, Mariko [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine (Japan); Kuribayashi, Kagemasa [Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine (Japan)

    2013-11-15

    In the past few decades, there has been a significant increase in incidence of allergic diseases. The hygiene hypothesis may provide some clues to explain this rising trend, but it may also be attributable to other environmental factors that exert a proallergic adjuvant effects. However, there is limited information on the risks of developing allergic asthma and related diseases through the ingestion of environmental chemicals found in food contaminants. In the present study, we have shown that oral administration of tributyltin, used as a model environmental chemical, induced oxidative-stress status in the bronchial lymph node, mesenteric lymph node and spleen, but not in the lung, where the initial step of allergic asthma pathogenesis takes place. Mice exposed to tributyltin exhibited heightened Th2 immunity to the allergen with more severe airway inflammation. Tributyltin also induced Treg cells apoptosis preferentially over non-Treg cells. All these effects of tributyltin exposure were canceled by the administration of glutathione monoethyl ester. Meanwhile, tributyltin did not affect airway inflammation of mice transferred with allergen-specific Th2 cells. Collectively, these results suggest that tributyltin exerts its pathological effect during the sensitization phase through oxidative stress that enhances the development of allergic diseases. The current study dissects the pathogenic role of oxidative stress induced by oral exposure to an environmental chemical during the sensitization phase of allergic airway inflammation and would be important for developing therapeutics for prevention of allergic diseases. - Highlights: • Oral exposure to TBT exacerbates airway inflammation. • TBT induces oxidative stress in secondary lymphoid organs, but not in the lung. • TBT preferentially induces regulatory T cell apoptosis over non-Treg cells. • TBT does not enhance pre-existing airway inflammation in sensitized mice. • Chemicals in food contaminants

  16. Exacerbation of allergic inflammation in mice exposed to diesel exhaust particles prior to viral infection

    Directory of Open Access Journals (Sweden)

    Chason Kelly D

    2009-08-01

    Full Text Available Abstract Background Viral infections and exposure to oxidant air pollutants are two of the most important inducers of asthma exacerbation. Our previous studies have demonstrated that exposure to diesel exhaust increases the susceptibility to influenza virus infections both in epithelial cells in vitro and in mice in vivo. Therefore, we examined whether in the setting of allergic asthma, exposure to oxidant air pollutants enhances the susceptibility to respiratory virus infections, which in turn leads to increased virus-induced exacerbation of asthma. Ovalbumin-sensitized (OVA male C57BL/6 mice were instilled with diesel exhaust particles (DEP or saline and 24 hours later infected with influenza A/PR/8. Animals were sacrificed 24 hours post-infection and analyzed for markers of lung injury, allergic inflammation, and pro-inflammatory cytokine production. Results Exposure to DEP or infection with influenza alone had no significant effects on markers of injury or allergic inflammation. However, OVA-sensitized mice that were exposed to DEP and subsequently infected with influenza showed increased levels of eosinophils in lung lavage and tissue. In addition Th2-type cytokines, such as IL-4 and IL-13, and markers of eosinophil chemotaxis, such as CCL11 and CCR3, were increased in OVA-sensitized mice exposed to DEP prior to infection with influenza. These mice also showed increased levels of IL-1α, but not IL-10, RANTES, and MCP-1 in lung homogenates. Conclusion These data suggest that in the setting of allergic asthma, exposure to diesel exhaust could enhance virus-induced exacerbation of allergic inflammation.

  17. Protective effect of soybean oil- or fish oil-rich diets on allergic airway inflammation

    Directory of Open Access Journals (Sweden)

    Navarro-Xavier RA

    2016-05-01

    Full Text Available Roberta Araujo Navarro-Xavier,1 Karina Vieira de Barros,1 Iracema Senna de Andrade,1 Zaira Palomino,2 Dulce Elena Casarini,2 Vera Lucia Flor Silveira3 1Departamento de Fisiologia, 2Departamento de Medicina, 3Departamento de Ciências Biológicas, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil Background: The increased prevalence of asthma and allergic diseases in westernized societies has been associated with increased intake of diets rich in n-6 fatty acids (FAs and poor in n-3 FAs. This study aimed to analyze the prophylactic effects of treatment with a soybean oil-rich diet (rich in n-6 or fish oil (rich in n-3 in an allergic airway inflammation model on lung inflammation score, leukocyte migration, T-helper cell (Th-2 (interleukin [IL]-4, IL-5 and Th1 (interferon [IFN]-γ, tumor necrosis factor-α cytokines, lipoxin A4, nitric oxide, bradykinin, and corticosterone levels in bronchoalveolar lavage (BAL or lungs. Methods: Male Wistar rats fed with soybean oil- or fish oil-rich diet or standard rat chow were sensitized twice with ovalbumin–alumen and challenged twice with ovalbumin aerosol. The BAL and lungs were examined 24 hours later. Results: Both diets, rich in n-6 or n-3 FAs, impaired the allergic lung inflammation and reduced leukocyte migration, eosinophil and neutrophil percentages, and IL-4/IL-5/bradykinin levels in BAL and/or lungs, as well as increased the nitric oxide levels in BAL. The soybean oil-rich diet additionally increased the levels of lipoxin A4 and corticosterone in the lungs. Conclusion: Data presented demonstrated that the n-6 FA-rich diet had protective effect upon allergic airway inflammation and was as anti-inflammatory as the n-3 FA-rich diet, although through different mechanisms, suggesting that both diets could be considered as complementary therapy or a prophylactic alternative for allergic airway inflammation. Keywords: asthma, nitric oxide, n-6 fatty acids, n-3 fatty acids, cytokines

  18. Biosignature for airway inflammation in a house dust mite-challenged murine model of allergic asthma

    Directory of Open Access Journals (Sweden)

    Hadeesha Piyadasa

    2016-02-01

    Full Text Available House dust mite (HDM challenge is commonly used in murine models of allergic asthma for preclinical pathophysiological studies. However, few studies define objective readouts or biomarkers in this model. In this study we characterized immune responses and defined molecular markers that are specifically altered after HDM challenge. In this murine model, we used repeated HDM challenge for two weeks which induced hallmarks of allergic asthma seen in humans, including airway hyper-responsiveness (AHR and elevated levels of circulating total and HDM-specific IgE and IgG1. Kinetic studies showed that at least 24 h after last HDM challenge results in significant AHR along with eosinophil infiltration in the lungs. Histologic assessment of lung revealed increased epithelial thickness and goblet cell hyperplasia, in the absence of airway wall collagen deposition, suggesting ongoing tissue repair concomitant with acute allergic lung inflammation. Thus, this model may be suitable to delineate airway inflammation processes that precede airway remodeling and development of fixed airway obstruction. We observed that a panel of cytokines e.g. IFN-γ, IL-1β, IL-4, IL-5, IL-6, KC, TNF-α, IL-13, IL-33, MDC and TARC were elevated in lung tissue and bronchoalveolar fluid, indicating local lung inflammation. However, levels of these cytokines remained unchanged in serum, reflecting lack of systemic inflammation in this model. Based on these findings, we further monitored the expression of 84 selected genes in lung tissues by quantitative real-time PCR array, and identified 31 mRNAs that were significantly up-regulated in lung tissue from HDM-challenged mice. These included genes associated with human asthma (e.g. clca3, ear11, il-13, il-13ra2, il-10, il-21, arg1 and chia1 and leukocyte recruitment in the lungs (e.g. ccl11, ccl12 and ccl24. This study describes a biosignature to enable broad and systematic interrogation of molecular mechanisms and intervention

  19. Biosignature for airway inflammation in a house dust mite-challenged murine model of allergic asthma.

    Science.gov (United States)

    Piyadasa, Hadeesha; Altieri, Anthony; Basu, Sujata; Schwartz, Jacquie; Halayko, Andrew J; Mookherjee, Neeloffer

    2016-01-01

    House dust mite (HDM) challenge is commonly used in murine models of allergic asthma for preclinical pathophysiological studies. However, few studies define objective readouts or biomarkers in this model. In this study we characterized immune responses and defined molecular markers that are specifically altered after HDM challenge. In this murine model, we used repeated HDM challenge for two weeks which induced hallmarks of allergic asthma seen in humans, including airway hyper-responsiveness (AHR) and elevated levels of circulating total and HDM-specific IgE and IgG1. Kinetic studies showed that at least 24 h after last HDM challenge results in significant AHR along with eosinophil infiltration in the lungs. Histologic assessment of lung revealed increased epithelial thickness and goblet cell hyperplasia, in the absence of airway wall collagen deposition, suggesting ongoing tissue repair concomitant with acute allergic lung inflammation. Thus, this model may be suitable to delineate airway inflammation processes that precede airway remodeling and development of fixed airway obstruction. We observed that a panel of cytokines e.g. IFN-γ, IL-1β, IL-4, IL-5, IL-6, KC, TNF-α, IL-13, IL-33, MDC and TARC were elevated in lung tissue and bronchoalveolar fluid, indicating local lung inflammation. However, levels of these cytokines remained unchanged in serum, reflecting lack of systemic inflammation in this model. Based on these findings, we further monitored the expression of 84 selected genes in lung tissues by quantitative real-time PCR array, and identified 31 mRNAs that were significantly up-regulated in lung tissue from HDM-challenged mice. These included genes associated with human asthma (e.g. clca3, ear11, il-13, il-13ra2, il-10, il-21, arg1 and chia1) and leukocyte recruitment in the lungs (e.g. ccl11, ccl12 and ccl24). This study describes a biosignature to enable broad and systematic interrogation of molecular mechanisms and intervention strategies for

  20. Acanthamoeba protease activity promotes allergic airway inflammation via protease-activated receptor 2.

    Directory of Open Access Journals (Sweden)

    Mi Kyung Park

    Full Text Available Acanthamoeba is a free-living amoeba commonly present in the environment and often found in human airway cavities. Acanthamoeba possesses strong proteases that can elicit allergic airway inflammation. To our knowledge, the aeroallergenicity of Acanthamoeba has not been reported. We repeatedly inoculated mice with Acanthamoeba trophozoites or excretory-secretory (ES proteins intra-nasally and evaluated symptoms and airway immune responses. Acanthamoeba trophozoites or ES proteins elicited immune responses in mice that resembled allergic airway inflammation. ES proteins had strong protease activity and activated the expression of several chemokine genes (CCL11, CCL17, CCL22, TSLP, and IL-25 in mouse lung epithelial cells. The serine protease inhibitor phenyl-methane-sulfonyl fluoride (PMSF inhibited ES protein activity. ES proteins also stimulated dendritic cells and enhanced the differentiation of naive T cells into IL-4-secreting T cells. After repeated inoculation of the protease-activated receptor 2 knockout mouse with ES proteins, airway inflammation and Th2 immune responses were markedly reduced, but not to basal levels. Furthermore, asthma patients had higher Acanthamoeba-specific IgE titers than healthy controls and we found Acanthamoeba specific antigen from house dust in typical living room. Our findings suggest that Acanthamoeba elicits allergic airway symptoms in mice via a protease allergen. In addition, it is possible that Acanthamoeba may be one of the triggers human airway allergic disease.

  1. Protective Effects of Surfactant Protein D (SP-D) Treatment in 1,3-β-glucan-modulated Allergic Inflammation

    DEFF Research Database (Denmark)

    Fakih, Dalia; Pilecki, Bartosz; Schlosser, Anders;

    2015-01-01

    -γ production. rfhSP-D treatment further reduced mucous metaplasia and Th2 cytokine secretion to background levels. In summary, rfhSP-D treatment resulted in attenuation of both allergic inflammation and 1,3-β-glucan mediated neutrophilic inflammation. Our data suggest that treatment with high dose SP......SP-D is a pulmonary collectin important in lung immunity. SP-D-deficient mice (Sftpd(-/-)) are reported to be susceptible to ovalbumin (OVA)- and fungal allergen-induced pulmonary inflammation, while treatment with exogenous SP-D has therapeutic effects in such disease models. β-glucans are a...... diverse group of polysaccharides previously suggested to serve as fungal ligands for SP-D. We set out to investigate if SP-D could interact with 1,3-β-glucan and attenuate allergic pulmonary inflammation in the presence of 1,3-β-glucan. Allergic airway disease was induced in Sftpd(-/-) and Sftpd(+/+) mice...

  2. The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo

    OpenAIRE

    Doganci, Aysefa; Eigenbrod, Tatjana; Krug, Norbert; De Sanctis, George T.; Hausding, Michael; Erpenbeck, Veit J.; Haddad, El-Bdaoui; Schmitt, Edgar; Bopp, Tobias; Kallen, Karl-J.; Herz, Udo; Schmitt, Steffen; Luft, Cornelia; Hecht, Olaf; Jens M Hohlfeld

    2005-01-01

    The cytokine IL-6 acts via a specific receptor complex that consists of the membrane-bound IL-6 receptor (mIL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). In this study, we investigated the role of IL-6R components in asthma. We observed increased levels of sIL-6R in the airways of patients with allergic asthma as compared to those in controls. In addition, local blockade of the sIL-6R in a murine model of late-phase asthma after OVA sensitization by gp130–fraction ...

  3. A geranyl acetophenone targeting cysteinyl leukotriene synthesis prevents allergic airway inflammation in ovalbumin-sensitized mice

    International Nuclear Information System (INIS)

    Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The current use of corticosteroids in the management of asthma has recently raised issues regarding safety and lack of responsiveness in 5–10% of asthmatic individuals. The aim of the present study was to investigate the therapeutic effect of a non-steroidal small molecule that has cysteinyl leukotriene (cysLT) inhibitory activity, upon attenuation of allergic lung inflammation in an acute murine model. Mice were sensitized with ovalbumin (OVA) and treated with several intraperitoneal doses (100, 20, 2 and 0.2 mg/kg) of 2,4,6,-trihydroxy-3-geranylacetophenone (tHGA). Bronchoalveolar lavage was performed, blood and lung samples were obtained and respiratory function was measured. OVA sensitization increased pulmonary inflammation and pulmonary allergic inflammation was significantly reduced at doses of 100, 20 and 2 mg/kg with no effect at the lowest dose of 0.2 mg/kg. The beneficial effects in the lung were associated with reduced eosinophilic infiltration and reduced secretion of Th2 cytokines and cysLTs. Peripheral blood reduction of total IgE was also a prominent feature. Treatment with tHGA significantly attenuated altered airway hyperresponsiveness as measured by the enhanced pause (Penh) response to incremental doses of methacholine. These data demonstrate that tHGA, a synthetic non-steroidal small molecule, can prevent acute allergic inflammation. This proof of concept opens further avenues of research and development of tHGA as an additional option to the current armamentarium of anti-asthma therapeutics. -- Highlights: ► Safer and effective anti-asthmatic drugs are in great demand. ► tHGA is a new 5-LO/cysLT inhibitor that inhibits allergic asthma in mice. ► tHGA is a natural compound that can be synthesized. ► Doses as low as 2 mg/kg alleviate lung pathology in experimental asthma. ► tHGA is a potential drug lead for the treatment of allergic asthma.

  4. A geranyl acetophenone targeting cysteinyl leukotriene synthesis prevents allergic airway inflammation in ovalbumin-sensitized mice

    Energy Technology Data Exchange (ETDEWEB)

    Ismail, Norazren; Jambari, Nuzul Nurahya [Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor (Malaysia); Zareen, Seema; Akhtar, Mohamad Nadeem; Shaari, Khozirah [Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor (Malaysia); Zamri-Saad, Mohamad [Department of Veterinary Pathology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Selangor (Malaysia); Tham, Chau Ling; Sulaiman, Mohd Roslan [Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor (Malaysia); Lajis, Nordin Hj [Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor (Malaysia); Israf, Daud Ahmad, E-mail: daud.israf@gmail.com [Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor (Malaysia)

    2012-03-01

    Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The current use of corticosteroids in the management of asthma has recently raised issues regarding safety and lack of responsiveness in 5–10% of asthmatic individuals. The aim of the present study was to investigate the therapeutic effect of a non-steroidal small molecule that has cysteinyl leukotriene (cysLT) inhibitory activity, upon attenuation of allergic lung inflammation in an acute murine model. Mice were sensitized with ovalbumin (OVA) and treated with several intraperitoneal doses (100, 20, 2 and 0.2 mg/kg) of 2,4,6,-trihydroxy-3-geranylacetophenone (tHGA). Bronchoalveolar lavage was performed, blood and lung samples were obtained and respiratory function was measured. OVA sensitization increased pulmonary inflammation and pulmonary allergic inflammation was significantly reduced at doses of 100, 20 and 2 mg/kg with no effect at the lowest dose of 0.2 mg/kg. The beneficial effects in the lung were associated with reduced eosinophilic infiltration and reduced secretion of Th2 cytokines and cysLTs. Peripheral blood reduction of total IgE was also a prominent feature. Treatment with tHGA significantly attenuated altered airway hyperresponsiveness as measured by the enhanced pause (Penh) response to incremental doses of methacholine. These data demonstrate that tHGA, a synthetic non-steroidal small molecule, can prevent acute allergic inflammation. This proof of concept opens further avenues of research and development of tHGA as an additional option to the current armamentarium of anti-asthma therapeutics. -- Highlights: ► Safer and effective anti-asthmatic drugs are in great demand. ► tHGA is a new 5-LO/cysLT inhibitor that inhibits allergic asthma in mice. ► tHGA is a natural compound that can be synthesized. ► Doses as low as 2 mg/kg alleviate lung pathology in experimental asthma. ► tHGA is a potential drug lead for the treatment of allergic asthma.

  5. Allergic rhinitis and asthma: inflammation in a one-airway condition

    Directory of Open Access Journals (Sweden)

    Haahtela Tari

    2006-11-01

    Full Text Available Abstract Background Allergic rhinitis and asthma are conditions of airway inflammation that often coexist. Discussion In susceptible individuals, exposure of the nose and lungs to allergen elicits early phase and late phase responses. Contact with antigen by mast cells results in their degranulation, the release of selected mediators, and the subsequent recruitment of other inflammatory cell phenotypes. Additional proinflammatory mediators are released, including histamine, prostaglandins, cysteinyl leukotrienes, proteases, and a variety of cytokines, chemokines, and growth factors. Nasal biopsies in allergic rhinitis demonstrate accumulations of mast cells, eosinophils, and basophils in the epithelium and accumulations of eosinophils in the deeper subepithelium (that is, lamina propria. Examination of bronchial tissue, even in mild asthma, shows lymphocytic inflammation enriched by eosinophils. In severe asthma, the predominant pattern of inflammation changes, with increases in the numbers of neutrophils and, in many, an extension of the changes to involve smaller airways (that is, bronchioli. Structural alterations (that is, remodeling of bronchi in mild asthma include epithelial fragility and thickening of its reticular basement membrane. With increasing severity of asthma there may be increases in airway smooth muscle mass, vascularity, interstitial collagen, and mucus-secreting glands. Remodeling in the nose is less extensive than that of the lower airways, but the epithelial reticular basement membrane may be slightly but significantly thickened. Conclusion Inflammation is a key feature of both allergic rhinitis and asthma. There are therefore potential benefits for application of anti-inflammatory strategies that target both these anatomic sites.

  6. Adipose-Derived Stem Cells Ameliorate Allergic Airway Inflammation by Inducing Regulatory T Cells in a Mouse Model of Asthma

    Directory of Open Access Journals (Sweden)

    Kyu-Sup Cho

    2014-01-01

    Full Text Available Although several studies have demonstrated that mesenchymal stem cells derived from adipose tissue (ASCs can ameliorate allergic airway inflammation, the immunomodulatory mechanism of ASCs remains unclear. In this study, we investigated whether regulatory T cells (Tregs induction is a potential mechanism in immunomodulatory effects of ASCs on allergic airway disease and how these induced Tregs orchestrate allergic inflammation. Intravenous administration of ASCs significantly reduced allergic symptoms and inhibited eosinophilic inflammation. Airway hyperresponsiveness, total immune cell and eosinophils in the bronchoalveolar lavage fluid, mucus production, and serum allergen-specific IgE and IgG1 were significantly reduced after ASCs administration. ASCs significantly inhibited Th2 cytokines (IL-4, IL-5, and IL-13 and enhanced Th1 cytokine (IFN-γ and regulatory cytokines (IL-10 and TGF-β in the bronchoalveolar lavage fluid and lung draining lymph nodes. Furthermore, levels of IDO, TGF-β, and PGE2 were significantly increased after ASCs administration. Interestingly, this upregulation was accompanied by increased Treg populations. In conclusion, ASCs ameliorated allergic airway inflammation and improved lung function through the induction of Treg expansion. The induction of Treg by ASCs involves the secretion of soluble factors such as IDO, TGF-β, and PGE2 and Treg might be involved in the downregulation of Th2 cytokines and upregulation of Th1 cytokines production.

  7. Adipose-derived stem cells ameliorate allergic airway inflammation by inducing regulatory T cells in a mouse model of asthma.

    Science.gov (United States)

    Cho, Kyu-Sup; Park, Mi-Kyung; Kang, Shin-Ae; Park, Hee-Young; Hong, Sung-Lyong; Park, Hye-Kyung; Yu, Hak-Sun; Roh, Hwan-Jung

    2014-01-01

    Although several studies have demonstrated that mesenchymal stem cells derived from adipose tissue (ASCs) can ameliorate allergic airway inflammation, the immunomodulatory mechanism of ASCs remains unclear. In this study, we investigated whether regulatory T cells (Tregs) induction is a potential mechanism in immunomodulatory effects of ASCs on allergic airway disease and how these induced Tregs orchestrate allergic inflammation. Intravenous administration of ASCs significantly reduced allergic symptoms and inhibited eosinophilic inflammation. Airway hyperresponsiveness, total immune cell and eosinophils in the bronchoalveolar lavage fluid, mucus production, and serum allergen-specific IgE and IgG1 were significantly reduced after ASCs administration. ASCs significantly inhibited Th2 cytokines (IL-4, IL-5, and IL-13) and enhanced Th1 cytokine (IFN-γ) and regulatory cytokines (IL-10 and TGF-β) in the bronchoalveolar lavage fluid and lung draining lymph nodes. Furthermore, levels of IDO, TGF-β, and PGE2 were significantly increased after ASCs administration. Interestingly, this upregulation was accompanied by increased Treg populations. In conclusion, ASCs ameliorated allergic airway inflammation and improved lung function through the induction of Treg expansion. The induction of Treg by ASCs involves the secretion of soluble factors such as IDO, TGF-β, and PGE2 and Treg might be involved in the downregulation of Th2 cytokines and upregulation of Th1 cytokines production. PMID:25246732

  8. Induction of eosinophil apoptosis by hydrogen peroxide promotes the resolution of allergic inflammation.

    Science.gov (United States)

    Reis, A C; Alessandri, A L; Athayde, R M; Perez, D A; Vago, J P; Ávila, T V; Ferreira, T P T; de Arantes, A C S; Coutinho, D de Sá; Rachid, M A; Sousa, L P; Martins, M A; Menezes, G B; Rossi, A G; Teixeira, M M; Pinho, V

    2015-01-01

    Eosinophils are effector cells that have an important role in the pathogenesis of allergic disease. Defective removal of these cells likely leads to chronic inflammatory diseases such as asthma. Thus, there is great interest in understanding the mechanisms responsible for the elimination of eosinophils from inflammatory sites. Previous studies have demonstrated a role for certain mediators and molecular pathways responsible for the survival and death of leukocytes at sites of inflammation. Reactive oxygen species have been described as proinflammatory mediators but their role in the resolution phase of inflammation is poorly understood. The aim of this study was to investigate the effect of reactive oxygen species in the resolution of allergic inflammatory responses. An eosinophilic cell line (Eol-1) was treated with hydrogen peroxide and apoptosis was measured. Allergic inflammation was induced in ovalbumin sensitized and challenged mouse models and reactive oxygen species were administered at the peak of inflammatory cell infiltrate. Inflammatory cell numbers, cytokine and chemokine levels, mucus production, inflammatory cell apoptosis and peribronchiolar matrix deposition was quantified in the lungs. Resistance and elastance were measured at baseline and after aerosolized methacholine. Hydrogen peroxide accelerates resolution of airway inflammation by induction of caspase-dependent apoptosis of eosinophils and decrease remodeling, mucus deposition, inflammatory cytokine production and airway hyperreactivity. Moreover, the inhibition of reactive oxygen species production by apocynin or in gp91(phox-/-) mice prolonged the inflammatory response. Hydrogen peroxide induces Eol-1 apoptosis in vitro and enhances the resolution of inflammation and improves lung function in vivo by inducing caspase-dependent apoptosis of eosinophils. PMID:25675292

  9. Early phase resolution of mucosal eosinophilic inflammation in allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Erjefält Jonas S

    2010-05-01

    Full Text Available Abstract Background It is widely assumed that apoptosis of eosinophils is a central component of resolution of allergic airway disease. However, this has not been demonstrated in human allergic airways in vivo. Based on animal in vivo observations we hypothesised that steroid-induced resolution of human airway eosinophilic inflammation involves inhibition of CCL5 (RANTES, a CC-chemokine regulating eosinophil and lymphocyte traffic, and elimination of eosinophils without evident occurrence of apoptotic eosinophils in the diseased tissue. Objective To determine mucosal eosinophilia, apoptotic eosinophils, general cell apoptosis and cell proliferation, and expression of CCL5 and CCL11 (eotaxin in human allergic airway tissues in vivo at resolution of established symptomatic eosinophilic inflammation. Methods Twenty-one patients with intermittent (birch and/or grass allergic rhinitis received daily nasal allergen challenges for two seven days' periods separated by more than two weeks washout. Five days into these "artificial pollen seasons", nasal treatment with budesonide was instituted and continued for six days in a double blinded, randomized, placebo-controlled, and crossover design. This report is a parallel group comparison of nasal biopsy histochemistry data obtained on the final day of the second treatment period. Results Treatments were instituted when clinical rhinitis symptoms had been established. Compared to placebo, budesonide reduced tissue eosinophilia, and subepithelial more than epithelial eosinophilia. Steroid treatment also attenuated tissue expression of CCL5, but CCL11 was not reduced. General tissue cell apoptosis and epithelial cell proliferation were reduced by budesonide. However, apoptotic eosinophils were not detected in any biopsies, irrespective of treatment. Conclusions Inhibition of CCL5-dependent recruitment of cells to diseased airway tissue, and reduced cell proliferation, reduced general cell apoptosis, but not

  10. The Effects of Proresolution of Ellagic Acid in an Experimental Model of Allergic Airway Inflammation

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    Claudiney de Freitas Alves

    2013-01-01

    Full Text Available Asthma is a disease of airway inflammation characterized by airway hyperresponsiveness, eosinophilic inflammation, and hypersecretion of mucus. Ellagic acid, a compound derived from medicinal plants and fruits, has shown anti-inflammatory activity in several experimental disease models. We used the classical experimental model, in BALB/c mice, of sensibilization with ovalbumin to determine the effect of ellagic acid (10 mg/kg; oral route in the resolution of allergic airways response. Dexamethasone (1 mg/kg; subcutaneous route was used as a positive control. The control group consisted of nonimmunized mice that received challenge with ovalbumin. Ellagic acid and dexamethasone or vehicle (water were administered before or after intranasal allergen challenge. Ellagic acid accelerated the resolution of airways inflammation by decreasing total leukocytes and eosinophils numbers in the bronchoalveolar lavage fluid (BALF, the mucus production and lung inflammation in part by reducing IL-5 concentration, eosinophil peroxidase (EPO activity, and P-selectin expression, but not activator protein 1 (AP-1 and nuclear factor kappa B (NF-κB pathways. In addition, ellagic acid enhanced alveolar macrophage phagocytosis of IgG-OVA-coated beads ex vivo, a new proresolving mechanism for the clearance of allergen from the airways. Together, these findings identify ellagic acid as a potential therapeutic agent for accelerating the resolution of allergic airways inflammation.

  11. IL-33-Responsive Lineage−CD25+CD44hi Lymphoid Cells Mediate Innate Type-2 Immunity and Allergic Inflammation in the Lungs1

    OpenAIRE

    Bartemes, Kathleen R.; Iijima, Koji; Kobayashi, Takao; Gail M Kephart; McKenzie, Andrew N; Kita, Hirohito

    2011-01-01

    Innate immunity provides the first line of response to invading pathogens and a variety of environmental insults. Recent studies identified novel subsets of innate lymphoid cells that are capable of mediating immune responses in mucosal organs. Here we describe a subset of lymphoid cells that is involved in innate type-2 immunity in the lungs. Airway exposure of naïve BALB/c or C57BL mice to IL-33 results in a rapid (< 12 h) production of IL-5 and IL-13 and marked airway eosinophilia independ...

  12. T cells are necessary for ILC2 activation in house dust mite-induced allergic airway inflammation in mice.

    Science.gov (United States)

    Li, Bobby W S; de Bruijn, Marjolein J W; Tindemans, Irma; Lukkes, Melanie; KleinJan, Alex; Hoogsteden, Henk C; Hendriks, Rudi W

    2016-06-01

    Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL-5 and IL-13. Here, we used a house dust mite (HDM)-driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T-cell activation precedes ILC2 induction. During HDM-driven allergic airway inflammation the accumulation of ILC2s in BALF is IL-33 independent, although infiltrating ILC2s produce less cytokines in Il33(-/-) mice. Transfer of in vitro polarized OVA-specific OT-II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T-cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM-mediated allergic airway inflammation in mice critically depends on activation of T cells. PMID:27062360

  13. Suppression of allergic airway inflammation in a mouse model of asthma by exogenous mesenchymal stem cells.

    Science.gov (United States)

    Ou-Yang, Hai-Feng; Huang, Yun; Hu, Xing-Bin; Wu, Chang-Gui

    2011-12-01

    Mesenchymal stem cells (MSCs) have significant immunomodulatory effects in the development of acute lung inflammation and fibrosis. However, it is still unclear as to whether MSCs could attenuate allergic airway inflammation in a mouse model of asthma. We firstly investigated whether exogenous MSCs can relocate to lung tissues in asthmatic mice and analyzed the chemotactic mechanism. Then, we evaluated the in vivo immunomodulatory effect of exogenous MSCs in asthma. MSCs (2 × 10(6)) were administered through the tail vein to mice one day before the first airway challenge. Migration of MSCs was evaluated by flow cytometry. The immunomodulatory effect of MSCs was evaluated by cell counting in bronchoalveolar lavage fluid (BALF), histology, mast cell degranulation, airway hyperreactivity and cytokine profile in BALF. Exogenous MSCs can migrate to sites of inflammation in asthmatic mice through a stromal cell-derived factor-1α/CXCR4-dependent mechanism. MSCs can protect mice against a range of allergic airway inflammatory pathologies, including the infiltration of inflammatory cells, mast cell degranulation and airway hyperreactivity partly via shifting to a T-helper 1 (Th1) from a Th2 immune response to allergens. So, immunotherapy based on MSCs may be a feasible, efficient therapy for asthma. PMID:22114062

  14. The hyaluronic acid-HDAC3-miRNA network in allergic inflammation

    Directory of Open Access Journals (Sweden)

    Youngmi eKim

    2015-04-01

    Full Text Available We previously reported the anti-allergic effect of high molecular weight form of hyaluronic acid (HMW-HA. In doing so, HA targets CD44 and inhibits FcεRI signaling and cross-talk between epidermal growth factor receptor (EGFR and FcεRI. We previously reported the role of histone deacetylases (HDACs in allergic inflammation and allergic inflammation-promoted enhanced tumorigenic potential. We reported regulatory role of HA in the expression of HDAC3. In this review, we will discuss molecular mechanisms associated with anti-allergic effect of hyaluronic acid in relation with HDACs. The role of microRNAs (miRNAs in allergic inflammation has been reported. We will also discuss the role of miRNAs in allergic inflammation in relation with HA-mediated anti-allergic effects.

  15. Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice.

    Science.gov (United States)

    Sun, Yue-Qi; Deng, Meng-Xia; He, Jia; Zeng, Qing-Xiang; Wen, Weiping; Wong, David S H; Tse, Hung-Fat; Xu, Geng; Lian, Qizhou; Shi, Jianbo; Fu, Qing-Ling

    2012-12-01

    We previously found that mesenchymal stem cells (MSCs) derived from human-induced pluripotent stem cells (iPSCs) exerted immunomodulatory effects on Th2-mediated allergic rhinitis in vitro. However, their contribution to the asthma and allergic rhinitis in animal models remains unclear. In this study, we developed a mouse model of ovalbumin (OVA)-induced allergic inflammation in both the upper and lower airways and evaluated the effects of the systemic administration of human iPSC-MSCs and bone marrow-derived MSCs (BM-MSCs) on allergic inflammation. Our results showed that treatments with both the iPSC-MSCs and BM-MSCs before the challenge phase protected the animals from the majority of allergy-specific pathological changes. This protection included an inhibition of inflammatory cell infiltration and mucus production in the lung, a reduction in eosinophil infiltration in the nose, and a decrease in inflammatory cell infiltration in both the bronchoalveolar and nasal lavage fluids. In addition, treatment with iPSC-MSCs or BM-MSCs before the challenge phase resulted in reduced serum levels of Th2 immunoglobulins (e.g., IgE) and decreased levels of Th2 cytokines including interleukin (IL)-4, IL-5, or IL-13 in the bronchoalveolar and/or nasal lavage fluids. Similar therapeutic effects were observed when the animals were pretreated with human iPSC-MSCs before the sensitization phase. These data suggest that iPSC-MSCs may be used as an alternative strategy to adult MSCs in the treatment of asthma and allergic rhinitis. PMID:22987325

  16. Toxoplasma gondii infection induces suppression in a mouse model of allergic airway inflammation.

    Directory of Open Access Journals (Sweden)

    Ignacio M Fenoy

    Full Text Available Allergic asthma is an inflammatory disorder characterized by infiltration of the airway wall with inflammatory cells driven mostly by activation of Th2-lymphocytes, eosinophils and mast cells. There is a link between increased allergy and a reduction of some infections in Western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofecal and foodborne microbes such as Toxoplasma gondii. We previously showed that both acute and chronic parasite T. gondii infection substantially blocked development of airway inflammation in adult BALB/c mice. Based on the high levels of IFN-γ along with the reduction of Th2 phenotype, we hypothesized that the protective effect might be related to the strong Th1 immune response elicited against the parasite. However, other mechanisms could also be implicated. The possibility that regulatory T cells inhibit allergic diseases has received growing support from both animal and human studies. Here we investigated the cellular mechanisms involved in T. gondii induced protection against allergy. Our results show for the first time that thoracic lymph node cells from mice sensitized during chronic T. gondii infection have suppressor activity. Suppression was detected both in vitro, on allergen specific T cell proliferation and in vivo, on allergic lung inflammation after adoptive transference from infected/sensitized mice to previously sensitized animals. This ability was found to be contact-independent and correlated with high levels of TGF-β and CD4(+FoxP3(+ cells.

  17. Abietic acid attenuates allergic airway inflammation in a mouse allergic asthma model.

    Science.gov (United States)

    Gao, Yi; Zhaoyu, Liu; Xiangming, Fang; Chunyi, Lin; Jiayu, Pan; Lu, Shen; Jitao, Chen; Liangcai, Chen; Jifang, Liu

    2016-09-01

    Abietic acid (AA), one of the terpenoids isolated from Pimenta racemosa var. grissea, has been reported to have anti-inflammatory and immunomodulatory effects. However, the anti-allergic effects of AA remain unclear. The aim of this study was to investigate the anti-allergic effects of AA in an ovalbumin (OVA)-induced asthma murine model. The model of mouse asthma was established by induction of OVA. AA (10, 20, 40mg/kg) was administered by oral gavage 1h after the OVA treatment on days 21 to 23. At 24h after the last challenge, bronchoalveolar lavage fluid (BALF) and lung tissues were collected to assess pathological changes, cytokines production, and NF-κB expression. The results showed that AA attenuated lung histopathologic changes, inflammatory cells infiltration, and bronchial hyper-responsiveness. AA also inhibited OVA-induced the nitric oxide (NO), IL-4, IL-5, IL-13, and OVA-specific IgE production, as well as NF-κB activation. In conclusion, the current study demonstrated that AA exhibited protective effects against OVA-induced allergic asthma in mice and the possible mechanism was involved in inhibiting NF-κB activation. PMID:27318791

  18. Clusterin Modulates Allergic Airway Inflammation by Attenuating CCL20-Mediated Dendritic Cell Recruitment.

    Science.gov (United States)

    Hong, Gyong Hwa; Kwon, Hyouk-Soo; Moon, Keun-Ai; Park, So Young; Park, Sunjoo; Lee, Kyoung Young; Ha, Eun Hee; Kim, Tae-Bum; Moon, Hee-Bom; Lee, Heung Kyu; Cho, You Sook

    2016-03-01

    Recruitment and activation of dendritic cells (DCs) in the lungs are critical for Th2 responses in asthma, and CCL20 secreted from bronchial epithelial cells (BECs) is known to influence the recruitment of DCs. Because asthma is a disease that is closely associated with oxidative stress, we hypothesized that clusterin, an oxidative stress regulatory molecule, may have a role in the development of allergic airway inflammation. The aim of this study was to examine whether clusterin regulates CCL20 production from the BECs and the subsequent DC recruitment in the lungs. To verify the idea, clusterin knockout (Clu(-/-)), clusterin heterogeneous (Clu(+/-)), and wild-type mice were exposed intranasally to house dust mite (HDM) extract to induce allergic airway inflammation. We found that the total number of immune cells in bronchoalveolar lavage fluid and the lung was increased in Clu(-/-) and Clu(+/-) mice. Of these immune cells, inflammatory DCs (CD11b(+)CD11c(+)) and Ly6C(high) monocyte populations in the lung were significantly increased, which was accompanied by increased levels of various chemokines, including CCL20 in bronchoalveolar lavage fluid, and increased oxidative stress markers in the lung. Moreover, HDM-stimulated human BECs with either up- or downregulated clusterin expression showed that CCL20 secretion was negatively associated with clusterin expression. Interestingly, clusterin also reduced the level of intracellular reactive oxygen species, which is related to induction of CCL20 expression after HDM stimulation. Thus, the antioxidant property of clusterin is suggested to regulate the expression of CCL20 in BECs and the subsequent recruitment of inflammatory DCs in the airway. PMID:26826245

  19. Interleukin-4 and interleukin-5 as targets for the inhibition of eosinophilic inflammation and allergic airways hyperreactivity

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    Foster Paul S

    1997-01-01

    Full Text Available Clinical and experimental investigations suggest that allergen-specific CD4+ T-cells, IgE and the cytokines IL-4 and IL-5 play central roles in initiating and sustaining an asthmatic response by regulating the recruitment and/or activation of airways mast cells and eosinophils. IL-5 plays a unique role in eosinophil development and activation and has been strongly implicated in the aetiology of asthma. The present paper summarizes our recent investigations on the role of these cytokines using cytokine knockout mice and a mouse aeroallergen model. Investigations in IL-5-/- mice indicate that this cytokine is critical for regulating aeroallergen-induced eosinophilia, the onset of lung damage and airways hyperreactivity during allergic airways inflammation. While IL-4 and allergen-specific IgE play important roles in the regulation of allergic disease, recent investigations in IL4-/- mice suggest that allergic airways inflammation can occur via pathways which operate independently of these molecules. Activation of these IL-4 independent pathways are also intimately associated with CD4+ T-cells, IL-5 signal transduction and eosinophilic inflammation. Such IL-5 regulated pathways may also play a substantive role in the aetiology of asthma. Thus, evidence is now emerging that allergic airways disease is regulated by humoral and cell mediated processes. The central role of IL-5 in both components of allergic disease highlights the requirements for highly specific therapeutic agents which inhibit the production or action of this cytokine.

  20. Lunasin alleviates allergic airway inflammation while increases antigen-specific Tregs.

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    Xiaowei Yang

    Full Text Available Lunasin is a naturally occurring peptide isolated from soybeans and has been explored in cancer treatment. Lunasin inhibits NF-κB activation and thus pro-inflammatory cytokine and mediator production in macrophages. In this study we demonstrate that lunasin can effectively suppress allergic airway inflammation in two murine models of asthma. In an OVA+Alum sensitization model, intranasal lunasin treatment at the time of OVA challenges significantly reduced total cells counts in bronchoalveolar lavage (BAL fluid and eosinophilia, peribronchiolar inflammatory infiltration, goblet cell metaplasia and airway IL-4 production. In an OVA+LPS intranasal sensitization model, lunasin treatment either at the time of sensitization or challenge has similar effects in suppress allergic airway inflammation including significantly reduced total cell and eosinophil counts in BAL fluid, inflammatory gene Fizz1 expression in the lung, and IL-4 production by OVA re-stimulated cells from mediastinal lymph nodes. We further show that intranasal instillation of OVA+lunasin significantly increases OVA-specific regulatory T cell (Treg accumulation in the lung comparing to OVA only treatment. Taken together, our results suggest lunasin as an anti-inflammatory agent can be potentially used in asthma therapy or as an adjuvant to enhance the induction of antigen-specific Tregs and thus boost the efficacy of allergy immunotherapy.

  1. Specific allergen immunotherapy attenuates allergic airway inflammation in a rat model of Alstonia scholaris pollen induced airway allergy.

    Science.gov (United States)

    Datta, Ankur; Moitra, Saibal; Hazra, Iman; Mondal, Somnath; Das, Prasanta Kumar; Singh, Manoj Kumar; Chaudhuri, Suhnrita; Bhattacharya, Debanjan; Tripathi, Santanu Kumar; Chaudhuri, Swapna

    2016-01-01

    Pollen grains are well established to be an important cause of respiratory allergy. Current pharmacologic therapies for allergic asthma do not cure the disease. Allergen specific immunotherapy is the only treatment method which re-directs the immune system away from allergic response leading to a long lasting effect. The mechanism by which immunotherapy achieves this goal is an area of active research world-wide. The present experimental study was designed to develop an experimental model of allergic lung inflammation based on a relevant human allergen, Alstonia scholaris pollen, and to establish the immunological and cellular features of specific allergen immunotherapy using this same pollen extract. Our results revealed that Alstonia scholaris pollen sensitization and challenge causes eosinophilic airway inflammation with mucin hypersecretion. This is associated with increased total IgE, increased expression of FcɛRI on lung mast cells and increased levels of IL-4, IL-5 & IL-13 as confirmed by ELISA, in-situ immunofluorescence and FACS assay. Allergen specific immunotherapy reduced airway inflammation and also decreased total IgE level, FcɛRI expression, IL-4, IL-5 & IL-13 levels. It was further noted that the reduction of these levels was more by intra-nasal route than by intra-peritoneal route. Thus we present a novel animal model of Alstonia scholaris pollen allergic disease and specific allergen immunotherapy which will pave the way towards the development of better treatment modalities. PMID:26667977

  2. Adoptive Transfer of Induced-Treg Cells Effectively Attenuates Murine Airway Allergic Inflammation

    OpenAIRE

    Wei Xu; Qin Lan; Maogen Chen; Hui Chen; Ning Zhu; Xiaohui Zhou; Julie Wang; Huimin Fan; Chun-Song Yan; Jiu-Long Kuang; David Warburton; Dieudonnée Togbe; Bernhard Ryffel; Song-Guo Zheng; Wei Shi

    2012-01-01

    Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic...

  3. Hyaluronan fragments as mediators of inflammation in allergic pulmonary disease.

    Science.gov (United States)

    Ghosh, Sumit; Hoselton, Scott A; Dorsam, Glenn P; Schuh, Jane M

    2015-05-01

    Asthma is frequently caused and/or exacerbated by sensitization to allergens, which are ubiquitous in many indoor and outdoor environments. Severe asthma is characterized by airway hyperresponsiveness and bronchial constriction in response to an inhaled allergen, leading to a disease course that is often very difficult to treat with standard asthma therapies. As a result of interactions among inflammatory cells, structural cells, and the intercellular matrix of the allergic lung, patients with sensitization to allergens may experience a greater degree of tissue injury followed by airway wall remodeling and progressive, accumulated pulmonary dysfunction as part of the disease sequela. In addition, turnover of extracellular matrix (ECM) components is a hallmark of tissue injury and repair. This review focuses on the role of the glycosaminoglycan hyaluronan (HA), a component of the ECM, in pulmonary injury and repair with an emphasis on allergic asthma. Both the synthesis and degradation of the ECM are critical contributors to tissue repair and remodeling. Fragmented HA accumulates during tissue injury and functions in ways distinct from the larger native polymer. There is gathering evidence that HA degradation products are active participants in stimulating the expression of inflammatory genes in a variety of immune cells at the injury site. In this review, we will consider recent advances in the understanding of the mechanisms that are associated with HA accumulation and inflammatory cell recruitment in the asthmatic lung. PMID:25582403

  4. Measurement of airway function using invasive and non-invasive methods in mild and severe models for allergic airway inflammation in mice

    OpenAIRE

    Verheijden, Kim A T; Henricks, Paul A.J.; Redegeld, Frank A.; Garssen, Johan; Folkerts, Gert

    2014-01-01

    In this study a direct comparison was made between non-invasive and non-ventilated unrestrained whole body plethysmography (Penh) (conscious animals) and the invasive ventilated lung resistance (RL) method (anesthetized animals) in both mild and severe allergic airway inflammation models. Mild inflammation was induced by intraperitoneal sensitization and aerosols of ovalbumin. Severe inflammation was induced by intraperitoneal sensitization using trinitrophenyl-ovalbumin, followed by intranas...

  5. Measurement of airway function using invasive and non-invasive methodsin mild and severe models for allergic airway inflammation in mice

    OpenAIRE

    Kim eVerheijden; Paul eHenricks; Redegeld, Frank A.; Johan eGarssen; Gert eFolkerts

    2014-01-01

    In this study a direct comparison was made between non-invasive and non-ventilated unrestrained whole body plethysmography (Penh) (conscious animals) and the invasive ventilated lung resistance (RL) method (anaesthetized animals) in both mild and severe allergic airway inflammation models. Mild inflammation was induced by intraperitoneal sensitization and aerosols of ovalbumin. Severe inflammation was induced by intraperitoneal sensitization using trinitrophenyl-ovalbumin, followed by intrana...

  6. Aggravation of Allergic Airway Inflammation by Cigarette Smoke in Mice Is CD44-Dependent.

    Directory of Open Access Journals (Sweden)

    Smitha Kumar

    Full Text Available Although epidemiological studies reveal that cigarette smoke (CS facilitates the development and exacerbation of allergic asthma, these studies offer limited information on the mechanisms involved. The transmembrane glycoprotein CD44 is involved in cell adhesion and acts as a receptor for hyaluronic acid and osteopontin. We aimed to investigate the role of CD44 in a murine model of CS-facilitated allergic airway inflammation.Wild type (WT and CD44 knock-out (KO mice were exposed simultaneously to house dust mite (HDM extract and CS. Inflammatory cells, hyaluronic acid (HA and osteopontin (OPN levels were measured in bronchoalveolar lavage fluid (BALF. Proinflammatory mediators, goblet cell metaplasia and peribronchial eosinophilia were assessed in lung tissue. T-helper (Th 1, Th2 and Th17 cytokine production was evaluated in mediastinal lymph node cultures.In WT mice, combined HDM/CS exposure increased the number of inflammatory cells and the levels of HA and OPN in BALF and Th2 cytokine production in mediastinal lymph nodes compared to control groups exposed to phosphate buffered saline (PBS/CS, HDM/Air or PBS/Air. Furthermore, HDM/CS exposure significantly increased goblet cell metaplasia, peribronchial eosinophilia and inflammatory mediators in the lung. CD44 KO mice exposed to HDM/CS had significantly fewer inflammatory cells in BALF, an attenuated Th2 cytokine production, as well as decreased goblet cells and peribronchial eosinophils compared to WT mice. In contrast, the levels of inflammatory mediators were similar or higher than in WT mice.We demonstrate for the first time that the aggravation of pulmonary inflammation upon combined exposure to allergen and an environmental pollutant is CD44-dependent. Data from this murine model of concomitant exposure to CS and HDM might be of importance for smoking allergic asthmatics.

  7. Size effects of latex nanomaterials on lung inflammation in mice

    International Nuclear Information System (INIS)

    Effects of nano-sized materials (nanomaterials) on sensitive population have not been well elucidated. This study examined the effects of pulmonary exposure to (latex) nanomaterials on lung inflammation related to lipopolysaccharide (LPS) or allergen in mice, especially in terms of their size-dependency. In protocol 1, ICR male mice were divided into 8 experimental groups that intratracheally received a single exposure to vehicle, latex nanomaterials (250 μg/animal) with three sizes (25, 50, and 100 nm), LPS (75 μg/animal), or LPS plus latex nanomaterials. In protocol 2, ICR male mice were divided into 8 experimental groups that intratracheally received repeated exposure to vehicle, latex nanomaterials (100 μg/animal), allergen (ovalbumin: OVA; 1 μg/animal), or allergen plus latex nanomaterials. In protocol 1, latex nanomaterials with all sizes exacerbated lung inflammation elicited by LPS, showing an overall trend of amplified lung expressions of proinflammatory cytokines. Furthermore, LPS plus nanomaterials, especially with size less than 50 nm, significantly elevated circulatory levels of fibrinogen, macrophage chemoattractant protein-1, and keratinocyte-derived chemoattractant, and von Willebrand factor as compared with LPS alone. The enhancement tended overall to be greater with the smaller nanomaterials than with the larger ones. In protocol 2, latex nanomaterials with all sizes did not significantly enhance the pathophysiology of allergic asthma, characterized by eosinophilic lung inflammation and Igs production, although latex nanomaterials with less than 50 nm significantly induced/enhanced neutrophilic lung inflammation. These results suggest that latex nanomaterials differentially affect two types of (innate and adaptive immunity-dominant) lung inflammation

  8. Resolution of acute inflammation in the lung.

    Science.gov (United States)

    Levy, Bruce D; Serhan, Charles N

    2014-01-01

    Acute inflammation in the lung is essential to health. So too is its resolution. In response to invading microbes, noxious stimuli, or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized proresolving mediators, specifically lipoxins, resolvins, protectins, and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung. PMID:24313723

  9. Thalidomide attenuates airway hyperresponsiveness and eosinophilic inflammation in a murine model of allergic asthma.

    Science.gov (United States)

    Asano, Toshiaki; Kume, Hiroaki; Taki, Fumitaka; Ito, Satoru; Hasegawa, Yoshinori

    2010-01-01

    Asthma is characterized by chronic eosinophilic inflammation and hyperresponsiveness of the airways. We hypothesized that thalidomide, which has numerous immunomodulatory properties, may have anti-inflammatory effects in allergic asthma. BALB/c mice sensitized and challenged with ovalbumin (OVA) were treated orally with thalidomide (30, 100, or 300 mg/kg) or a vehicle. When thalidomide was administered to OVA-challenged mice, the number of eosinophils in bronchoalveolar lavage fluid (BALF) was significantly decreased. The numbers of inflammatory cells other than eosinophils were not reduced by thalidomide. Thalidomide inhibited the elevated levels of interleukin-5 (IL-5) and tumor necrosis factor-alpha (TNF-alpha) in BALF by OVA challenges. Histological analysis of the lung revealed that both the infiltration of inflammatory cells and the hyperplasia of goblet cells were significantly suppressed by thalidomide treatment. Furthermore, thalidomide significantly inhibited the response to methacholine induced by OVA challenges. Taken together, thalidomide treatment decreased airway inflammation and hyperresponsiveness in a murine model of allergic asthma. These results might provide an opportunity for the development of novel therapeutics to treat severe asthma. PMID:20522972

  10. Therapy with resveratrol attenuates obesity-associated allergic airway inflammation in mice.

    Science.gov (United States)

    André, Diana Majolli; Calixto, Marina Ciarallo; Sollon, Carolina; Alexandre, Eduardo Costa; Leiria, Luiz O; Tobar, Natalia; Anhê, Gabriel Forato; Antunes, Edson

    2016-09-01

    Obesity and insulin resistance have been associated with deterioration in asthma outcomes. High oxidative stress and deficient activation of AMP-activated protein kinase (AMPK) have emerged as important regulators linking insulin resistance and inflammation. This study aimed to evaluate the effects of resveratrol on obesity-associated allergic pulmonary inflammation. Male C57/Bl6 mice fed with high-fat diet to induce obesity (obese group) or standard-chow diet (lean group) were treated or not with resveratrol (100mg/kg/day, two weeks). Mice were sensitized and challenged with ovalbumin (OVA). At 48h thereafter, bronchoalveolar lavage fluid was performed, and lungs collected for morphological studies and Western blot analysis. Treatment of obese mice with resveratrol significantly reduced hyperglycemia and insulin resistance, as well as the body measures (body mass, fat mass, % fat, and body area). OVA-challenge promoted a higher increase in pulmonary eosinophil infiltration in obese compared with lean mice, which was nearly abrogated by resveratrol treatment. Resveratrol markedly increased the phosphorylated AMPK expression in lung tissues of obese compared with lean mice. Resveratrol reduced the p47phox expression and reactive-oxygen species (ROS) production, and elevated the superoxide dismutase (SOD) levels in lung tissues of obese mice. The increased pulmonary levels of TNF-α and inducible nitric oxide synthase (iNOS) in obese mice were also normalized after resveratrol treatment. In lean mice, resveratrol failed to affect the levels of fasting glucose, p47phox, ROS levels, TNF-α, iNOS and phosphorylated AMPK. Resveratrol exhibits protective effects in obesity-associated lung inflammation that is accompanied by local AMPK activation and antioxidant property. PMID:27344038

  11. Epidermal Neuromedin U Attenuates IgE-Mediated Allergic Skin Inflammation

    Science.gov (United States)

    Mizukawa, Yoshiko; Doi, Takaaki; Yamazaki, Yoshimi; Kudo, Akihiko; Shiohara, Tetsuo

    2016-01-01

    Although keratinocyte-derived neuropeptide neuromedin U (NMU) mediates the proinflammatory effects of innate-type mast cell activation, no information is available on the physiological roles. Here, to investigate the effects of NMU on IgE-mediated allergic skin inflammation, we determined whether IgE-mediated inflammation associated with severe scratching was induced in Nmu-/- mice administered repeated hapten applications to the ear or footpad. Dry skin was induced by targeted deletion of Nmu. Mice administered repeated hapten application developed IgE-mediated allergic inflammation characterized by severe scratching and increased serum IgE levels only when the ear, and not the footpad, was subjected to scratching, indicating that depletion of NMU from the epidermis alone does not drive such allergic inflammation. Thus, the susceptibility of Nmu-/- mice to allergic inflammation depends primarily on scratching dry skin. Further, allergic skin inflammation mediated by FcεRI cross-linking in Nmu-/-mice was inhibited by prior injection of NMU. These results indicate that NMU plays an important physiological role as a negative regulator during the late stage of IgE-mediated allergic skin inflammation. PMID:27463114

  12. Epidermal Neuromedin U Attenuates IgE-Mediated Allergic Skin Inflammation.

    Science.gov (United States)

    Mizukawa, Yoshiko; Doi, Takaaki; Yamazaki, Yoshimi; Kudo, Akihiko; Shiohara, Tetsuo

    2016-01-01

    Although keratinocyte-derived neuropeptide neuromedin U (NMU) mediates the proinflammatory effects of innate-type mast cell activation, no information is available on the physiological roles. Here, to investigate the effects of NMU on IgE-mediated allergic skin inflammation, we determined whether IgE-mediated inflammation associated with severe scratching was induced in Nmu-/- mice administered repeated hapten applications to the ear or footpad. Dry skin was induced by targeted deletion of Nmu. Mice administered repeated hapten application developed IgE-mediated allergic inflammation characterized by severe scratching and increased serum IgE levels only when the ear, and not the footpad, was subjected to scratching, indicating that depletion of NMU from the epidermis alone does not drive such allergic inflammation. Thus, the susceptibility of Nmu-/- mice to allergic inflammation depends primarily on scratching dry skin. Further, allergic skin inflammation mediated by FcεRI cross-linking in Nmu-/-mice was inhibited by prior injection of NMU. These results indicate that NMU plays an important physiological role as a negative regulator during the late stage of IgE-mediated allergic skin inflammation. PMID:27463114

  13. Epidermal Neuromedin U Attenuates IgE-Mediated Allergic Skin Inflammation.

    Directory of Open Access Journals (Sweden)

    Yoshiko Mizukawa

    Full Text Available Although keratinocyte-derived neuropeptide neuromedin U (NMU mediates the proinflammatory effects of innate-type mast cell activation, no information is available on the physiological roles. Here, to investigate the effects of NMU on IgE-mediated allergic skin inflammation, we determined whether IgE-mediated inflammation associated with severe scratching was induced in Nmu-/- mice administered repeated hapten applications to the ear or footpad. Dry skin was induced by targeted deletion of Nmu. Mice administered repeated hapten application developed IgE-mediated allergic inflammation characterized by severe scratching and increased serum IgE levels only when the ear, and not the footpad, was subjected to scratching, indicating that depletion of NMU from the epidermis alone does not drive such allergic inflammation. Thus, the susceptibility of Nmu-/- mice to allergic inflammation depends primarily on scratching dry skin. Further, allergic skin inflammation mediated by FcεRI cross-linking in Nmu-/-mice was inhibited by prior injection of NMU. These results indicate that NMU plays an important physiological role as a negative regulator during the late stage of IgE-mediated allergic skin inflammation.

  14. Studies on neuroimmune interactions in allergic inflammation with focus on neurotrophins

    OpenAIRE

    Kemi, Cecilia

    2006-01-01

    Allergic asthma is a chronic airway disease characterized by an eosinophilic inflammation, bronchoconstriction, increased mucus production and bronchial hyperreactivity. The disease involves several mediators and cell types and is associated with a Th2-mediated immune response. Stress is a factor reported to deteriorate the allergic inflammation. Stress can influence the immune system by activating the HPA axis, resulting in release of glucocorticoids which could effects...

  15. Cysteinyl leukotriene receptor antagonist regulates allergic airway inflammation in an organ- and cytokine-specific manner

    OpenAIRE

    Kawano, Tetsuya; Matsuse, Hiroto; Tsuchida, Tomoko; Fukahori, Susumu; Fukushima, Chizu; Nishino, Tomoya; Kohno, Shigeru

    2014-01-01

    Background Cysteinyl leukotrienes (cys-LTs) are very important factors in the pathophysiology of bronchial asthma. Cys-LT receptor antagonists (LTRAs) decrease allergic airway inflammation. The aim of the present study was to determine the differential effects of LTRAs and corticosteroids on allergic airway inflammation and allergen-specific cytokine production from lymphoid tissues using a murine model of asthma. Material/Methods Four groups of female BALB/c mice [control (Cont); Dermatophag...

  16. Polyopes affinis alleviates airway inflammation in a murine model of allergic asthma

    Indian Academy of Sciences (India)

    Dae-Sung Lee; Won Sun Park; Soo-Jin Heo; Seon-Heui Cha; Daekyung Kim; You-Jin Jeon; Sae-Gwang Park; Su-Kil Seo; Jung Sik Choi; Sung-Jae Park; Eun Bo Shim; Il-Whan Choi; Won-Kyo Jung

    2011-12-01

    Marine algae have been utilized in food as well as medicine products for a variety of purposes. The purpose of this study was to determine whether an ethanol extract of Polyopes affinis (P.affinis) can inhibit the pathogenesis of T helper 2 (Th2)-mediated allergen-induced airway inflammation in a murine model of asthma. Mice that were sensitized and challenged with ovalbumin (OVA) evidenced typical asthmatic reactions such as the following: an increase in the number of eosinophils in the bronchoalveolar lavage (BAL) fluid; a marked influx of inflammatory cells into the lung around blood vessels and airways as well as the narrowing of the airway luminal; the development of airway hyperresponsiveness (AHR); the presence of pulmonary Th2 cytokines; and the presence of allergen-specific immunoglobulin E (IgE) in the serum. The successive intraperitoneal administration of P. affinis ethanolic extracts before the last airway OVA-challenge resulted in a significant inhibition of all asthmatic reactions. These data suggest that P. affinis ethanolic extracts possess therapeutic potential for the treatment of pulmonary allergic disorders such as allergic asthma.

  17. Adipose-Derived Stem Cells Ameliorate Allergic Airway Inflammation by Inducing Regulatory T Cells in a Mouse Model of Asthma

    OpenAIRE

    Kyu-Sup Cho; Mi-Kyung Park; Shin-Ae Kang; Hee-Young Park; Sung-Lyong Hong; Hye-Kyung Park; Hak-Sun Yu; Hwan-Jung Roh

    2014-01-01

    Although several studies have demonstrated that mesenchymal stem cells derived from adipose tissue (ASCs) can ameliorate allergic airway inflammation, the immunomodulatory mechanism of ASCs remains unclear. In this study, we investigated whether regulatory T cells (Tregs) induction is a potential mechanism in immunomodulatory effects of ASCs on allergic airway disease and how these induced Tregs orchestrate allergic inflammation. Intravenous administration of ASCs significantly reduced allerg...

  18. Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus

    OpenAIRE

    McSorley, Henry J; O'Gorman, Mary T.; Blair, Natalie; Sutherland, Tara E.; Filbey, Kara J.; Maizels, Rick M.

    2012-01-01

    Allergic asthma is less prevalent in countries with parasitic helminth infections, and mice infected with parasites such as Heligmosomoides polygyrus are protected from allergic airway inflammation. To establish whether suppression of allergy could be mediated by soluble products of this helminth, we tested H. polygyrus excretory-secretory (HES) material for its ability to impair allergic inflammation. When HES was added to sensitising doses of ovalbumin, the subsequent allergic airway respon...

  19. Surfactant protein-A suppresses eosinophil-mediated killing of Mycoplasma pneumoniae in allergic lungs.

    Directory of Open Access Journals (Sweden)

    Julie G Ledford

    Full Text Available Surfactant protein-A (SP-A has well-established functions in reducing bacterial and viral infections but its role in chronic lung diseases such as asthma is unclear. Mycoplasma pneumoniae (Mp frequently colonizes the airways of chronic asthmatics and is thought to contribute to exacerbations of asthma. Our lab has previously reported that during Mp infection of non-allergic airways, SP-A aides in maintaining airway homeostasis by inhibiting an overzealous TNF-alpha mediated response and, in allergic mice, SP-A regulates eosinophilic infiltration and inflammation of the airway. In the current study, we used an in vivo model with wild type (WT and SP-A(-/- allergic mice challenged with the model antigen ovalbumin (Ova that were concurrently infected with Mp (Ova+Mp to test the hypothesis that SP-A ameliorates Mp-induced stimulation of eosinophils. Thus, SP-A could protect allergic airways from injury due to release of eosinophil inflammatory products. SP-A deficient mice exhibit significant increases in inflammatory cells, mucus production and lung damage during concurrent allergic airway disease and infection (Ova+Mp as compared to the WT mice of the same treatment group. In contrast, SP-A deficient mice have significantly decreased Mp burden compared to WT mice. The eosinophil specific factor, eosinophil peroxidase (EPO, which has been implicated in pathogen killing and also in epithelial dysfunction due to oxidative damage of resident lung proteins, is enhanced in samples from allergic/infected SP-A(-/- mice as compared to WT mice. In vitro experiments using purified eosinophils and human SP-A suggest that SP-A limits the release of EPO from Mp-stimulated eosinophils thereby reducing their killing capacity. These findings are the first to demonstrate that although SP-A interferes with eosinophil-mediated biologic clearance of Mp by mediating the interaction of Mp with eosinophils, SP-A simultaneously benefits the airway by limiting inflammation

  20. Treatment of Allergic Airway Inflammation and Hyperresponsiveness by Antisense-Induced Local Blockade of Gata-3 Expression

    OpenAIRE

    Finotto, Susetta; De Sanctis, George T.; Lehr, Hans A.; Herz, Udo; Buerke, Michael; Schipp, Mechthild; Bartsch, Brigitte; Atreya, Raja; Schmitt, Edgar; Peter R. Galle; Renz, Harald; Neurath, Markus F

    2001-01-01

    Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we ana...

  1. α-Tocopherol supplementation of allergic female mice inhibits development of CD11c+CD11b+ dendritic cells in utero and allergic inflammation in neonates

    Science.gov (United States)

    Abdala-Valencia, Hiam; Berdnikovs, Sergejs; Soveg, Frank W.

    2014-01-01

    α-Tocopherol blocks responses to allergen challenge in allergic adult mice, but it is not known whether α-tocopherol regulates the development of allergic disease. Development of allergic disease often occurs early in life. In clinical studies and animal models, offspring of allergic mothers have increased responsiveness to allergen challenge. Therefore, we determined whether α-tocopherol blocked development of allergic responses in offspring of allergic female mice. Allergic female mice were supplemented with α-tocopherol starting at mating. The pups from allergic mothers developed allergic lung responses, whereas pups from saline-treated mothers did not respond to the allergen challenge, and α-tocopherol supplementation of allergic female mice resulted in a dose-dependent reduction in eosinophils in the pup bronchoalveolar lavage and lungs after allergen challenge. There was also a reduction in pup lung CD11b+ dendritic cell subsets that are critical to development of allergic responses, but there was no change in several CD11b− dendritic cell subsets. Furthermore, maternal supplementation with α-tocopherol reduced the number of fetal liver CD11b+ dendritic cells in utero. In the pups, there was reduced allergen-induced lung mRNA expression of IL-4, IL-33, TSLP, CCL11, and CCL24. Cross-fostering pups at the time of birth demonstrated that α-tocopherol had a regulatory function in utero. In conclusion, maternal supplementation with α-tocopherol reduced fetal development of subsets of dendritic cells that are critical for allergic responses and reduced development of allergic responses in pups from allergic mothers. These results have implications for supplementation of allergic mothers with α-tocopherol. PMID:25015974

  2. Airborne pollutant ROFA enhances the allergic airway inflammation through direct modulation of dendritic cells in an uptake-dependent mechanism.

    Science.gov (United States)

    Arantes-Costa, Fernanda Magalhaes; Grund, Lidiane Zito; Martins, Milton Arruda; Lima, Carla

    2014-09-01

    Studies suggest that airborne pollutants are important cofactors in the exacerbation of lung diseases. The role of DC on the exacerbation of lung inflammation induced by particulate matter pollutants is unclear. We evaluated the effects of residual oil fly ash (ROFA) on the phenotype and function of bone marrow-derived dendritic cells (BMDCs) in vitro and lung dendritic cells (DCs) in vivo, and the subsequent T-cell response. In a model of asthma, exposure to ROFA exacerbated pulmonary inflammation, which was attributed to the increase of eosinophils, IL-5- and IFN-γ-producing T cells, and goblet cells as well as decreased number of Treg and pDC. However, the ROFA showed no ability to modulate the production of anaphylactic IgE. In vitro studies showed that ROFA directly induced the maturation of DCs up-regulating the expression of co-stimulatory molecules and cytokines and MMP production in an uptake-dependent and oxidative stress-dependent manner. Furthermore, ROFA-pulsed BMDC transferred to allergic mice exacerbated eosinophilic inflammation as well as promoted increased epithelial and goblet cells changes. Thus, pollutants may constitute an important and risk factor in the exacerbation of asthma with inhibition of the negative regulatory signals in the lung, with enhanced mDC activation that sustains the recruitment of effector T lymphocytes and eosinophil. PMID:24975839

  3. γ-Tocopherol supplementation of allergic female mice augments development of CD11c+CD11b+ dendritic cells in utero and allergic inflammation in neonates.

    Science.gov (United States)

    Abdala-Valencia, Hiam; Soveg, Frank; Cook-Mills, Joan M

    2016-04-15

    γ-Tocopherol increases responses to allergen challenge in allergic adult mice, but it is not known whether γ-tocopherol regulates the development of allergic disease. Development of allergic disease often occurs early in life. In clinical studies and animal models, offspring of allergic mothers have increased responsiveness to allergen challenge. Therefore, we determined whether γ-tocopherol augments development of allergic responses in offspring of allergic female mice. Allergic female mice were supplemented with γ-tocopherol starting at mating. The pups from allergic mothers developed allergic lung responses, whereas pups from saline-treated mothers did not respond to allergen challenge. The γ-tocopherol supplementation of allergic female mice increased the numbers of eosinophils twofold in the pup bronchoalveolar lavage and lungs after allergen challenge. There was also about a twofold increase in pup lung CD11b(+) subsets of CD11c(+) dendritic cells and in numbers of these dendritic cells expressing the transcription factor IRF4. There was no change in several CD11b(-) dendritic cell subsets. Furthermore, maternal supplementation with γ-tocopherol increased the number of fetal liver CD11b(+)CD11c(+) dendritic cells twofold in utero. In the pups, γ-tocopherol increased lung expression of the inflammatory mediators CCL11, amphiregulin, activin A, and IL-5. In conclusion, maternal supplementation with γ-tocopherol increased fetal development of subsets of dendritic cells that are critical for allergic responses and increased development of allergic responses in pups from allergic mothers. These results have implications for supplementation of allergic mothers with γ-tocopherol in prenatal vitamins. PMID:26801566

  4. In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome.

    Directory of Open Access Journals (Sweden)

    Kenneth R Eyring

    Full Text Available Prenatal and postnatal cigarette smoke exposure enhances the risk of developing asthma. Despite this as well as other smoking related risks, 11% of women still smoke during pregnancy. We hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that correlates with disease. In a house dust mite (HDM model of allergic airway disease, we measured airway hyperresponsiveness (AHR and airway inflammation between mice exposed prenatally to cigarette smoke (CS or filtered air (FA. DNA methylation and gene expression were then measured in lung tissue. We demonstrate that HDM-treated CS mice develop a more severe allergic airway disease compared to HDM-treated FA mice including increased AHR and airway inflammation. While DNA methylation changes between the two HDM-treated groups failed to reach genome-wide significance, 99 DMRs had an uncorrected p-value < 0.001. 6 of these 99 DMRs were selected for validation, based on the immune function of adjacent genes, and only 2 of the 6 DMRs confirmed the bisulfite sequencing data. Additionally, genes near these 6 DMRs (Lif, Il27ra, Tle4, Ptk7, Nfatc2, and Runx3 are differentially expressed between HDM-treated CS mice and HDM-treated FA mice. Our findings confirm that prenatal exposure to cigarette smoke is sufficient to modify allergic airway disease; however, it is unlikely that specific methylation changes account for the exposure-response relationship. These findings highlight the important role in utero cigarette smoke exposure plays in the development of allergic airway disease.

  5. Tyrosol Suppresses Allergic Inflammation by Inhibiting the Activation of Phosphoinositide 3-Kinase in Mast Cells.

    Directory of Open Access Journals (Sweden)

    In-Gyu Je

    Full Text Available Allergic diseases such as atopic dermatitis, rhinitis, asthma, and anaphylaxis are attractive research areas. Tyrosol (2-(4-hydroxyphenylethanol is a polyphenolic compound with diverse biological activities. In this study, we investigated whether tyrosol has anti-allergic inflammatory effects. Ovalbumin-induced active systemic anaphylaxis and immunoglobulin E-mediated passive cutaneous anaphylaxis models were used for the immediate-type allergic responses. Oral administration of tyrosol reduced the allergic symptoms of hypothermia and pigmentation in both animal models. Mast cells that secrete allergic mediators are key regulators on allergic inflammation. Tyrosol dose-dependently decreased mast cell degranulation and expression of inflammatory cytokines. Intracellular calcium levels and activation of inhibitor of κB kinase (IKK regulate cytokine expression and degranulation. Tyrosol blocked calcium influx and phosphorylation of the IKK complex. To define the molecular target for tyrosol, various signaling proteins involved in mast cell activation such as Lyn, Syk, phosphoinositide 3-kinase (PI3K, and Akt were examined. Our results showed that PI3K could be a molecular target for tyrosol in mast cells. Taken together, these findings indicated that tyrosol has anti-allergic inflammatory effects by inhibiting the degranulation of mast cells and expression of inflammatory cytokines; these effects are mediated via PI3K. Therefore, we expect tyrosol become a potential therapeutic candidate for allergic inflammatory disorders.

  6. Negative regulation of pulmonary Th17 responses by C3a anaphylatoxin during allergic inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Hoyong Lim

    Full Text Available Activation of complement is one of the earliest immune responses to exogenous threats, resulting in various cleavage products including anaphylatoxin C3a. In addition to its contribution to host defense, C3a has been shown to mediate Th2 responses in animal models of asthma. However, the role of C3a on pulmonary Th17 responses during allergic inflammation remains unclear. Here, we show that mice deficient in C3a receptor (C3aR exhibited (i higher percentages of endogenous IL-17-producing CD4(+ T cells in the lungs, (ii higher amounts of IL-17 in the bronchoalveolar lavage fluid, and (iii more neutrophils in the lungs than wild-type mice when challenged with intranasal allergens. Moreover, adoptive transfer experiments showed that the frequencies of antigen-specific IL-17-producing CD4(+ T cells were significantly higher in the lungs and bronchial lymph nodes of C3aR-deficient recipients than those of wild-types recipients. Bone-marrow reconstitution study indicated that C3aR-deficiency on hematopoietic cells was required for the increased Th17 responses. Furthermore, C3aR-deficient mice exhibited increased percentages of Foxp3(+ regulatory T cells; however, depletion of these cells minimally affected the induction of antigen-specific Th17 cell population in the lungs. Neutralization of IL-17 significantly reduced the number of neutrophils in bronchoalveolar lavage fluid of C3aR-deficient mice. Our findings demonstrate that C3a signals negatively regulate antigen-specific Th17 responses during allergic lung inflammation and the size of Foxp3(+ regulatory T cell population in the periphery.

  7. Intestinal allergic inflammation in birch pollen allergic patients in relation to pollen season, IgE sensitization profile and gastrointestinal symptoms

    OpenAIRE

    Rentzos, Georgios; Lundberg, Vanja; Stotzer, Per-Ove; Pullerits, Teet; Telemo, Esbjörn

    2014-01-01

    Background Birch pollen allergic patients frequently experience gastrointestinal upset accompanied by a local allergic inflammation in the small intestine especially during the pollen season. However, it is not known if the GI pathology is connected to the subjective symptoms of the patient. The objective of this study was to evaluate the immune pathology of the duodenal mucosa and the serum IgE antibody profiles in birch pollen allergic patients in relation to their gastrointestinal symptoms...

  8. The histamine H4 -receptor (H4 R) regulates eosinophilic inflammation in ovalbumin-induced experimental allergic asthma in mice.

    Science.gov (United States)

    Hartwig, Christina; Munder, Antje; Glage, Silke; Wedekind, Dirk; Schenk, Heiko; Seifert, Roland; Neumann, Detlef

    2015-04-01

    Via the histamine H4 -receptor (H4 R), histamine promotes the pathogenesis of experimental allergic asthma in mice. Application of H4 R antagonists during sensitization as well as during provocation reduces the severity of the disease. However, the specific cell types functionally expressing H4 R in experimental allergic asthma have not been well characterized in vivo. In this study, we identified the cell type(s) responsible for H4 R activity in experimental asthma and related physiological mechanisms. Using H4 R-deficient mice, we studied the role of H4 R in the sensitization and effector phase. DCs lacking H4 R expression during the in vitro sensitization reaction resulted in effector T cells unable to induce an entire eosinophilic inflammation in the lung upon adoptive transfer in vivo. Recipient mice lacking H4 R expression, which were adoptively transferred with H4 R(+/+) T cells polarized in the presence of H4 R(+/+) DCs, showed reduced signs of inflammation and ameliorated lung function. Here, we provide in vivo evidence that in experimental asthma in mice the H4 R specifically regulates activation of DCs during sensitization, while in the effector phase the H4 R is active in cells involved in the activation of eosinophils, and possibly other cells. A putative therapy targeting the H4 R may be an option for asthma patients developing IL-5-dependent eosinophilia. PMID:25501767

  9. Regulatory B cells in allergic asthma and schistosomiasis : controlling inflammation

    NARCIS (Netherlands)

    Vlugt, Elisabeth Petronella Maria van der

    2015-01-01

    In the last few decades, childhood allergy has alarmingly increased to epidemic levels in industrialized countries. Conversely, chronic helminth infections, which are highly prevalent in developing countries, are negatively associated with allergic disorders. The work in this thesis revealed that, u

  10. An ovine tracheal explant culture model for allergic airway inflammation

    Directory of Open Access Journals (Sweden)

    Abeynaike Latasha

    2010-08-01

    Full Text Available Abstract Background The airway epithelium is thought to play an important role in the pathogenesis of asthmatic disease. However, much of our understanding of airway epithelial cell function in asthma has been derived from in vitro studies that may not accurately reflect the interactive cellular and molecular pathways active between different tissue constituents in vivo. Methods Using a sheep model of allergic asthma, tracheal explants from normal sheep and allergic sheep exposed to house dust mite (HDM allergen were established to investigate airway mucosal responses ex vivo. Explants were cultured for up to 48 h and tissues were stained to identify apoptotic cells, goblet cells, mast cells and eosinophils. The release of cytokines (IL-1α, IL-6 and TNF-α by cultured tracheal explants, was assessed by ELISA. Results The general morphology and epithelial structure of the tracheal explants was well maintained in culture although evidence of advanced apoptosis within the mucosal layer was noted after culture for 48 h. The number of alcian blue/PAS positive mucus-secreting cells within the epithelial layer was reduced in all cultured explants compared with pre-cultured (0 h explants, but the loss of staining was most evident in allergic tissues. Mast cell and eosinophil numbers were elevated in the allergic tracheal tissues compared to naïve controls, and in the allergic tissues there was a significant decline in mast cells after 24 h culture in the presence or absence of HDM allergen. IL-6 was released by allergic tracheal explants in culture but was undetected in cultured control explants. Conclusions Sheep tracheal explants maintain characteristics of the airway mucosa that may not be replicated when studying isolated cell populations in vitro. There were key differences identified in explants from allergic compared to control airways and in their responses in culture for 24 h. Importantly, this study establishes the potential for the

  11. The Protease Allergen Pen c 13 Induces Allergic Airway Inflammation and Changes in Epithelial Barrier Integrity and Function in a Murine Model*

    OpenAIRE

    Chen, Jui-Chieh; Chuang, Jiing-Guang; Su, Yu-Yi; Chiang, Bor-Luen; Lin, You-Shuei; Chow, Lu-Ping

    2011-01-01

    Fungal allergens are associated with the development of asthma, and some have been characterized as proteases. Here, we established an animal model of allergic airway inflammation in response to continuous exposure to proteolytically active Pen c 13, a major allergen secreted by Penicillium citrinum. In functional analyses, Pen c 13 exposure led to increased airway hyperresponsiveness, significant inflammatory cell infiltration, mucus overproduction, and collagen deposition in the lung, drama...

  12. S-nitrosoglutathione reductase inhibition regulates allergen-induced lung inflammation and airway hyperreactivity.

    Directory of Open Access Journals (Sweden)

    Maria E Ferrini

    Full Text Available Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1 in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4(+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation.

  13. Recruited alveolar macrophages, in response to airway epithelial-derived monocyte chemoattractant protein 1/CCl2, regulate airway inflammation and remodeling in allergic asthma.

    Science.gov (United States)

    Lee, Yong Gyu; Jeong, Jong Jin; Nyenhuis, Sharmilee; Berdyshev, Evgeny; Chung, Sangwoon; Ranjan, Ravi; Karpurapu, Manjula; Deng, Jing; Qian, Feng; Kelly, Elizabeth A B; Jarjour, Nizar N; Ackerman, Steven J; Natarajan, Viswanathan; Christman, John W; Park, Gye Young

    2015-06-01

    Although alveolar macrophages (AMs) from patients with asthma are known to be functionally different from those of healthy individuals, the mechanism by which this transformation occurs has not been fully elucidated in asthma. The goal of this study was to define the mechanisms that control AM phenotypic and functional transformation in response to acute allergic airway inflammation. The phenotype and functional characteristics of AMs obtained from human subjects with asthma after subsegmental bronchoprovocation with allergen was studied. Using macrophage-depleted mice, the role and trafficking of AM populations was determined using an acute allergic lung inflammation model. We observed that depletion of AMs in a mouse allergic asthma model attenuates Th2-type allergic lung inflammation and its consequent airway remodeling. In both human and mouse, endobronchial challenge with allergen induced a marked increase in monocyte chemotactic proteins (MCPs) in bronchoalveolar fluid, concomitant with the rapid appearance of a monocyte-derived population of AMs. Furthermore, airway allergen challenge of allergic subjects with mild asthma skewed the pattern of AM gene expression toward high levels of the receptor for MCP1 (CCR2/MCP1R) and expression of M2 phenotypic proteins, whereas most proinflammatory genes were highly suppressed. CCL2/MCP-1 gene expression was prominent in bronchial epithelial cells in a mouse allergic asthma model, and in vitro studies indicate that bronchial epithelial cells produced abundant MCP-1 in response to house dust mite allergen. Thus, our study indicates that bronchial allergen challenge induces the recruitment of blood monocytes along a chemotactic gradient generated by allergen-exposed bronchial epithelial cells. PMID:25360868

  14. Ionotropic and Metabotropic Proton-Sensing Receptors Involved in Airway Inflammation in Allergic Asthma

    Directory of Open Access Journals (Sweden)

    Haruka Aoki

    2014-01-01

    Full Text Available An acidic microenvironment has been shown to evoke a variety of airway responses, including cough, bronchoconstriction, airway hyperresponsiveness (AHR, infiltration of inflammatory cells in the lung, and stimulation of mucus hyperproduction. Except for the participation of transient receptor potential vanilloid-1 (TRPV1 and acid-sensing ion channels (ASICs in severe acidic pH (of less than 6.0-induced cough and bronchoconstriction through sensory neurons, the molecular mechanisms underlying extracellular acidic pH-induced actions in the airways have not been fully understood. Recent studies have revealed that ovarian cancer G protein-coupled receptor 1 (OGR1-family G protein-coupled receptors, which sense pH of more than 6.0, are expressed in structural cells, such as airway smooth muscle cells and epithelial cells, and in inflammatory and immune cells, such as eosinophils and dendritic cells. They function in a variety of airway responses related to the pathophysiology of inflammatory diseases, including allergic asthma. In the present review, we discuss the roles of ionotropic TRPV1 and ASICs and metabotropic OGR1-family G protein-coupled receptors in the airway inflammation and AHR in asthma and respiratory diseases.

  15. Prostaglandin E2 and Transforming Growth Factor-β Play a Critical Role in Suppression of Allergic Airway Inflammation by Adipose-Derived Stem Cells.

    Directory of Open Access Journals (Sweden)

    Kyu-Sup Cho

    Full Text Available The role of soluble factors in the suppression of allergic airway inflammation by adipose-derived stem cells (ASCs remains to be elucidated. Moreover, the major soluble factors responsible for the immunomodulatory effects of ASCs in allergic airway diseases have not been well documented. We evaluated the effects of ASCs on allergic inflammation in asthmatic mice treated with a prostaglandin E2 (PGE2 inhibitor or transforming growth factor-β (TGF-β neutralizing antibodies.Asthmatic mice were injected intraperitoneally with a PGE2 inhibitor or TGF-β neutralizing antibodies at approximately the same time as ASCs injection and were compared with non-treated controls. In asthmatic mice, ASCs significantly reduced airway hyperresponsiveness, the number of total inflammatory cells and eosinophils in the bronchoalveolar lavage fluid (BALF, eosinophilic inflammation, goblet cell hyperplasia, and serum total and allergen-specific IgE and IgG1. ASCs significantly inhibited Th2 cytokines, such as interleukin (IL-4, IL-5, and IL-13, and enhanced the Th1 cytokine (Interferon-γ and regulatory cytokines (IL-10 and TGF-β in the BALF and lung draining lymph nodes (LLNs. ASCs engraftment caused significant increases in the regulatory T cell (Treg and IL-10+ T cell populations in LLNs. However, blocking PGE2 or TGF-β eliminated the immunosuppressive effect of ASCs in allergic airway inflammation.ASCs are capable of secreting PGE2 and TGF-β, which may play a role in inducing Treg expansion. Furthermore, treatment with a PGE2 inhibitor or TGF-β neutralizing antibodies eliminated the beneficial effect of ASCs treatment in asthmatic mice, suggesting that PGE2 and TGF-β are the major soluble factors responsible for suppressing allergic airway inflammation.

  16. Dietary Fiber Intake Regulates Intestinal Microflora and Inhibits Ovalbumin-Induced Allergic Airway Inflammation in a Mouse Model.

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    Zhiyu Zhang

    Full Text Available Recently, academic studies suggest that global growth of airway allergic disease has a close association with dietary changes including reduced consumption of fiber. Therefore, appropriate dietary fiber supplementation might be potential to prevent airway allergic disease (AAD.We investigated whether dietary fiber intake suppressed the induction of AAD and tried to elucidate the possible underlying mechanisms.The control mice and AAD model mice fed with 4% standard-fiber chow, while low-fiber group of mice fed with a 1.75% low-fiber chow. The two fiber-intervened groups including mice, apart from a standard-fiber diet, were also intragastric (i.g. administrated daily with poorly fermentable cellulose or readily fermentable pectin (0.4% of daily body weight, respectively. All animals except normal mice were sensitized and challenged with ovalbumin (OVA to induce airway allergic inflammation. Hallmarks of AAD were examined by histological analysis and ELISA. The variation in intestinal bacterial composition was assessed by qualitative analysis of 16S ribosomal DNA (rDNA content in fecal samples using real-time PCR.Low-fiber diet aggravated inflammatory response in ovalbumin-induced allergic mice, whereas dietary fiber intake significantly suppressed the allergic responses, attenuated allergic symptoms of nasal rubbing and sneezing, decreased the pathology of eosinophil infiltration and goblet cell metaplasia in the nasal mucosa and lung, inhibited serum OVA-specific IgE levels, and lowered the levels of Th2 cytokines in NALF and BALF, but, increased Th1 (IFN-γ cytokines. Additionally, dietary fiber intake also increased the proportion of Bacteroidetes and Actinobacteria, and decreased Firmicutes and Proteobacteria. Levels of probiotic bacteria, such as Lactobacillus and Bifidobacterium, were upgraded significantly.Long-term deficiency of dietary fiber intake increases the susceptibility to AAD, whereas proper fiber supplementation promotes

  17. Protective effects of surfactant protein D treatment in 1,3-β-glucan-modulated allergic inflammation.

    Science.gov (United States)

    Fakih, Dalia; Pilecki, Bartosz; Schlosser, Anders; Jepsen, Christine S; Thomsen, Laura K; Ormhøj, Maria; Watson, Alastair; Madsen, Jens; Clark, Howard W; Barfod, Kenneth K; Hansen, Soren; Marcussen, Niels; Jounblat, Rania; Chamat, Soulaima; Holmskov, Uffe; Sorensen, Grith L

    2015-12-01

    Surfactant protein D (SP-D) is a pulmonary collectin important in lung immunity. SP-D-deficient mice (Sftpd(-/-)) are reported to be susceptible to ovalbumin (OVA)- and fungal allergen-induced pulmonary inflammation, while treatment with exogenous SP-D has therapeutic effects in such disease models. β-Glucans are a diverse group of polysaccharides previously suggested to serve as fungal ligands for SP-D. We set out to investigate if SP-D could interact with 1,3-β-glucan and attenuate allergic pulmonary inflammation in the presence of 1,3-β-glucan. Allergic airway disease was induced in Sftpd(-/-) and Sftpd(+/+) mice by OVA sensitization and subsequent challenge with OVA, 1,3-β-glucan, or OVA/1,3-β-glucan together. Mice in the combined treatment group were further treated with a high dose of recombinant fragment of human SP-D (rfhSP-D). We demonstrated direct interaction between SP-D and 1,3-β-glucan. OVA-induced mucous cell metaplasia was increased in Sftpd(-/-) mice, supporting previously reported protective effects of endogenous SP-D in allergy. OVA-induced parenchymal CCL11 levels and eosinophilic infiltration in bronchoalveolar lavage were unaffected by 1,3-β-glucan, but were reversed with rfhSP-D treatment. 1,3-β-Glucan treatment did, however, induce pulmonary neutrophilic infiltration and increased TNF-α levels in bronchoalveolar lavage, independently of OVA-induced allergy. This infiltration was also reversed by treatment with rfhSP-D. 1,3-β-Glucan reduced OVA-induced mucous cell metaplasia, T helper 2 cytokines, and IFN-γ production. rfhSP-D treatment further reduced mucous metaplasia and T helper 2 cytokine secretion to background levels. In summary, rfhSP-D treatment resulted in attenuation of both allergic inflammation and 1,3-β-glucan-mediated neutrophilic inflammation. Our data suggest that treatment with high-dose SP-D protects from mold-induced exacerbations of allergic asthma. PMID:26432866

  18. Adoptive transfer of induced-Treg cells effectively attenuates murine airway allergic inflammation.

    Directory of Open Access Journals (Sweden)

    Wei Xu

    Full Text Available Both nature and induced regulatory T (Treg lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4(+FoxP3(+ and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma.

  19. Adoptive transfer of induced-Treg cells effectively attenuates murine airway allergic inflammation.

    Science.gov (United States)

    Xu, Wei; Lan, Qin; Chen, Maogen; Chen, Hui; Zhu, Ning; Zhou, Xiaohui; Wang, Julie; Fan, Huimin; Yan, Chun-Song; Kuang, Jiu-Long; Warburton, David; Togbe, Dieudonnée; Ryffel, Bernhard; Zheng, Song-Guo; Shi, Wei

    2012-01-01

    Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4(+)FoxP3(+)) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma. PMID:22792275

  20. Glucocorticoids decrease Treg cell numbers in lungs of allergic mice.

    Science.gov (United States)

    Olsen, P C; Kitoko, J Z; Ferreira, T P; de-Azevedo, C T; Arantes, A C; Martins, Μ A

    2015-01-15

    Glucocorticoids have been the hallmark anti-inflammatory drug used to treat asthma. It has been shown that glucocorticoids ameliorate asthma by increasing numbers and activity of Tregs, in contrast recent data show that glucocorticoid might have an opposite effect on Treg cells from normal mice. Since Tregs are target cells that act on the resolution of asthma, the aim of this study was to elucidate the effect of glucocorticoid treatment on lung Tregs in mouse models of asthma. Allergen challenged mice were treated with either oral dexamethasone or nebulized budesonide. Broncoalveolar lavage and airway hyperresponsiveness were evaluated after allergenic challenge. Lung, thymic and lymph node cells were phenotyped on Treg through flow cytometry. Lung cytokine secretion was detected by ELISA. Although dexamethasone inhibited airway inflammation and hyperresponsiveness, improving resolution, we have found that both dexamethasone and budesonide induce a reduction of Treg numbers on lungs and lymphoid organs of allergen challenged mice. The reduction of lung Treg levels was independent of mice strain or type of allergen challenge. Our study also indicates that both glucocorticoids do not increase Treg activity through production of IL-10. Glucocorticoid systemic or localized treatment induced thymic atrophy. Taken together, our results demonstrate that glucocorticoids decrease Treg numbers and activity in different asthma mouse models, probably by reducing thymic production of T cells. Therefore, it is possible that glucocorticoids do not have beneficial effects on lung populations of Treg cells from asthmatic patients. PMID:25499819

  1. Targeting kit activation: a potential therapeutic approach in the treatment of allergic inflammation

    DEFF Research Database (Denmark)

    Jensen, Bettina M; Metcalfe, Dean D; Gilfillan, Alasdair M

    2007-01-01

    The prevalence of allergic diseases is increasing worldwide. Hence, there is continued need for novel pharmacological therapies for the treatment of these disorders. As the mast cell is one of the essential cells that contributes to the inflammation associated with allergic diseases, this cell type...... biology, however, may provide us with an alternative or adjunct therapy. SCF is necessary for mast cell development, proliferation and survival, but it is also known to play a role in homing and adhesion of mast cells. Furthermore, there is an increasing amount of literature demonstrating that SCF is...

  2. Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives

    OpenAIRE

    Konstantinos Samitas; Vasiliki Delimpoura; Eleftherios Zervas; Mina Gaga

    2015-01-01

    Asthma is a disorder of the airways involving various inflammatory cells and mediators and characterised by bronchial hyperresponsiveness, chronic inflammation and structural alterations in the airways, also known as remodelling. IgE is an important mediator of allergic reactions and has a central role in allergic asthma pathophysiology, as it is implicated in both the early and late phase allergic response. Moreover, clinical and mechanistic evidence has lately emerged, implicating IgE in th...

  3. Insulin modulates cytokine release and selectin expression in the early phase of allergic airway inflammation in diabetic rats

    Directory of Open Access Journals (Sweden)

    Vianna Elcio O

    2010-07-01

    Full Text Available Abstract Background Clinical and experimental data suggest that the inflammatory response is impaired in diabetics and can be modulated by insulin. The present study was undertaken to investigate the role of insulin on the early phase of allergic airway inflammation. Methods Diabetic male Wistar rats (alloxan, 42 mg/Kg, i.v., 10 days and controls were sensitized by s.c. injection of ovalbumin (OA in aluminium hydroxide 14 days before OA (1 mg/0.4 mL or saline intratracheal challenge. The following analyses were performed 6 hours thereafter: a quantification of interleukin (IL-1β, tumor necrosis factor (TNF-α and cytokine-induced neutrophil chemoattractant (CINC-1 in the bronchoalveolar lavage fluid (BALF by Enzyme-Linked Immunosorbent Assay, b expression of E- and P- selectins on lung vessels by immunohistochemistry, and c inflammatory cell infiltration into the airways and lung parenchyma. NPH insulin (4 IU, s.c. was given i.v. 2 hours before antigen challenge. Results Diabetic rats exhibited significant reduction in the BALF concentrations of IL-1β (30% and TNF-α (45%, and in the lung expression of P-selectin (30% compared to non-diabetic animals. This was accompanied by reduced number of neutrophils into the airways and around bronchi and blood vessels. There were no differences in the CINC-1 levels in BALF, and E-selectin expression. Treatment of diabetic rats with NPH insulin, 2 hours before antigen challenge, restored the reduced levels of IL-1β, TNF-α and P-selectin, and neutrophil migration. Conclusion Data presented suggest that insulin modulates the production/release of TNF-α and IL-1β, the expression of P- and E-selectin, and the associated neutrophil migration into the lungs during the early phase of the allergic inflammatory reaction.

  4. Antenatal infection/inflammation and postnatal lung maturation and injury

    Directory of Open Access Journals (Sweden)

    Ikegami Machiko

    2001-01-01

    Full Text Available Abstract Chorioamnionitis is frequently associated with preterm deliveries before 30 weeks gestation. Chorioamnionitis correlates both with an increased risk of bronchopulmonary dysplasia and with a decreased risk of respiratory distress syndrome. Both interleukin-1α and endotoxin can induce inflammation in the fetal lungs and lung maturation after preterm birth when given by intra-amniotic injection. Inflammation can also result in an arrest of alveolarization, and this lung developmental abnormality is prominent in the lungs of preterm infants that die of bronchopulmonary dysplasia. The mechanisms by which infection/inflammation can have both beneficial and injurious effects on the preterm lung remain to be characterized.

  5. The Role of Ion Channels to Regulate Airway Ciliary Beat Frequency During Allergic Inflammation.

    Science.gov (United States)

    Joskova, M; Sutovska, M; Durdik, P; Koniar, D; Hargas, L; Banovcin, P; Hrianka, M; Khazaei, V; Pappova, L; Franova, S

    2016-01-01

    Overproduction of mucus is a hallmark of asthma. The aim of this study was to identify potentially effective therapies for removing excess mucus. The role of voltage-gated (Kir 6.1, KCa 1.1) and store-operated ion channels (SOC, CRAC) in respiratory cilia, relating to the tracheal ciliary beat frequency (CBF), was compared under the physiological and allergic airway conditions. Ex vivo experiments were designed to test the local effects of Kir 6.1, KCa 1.1 and CRAC ion channel modulators in a concentration-dependent manner on the CBF. Cilia, obtained with the brushing method, were monitored by a high-speed video camera and analyzed with ciliary analysis software. In natural conditions, a Kir 6.1 opener accelerated CBF, while CRAC blocker slowed it in a concentration-dependent manner. In allergic inflammation, the effect of Kir 6.1 opener was insignificant, with a tendency to decrease CBF. A cilio-inhibitory effect of a CRAC blocker, while gently reduced by allergic inflammation, remained significant. A KCa 1.1 opener turned out to significantly enhance the CBF under the allergic OVA-sensitized conditions. We conclude that optimally attuned concentration of KCa 1.1 openers or special types of bimodal SOC channel blockers, potentially given by inhalation, might benefit asthma. PMID:27369295

  6. Schistosoma mansoni-mediated suppression of allergic airway inflammation requires patency and Foxp3+ Treg cells.

    Directory of Open Access Journals (Sweden)

    Laura E Layland

    Full Text Available The continual rise of asthma in industrialised countries stands in strong contrast to the situation in developing lands. According to the modified Hygiene Hypothesis, helminths play a major role in suppressing bystander immune responses to allergens, and both epidemiological and experimental studies suggest that the tropical parasitic trematode Schistosoma mansoni elicits such effects. The focus of this study was to investigate which developmental stages of schistosome infection confer suppression of allergic airway inflammation (AAI using ovalbumin (OVA as a model allergen. Moreover, we assessed the functional role and localization of infection-induced CD4(+Foxp3(+ regulatory T cells (Treg in mediating such suppressive effects. Therefore, AAI was elicited using OVA/adjuvant sensitizations with subsequent OVA aerosolic challenge and was induced during various stages of infection, as well as after successful anti-helminthic treatment with praziquantel. The role of Treg was determined by specifically depleting Treg in a genetically modified mouse model (DEREG during schistosome infection. Alterations in AAI were determined by cell infiltration levels into the bronchial system, OVA-specific IgE and Th2 type responses, airway hyper-sensitivity and lung pathology. Our results demonstrate that schistosome infection leads to a suppression of OVA-induced AAI when mice are challenged during the patent phase of infection: production of eggs by fecund female worms. Moreover, this ameliorating effect does not persist after anti-helminthic treatment, and depletion of Treg reverts suppression, resulting in aggravated AAI responses. This is most likely due to a delayed reconstitution of Treg in infected-depleted animals which have strong ongoing immune responses. In summary, we conclude that schistosome-mediated suppression of AAI requires the presence of viable eggs and infection-driven Treg cells. These data provide evidence that helminth derived products

  7. Evaluation on Potential Contributions of Protease Activated Receptors Related Mediators in Allergic Inflammation

    OpenAIRE

    Huiyun Zhang; Xiaoning Zeng; Shaoheng He

    2014-01-01

    Protease activated receptors (PARs) have been recognized as a distinctive four-member family of seven transmembrane G protein-coupled receptors (GPCRs) that can be cleaved by certain serine proteases. In recent years, there has been considerable interest in the role of PARs in allergic inflammation, the fundamental pathologic changes of allergy, but the potential roles of PARs in allergy remain obscure. Since many of these proteases are produced and actively involved in the pathologic process...

  8. Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF-mediated mechanism.

    Science.gov (United States)

    Cates, Elizabeth C; Fattouh, Ramzi; Wattie, Jennifer; Inman, Mark D; Goncharova, Susanna; Coyle, Anthony J; Gutierrez-Ramos, José-Carlos; Jordana, Manel

    2004-11-15

    It is now well established that passive exposure to inhaled OVA leads to a state of immunological tolerance. Therefore, to elicit allergic sensitization, researchers have been compelled to devise alternative strategies, such as the systemic delivery of OVA in the context of powerful adjuvants, which are alien to the way humans are exposed and sensitized to allergens. The objectives of these studies were to investigate immune-inflammatory responses to intranasal delivery of a purified house dust mite (HDM) extract and to evaluate the role of GM-CSF in this process. HDM was delivered to BALB/c mice daily for 10 days. After the last exposure, mice were killed, bronchoalveolar lavage was performed, and samples were obtained. Expression/production of Th2-associated molecules in the lymph nodes, lung, and spleen were evaluated by real-time quantitative PCR and ELISA, respectively. Using this exposure protocol, exposure to HDM alone generated Th2 sensitization based on the expression/production of Th2 effector molecules and airway eosinophilic inflammation. Flow cytometric analysis demonstrated expansion and activation of APCs in the lung and an influx of activated Th2 effector cells. Moreover, this inflammation was accompanied by airways hyper-responsiveness and a robust memory-driven immune response. Finally, administration of anti-GM-CSF-neutralizing Abs markedly reduced immune-inflammatory responses in both lung and spleen. Thus, intranasal delivery of HDM results in Th2 sensitization and airway eosinophilic inflammation that appear to be mediated, at least in part, by endogenous GM-CSF production. PMID:15528378

  9. Effects of Corni fructus on ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of allergic asthma

    Directory of Open Access Journals (Sweden)

    Kim Seung-Hyung

    2012-03-01

    Full Text Available Abstract Background Allergic asthma is a chronic inflammatory lung disease that is characterized by airway hyperresponsiveness (AHR to allergens, airway oedema, increased mucus secretion, excess production of T helper-2 (Th2 cytokines, and eosinophil accumulation in the lungs. Corni fructus (CF is a fruit of Cornus officinalis Sieb. Et. Zucc. (Cornaceae and has been used in traditional Korean medicine as an anti-inflammatory, analgesic, and diuretic agent. To investigate the anti-asthmatic effects of CF and their underlying mechanism, we examined the influence of CF on the development of pulmonary eosinophilic inflammation and airway hyperresponsiveness in a mouse model of allergic asthma. Methods In this study, BALB/c mice were systemically sensitized to ovalbumin (OVA by intraperitoneal (i.p., intratracheal (i.t. injections and intranasal (i.n. inhalation of OVA. We investigated the effect of CF on airway hyperresponsiveness, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokine production, and OVA-specific immunoglobulin E (IgE production. Results The CF-treated groups showed suppressed eosinophil infiltration, allergic airway inflammation, and AHR via reduced production of interleuin (IL -5, IL-13, and OVA-specific IgE. Conclusions Our data suggest that the therapeutic effects of CF in asthma are mediated by reduced production of Th2 cytokines (IL-5, eotaxin, and OVA-specific IgE and reduced eosinophil infiltration.

  10. Group 2 innate lymphoid cells in lung inflammation

    NARCIS (Netherlands)

    B.W.S. Li (Bobby W.); R.W. Hendriks (Rudi)

    2013-01-01

    textabstractSummary: Although allergic asthma is a heterogeneous disease, allergen-specific T helper 2 (Th2) cells producing the key cytokines involved in type 2 inflammation, interleukin-4 (IL-4), IL-5 and IL-13, are thought to play a major role in asthma pathogenesis. This model is challenged by t

  11. Novel basophil- or eosinophil-depleted mouse models for functional analyses of allergic inflammation.

    Directory of Open Access Journals (Sweden)

    Kunie Matsuoka

    Full Text Available Basophils and eosinophils play important roles in various host defense mechanisms but also act as harmful effectors in allergic disorders. We generated novel basophil- and eosinophil-depletion mouse models by introducing the human diphtheria toxin (DT receptor gene under the control of the mouse CD203c and the eosinophil peroxidase promoter, respectively, to study the critical roles of these cells in the immunological response. These mice exhibited selective depletion of the target cells upon DT administration. In the basophil-depletion model, DT administration attenuated a drop in body temperature in IgG-mediated systemic anaphylaxis in a dose-dependent manner and almost completely abolished the development of ear swelling in IgE-mediated chronic allergic inflammation (IgE-CAI, a typical skin swelling reaction with massive eosinophil infiltration. In contrast, in the eosinophil-depletion model, DT administration ameliorated the ear swelling in IgE-CAI whether DT was administered before, simultaneously, or after, antigen challenge, with significantly lower numbers of eosinophils infiltrating into the swelling site. These results confirm that basophils and eosinophils act as the initiator and the effector, respectively, in IgE-CAI. In addition, antibody array analysis suggested that eotaxin-2 is a principal chemokine that attracts proinflammatory cells, leading to chronic allergic inflammation. Thus, the two mouse models established in this study are potentially useful and powerful tools for studying the in vivo roles of basophils and eosinophils. The combination of basophil- and eosinophil-depletion mouse models provides a new approach to understanding the complicated mechanism of allergic inflammation in conditions such as atopic dermatitis and asthma.

  12. Hu.4-1BB-Fc fusion protein inhibits allergic inflammation and airway hyperresponsiveness in a murine model of asthma

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    Byoung-Ju Kim

    2011-09-01

    Full Text Available Purpose : 4-1BB (CD 137 is a costimulatory molecule expressed on activated T-cells. Repression by 4-1BB is thought to attenuate Th2-mediated allergic reactions. The aim of this study was to investigate the effect of 4-1BB on allergic airway inflammation in a murine asthma model. Methods : BALB/c mice were sensitized to and challenged with ovalbumin (OVA. Hu.4-1BB-Fc was administered 1 day before the first OVA sensitization or 1 day after the second OVA sensitization. Following antigen challenge, airway responsiveness to methacholine was assessed and bronchoalveolar lavage (BAL fluid was analyzed. Total immunoglobulin (Ig E, OVA-specific IgE, IgG1, and IgG2a levels in sera were measured by enzyme-linked immunosorbent assay. Lung pathology was also evaluated. Results : In mice treated with Hu.4-1BB-Fc before the first OVA sensitization, there was a marked decrease in airway hyperresponsiveness, total cell count, and eosinophil count in the BAL fluid. In addition, Hu.4-1BB-Fc treatment decreased serum OVA-specific IgG1 levels and increased serum IgG2a level significantly compared with the corresponding levels in mice sensitized to and challenged with OVA. Hu.4-1BB-Fc-treated mice also showed suppressed peribronchial and perivascular inflammatory cell infiltration. In contrast, treatment with Hu.4-1BB-Fc 1 day after sensitization had no effect on airway hyperresponsiveness and showed less suppression of inflammation in lung tissue. Conclusion : Administration of Hu.4-1BB-Fc can attenuate airway inflammation and hyperreactivity in a mouse model of allergic airway inflammation. In addition, administration before sensitization may be more effective. These findings suggest that 4-1BB may be a useful therapeutic molecule against asthma.

  13. IL-23 and T(H)17-mediated inflammation in human allergic contact dermatitis

    DEFF Research Database (Denmark)

    Larsen, Jeppe Madura; Bonefeld, Charlotte Menné; Poulsen, Steen Seier;

    2009-01-01

    . OBJECTIVE: To investigate T(H)17-mediated inflammation in human beings with allergic contact dermatitis; in particular, the innate response of keratinocytes to contact allergen, the induction of allergen-specific T(H)17 cells, and the presence of T(H)17-related effector cells in inflamed skin. METHODS......-term ex vivo assay. Nickel patch test lesions and normal skin were analyzed for the expression of T(H)17-related cells and molecules by using immunohistochemistry. RESULTS: Keratinocytes were found to produce IL-23, but no detectable IL-12, in a response to nickel stimulation. Memory T cells isolated from...... peripheral blood of individuals with nickel allergy, but not healthy controls, contained T(H)17 and T(H)1 cells proliferating in response to nickel-pulsed DCs. Inflamed skin of nickel-challenged allergic individuals contained infiltrating neutrophils and cells expressing IL-17, IL-22, CCR6, and IL-22R...

  14. The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma

    Science.gov (United States)

    Van der Velden, Joanne; Harkness, Louise M.; Barker, Donna M.; Barcham, Garry J.; Ugalde, Cathryn L.; Koumoundouros, Emmanuel; Bao, Heidi; Organ, Louise A.; Tokanovic, Ana; Burgess, Janette K.; Snibson, Kenneth J.

    2016-01-01

    Tumstatin, a protein fragment of the alpha-3 chain of Collagen IV, is known to be significantly reduced in the airways of asthmatics. Further, there is evidence that suggests a link between the relatively low level of tumstatin and the induction of angiogenesis and inflammation in allergic airway disease. Here, we show that the intra-segmental administration of tumstatin can impede the development of vascular remodelling and allergic inflammatory responses that are induced in a segmental challenge model of experimental asthma in sheep. In particular, the administration of tumstatin to lung segments chronically exposed to house dust mite (HDM) resulted in a significant reduction of airway small blood vessels in the diameter range 10+–20 μm compared to controls. In tumstatin treated lung segments after HDM challenge, the number of eosinophils was significantly reduced in parenchymal and airway wall tissues, as well as in the bronchoalveolar lavage fluid. The expression of VEGF in airway smooth muscle was also significantly reduced in tumstatin-treated segments compared to control saline-treated segments. Allergic lung function responses were not attenuated by tumstatin administration in this model. The data are consistent with the concept that tumstatin can act to suppress vascular remodelling and inflammation in allergic airway disease. PMID:27199164

  15. The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma.

    Science.gov (United States)

    Van der Velden, Joanne; Harkness, Louise M; Barker, Donna M; Barcham, Garry J; Ugalde, Cathryn L; Koumoundouros, Emmanuel; Bao, Heidi; Organ, Louise A; Tokanovic, Ana; Burgess, Janette K; Snibson, Kenneth J

    2016-01-01

    Tumstatin, a protein fragment of the alpha-3 chain of Collagen IV, is known to be significantly reduced in the airways of asthmatics. Further, there is evidence that suggests a link between the relatively low level of tumstatin and the induction of angiogenesis and inflammation in allergic airway disease. Here, we show that the intra-segmental administration of tumstatin can impede the development of vascular remodelling and allergic inflammatory responses that are induced in a segmental challenge model of experimental asthma in sheep. In particular, the administration of tumstatin to lung segments chronically exposed to house dust mite (HDM) resulted in a significant reduction of airway small blood vessels in the diameter range 10(+)-20 μm compared to controls. In tumstatin treated lung segments after HDM challenge, the number of eosinophils was significantly reduced in parenchymal and airway wall tissues, as well as in the bronchoalveolar lavage fluid. The expression of VEGF in airway smooth muscle was also significantly reduced in tumstatin-treated segments compared to control saline-treated segments. Allergic lung function responses were not attenuated by tumstatin administration in this model. The data are consistent with the concept that tumstatin can act to suppress vascular remodelling and inflammation in allergic airway disease. PMID:27199164

  16. Cytotoxic T lymphocytes mediate chronic inflammation of the nasal mucosa of patients with atypical allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Shuqi Qiu

    2011-01-01

    Full Text Available Background : The prevalence of chronic rhinitis is increasing rapidly; its pathogenesis is to be further understood; immune inflammation is one of the possible causative factors. Antigen specific CD8+ T cells play a critical role in the induction of chronic inflammation. Aims : This study aimed to investigate the role of antigen specific CD8+ T cells in the pathogenesis of chronic atypical allergic rhinitis. Material and Methods : Nasal mucosal epithelial surface scratching samples were obtained from patients with chronic obstruction atypical allergic rhinitis. Exosomes were purified from the scratching samples and examined by immune gold electron microscopy. The effect of exosomes on modulating dendritic cell′s properties, the effect of exosome-pulsed dendritic cells on naïve T cell differentiation and the antigen specific CD8+ T cell activation were observed by cell culture models. Results : Exosomes purified from patients with chronic atypical allergic rhinitis carried microbial products, Staphylococcal enterotoxin B (SEB, and airborne antigen, Derp1. Dendritic cells pulsed by SEB/Derp1-carrying exosomes showed high levels of CD80, CD86 and the major histocompatibility class I (MHCI. Exosome-pulsed dendritic cells could induce the naïve CD3+ T cells to differentiate into CD8+ T cells. Upon the exposure to a specific antigen, the CD8+ T cells released granzyme B and perforin; more than 30% antigen specific CD8+ T cells proliferated. Conclusions : Antigen specific CD8+ T cells play an important role in the pathogenesis of chronic obstruction atypical allergic rhinitis.

  17. Liver-Specific Allergen Gene Transfer by Adeno-Associated Virus Suppresses Allergic Airway Inflammation in Mice.

    Science.gov (United States)

    Chan, Cheng-Chi; Lai, Chin-Wen; Wu, Chia-Jen; Chen, Li-Chen; Tao, Mi-Hua; Kuo, Ming-Ling

    2016-08-01

    Allergic airway inflammation driven by T helper 2 (Th2)-type immunity is characterized by airway hyperresponsiveness, eosinophilic infiltration, and elevated IgE production. Various novel strategies for managing asthma have been explored, such as DNA vaccines, T-cell peptides, and allergen-specific immunotherapy. A principal goal of most immunotherapeutic approaches is active and long-term allergen-specific tolerance. Liver-specific gene transfer using adeno-associated virus (AAV) has been shown to favorably induce tolerogenic responses to therapeutic products in various experimental models. AAV8 has strong liver tropism and induces immune tolerance in mice. The present study aimed to determine whether hepatocyte-specific allergen expression by pseudotyped AAV2/8 alleviates asthmatic symptoms in ovalbumin (OVA)-sensitized mice. Mice were intravenously injected with AAV2/8 vector carrying membrane-bound OVA transgene under transcriptional control of a hepatocyte-specific alpha 1 antitrypsin promoter (AAV2/8-OVA) and then sensitized with OVA. AAV2/8-OVA specifically transduced the OVA transgene in the liver. Airway hyperresponsiveness, eosinophilia, mucus hypersecretion, and Th2 cytokines were significantly suppressed in both the lungs and secondary lymphoid organs of asthmatic mice infected with AAV2/8-OVA. Significant reduction of OVA-specific antibodies was detected in the bronchoalveolar lavage fluid from AAV2/8-OVA-treated mice. Moreover, AAV2/8-OVA treatment prominently promoted the expression of Foxp3, IL-10, and TGF-β in the liver. Enhanced Foxp3 expression was also detected in the lungs of asthmatic mice after AAV2/8-OVA treatment. Taken together, these results suggest that the induction of immune tolerance by hepatic AAV gene transfer may be beneficial for modulating allergic asthma. PMID:27178525

  18. Activating transcription factor 3 is a negative regulator of allergic pulmonary inflammation

    OpenAIRE

    Gilchrist, Mark; Henderson, William R.; Clark, April E.; Simmons, Randi M.; Ye, Xin; Smith, Kelly D.; Aderem, Alan

    2008-01-01

    We recently demonstrated the pivotal role of the transcription factor (TF) activating TF 3 (ATF3) in dampening inflammation. We demonstrate that ATF3 also ameliorates allergen-induced airway inflammation and hyperresponsiveness in a mouse model of human asthma. ATF3 expression was increased in the lungs of mice challenged with ovalbumin allergen, and this was associated with its recruitment to the promoters of genes encoding Th2-associated cytokines. ATF3-deficient mice developed significantl...

  19. Effects of Respiratory Mycoplasma pneumoniae Infection on Allergen-Induced Bronchial Hyperresponsiveness and Lung Inflammation in Mice

    OpenAIRE

    Chu, Hong Wei; Honour, Joyce M.; Rawlinson, Catherine A.; Harbeck, Ronald J.; Richard J Martin

    2003-01-01

    Airway mycoplasma infection may be associated with asthma pathophysiology. However, the direct effects of mycoplasma infection on asthma remain unknown. Using a murine allergic-asthma model, we evaluated the effects of different timing of airway Mycoplasma pneumoniae infection on bronchial hyperresponsiveness (BHR), lung inflammation, and the protein levels of Th1 (gamma interferon [IFN-γ]) and Th2 (interleukin 4 [IL-4]) cytokines in bronchoalveolar lavage fluid. When mycoplasma infection occ...

  20. An Allergic Lung Microenvironment Suppresses Carbon Nanotube-Induced Inflammasome Activation via STAT6-Dependent Inhibition of Caspase-1.

    Directory of Open Access Journals (Sweden)

    Kelly A Shipkowski

    Full Text Available Multi-walled carbon nanotubes (MWCNTs represent a human health risk as mice exposed by inhalation display pulmonary fibrosis. Production of IL-1β via inflammasome activation is a mechanism of MWCNT-induced acute inflammation and has been implicated in chronic fibrogenesis. Mice sensitized to allergens have elevated T-helper 2 (Th2 cytokines, IL-4 and IL-13, and are susceptible to MWCNT-induced airway fibrosis. We postulated that Th2 cytokines would modulate MWCNT-induced inflammasome activation and IL-1β release in vitro and in vivo during allergic inflammation.THP-1 macrophages were primed with LPS, exposed to MWCNTs and/or IL-4 or IL-13 for 24 hours, and analyzed for indicators of inflammasome activation. C57BL6 mice were sensitized to house dust mite (HDM allergen and MWCNTs were delivered to the lungs by oropharyngeal aspiration. Mice were euthanized 1 or 21 days post-MWCNT exposure and evaluated for lung inflammasome components and allergic inflammatory responses.Priming of THP-1 macrophages with LPS increased pro-IL-1β and subsequent exposure to MWCNTs induced IL-1β secretion. IL-4 or IL-13 decreased MWCNT-induced IL-1β secretion by THP-1 cells and reduced pro-caspase-1 but not pro-IL-1β. Treatment of THP-1 cells with STAT6 inhibitors, either Leflunomide or JAK I inhibitor, blocked suppression of caspase activity by IL-4 and IL-13. In vivo, MWCNTs alone caused neutrophilic infiltration into the lungs of mice 1 day post-exposure and increased IL-1β in bronchoalveolar lavage fluid (BALF and pro-caspase-1 immuno-staining in macrophages and airway epithelium. HDM sensitization alone caused eosinophilic inflammation with increased IL-13. MWCNT exposure after HDM sensitization increased total cell numbers in BALF, but decreased numbers of neutrophils and IL-1β in BALF as well as reduced pro-caspase-1 in lung tissue. Despite reduced IL-1β mice exposed to MWCNTs after HDM developed more severe airway fibrosis by 21 days and had increased

  1. Eosinophils in the lung – modulating apoptosis and efferocytosis in airway inflammation

    Directory of Open Access Journals (Sweden)

    Jennifer M Felton

    2014-07-01

    Full Text Available Due to the key role of the lung in efficient transfer of oxygen in exchange for carbon dioxide, a controlled inflammatory response is essential for restoration of tissue homeostasis following airway exposure to bacterial pathogens or environmental toxins. Unregulated or prolonged inflammatory responses in the lungs can lead to tissue damage, disrupting normal tissue architecture and consequently compromising efficient gaseous exchange. Failure to resolve inflammation underlies the development and/or progression of a number of inflammatory lung diseases including asthma. Eosinophils, granulocytic cells of the innate immune system, are primarily involved in defence against parasitic infections. However, the propagation of the allergic inflammatory response in chronic asthma is thought to involve excessive recruitment and impaired apoptosis of eosinophils together with defective phagocytic clearance of apoptotic cells (efferocytosis. In terms of therapeutic approaches for treatment of asthma, the widespread use of glucocorticoids is associated with a number of adverse health consequences after long-term use, while some patients suffer from steroid-resistant disease. A new approach for therapeutic intervention would be to promote the resolution of inflammation via modulation of eosinophil apoptosis and the phagocytic clearance of apoptotic cells. This review focuses on the mechanisms underpinning eosinophil-mediated lung damage, currently available treatments and therapeutic targets that might in future be harnessed to facilitate inflammation resolution by the manipulation of cell survival and clearance pathways.

  2. Eosinophils in the lung - modulating apoptosis and efferocytosis in airway inflammation.

    Science.gov (United States)

    Felton, Jennifer M; Lucas, Christopher D; Rossi, Adriano G; Dransfield, Ian

    2014-01-01

    Due to the key role of the lung in efficient transfer of oxygen in exchange for carbon dioxide, a controlled inflammatory response is essential for restoration of tissue homeostasis following airway exposure to bacterial pathogens or environmental toxins. Unregulated or prolonged inflammatory responses in the lungs can lead to tissue damage, disrupting normal tissue architecture, and consequently compromising efficient gaseous exchange. Failure to resolve inflammation underlies the development and/or progression of a number of inflammatory lung diseases including asthma. Eosinophils, granulocytic cells of the innate immune system, are primarily involved in defense against parasitic infections. However, the propagation of the allergic inflammatory response in chronic asthma is thought to involve excessive recruitment and impaired apoptosis of eosinophils together with defective phagocytic clearance of apoptotic cells (efferocytosis). In terms of therapeutic approaches for the treatment of asthma, the widespread use of glucocorticoids is associated with a number of adverse health consequences after long-term use, while some patients suffer from steroid-resistant disease. A new approach for therapeutic intervention would be to promote the resolution of inflammation via modulation of eosinophil apoptosis and the phagocytic clearance of apoptotic cells. This review focuses on the mechanisms underpinning eosinophil-mediated lung damage, currently available treatments and therapeutic targets that might in future be harnessed to facilitate inflammation resolution by the manipulation of cell survival and clearance pathways. PMID:25071763

  3. Aryl Hydrocarbon Receptor Protects Lungs from Cockroach Allergen-Induced Inflammation by Modulating Mesenchymal Stem Cells.

    Science.gov (United States)

    Xu, Ting; Zhou, Yufeng; Qiu, Lipeng; Do, Danh C; Zhao, Yilin; Cui, Zhuang; Wang, Heng; Liu, Xiaopeng; Saradna, Arjun; Cao, Xu; Wan, Mei; Gao, Peisong

    2015-12-15

    Exposure to cockroach allergen leads to allergic sensitization and increased risk of developing asthma. Aryl hydrocarbon receptor (AhR), a receptor for many common environmental contaminants, can sense not only environmental pollutants but also microbial insults. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to modulate immune responses. In this study, we investigated whether AhR can sense cockroach allergens and modulate allergen-induced lung inflammation through MSCs. We found that cockroach allergen-treated AhR-deficient (AhR(-/-)) mice showed exacerbation of lung inflammation when compared with wild-type (WT) mice. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, significantly suppressed allergen-induced mouse lung inflammation. MSCs were significantly reduced in cockroach allergen-challenged AhR(-/-) mice as compared with WT mice, but increased in cockroach allergen-challenged WT mice when treated with TCDD. Moreover, MSCs express AhR, and AhR signaling can be activated by cockroach allergen with increased expression of its downstream genes cyp1a1 and cyp1b1. Furthermore, we tracked the migration of i.v.-injected GFP(+) MSCs and found that cockroach allergen-challenged AhR(-/-) mice displayed less migration of MSCs to the lungs compared with WT. The AhR-mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium prepared from cockroach extract-challenged epithelial cells significantly induced MSC migration, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGF-β1-neutralizing Ab. These results suggest that AhR plays an important role in protecting lungs from allergen-induced inflammation by modulating MSC recruitment and their immune-suppressive activity. PMID:26561548

  4. Lung-homing of endothelial progenitor cells and airway vascularization is only partially dependant on eosinophils in a house dust mite-exposed mouse model of allergic asthma.

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    Nirooya Sivapalan

    Full Text Available Asthmatic responses involve a systemic component where activation of the bone marrow leads to mobilization and lung-homing of progenitor cells. This traffic may be driven by stromal cell derived factor-1 (SDF-1, a potent progenitor chemoattractant. We have previously shown that airway angiogenesis, an early remodeling event, can be inhibited by preventing the migration of endothelial progenitor cells (EPC to the lungs. Given intranasally, AMD3100, a CXCR4 antagonist that inhibits SDF-1 mediated effects, attenuated allergen-induced lung-homing of EPC, vascularization of pulmonary tissue, airway eosinophilia and development of airway hyperresponsiveness. Since SDF-1 is also an eosinophil chemoattractant, we investigated, using a transgenic eosinophil deficient mouse strain (PHIL whether EPC lung accumulation and lung vascularization in allergic airway responses is dependent on eosinophilic inflammation.Wild-type (WT BALB/c and eosinophil deficient (PHIL mice were sensitized to house dust mite (HDM using a chronic exposure protocol and treated with AMD3100 to modulate SDF-1 stimulated progenitor traffic. Following HDM challenge, lung-extracted EPCs were enumerated along with airway inflammation, microvessel density (MVD and airway methacholine responsiveness (AHR.Following Ag sensitization, both WT and PHIL mice exhibited HDM-induced increase in airway inflammation, EPC lung-accumulation, lung angiogenesis and AHR. Treatment with AMD3100 significantly attenuated outcome measures in both groups of mice. Significantly lower levels of EPC and a trend for lower vascularization were detected in PHIL versus WT mice.This study shows that while allergen-induced lung-homing of endothelial progenitor cells, increased tissue vascularization and development lung dysfunction can occur in the absence of eosinophils, the presence of these cells worsens the pathology of the allergic response.

  5. Inhibition of aldose reductase prevents experimental allergic airway inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Umesh C S Yadav

    Full Text Available BACKGROUND: The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR, contributes to the pathogenesis of oxidative stress-induced inflammation by affecting the NF-kappaB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma. METHODS AND FINDINGS: Primary Human Small Airway Epithelial Cells (SAEC were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-kappaB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS, cycloxygenase (COX-2, Prostaglandin (PG E(2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and

  6. Upper and lower airway pathology in young children with allergic- and non-allergic rhinitis

    DEFF Research Database (Denmark)

    Chawes, Bo Lk

    2011-01-01

    sensitization, and filaggrin mutations; levels of total IgE, FeNO, and blood-eosinophils; lung function and bronchial responsiveness to cold dry air. We found that asthma was similarly associated with allergic- and non-allergic rhinitis suggesting a link between upper and lower airway diseases beyond an allergy...... associated inflammation. Only children with allergic rhinitis had increased bronchial responsiveness and elevated FeNO suggesting different endotypes of asthma symptoms in young children with allergic- and non-allergic rhinitis. We also found bronchial hyperresponsiveness and raised values of FeNO in...... children with allergic rhinitis without asthma suggesting sub-clinical bronchial inflammation and supporting the allergic disease process to involve both upper and lower airways. In conclusion, these observations objectively show marked differences in nasal pathology in young children with allergic- and...

  7. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis.

    Science.gov (United States)

    Liu, Boyi; Escalera, Jasmine; Balakrishna, Shrilatha; Fan, Lu; Caceres, Ana I; Robinson, Eve; Sui, Aiwei; McKay, M Craig; McAlexander, M Allen; Herrick, Christina A; Jordt, Sven E

    2013-09-01

    Allergic contact dermatitis is a common skin disease associated with inflammation and persistent pruritus. Transient receptor potential (TRP) ion channels in skin-innervating sensory neurons mediate acute inflammatory and pruritic responses following exogenous stimulation and may contribute to allergic responses. Genetic ablation or pharmacological inhibition of TRPA1, but not TRPV1, inhibited skin edema, keratinocyte hyperplasia, nerve growth, leukocyte infiltration, and antihistamine-resistant scratching behavior in mice exposed to the haptens, oxazolone and urushiol, the contact allergen of poison ivy. Hapten-challenged skin of TRPA1-deficient mice contained diminished levels of inflammatory cytokines, nerve growth factor, and endogenous pruritogens, such as substance P (SP) and serotonin. TRPA1-deficient sensory neurons were defective in SP signaling, and SP-induced scratching behavior was abolished in Trpa1(-/-) mice. SP receptor antagonists, such as aprepitant inhibited both hapten-induced cutaneous inflammation and scratching behavior. These findings support a central role for TRPA1 and SP in the integration of immune and neuronal mechanisms leading to chronic inflammatory responses and pruritus associated with contact dermatitis. PMID:23722916

  8. An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers.

    Science.gov (United States)

    Morita, Hideaki; Arae, Ken; Unno, Hirotoshi; Miyauchi, Kousuke; Toyama, Sumika; Nambu, Aya; Oboki, Keisuke; Ohno, Tatsukuni; Motomura, Kenichiro; Matsuda, Akira; Yamaguchi, Sachiko; Narushima, Seiko; Kajiwara, Naoki; Iikura, Motoyasu; Suto, Hajime; McKenzie, Andrew N J; Takahashi, Takao; Karasuyama, Hajime; Okumura, Ko; Azuma, Miyuki; Moro, Kazuyo; Akdis, Cezmi A; Galli, Stephen J; Koyasu, Shigeo; Kubo, Masato; Sudo, Katsuko; Saito, Hirohisa; Matsumoto, Kenji; Nakae, Susumu

    2015-07-21

    House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells. PMID:26200013

  9. Candida soluble cell wall β-glucan facilitates ovalbumin-induced allergic airway inflammation in mice: Possible role of antigen-presenting cells

    Directory of Open Access Journals (Sweden)

    Tamura Hiroshi

    2009-07-01

    Full Text Available Abstract Background Although fungi have been implicated as initiating/deteriorating factors for allergic asthma, their contributing components have not been fully elucidated. We previously isolated soluble β-glucan from Candida albicans (CSBG (Ohno et al., 2007. In the present study, the effects of CSBG exposure on airway immunopathology in the presence or absence of other immunogenic allergen was investigated in vivo, and their cellular mechanisms were analyzed both in vivo and in vitro. Methods In vivo, ICR mice were divided into 4 experimental groups: vehicle, CSBG (25 μg/animal, ovalbumin (OVA: 2 μg/animal, and CSBG + OVA were repeatedly administered intratracheally. The bronchoalveolar lavage cellular profile, lung histology, levels of cytokines and chemokines in the lung homogenates, the expression pattern of antigen-presenting cell (APC-related molecules in the lung digests, and serum immunoglobulin values were studied. In vitro, the impacts of CSBG (0–12.5 μg/ml on the phenotype and function of immune cells such as splenocytes and bone marrow-derived dendritic cells (BMDCs were evaluated in terms of cell proliferation, the surface expression of APC-related molecules, and OVA-mediated T-cell proliferating activity. Results In vivo, repeated pulmonary exposure to CSBG induced neutrophilic airway inflammation in the absence of OVA, and markedly exacerbated OVA-related eosinophilic airway inflammation with mucus metaplasia in mice, which was concomitant with the amplified lung expression of Th2 cytokines and IL-17A and chemokines related to allergic response. Exposure to CSBG plus OVA increased the number of cells bearing MHC class II with or without CD80 in the lung compared to that of others. In vitro, CSBG significantly augmented splenocyte proliferation in the presence or absence of OVA. Further, CSBG increased the expression of APC-related molecules such as CD80, CD86, and DEC205 on BMDCs and amplified OVA-mediated T

  10. Effect of dexamethasone and Nigella sativa on inducible nitric oxide synthase in the lungs of a murine model of allergic Asthma.

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    Mohamed Abdel-Aziz

    2014-10-01

    Full Text Available The aim of this study was to investigate the effects of Nigella sativa (NS fixed oil in comparison to dexamethasone (Dex on inducible nitric oxide synthase (iNOS, peripheral blood eosinophils (PBE, allergen specific serum IgG1 and interleukins and airway inflammation in a murine model of allergic asthma. Thirty-one mice were divided into four groups. Group I (n = 6 served as the control group. Group II (n = 10 mice were sensitized intraperitoneally and challenged intratracheally with cone albumin with no treatment. Group III(n = 6 mice were sensitized, challenged, and treated with Dex for 17 days starting at 24 hours after the first challenge. Group IV (n = 9 mice were sensitized, challenged, and treated with NS fixed oil for 17 days as well. For all groups, the following procedures were carried out: immunohistochemical study of iNOS in lung tissues, detection of PBE percentage, and histopathological examination of lung tissues for inflammatory cells. Lung tissue iNOS expression increased in sensitized, non-treated mice compared with controls, but this increase was not significant. NS fixed oil treatment significantly reduced PBE and lung inflammation but did not significantly reduce lung tissue iNOS expression compared with the control group. These effects were comparable to the effects of Dex. These results suggest that Nigella sativa exhibits immunomodulatory and anti-inflammatory effect which may be useful for treatment of allergic asthma.

  11. Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives

    Directory of Open Access Journals (Sweden)

    Konstantinos Samitas

    2015-12-01

    Full Text Available Asthma is a disorder of the airways involving various inflammatory cells and mediators and characterised by bronchial hyperresponsiveness, chronic inflammation and structural alterations in the airways, also known as remodelling. IgE is an important mediator of allergic reactions and has a central role in allergic asthma pathophysiology, as it is implicated in both the early and late phase allergic response. Moreover, clinical and mechanistic evidence has lately emerged, implicating IgE in the development of airway remodelling. The use of monoclonal antibodies targeting IgE, such as omalizumab, has proven very effective in improving respiratory symptoms and quality of life, while reducing asthma exacerbations, emergency room visits and the use of systemic corticosteroids in allergic severe asthma. These effects are believed to be mainly mediated by omalizumab's inhibitory effect on the initiation and further propagation of the allergic inflammation cascade. However, there is evidence to suggest that anti-IgE treatment remains effective long after it has been discontinued. In part, these findings could be attributed to the possible ameliorating effects of anti-IgE treatment on airway remodelling. In this review, we discuss recent findings supporting the notion that anti-IgE treatment modulates the complex immune responses that manifest clinically as asthma and ameliorates airway remodelling changes often observed in allergic severe asthma phenotypes.

  12. Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives.

    Science.gov (United States)

    Samitas, Konstantinos; Delimpoura, Vasiliki; Zervas, Eleftherios; Gaga, Mina

    2015-12-01

    Asthma is a disorder of the airways involving various inflammatory cells and mediators and characterised by bronchial hyperresponsiveness, chronic inflammation and structural alterations in the airways, also known as remodelling. IgE is an important mediator of allergic reactions and has a central role in allergic asthma pathophysiology, as it is implicated in both the early and late phase allergic response. Moreover, clinical and mechanistic evidence has lately emerged, implicating IgE in the development of airway remodelling. The use of monoclonal antibodies targeting IgE, such as omalizumab, has proven very effective in improving respiratory symptoms and quality of life, while reducing asthma exacerbations, emergency room visits and the use of systemic corticosteroids in allergic severe asthma. These effects are believed to be mainly mediated by omalizumab's inhibitory effect on the initiation and further propagation of the allergic inflammation cascade. However, there is evidence to suggest that anti-IgE treatment remains effective long after it has been discontinued. In part, these findings could be attributed to the possible ameliorating effects of anti-IgE treatment on airway remodelling. In this review, we discuss recent findings supporting the notion that anti-IgE treatment modulates the complex immune responses that manifest clinically as asthma and ameliorates airway remodelling changes often observed in allergic severe asthma phenotypes. PMID:26621973

  13. Responses of Six-Weeks Aquatic Exercise on the Autonomic Nervous System, Peak Nasal Inspiratory Flow and Lung Functions in Young Adults with Allergic Rhinitis

    OpenAIRE

    Taweesak Janyacharoen; Narupon Kunbootsri; Preeda Arayawichanon; Seksun Chainansamit; Kittisak Sawanyawisuth

    2015-01-01

    Allergic rhinitis is a chronic respiratory disease. Sympathetic hypofunction is identified in all of the allergic rhinitis patients. Moreover, allergic rhinitis is associated with decreased peak nasal inspiratory flow (PNIF) and impaired lung functions. The aim of this study was to investigate effects of six-week of aquatic exercise on the autonomic nervous system function, PNIF and lung functions in allergic rhinitis patients.Twenty-six allergic rhinitis patients, 12 males and 14 females wer...

  14. Therapeutic expansion of CD4+FoxP3+ regulatory T cells limits allergic airway inflammation during pulmonary fungal infection.

    Science.gov (United States)

    Schulze, Bianca; Piehler, Daniel; Eschke, Maria; Heyen, Laura; Protschka, Martina; Köhler, Gabriele; Alber, Gottfried

    2016-06-01

    Allergic asthma can be frequently caused and exacerbated by sensitization to ubiquitous fungal allergens associated with pulmonary mucus production, airway hyperresponsiveness and bronchial constriction, resulting in a complex disease that is often difficult to treat. Fungal infections are frequently complicated by the development of a type 2 immune response that prevents successful elimination of the fungal pathogen. Furthermore, production of type 2 cytokines triggers allergic airway inflammation. Following intranasal infection of BALB/c mice with the fungusCryptococcus neoformans, we recently described a more pronounced type 2 immune response in the absence of regulatory T (Treg) cells. To determine whether Treg cell expansion is able to suppress type 2-related fungal allergic inflammation, we increased Treg cell numbers during pulmonaryC. neoformansinfection by administration of an interleukin (IL)-2/anti-IL-2 complex. Expansion of Treg cells resulted in reduced immunoglobulin E production and decreased allergic airway inflammation including reduced production of pulmonary mucus and type 2 cytokines as well as production of immunosuppressive cytokines such as IL-10 and transforming growth factor-β1. From our data we conclude that Treg cells and/or their suppressive mediators represent potential targets for therapeutic intervention during allergic fungal airway disease. PMID:27001975

  15. Local immunotherapy in experimental murine lung inflammation

    OpenAIRE

    sprotocols

    2015-01-01

    Authors: Caroline Uebel, Sonja Koch, Anja Maier, Nina Sopel, Anna Graser, Stephanie Mousset & Susetta Finotto ### Abstract Innovative local immunotherapy for severe lung diseases such as asthma, chronic obstructive pulmonary disease or lung cancer requires a successful delivery to access the desired cellular target in the lung. An important route is the direct instillation into the airways in contrast to delivery through the digestive tract. This protocol details a method to deliv...

  16. Antigen-Specific IgG ameliorates allergic airway inflammation via Fcγ receptor IIB on dendritic cells

    Directory of Open Access Journals (Sweden)

    Karasuyama Hajime

    2011-04-01

    Full Text Available Abstract Background There have been few reports on the role of Fc receptors (FcRs and immunoglobulin G (IgG in asthma. The purpose of this study is to clarify the role of inhibitory FcRs and antigen presenting cells (APCs in pathogenesis of asthma and to evaluate antigen-transporting and presenting capacity by APCs in the tracheobronchial mucosa. Methods In FcγRIIB deficient (KO and C57BL/6 (WT mice, the effects of intratracheal instillation of antigen-specific IgG were analysed using the model with sensitization and airborne challenge with ovalbumin (OVA. Thoracic lymph nodes instilled with fluorescein-conjugated OVA were analysed by fluorescence microscopy. Moreover, we analysed the CD11c+ MHC class II+ cells which intaken fluorescein-conjugated OVA in thoracic lymph nodes by flow cytometry. Also, lung-derived CD11c+ APCs were analysed by flow cytometry. Effects of anti-OVA IgG1 on bone marrow dendritic cells (BMDCs in vitro were also analysed. Moreover, in FcγRIIB KO mice intravenously transplanted dendritic cells (DCs differentiated from BMDCs of WT mice, the effects of intratracheal instillation of anti-OVA IgG were evaluated by bronchoalveolar lavage (BAL. Results In WT mice, total cells and eosinophils in BAL fluid reduced after instillation with anti-OVA IgG1. Anti-OVA IgG1 suppressed airway inflammation in hyperresponsiveness and histology. In addition, the number of the fluorescein-conjugated OVA in CD11c+ MHC class II+ cells of thoracic lymph nodes with anti-OVA IgG1 instillation decreased compared with PBS. Also, MHC class II expression on lung-derived CD11c+ APCs with anti-OVA IgG1 instillation reduced. Moreover, in vitro, we showed that BMDCs with anti-OVA IgG1 significantly decreased the T cell proliferation. Finally, we demonstrated that the lacking effects of anti-OVA IgG1 on airway inflammation on FcγRIIB KO mice were restored with WT-derived BMDCs transplanted intravenously. Conclusion Antigen-specific IgG ameliorates

  17. Inactivation of capsaicin-sensitive nerves reduces pulmonary remodeling in guinea pigs with chronic allergic pulmonary inflammation

    OpenAIRE

    C.M. Prado; G.Z. da Rocha; E.A. Leick-Maldonado; C.M. Starling; V.L. Capelozzi; M. A. Martins; I.F.L.C. Tibério

    2011-01-01

    Pulmonary remodeling is an important feature of asthma physiopathology that can contribute to irreversible changes in lung function. Although neurokinins influence lung inflammation, their exact role in the extracellular matrix (ECM) remodeling remains to be determined. Our objective was to investigate whether inactivation of capsaicin-sensitive nerves modulates pulmonary ECM remodeling in animals with chronic lung inflammation. After 14 days of capsaicin (50 mg/kg, sc) or vehicle administrat...

  18. In children allergic to ragweed pollen, nasal inflammation is not influenced by monosensitization or polysensitization

    Science.gov (United States)

    Gelardi, Matteo; Bosoni, Mariangela; Morelli, Marco; Beretta, Silvia; Incorvaia, Cristoforo; Buttafava, Serena; Landi, Massimo; Masieri, Simonetta; Frati, Franco; Quaranta, Nicola; Zuccotti, Gian Vincenzo

    2016-01-01

    Background In patients polysensitized to pollen allergens, the priming effect, by which the sensitivity of the nasal mucosa to an allergen is increased by the previous exposure to another allergen, is a known phenomenon. This study was aimed at evaluating the degree of nasal inflammation, assessed by nasal cytology, in children with allergic rhinitis (AR) from ragweed pollen according to being monosensitized or polysensitized. Methods The study included 47 children. Of them, 24 suffered from AR caused by sensitization to grass pollen and ragweed pollen (group A) and 23 were sensitized only to ragweed pollen (group B). In all patients, the severity of AR was assessed according to the Allergic Rhinitis and Its Impact on Asthma guidelines, and comorbidities were also evaluated. Results In group A, 16.7% of children had a mild intermittent AR, 4.2% a moderate-to-severe intermittent, 33.3% a mild persistent, and 45.8% a moderate-to-severe persistent; in group B, 26.1% of children had a mild intermittent AR, 0% a moderate-to-severe intermittent, 52.2% a mild persistent, and 21.7% a moderate-to-severe persistent. No significant difference was detected in the number of the considered comorbidities between the two groups. The cell counts of neutrophils, eosinophils, lymphocytes/plasma cells, and mast cells were high but not significantly different in the two groups. Conclusion These findings show that the degree of nasal inflammation found in children with ragweed-induced AR is not influenced by additional allergy to grass pollen and confirm the previously reported absence of priming effect in ragweed allergy. PMID:27103838

  19. Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury

    OpenAIRE

    Shaver, Ciara M.; Grove, Brandon S.; Clune, Jennifer K.; Nigel Mackman; Lorraine B. Ware; Bastarache, Julie A

    2016-01-01

    Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-indu...

  20. In children allergic to ragweed pollen, nasal inflammation is not influenced by monosensitization or polysensitization

    Directory of Open Access Journals (Sweden)

    Gelardi M

    2016-04-01

    Full Text Available Matteo Gelardi,1 Mariangela Bosoni,2 Marco Morelli,2 Silvia Beretta,2 Cristoforo Incorvaia,3 Serena Buttafava,4 Massimo Landi,5 Simonetta Masieri,6 Franco Frati,4 Nicola Quaranta,1 Gian Vincenzo Zuccotti21Otolaryngology Section, Department of Neuroscience and Sensory Organs, University of Bari, 2Department of Pediatrics, Luigi Sacco Hospital, University of Milan, 3Allergy/Pulmonary Rehabilitation Unit, ICP Hospital, 4Medical and Scientific Department, Stallergenes Italy, Milan, 5Department of Pediatrics, ASL TO1, Turin, 6Department of Otorhinolaryngology, Sapienza University of Rome, Rome, ItalyBackground: In patients polysensitized to pollen allergens, the priming effect, by which the sensitivity of the nasal mucosa to an allergen is increased by the previous exposure to another allergen, is a known phenomenon. This study was aimed at evaluating the degree of nasal inflammation, assessed by nasal cytology, in children with allergic rhinitis (AR from ragweed pollen according to being monosensitized or polysensitized.Methods: The study included 47 children. Of them, 24 suffered from AR caused by sensitization to grass pollen and ragweed pollen (group A and 23 were sensitized only to ragweed pollen (group B. In all patients, the severity of AR was assessed according to the Allergic Rhinitis and Its Impact on Asthma guidelines, and comorbidities were also evaluated.Results: In group A, 16.7% of children had a mild intermittent AR, 4.2% a moderate-to-severe intermittent, 33.3% a mild persistent, and 45.8% a moderate-to-severe persistent; in group B, 26.1% of children had a mild intermittent AR, 0% a moderate-to-severe intermittent, 52.2% a mild persistent, and 21.7% a moderate-to-severe persistent. No significant difference was detected in the number of the considered comorbidities between the two groups. The cell counts of neutrophils, eosinophils, lymphocytes/plasma cells, and mast cells were high but not significantly different in the two groups

  1. The molecular fingerprint of lung inflammation after blunt chest trauma

    OpenAIRE

    Ehrnthaller, Christian; Flierl, Michael; Perl, Mario; Denk, Stephanie; Unnewehr, Heike; Ward, Peter A.; Radermacher, Peter; Ignatius, Anita; Gebhard, Florian; Chinnaiyan, Arul; Huber-Lang, Markus

    2015-01-01

    Background After severe blunt chest trauma, the development of an acute lung injury (ALI) is often associated with severe or even lethal complications. Especially in multiple injured patients after blunt chest trauma ALI/ARDS [acute respiratory distress syndrome (ARDS)] is frequent. However, in the initial posttraumatic phase, inflammatory clinical signs are often not apparent and underlying changes in gene-expression profile are unknown. Methods Therefore, inflammation in lung tissue followi...

  2. Biomarkers of in vivo fluorescence imaging in allergic airway inflammation.

    Science.gov (United States)

    Wang, Fa-Ping; Fan, Ying-Qi; Li, Su-Yun; Mao, Hui

    2016-04-01

    Airway inflammation is a central component of the manifestation of asthma but is relatively inaccessible to study. Current imaging techniques such as X-ray CT, MRI, and PET, have advanced noninvasive research on pulmonary diseases. However, these techniques mainly facilitate the anatomical or structural assessment of the diseased lung and/or typically use radioactive agents. In vivo fluorescence imaging is a novel method for noninvasive, real-time, and specific monitoring of lung airway inflammation, which is particularly important to gain a further understanding asthma. Compared to conventional techniques, fluorescent imaging has the advantages of rapid feedback, as well as high sensitivity and resolution. Recently, there has been an increase in the identification of biomarkers, including matrix metalloproteinases, cathepsins, selectins, folate receptor-beta, nanoparticles, as well as sialic acid-binding immunoglobulin-like lectin-F to assess the level of airway inflammation in asthma. Recent advances in our understanding of these biomarkers as molecular probes for in vivo imaging are discussed in this review. PMID:26902991

  3. Secretoglobin Superfamily Protein SCGB3A2 Deficiency Potentiates Ovalbumin-Induced Allergic Pulmonary Inflammation

    Directory of Open Access Journals (Sweden)

    Taketomo Kido

    2014-01-01

    Full Text Available Secretoglobin (SCGB 3A2, a cytokine-like secretory protein of small molecular weight, which may play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2, Scgb3a2−/− mice were generated and characterized. Scgb3a2−/− mice did not exhibit any overt phenotypes. In ovalbumin- (OVA- induced airway allergy inflammation model, Scgb3a2−/− mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenic Scgb3a2−/− mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates. These results indicate that the loss of SCGB3A2 function was influenced by a modifier gene(s in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent.

  4. Essential Role of Nuclear Factor κB in the Induction of Eosinophilia in Allergic Airway Inflammation

    OpenAIRE

    Yang, Liyan; Cohn, Lauren; Zhang, Dong-Hong; Homer, Robert; Ray, Anuradha; Ray, Prabir

    1998-01-01

    The molecular mechanisms that contribute to an eosinophil-rich airway inflammation in asthma are unclear. A predominantly T helper 2 (Th2)-type cell response has been documented in allergic asthma. Here we show that mice deficient in the p50 subunit of nuclear factor (NF)- κB are incapable of mounting eosinophilic airway inflammation compared with wild-type mice. This deficiency was not due to a block in T cell priming or proliferation in the p50−/− mice, nor was it due to a defect in the exp...

  5. Chrysin suppresses mast cell-mediated allergic inflammation: Involvement of calcium, caspase-1 and nuclear factor-κB

    International Nuclear Information System (INIS)

    A great number of people are suffering from allergic inflammatory diseases such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid contained in propolis, blue passion flower, and fruits. Several studies reported that chrysin has beneficial effects including anti-tumor and anti-oxidant activities. The aim of the present study was to elucidate whether chrysin modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. Chrysin inhibited immediate-type systemic hypersensitivity and serum histamine release. Chrysin attenuated immunoglobulin E-mediated local anaphylaxis. These inhibitory effects of chrysin on the systemic and local allergic reaction were more potent than cromolyn, a known anti-allergic drug. Chrysin reduced histamine release from mast cells. The inhibitory effect of chrysin on the histamine release was mediated by the modulation of intracellular calcium. In addition, chrysin decreased gene expression of pro-inflammatory cytokines such as, tumor necrosis factor-α, IL (interleukin)-1β, IL-4, and IL-6 in mast cells. The inhibitory effect of chrysin on the pro-inflammatory cytokine was nuclear factor-κB and caspase-1 dependent. Our findings provide evidence that chrysin inhibits mast cell-derived allergic inflammatory reactions by blocking histamine release and pro-inflammatory cytokine expression, and suggest the mechanisms of action. Furthermore, in vivo and in vitro anti-allergic inflammatory effect of chrysin suggests a possible therapeutic application of this agent in allergic inflammatory diseases. - Research Highlights: → Discovery of drugs for the allergic inflammation is important in human health. → Chrysin is a natural flavonoid contained in propolis, blue passion flower, and fruits. → Chrysin inhibited

  6. Interleukin-17 is a negative regulator of established allergic asthma

    OpenAIRE

    Schnyder-Candrian, Silvia; Togbe, Dieudonnée; Couillin, Isabelle; Mercier, Isabelle; Brombacher, Frank; Quesniaux, Valérie,; Fossiez, Francois; Ryffel, Bernhard; Schnyder, Bruno

    2006-01-01

    T helper (Th)17 cells producing interleukin (IL)-17 play a role in autoimmune and allergic inflammation. Here, we show that IL-23 induces IL-17 in the lung and IL-17 is required during antigen sensitization to develop allergic asthma, as shown in IL-17R–deficient mice. Since IL-17 expression increased further upon antigen challenge, we addressed its function in the effector phase. Most strikingly, neutralization of IL-17 augmented the allergic response in sensitized mice. Conversely, exogenou...

  7. Risk of Allergic Rhinitis, Allergic Conjunctivitis, and Eczema in Children Born to Mothers with Gum Inflammation during Pregnancy

    Science.gov (United States)

    Hsieh, Vivian Chia-Rong; Liu, Chin-Chen; Hsiao, Yu-Chen; Wu, Trong-Neng

    2016-01-01

    Purpose Despite links between maternal and child health status, evidence on the association between gum infection in pregnant mothers and childhood allergies is scarce. We aim to evaluate the risk of developing allergy in children born to periodontal mothers in a nationwide study. Methods We conducted a 9-year population-based, retrospective cohort study using Taiwan’s National Health Insurance database. A study cohort of 42,217 newborns born to mothers with periodontal disease during pregnancy was identified in 2001 and matched with 42,334 babies born to mothers without any infection (control) by mother’s age at delivery and baby sex. With a follow-up period from 2001 to 2010, we observed the incidence of allergic rhinitis (AR), allergic conjunctivitis (AC), and eczema in these children. Cox proportional hazards regression models were performed with premature deaths as competing risk for the estimation of allergic disease risks. Results Nine-year cumulative incidences were the highest among children born to periodontal mothers; they reached 46.8%, 24.2%, and 40.4% (vs. 39.5%, 18.3% and 34.8% in control) for AR, AC, and eczema, respectively. Our results showed moderately increased risks for the allergies in children born to periodontal mothers relative to their matched non-inflammatory control (adjusted HRs: 1.17, 95% CI: 1.15–1.20; 1.27, 1.24–1.31; 1.14, 1.12–1.17, respectively). Because the impact of food consumption and living environment cannot be considered using insurance data, we attempted to control it by adjusting for parental income and mother’s residential area. Conclusions Overall cumulative incidence and risks of children born to periodontal mothers for AR, AC, and eczema are significantly higher than those born to non-inflammatory mothers. Gum infection in women during pregnancy is an independent risk factor for allergic diseases in children, thus its intergenerational consequences should be considered in gestational care. PMID:27224053

  8. Lung inflammation caused by inhaled toxicants: a review

    OpenAIRE

    Wong, John

    2016-01-01

    John Wong, Bruce E Magun, Lisa J Wood School of Nursing, MGH Institute of Health Professions, Boston, MA, USA Abstract: Exposure of the lungs to airborne toxicants from different sources in the environment may lead to acute and chronic pulmonary or even systemic inflammation. Cigarette smoke is the leading cause of chronic obstructive pulmonary disease, although wood smoke in urban areas of underdeveloped countries is now recognized as a leading cause of respiratory disease. Mycotoxins from...

  9. GS143, an IκB ubiquitination inhibitor, inhibits allergic airway inflammation in mice

    International Nuclear Information System (INIS)

    Asthma is characterized by airway inflammation with intense eosinophil infiltration and mucus hyper-production, in which antigen-specific Th2 cells play critical roles. Nuclear factor-κB (NF-κB) pathway has been demonstrated to be essential for the production of Th2 cytokines and chemokines in the airways in murine asthma models. In the present study, we examined the effect of GS143, a novel small-molecule inhibitor of IκB ubiquitination, on antigen-induced airway inflammation and Th2 cytokine production in mice. Intranasal administration of GS143 prior to antigen challenge suppressed antigen-induced NF-κB activation in the lung of sensitized mice. Intranasal administration of GS143 also inhibited antigen-induced eosinophil and lymphocyte recruitment into the airways as well as the expression of Th2 cytokines and eotaxin in the airways. Moreover, GS143 inhibited antigen-induced differentiation of Th2 cells but not of Th1 cells in vitro. Taken together, these results suggest that IκB ubiquitination inhibitor may have therapeutic potential against asthma

  10. Aquaporin-3 potentiates allergic airway inflammation in ovalbumin-induced murine asthma

    Science.gov (United States)

    Ikezoe, Kohei; Oga, Toru; Honda, Tetsuya; Hara-Chikuma, Mariko; Ma, Xiaojun; Tsuruyama, Tatsuaki; Uno, Kazuko; Fuchikami, Jun-ichi; Tanizawa, Kiminobu; Handa, Tomohiro; Taguchi, Yoshio; Verkman, Alan S.; Narumiya, Shuh; Mishima, Michiaki; Chin, Kazuo

    2016-01-01

    Oxidative stress plays a pivotal role in the pathogenesis of asthma. Aquaporin-3 (AQP3) is a small transmembrane water/glycerol channel that may facilitate the membrane uptake of hydrogen peroxide (H2O2). Here we report that AQP3 potentiates ovalbumin (OVA)-induced murine asthma by mediating both chemokine production from alveolar macrophages and T cell trafficking. AQP3 deficient (AQP3−/−) mice exhibited significantly reduced airway inflammation compared to wild-type mice. Adoptive transfer experiments showed reduced airway eosinophilic inflammation in mice receiving OVA-sensitized splenocytes from AQP3−/− mice compared with wild-type mice after OVA challenge, consistently with fewer CD4+ T cells from AQP3−/− mice migrating to the lung than from wild-type mice. Additionally, in vivo and vitro experiments indicated that AQP3 induced the production of some chemokines such as CCL24 and CCL22 through regulating the amount of cellular H2O2 in M2 polarized alveolar macrophages. These results imply a critical role of AQP3 in asthma, and AQP3 may be a novel therapeutic target. PMID:27165276

  11. Aquaporin-3 potentiates allergic airway inflammation in ovalbumin-induced murine asthma.

    Science.gov (United States)

    Ikezoe, Kohei; Oga, Toru; Honda, Tetsuya; Hara-Chikuma, Mariko; Ma, Xiaojun; Tsuruyama, Tatsuaki; Uno, Kazuko; Fuchikami, Jun-Ichi; Tanizawa, Kiminobu; Handa, Tomohiro; Taguchi, Yoshio; Verkman, Alan S; Narumiya, Shuh; Mishima, Michiaki; Chin, Kazuo

    2016-01-01

    Oxidative stress plays a pivotal role in the pathogenesis of asthma. Aquaporin-3 (AQP3) is a small transmembrane water/glycerol channel that may facilitate the membrane uptake of hydrogen peroxide (H2O2). Here we report that AQP3 potentiates ovalbumin (OVA)-induced murine asthma by mediating both chemokine production from alveolar macrophages and T cell trafficking. AQP3 deficient (AQP3(-/-)) mice exhibited significantly reduced airway inflammation compared to wild-type mice. Adoptive transfer experiments showed reduced airway eosinophilic inflammation in mice receiving OVA-sensitized splenocytes from AQP3(-/-) mice compared with wild-type mice after OVA challenge, consistently with fewer CD4(+) T cells from AQP3(-/-) mice migrating to the lung than from wild-type mice. Additionally, in vivo and vitro experiments indicated that AQP3 induced the production of some chemokines such as CCL24 and CCL22 through regulating the amount of cellular H2O2 in M2 polarized alveolar macrophages. These results imply a critical role of AQP3 in asthma, and AQP3 may be a novel therapeutic target. PMID:27165276

  12. The Ameliorative Effect of Sophoricoside on Mast Cell-Mediated Allergic Inflammation in Vivo and in Vitro

    Directory of Open Access Journals (Sweden)

    Jae-Young Um

    2013-05-01

    Full Text Available Sophoricoside exhibits numerous pharmacological effects, including anti- inflammatory and anti-cancer actions, yet the exact mechanism that accounts for the anti-allergic effects of sophoricoside is not completely understood. The aim of the present study was to elucidate whether and how sophoricoside modulates the mast cell-mediated allergic inflammation in vitro and in vivo. We investigated the pharmacological effects of sophoricoside on both compound 48/80 or histamine-induced scratching behaviors and 2,4-dinitrochlorobenzene (DNCB-induced atopic dermatitis in mice. Additionally, to find a possible explanation for the anti-inflammatory effects of sophoricoside, we evaluated the effects of sophoricoside on the production of histamine and inflammatory cytokines and activation of nuclear factor-κB (NF-κB and caspase-1 in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI-stimulated human mast cells (HMC-1. The finding of this study demonstrated that sophoricoside reduced compound 48/80 or histamine-induced scratching behaviors and DNCB-induced atopic dermatitis in mice. Additionally, sophoricoside inhibited the production of inflammatory cytokines as well as the activation of NF-κB and caspase-1 in stimulated HMC-1. Collectively, the findings of this study provide us with novel insights into the pharmacological actions of sophoricoside as a potential molecule for use in the treatment of allergic inflammation diseases.

  13. Absence of Foxp3+ regulatory T cells during allergen provocation does not exacerbate murine allergic airway inflammation.

    Directory of Open Access Journals (Sweden)

    Abdul Mannan Baru

    Full Text Available Regulatory T cells (Tregs play a non-redundant role in maintenance of immune homeostasis. This is achieved by suppressing both, priming of naïve cells and effector cell functions. Although Tregs have been implicated in modulating allergic immune responses, their influence on distinct phases of development of allergies remains unclear. In this study, by using bacterial artificial chromosome (BAC-transgenic Foxp3-DTR (DEREG mice we demonstrate that the absence of Foxp3(+ Tregs during the allergen challenge surprisingly does not exacerbate allergic airway inflammation in BALB/c mice. As genetic disposition due to strain specificity may contribute significantly to development of allergies, we performed similar experiment in C57BL/6 mice, which are less susceptible to allergy in the model of sensitization used in this study. We report that the genetic background does not influence the consequence of this depletion regimen. These results signify the temporal regulation exerted by Foxp3(+ Tregs in limiting allergic airway inflammation and may influence their application as potential therapeutics.

  14. Allergic skin inflammation induced by chemical sensitizers is controlled by the transcription factor Nrf2.

    Science.gov (United States)

    El Ali, Zeina; Gerbeix, Cédric; Hemon, Patrice; Esser, Philipp R; Martin, Stefan F; Pallardy, Marc; Kerdine-Römer, Saadia

    2013-07-01

    Allergic contact dermatitis (ACD) is induced by low-molecular weight electrophilic chemicals and metal ions. Chemical contact sensitizers trigger reactive oxygen species production and provoke electrophilic stress, leading to the accumulation of the transcription factor nuclear-related factor 2 (Nrf2) in innate immune cell types. The objective of this work was to identify the role of Nrf2 in the regulation of ACD. We used the local lymph node assay (LLNA) and the mouse ear swelling test (MEST) to study the role of Nrf2 in both the sensitization and elicitation phase in nrf2 knockout (nrf2(-/-)) and wild-type (nrf2(+/+)) mice. Five chemicals were used: two compounds known to react with cysteine residues, 2,4-dinitrochlorobenzene (DNCB) and cinnamaldehyde (CinA); one sensitizer known to exhibit mixed reactivity to cysteine and lysine residues, isophorone diisocyanate; and one reacting specifically with lysine residues, trimellitic anhydride and croton oil, a well-known irritant. In the MEST assay, DNCB (1 and 2%) induced a significant increase in ear thickness in nrf2(-/-) compared with nrf2(+/+) mice, suggesting a role for Nrf2 in the control of the inflammatory process. When DNCB was used at 0.25 and 0.5% or when mice were treated with CinA, inflammation was found only in nrf2(-/-) mice. In the LLNA, all chemical sensitizers induced an increase of lymphocyte proliferation in nrf2(-/-) compared with nrf2(+/+) mice for the same chemical concentration. These results reveal an important role for Nrf2 in controlling ACD and lymphocyte proliferation in response to sensitizers. PMID:23564646

  15. Effects of Tityus serrulatus scorpion venom on lung mechanics and inflammation in mice.

    Science.gov (United States)

    Paneque Peres, Ana Claudia; Nonaka, Paula Naomi; de Carvalho, Paulo de Tarso Camillo; Toyama, Marcos Hikari; Silva, Cesar Augusto Melo e; Vieira, Rodolfo de Paula; Dolhnikoff, Marisa; Zamuner, Stella Regina; de Oliveira, Luis Vicente Franco

    2009-06-01

    The present study evaluated the effects of an intramuscular injection of Tityus serrulatus venom (TsV) (0.67 miocrog/g) on lung mechanics and lung inflammation at 15, 30, 60 and 180 min after inoculation. TsV inoculation resulted in increased lung elastance when compared with the control group (p T. serrulatus venom leads to acute lung injury, characterised by altered lung mechanics and increased pulmonary inflammation. PMID:19470319

  16. Lipopolysaccharide induced inflammation in the perivascular space in lungs

    Directory of Open Access Journals (Sweden)

    Pabst Reinhard

    2008-07-01

    Full Text Available Abstract Background Lipopolysaccharide (LPS contained in tobacco smoke and a variety of environmental and occupational dusts is a toxic agent causing lung inflammation characterized by migration of neutrophils and monocytes into alveoli. Although migration of inflammatory cells into alveoli of LPS-treated rats is well characterized, the dynamics of their accumulation in the perivascular space (PVS leading to a perivascular inflammation (PVI of pulmonary arteries is not well described. Methods Therefore, we investigated migration of neutrophils and monocytes into PVS in lungs of male Sprague-Dawley rats treated intratracheally with E. coli LPS and euthanized after 1, 6, 12, 24 and 36 hours. Control rats were treated with endotoxin-free saline. H&E stained slides were made and immunohistochemistry was performed using a monocyte marker and the chemokine Monocyte-Chemoattractant-Protein-1 (MCP-1. Computer-assisted microscopy was performed to count infiltrating cells. Results Surprisingly, the periarterial infiltration was not a constant finding in each animal although LPS-induced alveolitis was present. A clear tendency was observed that neutrophils were appearing in the PVS first within 6 hours after LPS application and were decreasing at later time points. In contrast, mononuclear cell infiltration was observed after 24 hours. In addition, MCP-1 expression was present in perivascular capillaries, arteries and the epithelium. Conclusion PVI might be a certain lung reaction pattern in the defense to infectious attacks.

  17. Th17 Responses in Chronic Allergic Airway Inflammation Abrogate Regulatory T cell-mediated Tolerance and Contribute to Airway Remodeling

    OpenAIRE

    Zhao, Jingyue; Lloyd, Clare M.; Noble, Alistair

    2012-01-01

    The role of Th17 responses in airway remodeling in asthma is currently unknown. We demonstrate that both parenteral and mucosal allergen sensitization followed by allergen inhalation leads to Th17-biased lung immune responses. Unlike Th17 cells generated in vitro, lung Th17 cells did not produce TNF-α or IL-22. Eosinophilia predominated in acute inflammation while neutrophilia and IL-17 increased in chronic disease. Allergen-induced tolerance involved Foxp3, Helios and GARP expressing regulat...

  18. Negative Regulation of Pulmonary Th17 Responses by C3a Anaphylatoxin during Allergic Inflammation in Mice

    OpenAIRE

    Hoyong Lim; Young Uk Kim; Drouin, Scott M.; Stacey Mueller-Ortiz; Kyoungah Yun; Eva Morschl; Wetsel, Rick A.; Yeonseok Chung

    2012-01-01

    Activation of complement is one of the earliest immune responses to exogenous threats, resulting in various cleavage products including anaphylatoxin C3a. In addition to its contribution to host defense, C3a has been shown to mediate Th2 responses in animal models of asthma. However, the role of C3a on pulmonary Th17 responses during allergic inflammation remains unclear. Here, we show that mice deficient in C3a receptor (C3aR) exhibited (i) higher percentages of endogenous IL-17-producing CD...

  19. Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses

    Directory of Open Access Journals (Sweden)

    Koga Hikari

    2013-01-01

    Full Text Available Abstract Background Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR in previously sensitized and challenged mice. Methods BALB/c mice were sensitized and challenged (primary with ovalbumin (OVA. Six weeks later, a single OVA aerosol (secondary challenge was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. Results Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. Conclusion These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the

  20. Inhibitory effect of putranjivain A on allergic inflammation through suppression of mast cell activation

    International Nuclear Information System (INIS)

    A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Putranjivain A (PJA), member of ellagitannin, is known to possess beneficial effects including anti-cancer and anti-viral activities. The aim of the present study was to elucidate whether PJA modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. The study was performed in anaphylaxis mouse model and cultured mast cells. PJA inhibited the expression of pro-inflammatory cytokines in immunoglobulin E-stimulated mast cells. PJA reduced this expression by inhibiting nuclear factor (NF)-κB and nuclear factor of activated T cell. The oral administration of PJA reduced systemic and cutaneous anaphylaxis, the release of serum histamine, and the expression of the histamine H1 receptor. In addition, PJA attenuated the activation of mast cells. PJA inhibited the release of histamine from various types of mast cells by the suppression of intracellular calcium. The inhibitory activity of PJA on the allergic reaction was similar to that of disodium cromoglycate, a known anti-allergic drug. These results suggest that PJA can facilitate the prevention or treatment of allergic inflammatory diseases mediated by mast cells. - Highlights: • PJA reduced the degranulation of mast cells. • PJA inhibited the production of inflammatory cytokines. • The effect of PJA on allergic reaction was comparable to the DSCG. • PJA might be a candidate for the treatment of allergic inflammatory diseases

  1. Inhibitory effect of putranjivain A on allergic inflammation through suppression of mast cell activation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hui-Hun; Park, Seung-Bin; Lee, Soyoung [CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of); Kwon, Taeg Kyu [Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701 (Korea, Republic of); Shin, Tae-Yong [College of Pharmacy, Woosuk University, Jeonju 565-701 (Korea, Republic of); Park, Pil-Hoon; Lee, Seung-Ho [College of Pharmacy, Youngnam University, Kyungsan 712-749 (Korea, Republic of); Kim, Sang-Hyun, E-mail: shkim72@knu.ac.kr [CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of)

    2014-02-01

    A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. Putranjivain A (PJA), member of ellagitannin, is known to possess beneficial effects including anti-cancer and anti-viral activities. The aim of the present study was to elucidate whether PJA modulates the allergic inflammatory reaction and to study its possible mechanisms of action using mast cell-based in vitro and in vivo models. The study was performed in anaphylaxis mouse model and cultured mast cells. PJA inhibited the expression of pro-inflammatory cytokines in immunoglobulin E-stimulated mast cells. PJA reduced this expression by inhibiting nuclear factor (NF)-κB and nuclear factor of activated T cell. The oral administration of PJA reduced systemic and cutaneous anaphylaxis, the release of serum histamine, and the expression of the histamine H{sub 1} receptor. In addition, PJA attenuated the activation of mast cells. PJA inhibited the release of histamine from various types of mast cells by the suppression of intracellular calcium. The inhibitory activity of PJA on the allergic reaction was similar to that of disodium cromoglycate, a known anti-allergic drug. These results suggest that PJA can facilitate the prevention or treatment of allergic inflammatory diseases mediated by mast cells. - Highlights: • PJA reduced the degranulation of mast cells. • PJA inhibited the production of inflammatory cytokines. • The effect of PJA on allergic reaction was comparable to the DSCG. • PJA might be a candidate for the treatment of allergic inflammatory diseases.

  2. Lung inflammation caused by inhaled toxicants: a review

    Science.gov (United States)

    Wong, John; Magun, Bruce E; Wood, Lisa J

    2016-01-01

    Exposure of the lungs to airborne toxicants from different sources in the environment may lead to acute and chronic pulmonary or even systemic inflammation. Cigarette smoke is the leading cause of chronic obstructive pulmonary disease, although wood smoke in urban areas of underdeveloped countries is now recognized as a leading cause of respiratory disease. Mycotoxins from fungal spores pose an occupational risk for respiratory illness and also present a health hazard to those living in damp buildings. Microscopic airborne particulates of asbestos and silica (from building materials) and those of heavy metals (from paint) are additional sources of indoor air pollution that contributes to respiratory illness and is known to cause respiratory illness in experimental animals. Ricin in aerosolized form is a potential bioweapon that is extremely toxic yet relatively easy to produce. Although the aforementioned agents belong to different classes of toxic chemicals, their pathogenicity is similar. They induce the recruitment and activation of macrophages, activation of mitogen-activated protein kinases, inhibition of protein synthesis, and production of interleukin-1 beta. Targeting either macrophages (using nanoparticles) or the production of interleukin-1 beta (using inhibitors against protein kinases, NOD-like receptor protein-3, or P2X7) may potentially be employed to treat these types of lung inflammation without affecting the natural immune response to bacterial infections. PMID:27382275

  3. Lung inflammation caused by inhaled toxicants: a review.

    Science.gov (United States)

    Wong, John; Magun, Bruce E; Wood, Lisa J

    2016-01-01

    Exposure of the lungs to airborne toxicants from different sources in the environment may lead to acute and chronic pulmonary or even systemic inflammation. Cigarette smoke is the leading cause of chronic obstructive pulmonary disease, although wood smoke in urban areas of underdeveloped countries is now recognized as a leading cause of respiratory disease. Mycotoxins from fungal spores pose an occupational risk for respiratory illness and also present a health hazard to those living in damp buildings. Microscopic airborne particulates of asbestos and silica (from building materials) and those of heavy metals (from paint) are additional sources of indoor air pollution that contributes to respiratory illness and is known to cause respiratory illness in experimental animals. Ricin in aerosolized form is a potential bioweapon that is extremely toxic yet relatively easy to produce. Although the aforementioned agents belong to different classes of toxic chemicals, their pathogenicity is similar. They induce the recruitment and activation of macrophages, activation of mitogen-activated protein kinases, inhibition of protein synthesis, and production of interleukin-1 beta. Targeting either macrophages (using nanoparticles) or the production of interleukin-1 beta (using inhibitors against protein kinases, NOD-like receptor protein-3, or P2X7) may potentially be employed to treat these types of lung inflammation without affecting the natural immune response to bacterial infections. PMID:27382275

  4. Inhibitory effects of Pycnogenol® (French maritime pine bark extract) on airway inflammation in ovalbumin-induced allergic asthma.

    Science.gov (United States)

    Shin, In-Sik; Shin, Na-Rae; Jeon, Chan-Mi; Hong, Ju-Mi; Kwon, Ok-Kyoung; Kim, Jong-Choon; Oh, Sei-Ryang; Hahn, Kyu-Woung; Ahn, Kyung-Seop

    2013-12-01

    Pycnogenol® (PYC) is a standardized extracts from the bark of the French maritime pine (Pinus maritime) and used as a herbal remedy for various diseases. In this study, we evaluated the effects of PYC on airway inflammation using a model of ovalbumin (OVA)-induced allergic asthma and RAW264.7 cells. PYC decreased nitric oxide production and reduced the interleukine (IL)-1β and IL-6 levels in LPS-stimulated RAW264.7 cells. PYC also reduced the expression of inducible nitric oxide synthase (iNOS) and matrix metalloproteinase (MMP)-9 and enhanced the expression of hemeoxygenase (HO)-1. In the in vivo experiment, PYC decreased the inflammatory cell count and the levels of IL-4, IL-5, IL-13, and immunoglobulin (Ig) E in BALF or serum. These results are consistent with the histological analysis findings, which showed that PYC attenuated the airway inflammation and mucus hypersecretion induced by OVA challenge. In addition, PYC enhanced the expression of HO-1. In contrast, PYC inhibited the elevated expression of iNOS and MMP-9 proteins induced by OVA challenge. In conclusion, PYC exhibits protective effects against OVA-induced asthma and LPS-stimulated RAW264.7 cells. These results suggest that PYC has potential as a therapeutic agent for the treatment of allergic asthma. PMID:24120901

  5. Eosinophil: central mediator of allergic asthma?

    Institute of Scientific and Technical Information of China (English)

    SHEN Hua-hao

    2005-01-01

    @@ Allergic asthma is a chronic disorder characterized by chronic airway inflammation, airway hyperresponsiveness, reversible airway obstruction, airway remodelling and mucus hypersecretion. It has been widely recognized that the infiltration of the lung with increased number of eosinophils is a hallmark of this disease.1

  6. Role of glutathione in immunity and inflammation in the lung

    Directory of Open Access Journals (Sweden)

    Pietro Ghezzi

    2011-01-01

    Full Text Available Pietro GhezziBrighton and Sussex Medical School, Trafford Centre, Falmer, Brighton, UKAbstract: Reactive oxygen species and thiol antioxidants, including glutathione (GSH, regulate innate immunity at various levels. This review outlines the redox-sensitive steps of the cellular mechanisms implicated in inflammation and host defense against infection, and describes how GSH is not only important as an antioxidant but also as a signaling molecule. There is an extensive literature of the role of GSH in immunity. Most reviews are biased by an oversimplified picture where “bad” free radicals cause all sorts of diseases and “good” antioxidants protect from them and prevent oxidative stress. While this may be the case in certain fields (eg, toxicology, the role of thiols (the topic of this review in immunity certainly requires wearing scientist’s goggles and being prepared to accept a more complex picture. This review aims at describing the role of GSH in the lung in the context of immunity and inflammation. The first part summarizes the history and basic concepts of this picture. The second part focuses on GSH metabolism/levels in pathology, the third on the role of GSH in innate immunity and inflammation, and the fourth gives 4 examples describing the importance of GSH in the response to infections.Keywords: antioxidants, oxidative stress, sepsis, infection, cysteine

  7. Mesenchymal stromal cells mediate Aspergillus hyphal extract-induced allergic airway inflammation by inhibition of the Th17 signaling pathway.

    Science.gov (United States)

    Lathrop, Melissa J; Brooks, Elice M; Bonenfant, Nick R; Sokocevic, Dino; Borg, Zachary D; Goodwin, Meagan; Loi, Roberto; Cruz, Fernanda; Dunaway, Chad W; Steele, Chad; Weiss, Daniel J

    2014-02-01

    Systemic administration of mesenchymal stromal cells (MSCs) suppresses airway inflammation and methacholine-induced airway hyper-responsiveness (AHR) in mouse models of T helper cell (Th) type 2-mediated eosinophilic allergic airway inflammation (AAI); however, the efficacy of MSCs in mouse models of severe Th17-mediated neutrophilic AAI has not yet been demonstrated. We assessed MSC effects in a mouse model of mixed Th2/Th17 AAI produced by mucosal exposure to Aspergillus fumigatus hyphal extract (AHE). Following sensitization produced by oropharyngeal AHE administration, systemic (tail vein) administration of syngeneic MSCs on the first day of challenge significantly reduced acute AHR predominantly through reduction of Th17-mediated airway inflammation. In parallel experiments, MSCs also mitigated AHR when administered during recurrent challenge 10 weeks after initial sensitization and challenge through reduction in systemic Th17-mediated inflammation. Investigation into potential mechanistic actions of MSCs in this model demonstrated that although T regulatory cells were increased in all AHE-treated mice, MSC administration did not alter T regulatory cell numbers in either the acute or recurrent model. Differential induction of interleukin-17a secretion was observed in ex vivo restimulation of mediastinal lymph node mixed-cell cytokine analyses. Although the mechanisms by which MSCs act to decrease inflammation and AHR in this model are not yet fully elucidated, decrease in Th17-mediated airway inflammation appears to play a significant role. These results provide a basis for further investigations of MSC administration as a potential therapeutic approach for severe refractory neutrophilic asthma. PMID:24436442

  8. IκB kinase β inhibitor, IMD-0354, prevents allergic asthma in a mouse model through inhibition of CD4(+) effector T cell responses in the lung-draining mediastinal lymph nodes.

    Science.gov (United States)

    Maślanka, Tomasz; Otrocka-Domagała, Iwona; Zuśka-Prot, Monika; Mikiewicz, Mateusz; Przybysz, Jagoda; Jasiecka, Agnieszka; Jaroszewski, Jerzy J

    2016-03-15

    IκB kinase (IKK) is important for nuclear factor (NF)-κB activation under inflammatory conditions. It has been demonstrated that IMD-0354, i.e. a selective inhibitor of IKKβ, inhibited allergic inflammation in a mouse model of ovalbumin (OVA)-induced asthma. The present study attempts to shed light on the involvement of CD4(+) effector (Teff) and regulatory (Treg) T cells in the anti-asthmatic action of IMD-0354. The animals were divided into three groups: vehicle treated, PBS-sensitized/challenged mice (PBS group); vehicle treated, OVA-sensitized/challenged mice (OVA group); and IMD-0354-treated, OVA-sensitized/challenged mice. The analyzed parameters included the absolute counts of Treg cells (Foxp3(+)CD25(+)CD4(+)), activated Teff cells (Foxp3(-)CD25(+)CD4(+)) and resting T cells (CD25(-)CD4(+)) in the mediastinal lymph nodes (MLNs), lungs and peripheral blood. Moreover, lung histopathology was performed to evaluate lung inflammation. It was found that the absolute number of cells in all studied subsets was considerably increased in the MLNs and lungs of mice from OVA group as compared to PBS group. All of these effects were fully prevented by treatment with IMD-0354. Histopathological examination showed that treatment with IMD-0354 protected the lungs from OVA-induced allergic airway inflammation. Our results indicate that IMD-0354 exerts anti-asthmatic action, at least partially, by blocking the activation and clonal expansion of CD4(+) Teff cells in the MLNs, which, consequently, prevents infiltration of the lungs with activated CD4(+) Teff cells. The beneficial effects of IMD-0354 in a mouse model of asthma are not mediated through increased recruitment of Treg cells into the MLNs and lungs and/or local generation of inducible Treg cells. PMID:26868187

  9. Adjuvant and anti-inflammatory properties of cigarette smoke in murine allergic airway inflammation.

    Science.gov (United States)

    Trimble, Nancy J; Botelho, Fernando M; Bauer, Carla M T; Fattouh, Ramzi; Stämpfli, Martin R

    2009-01-01

    The impact of cigarette smoke on allergic asthma remains controversial both clinically and experimentally. The objective of this study was to investigate, in a murine model, how cigarette smoke affects immune inflammatory processes elicited by a surrogate allergen. In our experimental design, mice were concurrently exposed to cigarette smoke and ovalbumin (OVA), an innocuous antigen that, unless introduced in the context of an adjuvant, induces inhalation tolerance. We show that cigarette smoke exposure has adjuvant properties, allowing for allergic mucosal sensitization to OVA. Specifically, concurrent exposure to cigarette smoke and OVA for 2 weeks led to airway eosinophilia and goblet cell hyperplasia. In vivo OVA recall challenge 1 month after the last smoke exposure showed that concurrent exposure to OVA and cigarette smoke induced antigen-specific memory. Robust eosinophilia and OVA-specific IgG1 and IgE characterized the ensuing inflammatory response. Mechanistically, allergic sensitization was, in part, granulocyte macrophage colony-stimulating factor (GM-CSF) dependent, as a significant reduction in BAL eosinophilia was observed in mice treated with an anti-GM-CSF antibody. Of note, continuous smoke exposure attenuated the OVA recall response; decreased airway eosinophilia was observed in mice continuously exposed to cigarette smoke compared with mice that ceased the smoke exposure protocol. In conclusion, we demonstrate experimentally that while cigarette smoke acts as an adjuvant allowing for allergic sensitization, it also attenuates the ensuing eosinophilic inflammatory response. PMID:18635815

  10. Azithromycin and the Treatment of Lymphocytic Airway Inflammation After Lung Transplantation

    OpenAIRE

    Vos, Rein; Verleden, S. E.; Ruttens, D.; Vandermeulen, E; Bellon, H.; Neyrinck, A.; Van Raemdonck, D. E.; Yserbyt, J.; Dupont, L J; Verbeken, E.K.; Moelants, E.; Mortier, A.; Proost, P.; Schols, D; Cox, B.

    2014-01-01

    Lymphocytic airway inflammation is a major risk factor for chronic lung allograft dysfunction, for which there is no established treatment. We investigated whether azithromycin could control lymphocytic airway inflammation and improve allograft function. Fifteen lung transplant recipients demonstrating acute allograft dysfunction due to isolated lymphocytic airway inflammation were prospectively treated with azithromycin for at least 6 months (NCT01109160). Spirometry (FVC, FEV1, FEF25-75, Ti...

  11. Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury.

    Science.gov (United States)

    Shaver, Ciara M; Grove, Brandon S; Clune, Jennifer K; Mackman, Nigel; Ware, Lorraine B; Bastarache, Julie A

    2016-01-01

    Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF(∆mye), LysM.Cre(+/-)TF(flox/flox)) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI. PMID:26924425

  12. Single systemic administration of Ag85B of mycobacteria DNA inhibits allergic airway inflammation in a mouse model of asthma

    Directory of Open Access Journals (Sweden)

    Karamatsu K

    2012-12-01

    Full Text Available Katsuo Karamatsu,1,2 Kazuhiro Matsuo,3 Hiroyasu Inada,4 Yusuke Tsujimura,1 Yumiko Shiogama,1,2 Akihiro Matsubara,1,2 Mitsuo Kawano,5 Yasuhiro Yasutomi1,21Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, 2Division of Immunoregulation, Department of Molecular and Experimental Medicine, Mie University Graduate School of Medicine, Tsu, 3Department of Research and Development, Japan BCG Laboratory, Tokyo, 4Department of Pathology, Suzuka University of Medical Science, Suzuka, 5Department of Microbiology and Molecular Genetics, Mie University Graduate School of Medicine, Tsu, JapanAbstract: The immune responses of T-helper (Th and T-regulatory cells are thought to play a crucial role in the pathogenesis of allergic airway inflammation observed in asthma. The correction of immune response by these cells should be considered in the prevention and treatment of asthma. Native antigen 85B (Ag85B of mycobacteria, which cross-reacts among mycobacteria species, may play an important biological role in host–pathogen interaction since it elicits various immune responses by activation of Th cells. The current study investigated the antiallergic inflammatory effects of DNA administration of Ag85B from Mycobacterium kansasii in a mouse model of asthma. Immunization of BALB/c mice with alum-adsorbed ovalbumin followed by aspiration with aerosolized ovalbumin resulted in the development of allergic airway inflammation. Administration of Ag85B DNA before the aerosolized ovalbumin challenge protected the mice from subsequent induction of allergic airway inflammation. Serum and bronchoalveolar lavage immunoglobulin E levels, extent of eosinophil infiltration, and levels of Th2-type cytokines in Ag85B DNA-administered mice were significantly lower than those in control plasmid-immunized mice, and levels of Th1- and T-regulatory-type cytokines were enhanced by Ag85B

  13. Formaldehyde induces lung inflammation by an oxidant and antioxidant enzymes mediated mechanism in the lung tissue.

    Science.gov (United States)

    Lino-dos-Santos-Franco, Adriana; Correa-Costa, Matheus; Durão, Ana Carolina Cardoso dos Santos; de Oliveira, Ana Paula Ligeiro; Breithaupt-Faloppa, Ana Cristina; Bertoni, Jônatas de Almeida; Oliveira-Filho, Ricardo Martins; Câmara, Niels Olsen Saraiva; Marcourakis, Tânia; Tavares-de-Lima, Wothan

    2011-12-15

    Formaldehyde (FA) is an indoor and outdoor pollutant widely used by many industries, and its exposure is associated with inflammation and oxidative stress in the airways. Our previous studies have demonstrated the role of reactive oxygen species (ROS) in lung inflammation induced by FA inhalation but did not identify source of the ROS. In the present study, we investigate the effects of FA on the activities and gene expression of glutathione peroxidase (GPX), glutathione reductase (GR), glutathione S-transferase (GST), superoxide dismutase (SOD) 1 and 2, catalase (CAT), nitric oxide synthase (iNOS and cNOS) and cyclooxygenase (COX) 1 and 2. The hypothesized link between NADPH-oxidase, nitric oxide synthase and cyclooxygenase, the lung inflammation after FA inhalation was also investigated. For experiments, male Wistar rats were submitted to FA inhalation (1%, 90 min daily) for 3 consecutive days. The treatments with apocynin and indomethacin before the FA exposure reduced the number of neutrophils recruited into the lung. Moreover, the treatments with apocynin and indomethacin blunted the effect of FA on the generation of IL-1β, while the treatments with L-NAME and apocynin reduced the generation of IL-6 by lung explants when compared to the untreated group. FA inhalation increased the levels of NO and hydrogen peroxide by BAL cells cultured and the treatments with apocynin and l-NAME reduced these generations. FA inhalation did not modify the activities of GPX, GR, GST and CAT but reduced the activity of SOD when compared to the naïve group. Significant increases in SOD-1 and -2, CAT, iNOS, cNOS and COX-1 expression were observed in the FA group compared to the naïve group. The treatments with apocynin, indomethacin and L-NAME reduced the gene expression of antioxidant and oxidant enzymes. In conclusion, our results indicate that FA causes a disruption of the physiological balance between oxidant and antioxidant enzymes in lung tissue, most likely favoring the

  14. Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure

    OpenAIRE

    Cristiane Miranda da Silva; Mayara Peres Leal; Robson Alexandre Brochetti; Tárcio Braga; Luana Beatriz Vitoretti; Niels Olsen Saraiva Câmara; Amílcar Sabino Damazo; Ana Paula Ligeiro-de-Oliveira; Maria Cristina Chavantes; Adriana Lino-Dos-Santos-Franco

    2015-01-01

    Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT) has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used f...

  15. 255 Chronic Obstructive Pulmonary Disease and Lung Cancer Share Inflammation Pathways

    OpenAIRE

    Kostas N. Syrigos; POLITI, EKATERINI; Makrilia, Nektaria; Tsimpoukis, Sotirios; Psarros, Fotis; Syrigou, Ekaterini; Dannos, Ioannis

    2012-01-01

    Background The relationship between inflammation, air obstruction and lung cancer is complex and there is still great uncertainty regarding their underlying pathophysiology. Our aim was to investigate the inflammation pathways that are implicated in both chronic obstructive pulmonary disease (COPD) and lung cancer. Methods A literature search was performed in PubMed to identify relative studies published until June 2011. Results The pathophysiology of both COPD and lung cancer includes dysreg...

  16. Enforced expression of Gata3 in T cells and group 2 innate lymphoid cells increases susceptibility to allergic airway inflammation in mice

    NARCIS (Netherlands)

    A. Kleinjan (Alex); R.G.J. Klein Wolterink (Roel); Y. Levani (Yelvi); M.J.W. de Bruijn (Marjolein); H.C. Hoogsteden (Henk); M. van Nimwegen (Menno); R.W. Hendriks (Rudi)

    2014-01-01

    textabstractAirway inflammation in allergic asthma reflects a threshold response of the innate immune system, including group 2 innate lymphoid cells (ILC2), followed by an adaptive Th2 cell-mediated response. Transcription factor Gata3 is essential for differentiation of both Th2 cells and ILC2. We

  17. Modulatory role of eosinophils in allergic inflammation: new evidence for a rather outdated concept

    Directory of Open Access Journals (Sweden)

    Christianne Bandeira-Melo

    1997-12-01

    Full Text Available The eosinophilic response has been identified as a key alteration in the pathogenesis of asthma and other allergic diseases. A close-correlation between disease severity and eosinophilia, and the eosinophil ability to provide toxic and pro-inflammatory agents are the major elements supporting the interpretation that there is indeed a causal relationship between these phenomena. Nevertheless, controversy still persists since some studies have clearly demonstrated that eosinophil infiltration is not necessarily accompanied by tissue damage or hyperresponsiveness. In addition, there are some examples in the literature in which such alterations are not modified following abrogation of eosinophil influx. In this review it will be argued, based on a model of IgE-dependent pleurisy, that eosinophil infiltration can be associated with down-regulation of allergic inflammatory response. The potential mechanism by which eosinophils could be acting as a immunomodulatory cells in this particular system will also be assessed.

  18. The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

    Science.gov (United States)

    Zaiss, Mario M.; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W.; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D.; Macpherson, Andrew J.; Croese, John; Giacomin, Paul R.; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J.; Harris, Nicola L.

    2015-01-01

    Summary Intestinal helminths are potent regulators of their host’s immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. PMID:26522986

  19. The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation.

    Science.gov (United States)

    Zaiss, Mario M; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D; Macpherson, Andrew J; Croese, John; Giacomin, Paul R; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J; Harris, Nicola L

    2015-11-17

    Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. PMID:26522986

  20. Protective effect of soybean oil- or fish oil-rich diets on allergic airway inflammation

    OpenAIRE

    Silveira, Vera

    2016-01-01

    Roberta Araujo Navarro-Xavier,1 Karina Vieira de Barros,1 Iracema Senna de Andrade,1 Zaira Palomino,2 Dulce Elena Casarini,2 Vera Lucia Flor Silveira3 1Departamento de Fisiologia, 2Departamento de Medicina, 3Departamento de Ciências Biológicas, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil Background: The increased prevalence of asthma and allergic diseases in westernized societies has been associated with increased intake of diets r...

  1. Increased alveolar soluble annexin V promotes lung inflammation and fibrosis.

    Science.gov (United States)

    Buckley, Susan; Shi, Wei; Xu, Wei; Frey, Mark R; Moats, Rex; Pardo, Annie; Selman, Moises; Warburton, David

    2015-11-01

    The causes underlying the self-perpetuating nature of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal disease, remain unknown. We hypothesised that alveolar soluble annexin V contributes to lung fibrosis, based on the observation that human IPF bronchoalveolar lavage fluid (BALF) containing high annexin V levels promoted fibroblast involvement in alveolar epithelial wound healing that was reduced when annexin V was depleted from the BALF. Conditioned medium from annexin V-treated alveolar epithelial type 2 cells (AEC2), but not annexin V per se, induced proliferation of human fibroblasts and contained pro-fibrotic, IPF-associated proteins, as well as pro-inflammatory cytokines that were found to correlate tightly (r>0.95) with annexin V levels in human BALF. ErbB2 receptor tyrosine kinase in AECs was activated by annexin V, and blockade reduced the fibrotic potential of annexin V-treated AEC-conditioned medium. In vivo, aerosol delivery of annexin V to mouse lung induced inflammation, fibrosis and increased hydroxyproline, with activation of Wnt, transforming growth factor-β, mitogen-activated protein kinase and nuclear factor-κB signalling pathways, as seen in IPF. Chronically increased alveolar annexin V levels, as reflected in increased IPF BALF levels, may contribute to the progression of IPF by inducing the release of pro-fibrotic mediators. PMID:26160872

  2. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines.

    Science.gov (United States)

    Thurmond, Robin L; Gelfand, Erwin W; Dunford, Paul J

    2008-01-01

    Histamine has a key role in allergic inflammatory conditions. The inflammatory responses resulting from the liberation of histamine have long been thought to be mediated by the histamine H1 receptor, and H1-receptor antagonists--commonly known as antihistamines--have been used to treat allergies for many years. However, the importance of histamine in the pathology of conditions such as asthma and chronic pruritus may have been underestimated. Here, we review accumulating evidence suggesting that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions. PMID:18172439

  3. Protective effect of soybean oil- or fish oil-rich diets on allergic airway inflammation

    OpenAIRE

    Navarro-Xavier RA; Barros KV; Andrade IS; Palomino Z; Casarini, DE; Flor Silveira VL

    2016-01-01

    Roberta Araujo Navarro-Xavier,1 Karina Vieira de Barros,1 Iracema Senna de Andrade,1 Zaira Palomino,2 Dulce Elena Casarini,2 Vera Lucia Flor Silveira3 1Departamento de Fisiologia, 2Departamento de Medicina, 3Departamento de Ciências Biológicas, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil Background: The increased prevalence of asthma and allergic diseases in westernized societies has been associated with increased intake of diets rich in n-6 fatty...

  4. Effect of Respiratory Syncytial Virus Infection on Plasmacytoid Dendritic Cell Regulation of Allergic Airway Inflammation.

    OpenAIRE

    Tsuchida, Tomoko; Matsuse, Hiroto; Fukahori, Susumu; Kawano, Tetsuya; Tomari, Shinya; Fukushima, Chizu; Kohno, Shigeru

    2011-01-01

    Background: Respiratory syncytial virus (RSV) can infect myeloid dendritic cells (mDCs) and regulate their function in the development of allergy. It has been widely reported that plasmacytoid DCs (pDCs) play a critical role in antiviral innate immunity. In contrast, not much is known about the role of pDCs in the interaction between allergy and viral infection. The purpose of the present study was to investigate the effect of RSV infection on pDC function in the regulation of allergic airway...

  5. Effects of Corni fructus on ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of allergic asthma

    OpenAIRE

    Kim Seung-Hyung; Kim Bok-Kyu; Lee Young-Cheol

    2012-01-01

    Abstract Background Allergic asthma is a chronic inflammatory lung disease that is characterized by airway hyperresponsiveness (AHR) to allergens, airway oedema, increased mucus secretion, excess production of T helper-2 (Th2) cytokines, and eosinophil accumulation in the lungs. Corni fructus (CF) is a fruit of Cornus officinalis Sieb. Et. Zucc. (Cornaceae) and has been used in traditional Korean medicine as an anti-inflammatory, analgesic, and diuretic agent. To investigate the anti-asthmati...

  6. Upper and lower airway pathology in young children with allergic- and non-allergic rhinitis

    DEFF Research Database (Denmark)

    Chawes, Bo Lk

    2011-01-01

    generalized diminished airway dimensions as a novel susceptibility factor for concurrent symptoms of asthma and rhinitis in early childhood and supports the notion of a common pathophysiology in asthma and rhinitis. The clinical interpretation of these findings is that all children presenting either rhinitis...... sensitization, and filaggrin mutations; levels of total IgE, FeNO, and blood-eosinophils; lung function and bronchial responsiveness to cold dry air. We found that asthma was similarly associated with allergic- and non-allergic rhinitis suggesting a link between upper and lower airway diseases beyond an allergy...... associated inflammation. Only children with allergic rhinitis had increased bronchial responsiveness and elevated FeNO suggesting different endotypes of asthma symptoms in young children with allergic- and non-allergic rhinitis. We also found bronchial hyperresponsiveness and raised values of FeNO in...

  7. Effects of organic chemicals derived from ambient particulate matter on lung inflammation related to lipopolysaccharide

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Ken-ichiro; Yanagisawa, Rie; Hirano, Seishiro; Kobayashi, Takahiro [National Institute for Environmental Studies, Environmental Health Sciences Division, Tsukuba, Ibaraki (Japan); Takano, Hirohisa [National Institute for Environmental Studies, Environmental Health Sciences Division, Tsukuba, Ibaraki (Japan); Kyoto Prefectural University of Medicine, Inflammation and Immunology, Graduate School of Medical Science, Kyoto (Japan); Ichinose, Takamichi [Oita University of Nursing and Health Sciences, Department of Health Science, Oita (Japan); Yoshikawa, Toshikazu [Kyoto Prefectural University of Medicine, Inflammation and Immunology, Graduate School of Medical Science, Kyoto (Japan)

    2006-12-15

    The effects of components of ambient particulate matter (PM) on individuals with predisposing respiratory disorders are not well defined. We have previously demonstrated that airway exposure to diesel exhaust particles (DEP) or organic chemicals (OC) extracted from DEP (DEP-OC) enhances lung inflammation related to bacterial endotoxin (lipopolysaccharide, LPS). The present study aimed to examine the effects of airway exposure to OC extracted from urban PM (PM-OC) on lung inflammation related to LPS. ICR mice were divided into four experimental groups that intratracheally received vehicle, LPS (2.5 mg/kg), PM-OC (4 mg/kg), or PM-OC + LPS. Lung inflammation, lung water content, and lung expression of cytokines were evaluated 24 h after intratracheal administration. LPS challenge elicited lung inflammation evidenced by cellular profiles of bronchoalveolar lavage fluid and lung histology, which was further aggravated by the combined challenge with PM-OC. The combination with PM-OC and LPS did not significantly exaggerate LPS-elicited pulmonary edema. LPS instillation induced elevated lung expression of interleukin-1{beta}, macrophage inflammatory protein-1{alpha}, macrophage chemoattractant protein-1, and keratinocyte chemoattractant, whereas the combined challenge with PM-OC did not influence these levels. All the results were consistent with our previous reports on DEP-OC. These results suggest that the extracted organic chemicals from PM exacerbate infectious lung inflammation. The mechanisms underlying the enhancing effects are not mediated via the enhanced local expression of proinflammatory cytokines. (orig.)

  8. Acute lung injury: How macrophages orchestrate resolution of inflammation and tissue repair

    Directory of Open Access Journals (Sweden)

    Susanne eHerold

    2011-11-01

    Full Text Available Lung macrophages are long living cells with broad differentiation potential, which reside in the lung interstitium and alveoli or are organ-recruited upon inflammatory stimuli. A role of resident and recruited macrophages in initiating and maintaining pulmonary inflammation in lung infection or injury has been convincingly demonstrated. More recent reports suggest that lung macrophages are main orchestrators of termination and resolution of inflammation and initiators of parenchymal repair processes that are essential for return to homeostasis with normal gas exchange. In this review we will discuss cellular cross-talk mechanisms and molecular pathways of macrophage plasticity which define their role in inflammation resolution and in initiation of lung barrier repair following lung injury.

  9. Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

    International Nuclear Information System (INIS)

    Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases. - Highlights: • First study in children evaluating lung inflammatory biomarkers and As levels

  10. Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

    Energy Technology Data Exchange (ETDEWEB)

    Olivas-Calderón, Edgar, E-mail: edgar_olivascalderon@hotmail.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); School of Medicine, University Juarez of Durango, Gomez Palacio, Durango (Mexico); Recio-Vega, Rogelio, E-mail: rrecio@yahoo.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); Gandolfi, A. Jay, E-mail: gandolfi@pharmacy.arizona.edu [Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ (United States); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ (United States); Lantz, R. Clark, E-mail: lantz@email.arizona.edu [Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ (United States); Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ (United States); González-Cortes, Tania, E-mail: taniagc2201@hotmail.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); Gonzalez-De Alba, Cesar, E-mail: cesargonzalezalba@hotmail.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); Froines, John R., E-mail: jfroines@ucla.edu [Center for Environmental and Occupational Health, School of Public Health, University of California at Los Angeles, Los Angeles, CA (United States); Espinosa-Fematt, Jorge A., E-mail: dr.jorge.espinosa@gmail.com [School of Medicine, University Juarez of Durango, Gomez Palacio, Durango (Mexico)

    2015-09-01

    Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases. - Highlights: • First study in children evaluating lung inflammatory biomarkers and As levels

  11. Effects of inflammation and fibrosis on pulmonary function in diffuse lung fibrosis.

    OpenAIRE

    Chinet, T; Jaubert, F; Dusser, D.; Danel, C.; Chrétien, J.; Huchon, G J

    1990-01-01

    To investigate the relation between lung function and inflammation and fibrosis in patients with diffuse lung fibrosis, a study was made of untreated patients without appreciable airway obstruction (14 patients with cryptogenic fibrosing alveolitis and seven with pneumoconiosis). Quantitative assessment of inflammatory infiltration and fibrosis was carried out on open lung biopsy specimens and compared with lung volumes, carbon monoxide transfer factor (TLCO), TLCO corrected for alveolar volu...

  12. Inhibitory effect of 1,2,4,5-tetramethoxybenzene on mast cell-mediated allergic inflammation through suppression of IκB kinase complex

    International Nuclear Information System (INIS)

    As the importance of allergic disorders such as atopic dermatitis and allergic asthma, research on potential drug candidates becomes more necessary. Mast cells play an important role as initiators of allergic responses through the release of histamine; therefore, they should be the target of pharmaceutical development for the management of allergic inflammation. In our previous study, anti-allergic effect of extracts of Amomum xanthioides was demonstrated. To further investigate improved candidates, 1,2,4,5-tetramethoxybenzene (TMB) was isolated from methanol extracts of A. xanthioides. TMB dose-dependently attenuated the degranulation of mast cells without cytotoxicity by inhibiting calcium influx. TMB decreased the expression of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-4 at both the transcriptional and translational levels. Increased expression of these cytokines was caused by translocation of nuclear factor-κB into the nucleus, and it was hindered by suppressing activation of IκB kinase complex. To confirm the effect of TMB in vivo, the ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA model, hypothermia was decreased by oral administration of TMB, which attenuated serum histamine, OVA-specific IgE, and IL-4 levels. Increased pigmentation of Evans blue was reduced by TMB in a dose-dependent manner in the PCA model. Our results suggest that TMB is a possible therapeutic candidate for allergic inflammatory diseases that acts through the inhibition of mast cell degranulation and expression of pro-inflammatory cytokines. - Highlights: • TMB reduced the degranulation of mast cells. • TMB inhibited the production of pro-inflammatory cytokines. • TMB suppressed both active and passive anaphylaxis. • Anti-allergic inflammatory effects of TMB might be due to the blocking IKK complex. • TMB might be a candidate for the treatment of

  13. Inhibitory effect of 1,2,4,5-tetramethoxybenzene on mast cell-mediated allergic inflammation through suppression of IκB kinase complex

    Energy Technology Data Exchange (ETDEWEB)

    Je, In-Gyu [Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of); Choi, Hyun Gyu [College of Pharmacy, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of); Kim, Hui-Hun; Lee, Soyoung; Choi, Jin Kyeong [Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of); Kim, Sung-Wan; Kim, Duk-Sil [Department of Thoracic and Cardiovascular Surgery, CHA Gumi Medical Center, CHA University, Gumi 730-040 (Korea, Republic of); Kwon, Taeg Kyu [Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701 (Korea, Republic of); Shin, Tae-Yong [College of Pharmacy, Woosuk University, Jeonju 565-701 (Korea, Republic of); Park, Pil-Hoon [College of Pharmacy, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of); Khang, Dongwoo, E-mail: dkhang@gachon.ac.kr [Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840 (Korea, Republic of); Kim, Sang-Hyun, E-mail: shkim72@knu.ac.kr [Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of)

    2015-09-01

    As the importance of allergic disorders such as atopic dermatitis and allergic asthma, research on potential drug candidates becomes more necessary. Mast cells play an important role as initiators of allergic responses through the release of histamine; therefore, they should be the target of pharmaceutical development for the management of allergic inflammation. In our previous study, anti-allergic effect of extracts of Amomum xanthioides was demonstrated. To further investigate improved candidates, 1,2,4,5-tetramethoxybenzene (TMB) was isolated from methanol extracts of A. xanthioides. TMB dose-dependently attenuated the degranulation of mast cells without cytotoxicity by inhibiting calcium influx. TMB decreased the expression of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-4 at both the transcriptional and translational levels. Increased expression of these cytokines was caused by translocation of nuclear factor-κB into the nucleus, and it was hindered by suppressing activation of IκB kinase complex. To confirm the effect of TMB in vivo, the ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA model, hypothermia was decreased by oral administration of TMB, which attenuated serum histamine, OVA-specific IgE, and IL-4 levels. Increased pigmentation of Evans blue was reduced by TMB in a dose-dependent manner in the PCA model. Our results suggest that TMB is a possible therapeutic candidate for allergic inflammatory diseases that acts through the inhibition of mast cell degranulation and expression of pro-inflammatory cytokines. - Highlights: • TMB reduced the degranulation of mast cells. • TMB inhibited the production of pro-inflammatory cytokines. • TMB suppressed both active and passive anaphylaxis. • Anti-allergic inflammatory effects of TMB might be due to the blocking IKK complex. • TMB might be a candidate for the treatment of

  14. Neonates with reduced neonatal lung function have systemic low-grade inflammation

    DEFF Research Database (Denmark)

    Chawes, Bo L.K.; Stokholm, Jakob; Bønnelykke, Klaus;

    2015-01-01

    14 days before, and asthmatic symptoms, as well as virus-induced wheezing, at any time before biomarker assessment at age 6 months did not affect the associations. Conclusion: Diminished neonatal lung function is associated with upregulated systemic inflammatory markers, such as hs-CRP.......Background: Children and adults with asthma and impaired lung function have been reported to have low-grade systemic inflammation, but it is unknown whether this inflammation starts before symptoms and in particular whether low-grade inflammation is present in asymptomatic neonates with reduced...... lung function. ObjectiveWe sought to investigate the possible association between neonatal lung function and biomarkers of systemic inflammation.  Methods: Plasma levels of high-sensitivity C-reactive protein (hs-CRP), IL-1β, IL-6, TNF-α, and CXCL8 (IL-8) were measured at age 6 months in 300 children...

  15. Perinatal maternal administration of Lactobacillus paracasei NCC 2461 prevents allergic inflammation in a mouse model of birch pollen allergy.

    Directory of Open Access Journals (Sweden)

    Irma Schabussova

    Full Text Available BACKGROUND: The hygiene hypothesis implies that microbial agents including probiotic bacteria may modulate foetal/neonatal immune programming and hence offer effective strategies for primary allergy prevention; however their mechanisms of action are poorly understood. We investigated whether oral administration of Lactobacillus paracasei NCC 2461 to mothers during gestation/lactation can protect against airway inflammation in offspring in a mouse model of birch pollen allergy, and examined the immune mechanisms involved. METHODS: BALB/c mice were treated daily with L. paracasei in drinking water or drinking water alone in the last week of gestation and during lactation. Their offspring were sensitized with recombinant Bet v 1, followed by aerosol challenge with birch pollen extract. RESULTS: Maternal exposure to L. paracasei prevented the development of airway inflammation in offspring, as demonstrated by attenuation of eosinophil influx in the lungs; reduction of IL-5 levels in bronchoalveolar lavage, and in lung and mediastinal lymph node cell cultures; and reduced peribronchial inflammatory infiltrate and mucus hypersecretion. While allergen-specific IgE and IgG antibody levels remained unchanged by the treatment, IL-4 and IL-5 production in spleen cell cultures were significantly reduced upon allergen stimulation in offspring of L. paracasei treated mice. Offspring of L. paracasei supplemented mothers had significantly reduced Bet v 1-specific as well as Concanavalin A-induced responses in spleen and mesenteric lymph node cell cultures, suggesting the modulation of both antigen-specific and mitogen-induced immune responses in offspring. These effects were associated with increased Foxp3 mRNA expression in the lungs and increased TGF-beta in serum. CONCLUSION: Our data show that in a mouse model of birch pollen allergy, perinatal administration of L. paracasei NCC 2461 to pregnant/lactating mothers protects against the development of airway

  16. Important role of platelets in modulating endotoxin-induced lung inflammation in CFTR-deficient mice.

    Directory of Open Access Journals (Sweden)

    Caiqi Zhao

    Full Text Available Mutation of CFTR (cystic fibrosis transmembrane conductance regulator leads to cystic fibrosis (CF. Patients with CF develop abnormalities of blood platelets and recurrent lung inflammation. However, whether CFTR-mutated platelets play a role in the development of lung inflammation is elusive. Therefore, we intratracheally challenged wildtype and F508del (a common type of CFTR mutation mice with LPS to observe changes of F508del platelets in the peripheral blood and indexes of lung inflammation (BAL neutrophils and protein levels. Furthermore, we investigated whether or not and how F508del platelets modulate the LPS-induced acute lung inflammation by targeting anti-platelet aggregation, depletion of neutrophils, reconstitution of bone marrow or neutrophils, blockade of P-selectin glycoprotein ligand-1 (PSGL-1, platelet activating factor (PAF, and correction of mutated CFTR trafficking. We found that LPS-challenged F508del mice developed severe thrombocytopenia and had higher levels of plasma TXB2 coincided with neutrophilic lung inflammation relative to wildtype control. Inhibition of F508del platelet aggregation or depletion of F508del neutrophils diminished the LPS-induced lung inflammation in the F508del mice. Moreover, wildtype mice reconstituted with either F508del bone marrow or neutrophils developed worse thrombocytopenia. Blocking PSGL-1, platelet activating factor (PAF, or rectifying trafficking of mutated CFTR in F508del mice diminished and alveolar neutrophil transmigration in the LPS-challenged F508del mice. These findings suggest that F508del platelets and their interaction with neutrophils are requisite for the development of LPS-induced lung inflammation and injury. As such, targeting platelets might be an emerging strategy for dampening recurrent lung inflammation in cystic fibrosis patients.

  17. Remodeling of the pulmonary circulation - a novel response to allergic airway inflammation

    OpenAIRE

    Rydell-Törmänen, Kristina

    2008-01-01

    Asthma is characterized, not only by inflammation but also by airway and vascular remodeling. Airway remodeling is established early in disease, structural alterations have been found in children, and is thought to contribute to asthma symptoms. Unfortunately, airway remodeling is considered difficult to reverse and it seldom resolves completely. Studies of vascular involvement in asthma have mainly focused on the tracheal and bronchial microcirculation, as these vessels are relatively easy t...

  18. Attenuation of allergic airway inflammation and hyperresponsiveness in a murine model of asthma by silver nanoparticles

    OpenAIRE

    Park, Hee Sun; Kim, Keun Hwa; Jang, Sunhyae; Ji Won PARK; Cha, Hye Rim; Lee, Jeong Eun; Kim, Ju Ock; Kim, Sun Young; Lee, Choong Sik; Kim, Joo Pyung; Jung, Sung Soo

    2010-01-01

    The use of silver in the past demonstrated the certain antimicrobial activity, though this has been replaced by other treatments. However, nanotechnology has provided a way of producing pure silver nanoparticles, and it shows cytoprotective activities and possible pro-healing properties. But, the mechanism of silver nanoparticles remains unknown. This study was aimed to investigate the effects of silver nanoparticles on bronchial inflammation and hyperresponsiveness. We used ovalbumin (OVA)-i...

  19. Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure.

    Directory of Open Access Journals (Sweden)

    Cristiane Miranda da Silva

    Full Text Available Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA, an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1% or vehicle (distillated water during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure. Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant.

  20. HIV Impairs Lung Epithelial Integrity and Enters the Epithelium to Promote Chronic Lung Inflammation.

    Directory of Open Access Journals (Sweden)

    Kieran A Brune

    can enter airway epithelial cells and alter their function by impairing cell-cell adhesion and increasing the expression of inflammatory mediators. These observed changes may contribute local inflammation, which can lead to lung function decline and increased susceptibility to COPD in HIV patients.

  1. Cholera toxin B suppresses allergic inflammation through induction of secretory IgA.

    Science.gov (United States)

    Smits, H H; Gloudemans, A K; van Nimwegen, M; Willart, M A; Soullié, T; Muskens, F; de Jong, E C; Boon, L; Pilette, C; Johansen, F-E; Hoogsteden, H C; Hammad, H; Lambrecht, B N

    2009-07-01

    In healthy individuals, humoral immune responses to allergens consist of serum IgA and IgG4, whereas cellular immune responses are controlled by regulatory T (Treg) cells. In search of new compounds that might prevent the onset of allergies by stimulating this type of immune response, we have focused on the mucosal adjuvant, cholera toxin B (CTB), as it induces the formation of Treg cells and production of IgA. Here, we have found that CTB suppresses the potential of dendritic cells to prime for Th2 responses to inhaled allergen. When we administered CTB to the airways of naïve and allergic mice, it strongly suppressed the salient features of asthma, such as airway eosinophilia, Th2 cytokine synthesis, and bronchial hyperreactivity. This beneficial effect was only transferable to other mice by transfer of B but not of T lymphocytes. CTB caused a transforming growth factor-beta-dependent rise in antigen-specific IgA in the airway luminal secretions, which was necessary for its preventive and curative effect, as all effects of CTB were abrogated in mice lacking the luminal IgA transporting polymeric Ig receptor. Not only do these findings show a novel therapeutic avenue for allergy, they also help to explain the complex relationship between IgA levels and risk of developing allergy in humans. PMID:19404246

  2. A study of allergic inflammation in the guinea-pig using radioisotopes

    International Nuclear Information System (INIS)

    A radioisotope technique was developed which enabled the rate of plasma exudation to be continuously monitored in an area of skin in the conscious guinea-pig. Three types of hypersensitivity reactions in skin were investigated; anaphylactic (Type I); Arthus (Type III); and delayed-type (Type IV). The time course of plasma exudation in the Type I reaction was rapid and similar to that produced by an intradermal injection of histamine; however the antihistamine mepyramine only abolished the histamine response. In the Type III reaction, maximal plasma exudation occurred shortly after initiation of the response. The subsequent protracted phase of low level exudation observed may have been mediated by substances secreted by polymorphonuclear leucocytes. Type IV reactions were clearly differentiated from antibody-mediated reactions by the slow time course of plasma exudation. No evidence was obtained for the involvement of low molecular weight mediators in Type IV reactions, using a range of inhibitors and antagonists. Prostaglandins produced little plasma exudation when injected alone into guinea-pig skin, but these substances markedly potentiated the plasma exudation induced by histamine and brady-kinin. Allergic reactions were similarly potentiated by prostaglandins. Exudation potentiation may result from vasodilator activity. (author)

  3. Sub-chronic lung inflammation after airway exposures to Bacillus thuringiensis biopesticides in mice

    DEFF Research Database (Denmark)

    Barfod, Kenneth K; Poulsen, Steen Seier; Hammer, Maria;

    2010-01-01

    The aim of the present study was to assess possible health effects of airway exposures to Bacillus thuringiensis (Bt) based biopesticides in mice. Endpoints were lung inflammation evaluated by presence of inflammatory cells in bronchoalveolar lavage fluid (BALF), clearance of bacteria from the lung...

  4. Surfactant Protein-D Inhibits Lung Inflammation Caused by Ventilation in Premature Newborn Lambs

    OpenAIRE

    Sato, Atsuyasu; Jeffrey A Whitsett; Scheule, Ronald K.; Ikegami, Machiko

    2010-01-01

    Rationale: Premature newborns frequently require manual ventilation for resuscitation during which lung injury occurs. Although surfactant protein (SP)-D regulates pulmonary inflammation, SP-D levels are low in the preterm lung. Commercial surfactants for treatment of respiratory distress syndrome do not contain SP-D.

  5. Ionotropic and Metabotropic Proton-Sensing Receptors Involved in Airway Inflammation in Allergic Asthma

    OpenAIRE

    2014-01-01

    An acidic microenvironment has been shown to evoke a variety of airway responses, including cough, bronchoconstriction, airway hyperresponsiveness (AHR), infiltration of inflammatory cells in the lung, and stimulation of mucus hyperproduction. Except for the participation of transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channels (ASICs) in severe acidic pH (of less than 6.0)-induced cough and bronchoconstriction through sensory neurons, the molecular mechanisms underly...

  6. Respiratory syncytial virus (RSV) and asthma : a study on the impact of RSV infection on allergic airway inflammation in a mouse model

    OpenAIRE

    Barends, Marion

    2004-01-01

    textabstractFor many years animal studies are performed to investigate the immunity induced by an RSV infection and the immune regulatory role of RSV infections on the development and exacerbation of respiratory allergies. Since different strategies of allergen sensitisation and challenge, moments of virus infection during allergen-sensitisation and -challenge, and timing of analysis after challenge are chosen, the precise role of RSV infection in allergic inflammation is still not clear. The...

  7. Protection against the allergic airway inflammation depends on the modulation of spleen dendritic cell function and induction of regulatory T cells in mice

    OpenAIRE

    Wang, Yaoli; Bai, Chunxue; Wang, Guansong; Wang, Diane; Cheng, Xiaoming; Huang, Jian; Jiang, Dongpo; Qian, Guisheng; Wang, Xiangdong

    2010-01-01

    Background Allergen-induced imbalance of specific T regulatory (Treg) cells and T helper 2 cells plays a decisive role in the development of immune response against allergens. Objective To evaluate effects and potential mechanisms of DNA vaccine containing ovalbumin (OVA) and Fc fusion on allergic airway inflammation. Methods Bronchoalveolar lavage (BAL) levels of inflammatory mediators and leukocyte infiltration, expression of CD11c +CD80 + and CD11c +CD86 + co-stimulatory molecules in splee...

  8. Quantitative assessment of global lung inflammation following radiation therapy using FDG PET/CT: a pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Abdulla, Sarah; Salavati, Ali; Saboury, Babak; Torigian, Drew A. [University of Pennsylvania, and Hospital of the University of Pennsylvania, Department of Radiology, Perelman School of Medicine, Philadelphia, PA (United States); Basu, Sandip [Bhabha Atomic Research Center, Tata Memorial Center Annexe, Radiation Medicine Center, Bombay (India); Alavi, Abass [University of Pennsylvania, and Hospital of the University of Pennsylvania, Department of Radiology, Perelman School of Medicine, Philadelphia, PA (United States); Hospital of the University of Pennsylvania, Department of Radiology, Division of Nuclear Medicine, Philadelphia, PA (United States)

    2014-02-15

    Radiation pneumonitis is the most severe dose-limiting complication in patients receiving thoracic radiation therapy. The aim of this study was to quantify global lung inflammation following radiation therapy using FDG PET/CT. We studied 20 subjects with stage III non-small-cell lung carcinoma who had undergone FDG PET/CT imaging before and after radiation therapy. On all PET/CT studies, the sectional lung volume (sLV) of each lung was calculated from each slice by multiplying the lung area by slice thickness. The sectional lung glycolysis (sLG) was calculated by multiplying the sLV and the lung sectional mean standardized uptake value (sSUVmean) on each slice passing through the lung. The lung volume (LV) was calculated by adding all sLVs from the lung, and the global lung glycolysis (GLG) was calculated by adding all sLGs from the lung. Finally, the lung SUVmean was calculated by dividing the GLG by the LV. The amount of inflammation in the lung parenchyma directly receiving radiation therapy was calculated by subtracting tumor measurements from GLG. In the lung directly receiving radiation therapy, the lung parenchyma SUVmean and global lung parenchymal glycolysis were significantly increased following therapy. In the contralateral lung (internal control), no significant changes were observed in lung SUVmean or GLG following radiation therapy. Global lung parenchymal glycolysis and lung parenchymal SUVmean may serve as potentially useful biomarkers to quantify lung inflammation on FDG PET/CT following thoracic radiation therapy. (orig.)

  9. Trichosanthin functions as Th2-type adjuvant in induction of allergic airway inflammation

    Institute of Scientific and Technical Information of China (English)

    Yuan Wang; Kairui Mao; Shuhui Sun; Guomei Lin; Xiaodong Wu; Gang Yao; Bing Sun

    2009-01-01

    It is important to understand the pathogenesis of asthma induced by natural allergens, which could exclude the interference of artificial adjuvant and provide insights of natural immune response in the disease. In the present study, we show that Trichosanthin (TCS) could induce airway inflammation even without the help of alum. Further-more, TCS appeared capable of replacing alum to promote OVA-specific airway inflammation. TCS induced accu-mulation of IL-4-producing eosinophiis in peritoneum at an early stage and the adjuvant function of TCS was elimi-nated by blockage of IL-4 at this stage. Finally, the eosinophils triggered by TCS from WT mice, but not from IL-4-deficient mice were shown to function as adjuvant for the induction of OVA-specific Th2 responses. Our data indicate that TCS is not only an allergen, but also a Th2-type adjuvant modulating the switching of immune responses to a Th2 pathway. This chain of events results from IL-4 production by eosinophils at an early stage of TCS-priming. In conclusion, TCS may be useful as a Th2 adjuvant, and innate immune cells, such as eosinophils, may be a good target to study the initiation of Th2 response.

  10. The IL-33 receptor (ST2) regulates early IL-13 production in fungus-induced allergic airway inflammation.

    Science.gov (United States)

    Piehler, D; Eschke, M; Schulze, B; Protschka, M; Müller, U; Grahnert, A; Richter, T; Heyen, L; Köhler, G; Brombacher, F; Alber, G

    2016-07-01

    Allergic airway inflammation (AAI) in response to environmental antigens is an increasing medical problem, especially in the Western world. Type 2 interleukins (IL) are central in the pathological response but their importance and cellular source(s) often rely on the particular allergen. Here, we highlight the cellular sources and regulation of the prototypic type 2 cytokine, IL-13, during the establishment of AAI in a fungal infection model using Cryptococcus neoformans. IL-13 reporter mice revealed a rapid onset of IL-13 competence within innate lymphoid cells type 2 (ILC2) and IL-33R(+) T helper (Th) cells. ILC2 showed IL-33-dependent proliferation upon infection and significant IL-13 production. Th cells essentially required IL-33 to become either GATA3(+) or GATA3(+)/Foxp3(+) hybrids. GATA3(+) Th cells almost exclusively contributed to IL-13 production but hybrid GATA3(+)/Foxp3(+) Th cells did not. In addition, alveolar macrophages upregulated the IL-33R and subsequently acquired a phenotype of alternative activation (Ym1(+), FIZZ1(+), and arginase-1(+)) linked to type 2 immunity. Absence of adaptive immunity in rag2(-/-) mice resulted in attenuated AAI, revealing the need for Th2 cells for full AAI development. Taken together, in pulmonary cryptococcosis ILC2 and GATA3(+) Th2 cells produce early IL-13 largely IL-33R-dependent, thereby promoting goblet cell metaplasia, pulmonary eosinophilia, and alternative activation of alveolar macrophages. PMID:26555705

  11. Brief exposures to NO2 augment the allergic inflammation in asthmatics

    International Nuclear Information System (INIS)

    Exposure to high ambient levels of nitrogen dioxide (NO2) enhances the airway reaction in humans to allergen, measured as decreased pulmonary function. We tested whether this NO2 effect is associated with an increased inflammatory response to allergen in the airways. To mimic real-life conditions, in which exposure to high ambient levels of NO2 occurs only during short periods of time but often several times a day, we used a repeated-exposure model. On day 1, 18 subjects with allergic asthma were exposed, in randomized order, to purified air or to 500 μg/m3 NO2 for 15 min, and on day 2 for 2x15 min. Allergen was inhaled 3-4 h after the NO2 exposures on both days. Symptoms, pulmonary function, and inflammatory response in sputum and blood were measured daily. Eosinophil cationic protein in both sputum and blood increased more from day 1 to day 3 after NO2+allergen than after air+allergen, whereas eosinophil counts did not differ. The change in myeloperoxidase was significantly greater after NO2+allergen than after air+allergen in blood but not in sputum. This finding was not accompanied by raised levels of neutrophils in sputum and blood. Symptoms and pulmonary function were equally affected by NO2+allergen and air+allergen. We conclude that two to three brief exposures to ambient levels of NO2 can prime circulating eosinophils and enhance the eosinophilic activity in sputum in response to inhaled allergen. This might be an important mechanism by which air pollutants amplify the inflammatory reactions in the airways

  12. Effect of Chicoric Acid on Mast Cell-Mediated Allergic Inflammation in Vitro and in Vivo.

    Science.gov (United States)

    Lee, Na Young; Chung, Kyung-Sook; Jin, Jong Sik; Bang, Keuk Soo; Eom, Ye-Jin; Hong, Chul-Hee; Nugroho, Agung; Park, Hee-Jun; An, Hyo-Jin

    2015-12-24

    Chicoric acid (dicaffeoyl-tartaric acid), is a natural phenolic compound found in a number of plants, such as chicory (Cichorium intybus) and Echinacea (Echinacea purpurea), which possesses antioxidant, anti-inflammatory, antiviral, and analgesic activities. Although these biological effects of chicoric acid have been investigated, there are no reports of its antiallergic-related anti-inflammatory effects in human mast cells (HMC)-1 or anaphylactic activity in a mouse model. Therefore, we investigated the antiallergic-related anti-inflammatory effect of chicoric acid and its underlying mechanisms of action using phorbol-12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated HMC-1 cells. Chicoric acid decreased the mRNA expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. We studied the inhibitory effects of chicoric acid on the nuclear translocation of nuclear factor kappa B (NF-κB) and activation of caspase-1. However, mitogen-activated protein kinase (MAPK) activation was not sufficient to abrogate the stimulus. In addition, we investigated the ability of chicoric acid to inhibit compound 48/80-induced systemic anaphylaxis in vivo. Oral administration of chicoric acid at 20 mg/kg inhibited histamine release and protected mice against compound 48/80-induced anaphylactic mortality. These results suggest that chicoric acid has an antiallergic-related anti-inflammatory effect that involves modulating mast cell-mediated allergic responses. Therefore, chicoric acid could be an efficacious agent for allergy-related inflammatory disorders. PMID:26593037

  13. Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation

    OpenAIRE

    Wittke, Anja; Chang, Andrew; Froicu, Monica; Harandi, Omid F.; Weaver, Veronika; August, Avery; Paulson, Robert F.; Cantorna, Margherita T.

    2007-01-01

    Mice lacking the vitamin D receptor (VDR) are resistant to airway inflammation. Pathogenic immune cells capable of transferring experimental airway inflammation to wildtype (WT) mice are present and primed in the VDR KO mice. Furthermore, the VDR KO immune cells homed to the WT lung in sufficient numbers to induce symptoms of asthma. Conversely, WT splenocytes, Th2 cells and hematopoetic cells induced some symptoms of experimental asthma when transferred to VDR KO mice, but the severity was l...

  14. Type 2 Innate Lymphoid Cells: Friends or Foes—Role in Airway Allergic Inflammation and Asthma

    Directory of Open Access Journals (Sweden)

    Abbas Pishdadian

    2012-01-01

    Full Text Available Innate-like lymphocytes (ILLs and innate lymphoid cells (ILCs are two newly characterized families of lymphocytes with limited and no rearranged antigen receptors, respectively. These soldiers provide a first line of defense against foreign insults by triggering a prompt innate immune response and bridging the gap of innate and adaptive immunity. Type 2 innate lymphoid cells (ILCs2 are newly identified members of the ILC family that play a key role in type 2 immune responses by prompt production of type 2 cytokines (especially IL-5 and IL-13 in response to antigen-induced IL-25/33 and by recruiting type 2 “immune franchise.” Regarding the two different roles of type 2 cytokines, helminth expulsion and type 2-related diseases, here we review the latest advances in ILC2 biology and examine the pivotal role of resident ILCs2 in allergen-specific airway inflammation and asthma.

  15. Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development.

    Science.gov (United States)

    Benjamin, John T; van der Meer, Riet; Im, Amanda M; Plosa, Erin J; Zaynagetdinov, Rinat; Burman, Ankita; Havrilla, Madeline E; Gleaves, Linda A; Polosukhin, Vasiliy V; Deutsch, Gail H; Yanagisawa, Hiromi; Davidson, Jeffrey M; Prince, Lawrence S; Young, Lisa R; Blackwell, Timothy S

    2016-07-01

    The highly orchestrated interactions between the epithelium and mesenchyme required for normal lung development can be disrupted by perinatal inflammation in preterm infants, although the mechanisms are incompletely understood. We used transgenic (inhibitory κB kinase β transactivated) mice that conditionally express an activator of the NF-κB pathway in airway epithelium to investigate the impact of epithelial-derived inflammation during lung development. Epithelial NF-κB activation selectively impaired saccular stage lung development, with a phenotype comprising rapidly progressive distal airspace dilation, impaired gas exchange, and perinatal lethality. Epithelial-derived inflammation resulted in disrupted elastic fiber organization and down-regulation of elastin assembly components, including fibulins 4 and 5, lysyl oxidase like-1, and fibrillin-1. Fibulin-5 expression by saccular stage lung fibroblasts was consistently inhibited by treatment with bronchoalveolar lavage fluid from inhibitory κB kinase β transactivated mice, Escherichia coli lipopolysaccharide, or tracheal aspirates from preterm infants exposed to chorioamnionitis. Expression of a dominant NF-κB inhibitor in fibroblasts restored fibulin-5 expression after lipopolysaccharide treatment, whereas reconstitution of fibulin-5 rescued extracellular elastin assembly by saccular stage lung fibroblasts. Elastin organization was disrupted in saccular stage lungs of preterm infants exposed to systemic inflammation. Our study reveals a critical window for elastin assembly during the saccular stage that is disrupted by inflammatory signaling and could be amenable to interventions that restore elastic fiber assembly in the developing lung. PMID:27181406

  16. Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration.

    Science.gov (United States)

    Patel, Aateka; Woods, A; Riffo-Vasquez, Yanira; Babin-Morgan, Anna; Jones, Marie-Christine; Jones, Stuart; Sunassee, Kavitha; Clark, Stephen; T M de Rosales, Rafael; Page, Clive; Spina, Domenico; Forbes, Ben; Dailey, Lea Ann

    2016-08-10

    Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50nm lipid nanocapsules, or is exacerbated by their pulmonary administration. Studies were conducted in mice with lipopolysaccharide-induced lung inflammation compared to healthy controls. Particle deposition and nanocapsule clearance kinetics were measured by single photon emission computed tomography/computed tomography (SPECT/CT) imaging over 48 h. A significantly lower lung dose of (111)In-LNC50 was achieved in the lipopolysaccharide (LPS)-treated animals compared with healthy controls (p<0.001). When normalised to the delivered lung dose, the clearance kinetics of (111)In-LNC50 from the lungs fit a first order model with an elimination half-life of 10.5±0.9h (R(2)=0.995) and 10.6±0.3h (R(2)=1.000) for healthy and inflamed lungs respectively (n=3). In contrast, (111)In-diethylene triamine pentaacetic acid (DTPA), a small hydrophilic molecule, was cleared rapidly from the lungs with the majority of the dose absorbed within 20min of administration. Biodistribution to lungs, stomach-intestine, liver, trachea-throat and blood at the end of the imaging period was unaltered by lung inflammation. This study demonstrated that lung clearance and whole body distribution of lipid nanocapsules were unaffected by the presence of acute lung inflammation. PMID:27180635

  17. Cohabitation with a sick partner increases allergic lung inflammatory response in mice.

    Science.gov (United States)

    Hamasato, Eduardo Kenji; de Lima, Ana Paula Nascimento; de Oliveira, Ana Paula Ligeiro; dos Santos Franco, Adriana Lino; de Lima, Wothan Tavares; Palermo-Neto, João

    2014-11-01

    results suggest that allergic lung inflammatory response exacerbation in CSP mice is a consequence of the psychological stress induced by forced cohabitation with the sick partner. Strong involvement of the sympathetic nervous system (SNS) through adrenaline and noradrenaline release and a shift of the Th1/Th2 cytokine profile toward a Th2 response were considered to be the mechanisms underlying the cell recruitment to the animal's airways. PMID:24929194

  18. Targeting IL-1β and IL-17A driven inflammation during influenza-induced exacerbations of chronic lung inflammation.

    OpenAIRE

    Sichelstiel A.; Yadava K.; Trompette A.; Salami O; Iwakura Y.; Nicod L.P.; Marsland B.J.

    2014-01-01

    For patients with chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), exacerbations are life-threatening events causing acute respiratory distress that can even lead to hospitalization and death. Although a great deal of effort has been put into research of exacerbations and potential treatment options, the exact underlying mechanisms are yet to be deciphered and no therapy that effectively targets the excessive inflammation is available. In this study, we report that...

  19. Targeting IL-1β and IL-17A Driven Inflammation during Influenza-Induced Exacerbations of Chronic Lung Inflammation

    OpenAIRE

    Sichelstiel, Anke; Yadava, Koshika; Trompette, Aurélien; Salami, Olawale; Iwakura, Yoichiro; Nicod, Laurent P.; Marsland, Benjamin J

    2014-01-01

    For patients with chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), exacerbations are life-threatening events causing acute respiratory distress that can even lead to hospitalization and death. Although a great deal of effort has been put into research of exacerbations and potential treatment options, the exact underlying mechanisms are yet to be deciphered and no therapy that effectively targets the excessive inflammation is available. In this study, we report that...

  20. Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function

    Directory of Open Access Journals (Sweden)

    Bunn Janice Y

    2010-03-01

    Full Text Available Abstract Background Asthma is a chronic inflammatory disease of the airway that is characterized by a Th2-type of immune response with increasing evidence for involvement of Th17 cells. The role of IL-6 in promoting effector T cell subsets suggest that IL-6 may play a functional role in asthma. Classically IL-6 has been viewed as an inflammatory marker, along with TNFα and IL-1β, rather than as regulatory cytokine. Objective To investigate the potential relationship between IL-6 and other proinflammatory cytokines, Th2/Th17 cytokines and lung function in allergic asthma, and thus evaluate the potential role of IL-6 in this disease. Methods Cytokine levels in induced sputum and lung function were measured in 16 healthy control and 18 mild-moderate allergic asthmatic subjects. Results The levels of the proinflammatory biomarkers TNFα and IL-1β were not different between the control and asthmatic group. In contrast, IL-6 levels were specifically elevated in asthmatic subjects compared with healthy controls (p S = 0.53, p Conclusions In mild-moderate asthma, IL-6 dissociates from other proinflammatory biomarkers, but correlates with IL-13 levels. Furthermore, IL-6 may contribute to impaired lung function in allergic asthma.

  1. Endothelial Semaphorin 7A Promotes Inflammation in Seawater Aspiration-Induced Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Minlong Zhang

    2014-10-01

    Full Text Available Inflammation is involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI. Although several studies have shown that Semaphorin 7A (SEMA7A promotes inflammation, there are limited reports regarding immunological function of SEMA7A in seawater aspiration-induced ALI. Therefore, we investigated the role of SEMA7A during seawater aspiration-induced ALI. Male Sprague–Dawley rats were underwent seawater instillation. Then, lung samples were collected at an indicated time for analysis. In addition, rat pulmonary microvascular endothelial cells (RPMVECs were cultured and then stimulated with 25% seawater for indicated time point. After these treatments, cells samples were collected for analysis. In vivo, seawater instillation induced lung histopathologic changes, pro-inflammation cytokines release and increased expression of SEMA7A. In vitro, seawater stimulation led to pro-inflammation cytokine release, cytoskeleton remodeling and increased monolayer permeability in pulmonary microvascular endothelial cells. In addition, knockdown of hypoxia-inducible factor (HIF-1α inhibited the seawater induced increase expression of SEMA7A. Meanwhile, knockdown of SEMA7A by specific siRNA inhibited the seawater induced aberrant inflammation, endothelial cytoskeleton remodeling and endothelial permeability. These results suggest that SEMA7A is critical in the development of lung inflammation and pulmonary edema in seawater aspiration-induced ALI, and may be a therapeutic target for this disease.

  2. Mycobacterium bovis bacillus Calmette-Guérin killed by extended freeze-drying targets plasmacytoid dendritic cells to regulate lung inflammation.

    Science.gov (United States)

    Lagranderie, Micheline; Abolhassani, Mohammad; Vanoirbeek, Jeroen A J; Lima, Carla; Balazuc, Anne-Marie; Vargaftig, B Boris; Marchal, Gilles

    2010-01-15

    We have previously shown that bacillus Calmette-Guérin (BCG) inactivated by extended freeze-drying (EFD) reduces airway hyperresponsiveness, whereas live and heat-killed BCG fail to do so. However, the cells involved in the protective effect and the signaling and transcriptional networks that could reprogram T cell commitment after EFD BCG treatment remained to be elucidated. We investigated whether EFD BCG targets plasmacytoid dendritic cells (pDCs) potentially involved in the polarization of regulatory T cells (Tregs) and the transcriptional factors that regulate allergic inflammation. OVA-sensitized mice were s.c. injected with EFD, live, or heat-killed BCG. We analyzed after the injection of the various BCG preparations: 1) pDCs recruited in the draining lymph nodes (day 4); 2) transcription factors involved in inflammation and T cell commitment in spleen and lungs after OVA challenge (day 28). Airway hyperresponsiveness and transcription factors were determined after in vivo depletion of pDCs or Tregs in EFD BCG-treated and OVA-challenged mice. EFD BCG reduced inflammation via the recruitment of pDCs polarizing the differentiation of naive CD4+ T lymphocytes into Tregs. In vivo, pDC or Treg depletion at the time of EFD BCG treatment abrogated the protection against inflammation. EFD BCG treatment upregulated Forkhead-winged helix transcription factor (Treg signature) and downregulated GATA-3 and RORgammat (Th2 and Th17 signatures) more efficiently than live and heat-killed BCG. Moreover, only EFD BCG enhanced peroxisome proliferator-activated receptor gamma expression and blocked NF-kappaB activation, cyclooxygenase expression, and p38 MAPK phosphorylation. EFD BCG reduced allergic inflammation by recruiting pDCs that promoted Tregs; EFD BCG acted as a peroxisome proliferator-activated receptor gamma agonist and thus could be used in asthma and other inflammatory diseases. PMID:20007537

  3. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats

    Directory of Open Access Journals (Sweden)

    Wei-Chi Chou

    2015-01-01

    Full Text Available Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group, sham-operation (Sham, or sham plus caffeine (n=12 in each group. To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P<0.001 and P=0.008, resp.. Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2 and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P<0.05. These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs.

  4. Effect of salbutamol on pulmonary responsiveness in chronic pulmonary allergic inflammation in guinea pigs

    Directory of Open Access Journals (Sweden)

    Kasahara D.I.

    2005-01-01

    Full Text Available Beta-2-agonists have been widely used by asthmatic subjects to relieve their obstructive symptoms. However, there are reports that continuous use could lead to loss of bronchial protection and exacerbation of asthma symptoms. We evaluated the effect of two regimens of salbutamol administration (twice and five times a week in a model of chronic airway inflammation in male Hartley guinea pigs (protocol starting weight: 286 ± 30 g induced by repeated exposures to aerosols of ovalbumin (OVA. After sensitization, guinea pigs were exposed to aerosols of 0.1 mg/ml salbutamol solution twice a week (OVA + S2x, N = 7 or five times a week (OVA + S5x, N = 8. We studied allergen-specific (OVA inhalation time and -nonspecific (response to methacholine respiratory system responsiveness. Seventy-two hours after the last OVA challenge, guinea pigs were anesthetized and tracheostomized, respiratory system resistance and elastance were measured and a dose-response curve to inhaled methacholine chloride was obtained. Specific IgG1 was also quantified by the passive cutaneous anaphylactic technique. OVA-sensitized guinea pigs (N = 8 showed reduction of the time of OVA exposure before the onset of respiratory distress, at the 5th, 6th and 7th exposures (P < 0.001. The OVA + S2x group (but not the OVA + S5x group showed a significant increase in OVA inhalation time. There were no significant differences in pulmonary responsiveness to methacholine among the experimental groups. OVA + S2x (but not OVA + S5x animals showed a decrease in the levels of IgG1-specific anaphylactic antibodies compared to the OVA group (P < 0.05. Our results suggest that, in this experimental model, frequent administration of ß2-agonists results in a loss of some of their protective effects against the allergen.

  5. Responses of Six-Weeks Aquatic Exercise on the Autonomic Nervous System, Peak Nasal Inspiratory Flow and Lung Functions in Young Adults with Allergic Rhinitis

    Directory of Open Access Journals (Sweden)

    Taweesak Janyacharoen

    2015-10-01

    Full Text Available Allergic rhinitis is a chronic respiratory disease. Sympathetic hypofunction is identified in all of the allergic rhinitis patients. Moreover, allergic rhinitis is associated with decreased peak nasal inspiratory flow (PNIF and impaired lung functions. The aim of this study was to investigate effects of six-week of aquatic exercise on the autonomic nervous system function, PNIF and lung functions in allergic rhinitis patients.Twenty-six allergic rhinitis patients, 12 males and 14 females were recruited in this study. Subjects were diagnosed by a physician based on history, physical examination, and positive reaction to a skin prick test. Subjects were randomly assigned to two groups. The control allergic rhinitis group received education and maintained normal life. The aquatic group performed aquatic exercise for 30 minutes a day, three days a week for six weeks. Heart rate variability, PNIF and lung functions were measured at the beginning, after three weeks and six weeks.There were statistically significant increased low frequency normal units (LF n.u., PNIF and showed decreased high frequency normal units (HF n.u. at six weeks after aquatic exercise compared with the control group.Six weeks of aquatic exercise could increase sympathetic activity and PNIF in allergicrhinitis patients.

  6. Treatment with the C5a receptor/CD88 antagonist PMX205 reduces inflammation in a murine model of allergic asthma.

    Science.gov (United States)

    Staab, Elizabeth B; Sanderson, Sam D; Wells, Sandra M; Poole, Jill A

    2014-08-01

    Allergic asthma is a chronic inflammatory airway disease arising from an aberrant immune response following exposure to environmental stimuli in genetically susceptible persons. The complement component 5 (C5)/C5a Receptor (C5aR/CD88) signaling pathway has been implicated in both experimental allergic asthma and human asthmatic disease. Targeting the C5a/C5aR signaling pathway in rodent models has been shown to either enhance or reduce allergic asthma consequences. Treatment with a recombinant humanized monoclonal antibody directed against C5 has shown unclear results in patients with asthma. The objective of this proof-of-concept animal study was to determine whether the low molecular weight C5aR peptidomimetic antagonist, PMX205, would reduce experimental allergic asthma consequences in mice. PMX205 or vehicle control was administered subcutaneously to BALB/c mice prior to and during standard ovalbumin (OVA) allergen sensitization and aerosolized challenge phases. PMX205 substantially reduced OVA-induced total cell (60%), neutrophil (66%) and eosinophil (65%) influxes in lavage fluid sampling. There were also significant reductions in OVA-induced lavage fluid IL-13 protein and lung Th2 cytokine gene expression with PMX205 administration. PMX205 treatment also diminished OVA-induced lung parenchyma cellular infiltration. PMX205 administration did not reduce OVA-induced serum IgE levels or epithelial mucous/goblet cell generation. There was no evidence of toxicity observed with PMX205 treatment in saline or OVA-challenged animals. These data provide evidence that pharmacologic blockade of C5aR by a low molecular weight antagonist (PMX205) reduces airway inflammatory cell and cytokine responses in experimental allergic asthma, and suggests that PMX205 might represent a novel therapeutic agent for reducing asthmatic outcomes. PMID:24859057

  7. Impact of psychosocial stress on airway inflammation and its mechanism in a murine model of allergic asthma

    Institute of Scientific and Technical Information of China (English)

    LI Bei; DUAN Xiao-hong; WU Jin-feng; LIU Bao-jun; LUO Qing-li; JIN Hua-liang; DU Yi-jie

    2013-01-01

    Background It has already been recognized that psychosocial stress evokes asthma exacerbation; however,the mechanism of how stress gets inside the body is not clear.This study aimed to observe the impact of psychosocial stress on airway inflammation and its mechanism in the ovalbumin-induced asthmatic mice combined with social disruption stress.Methods Thirty-six male BALB/c mice were randomly divided into:control group,asthma group (ovalbumin-induced),asthma plus social disruption stress group (SDR),and SDR group.The open field video tracking system was used to assess animal behaviors.The invasive pulmonary resistance (RL) and dynamic lung compliance (cdyn) test system from Buxco was applied to detect pulmonary function.The enzyme-linked immunosorbent assay (ELISA) was utilized to determine OVA-IgE,T-helper type 2 (Th2) cytokines (IL-4,IL-5,IL-13) and corticosterone in mouse serum,the Th2 cytokines (IL-4,IL-5,IL-13,IL-6,TNF-α) in bronchoalveolar lavage fluid (BALF),and IL-6 and TNF-α levels in the supernatant of splenocytes cultured in vitro.Hematoxylin-eosin (H&E) staining was used to assess airway inflammation in lung histology.The cell count kit-8 assay (CCK-8) was applied to evaluate the inhibitory effect of corticosterone on splenocyte proliferation induced by lipopolysacchadde (LPS).Real time-PCR and Western blotting were utilized to determine glucocorticoid receptor (GR) mRNA and GR protein expression in lungs.Results The open field test showed that combined allergen exposure and repeated stress significantly shortened the time the mice spent in the center of the open field (P <0.01),increased ambulatory activity (P <0.01) and the count of fecal boli (P <0.01),but deceased vertical activity (P <0.01).Results from pulmonary function demonstrated that airway hyperresponsiveness (AHR) was enhanced by psychosocial stress compared with allergy exposure alone.The ELISA results showed that cytokines in serum and BALF were significantly increased (P <0

  8. Usefulness of dynamic 18F-FDG PET scan in lung cancer and inflammation disease

    International Nuclear Information System (INIS)

    The diagnostic utility of fluorine-18 2-deoxy-D-glucose positron emission tomography (18F-FDG PET) for the non-invasive differentiation of focal lung lesions originated from cancer or inflammation disease by combined visual image interpretation and semi-quantitative uptake value analysis has been documented. In general, Standardized Uptake Value (SUV) is used to diagnose lung disease. But SUV dose not contain dynamic information of lung tissue for the glucose. Therefore, this study was undertaken to hypothesis that analysis of dynamic kinetics of focal lung lesions base on 18F-FDG PET may more accurately determine the lung disease. So we compared Time Activity Curve (TAC), Standardized Uptake Value-Dynamic Curve (SUV-DC) graph pattern with Glucose Metabolic Rate (MRGlu) from Patlak analysis. With lung disease, 17 patients were examined. They were injected with 18F-FDG over 30-s into peripheral vein while acquisition of the serial transaxial tomographic images were started. For acquisition protocol, we used twelve 10-s, four 30-s, sixteen 60-s, five 300-s and one 900-s frame for 60 mins. Its images were analyzed by visual interpretation TAC, SUV-DC and a kinetic analysis (Patlak analysis). The latter was based on region of interest (ROIs) which were drawn with the lung disease shape. Each optimized patterns were compared with itself. In TAC patterns, it hard to observe cancer type with inflammation disease in early pool blood area but over the time cancer type slope more remarkably increased than inflammation disease. SUV-DC was similar to TAC pattern. In the result of Patlak analysis, In time activity curve of aorta, even though inflammation disease showed higher blood activity than cancer, at first as time went by, blood activity of inflammation disease became the lowest. However, in time activity curve of tissue, cancer had the highest uptake and inflammation disease was in the middle. Through the examination, TAC and SUV-DC could approached the results that lung

  9. Role of TNF-α in lung tight junction alteration in mouse model of acute lung inflammation

    Directory of Open Access Journals (Sweden)

    Cuzzocrea Salvatore

    2007-10-01

    Full Text Available Abstract In the present study, we used tumor necrosis factor-R1 knock out mice (TNF-αR1KO to understand the roles of TNF-α on epithelial function in models of carrageenan-induced acute lung inflammation. In order to elucidate whether the observed anti-inflammatory status is related to the inhibition of TNF-α, we also investigated the effect of etanercept, a TNF-α soluble receptor construct, on lung TJ function. Pharmacological and genetic TNF-α inhibition significantly reduced the degree of (1 TNF-α production in pleural exudates and in the lung tissues, (2 the inflammatory cell infiltration in the pleural cavity as well as in the lung tissues (evaluated by MPO activity, (3 the alteration of ZO-1, Claudin-2, Claudin-4, Claudin-5 and β-catenin (immunohistochemistry and (4 apoptosis (TUNEL staining, Bax, Bcl-2 expression. Taken together, our results demonstrate that inhibition of TNF-α reduces the tight junction permeability in the lung tissues associated with acute lung inflammation, suggesting a possible role of TNF-α on lung barrier dysfunction.

  10. Lung function and airway inflammation monitoring after hematopoietic stem cell transplantation.

    OpenAIRE

    Moermans, Catherine; Poulet, Christophe; Henket, Monique; Bonnet, Christophe; WILLEMS, Evelyne; Baron, Frédéric; Beguin, Yves; Louis, Renaud

    2013-01-01

    Background Induced sputum is a non-invasive method to investigate airway inflammation, which has been used to assess pulmonary inflammatory diseases. However, this procedure has not been studied in the context of hematopoietic stem cell transplantation (HSCT). Methods We monitored lung function in 182 patients who underwent HSCT and measured airway inflammation by sputum induction in 80 of them. We prospectively measured FEV1, FVC, DLCO, KCO, TLC, RV, exhaled nitric oxide (FeNO) as ...

  11. Intrapulmonary Delivery of Ethyl Pyruvate Attenuates Lipopolysaccharide : and Lipoteichoic Acid-Induced Lung Inflammation in Vivo

    OpenAIRE

    van Zoelen, Marieke A.D.; de Vos, Alex F.; Larosa, Gregory J.; Draing, Christian; Aulock, Sonja von; van der Poll, Tom

    2007-01-01

    Ethyl pyruvate (EP) is a stable pyruvate derivative that has been shown to exert anti-inflammatory effects in various models of systemic inflammation including endotoxemia. We here sought to determine the local effects of EP, after intrapulmonary delivery, in models of lung inflammation induced by instillation via the airways of either lipopolysaccharide (LPS, a constituent of the gram-negative bacterial cell wall) or lipoteichoic acid (LTA, a component of the gram-positive bacterial cell wal...

  12. The Serine Protease Inhibitor, 4-(2-aminoethyl) Benzene Sulfonyl Fluoride Hydrochloride, Reduces Allergic Inflammation in a House Dust Mite Allergic Rhinitis Mouse Model

    OpenAIRE

    Kim, Boo-Young; Park, Hyang Rim; Shin, Ji-Hyeon; Kim, Sung Won; Cho, Jin Hee; Park, Yong Jin; Kim, Soo Whan

    2014-01-01

    Purpose Serine protease inhibitors are involved in immune development, anti-inflammatory mechanisms, and tissue repair. In the present study, the serine protease inhibitor 4-(2-aminoethyl) benzene sulfonyl fluoride hydrochloride (AEBSF) was evaluated for its prophylactic and therapeutic applications in a mouse model of allergic rhinitis (AR). Methods BALB/c mice were divided into 5 groups: contol (CON), Dermatophagoides farinae (Derf), AR mice treated with AEBSF before sensitization (S), AR m...

  13. The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease

    OpenAIRE

    Nichols, David P.; Ziady, Assem G.; Shank, Samuel L.; Eastman, Jean F.; Davis, Pamela B.

    2009-01-01

    Excessive inflammation in cystic fibrosis (CF) lung disease is a contributor to progressive pulmonary decline. Effective and well-tolerated anti-inflammatory therapy may preserve lung function, thereby improving quality and length of life. In this paper, we assess the anti-inflammatory effects of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) in preclinical models of CF airway inflammation. In our experiments, mice carrying the R117H Cftr mutation have sig...

  14. Stiffness-activated GEF-H1 expression exacerbates LPS-induced lung inflammation.

    Directory of Open Access Journals (Sweden)

    Isa Mambetsariev

    Full Text Available Acute lung injury (ALI is accompanied by decreased lung compliance. However, a role of tissue mechanics in modulation of inflammation remains unclear. We hypothesized that bacterial lipopolysacharide (LPS stimulates extracellular matrix (ECM production and vascular stiffening leading to stiffness-dependent exacerbation of endothelial cell (EC inflammatory activation and lung barrier dysfunction. Expression of GEF-H1, ICAM-1, VCAM-1, ECM proteins fibronectin and collagen, lysyl oxidase (LOX activity, interleukin-8 and activation of Rho signaling were analyzed in lung samples and pulmonary EC grown on soft (1.5 or 2.8 kPa and stiff (40 kPa substrates. LPS induced EC inflammatory activation accompanied by expression of ECM proteins, increase in LOX activity, and activation of Rho signaling. These effects were augmented in EC grown on stiff substrate. Stiffness-dependent enhancement of inflammation was associated with increased expression of Rho activator, GEF-H1. Inhibition of ECM crosslinking and stiffening by LOX suppression reduced EC inflammatory activation and GEF-H1 expression in response to LPS. In vivo, LOX inhibition attenuated LPS-induced expression of GEF-H1 and lung dysfunction. These findings present a novel mechanism of stiffness-dependent exacerbation of vascular inflammation and escalation of ALI via stimulation of GEF-H1-Rho pathway. This pathway represents a fundamental mechanism of positive feedback regulation of inflammation.

  15. Curcumin Attenuates Radiation-Induced Inflammation and Fibrosis in Rat Lungs

    OpenAIRE

    Cho, Yu Ji; Yi, Chin Ok; Jeon, Byeong Tak; Jeong, Yi Yeong; Kang, Gi Mun; Lee, Jung Eun; Roh, Gu Seob; Lee, Jong Deog

    2013-01-01

    A beneficial radioprotective agent has been used to treat the radiation-induced lung injury. This study was performed to investigate whether curcumin, which is known to have anti-inflammatory and antioxidant properties, could ameliorate radiation-induced pulmonary inflammation and fibrosis in irradiated lungs. Rats were given daily doses of intragastric curcumin (200 mg/kg) prior to a single irradiation and for 8 weeks after radiation. Histopathologic findings demonstrated that macrophage acc...

  16. Parameters of lung inflammation in asthmatic as compared to healthy children in a contaminated city

    OpenAIRE

    Linares Segovia, Benigno; Cortés Sandoval, Gabriela; Amador Licona, Norma; Guízar Mendoza, Juan Manuel; Núñez Lemus, Estela; Rocha Amador, Diana Olivia; Ramírez Gómez, Xóchitl Sofía; Monroy Torres, Rebeca

    2014-01-01

    Background The impact of air pollution on the respiratory system has been estimated on the basis of respiratory symptoms and lung function. However; few studies have compared lung inflammation in healthy and asthmatics children exposed to high levels of air pollution. The aim of the study was to elucidate the modulatory effect of air pollution on Cysteinyl-leukotrienes (Cys-LTs) levels in exhaled breath condensate (EBC) among healthy and asthmatic children. Methods We performed a cross-sectio...

  17. Heme oxygenase-1 inhibits basophil maturation and activation but promotes its apoptosis in T helper type 2-mediated allergic airway inflammation.

    Science.gov (United States)

    Zhong, Wenwei; Di, Caixia; Lv, Jiajia; Zhang, Yanjie; Lin, Xiaoliang; Yuan, Yufan; Lv, Jie; Xia, Zhenwei

    2016-03-01

    The anti-inflammatory role of heme oxygenase-1 (HO-1) has been studied extensively in many disease models including asthma. Many cell types are anti-inflammatory targets of HO-1, such as dendritic cells and regulatory T cells. In contrast to previous reports that HO-1 had limited effects on basophils, which participate in T helper type 2 immune responses and antigen-induced allergic airway inflammation, we demonstrated in this study, for the first time, that the up-regulation of HO-1 significantly suppressed the maturation of mouse basophils, decreased the expression of CD40, CD80, MHC-II and activation marker CD200R on basophils, blocked DQ-ovalbumin uptake and promoted basophil apoptosis both in vitro and in vivo, leading to the inhibition of T helper type 2 polarization. These effects of HO-1 were mimicked by exogenous carbon monoxide, which is one of the catalytic products of HO-1. Furthermore, adoptive transfer of HO-1-modified basophils reduced ovalbumin-induced allergic airway inflammation. The above effects of HO-1 can be reversed by the HO-1 inhibitor Sn-protoporphyrin IX. Moreover, conditional depletion of basophils accompanying hemin treatment further attenuated airway inflammation compared with the hemin group, indicating that the protective role of HO-1 may involve multiple immune cells. Collectively, our findings demonstrated that HO-1 exerted its anti-inflammatory function through suppression of basophil maturation and activation, but promotion of basophil apoptosis, providing a possible novel therapeutic target in allergic asthma. PMID:26879758

  18. Histamine is required for IL-4-driven eosinophilic allergic responses1

    OpenAIRE

    Swartzendruber, Julie A.; Byrne, Adam J.; Bryce, Paul J.

    2011-01-01

    Histamine is an important allergic mediator and studies have defined roles for both histamine 1 and 4 receptors (H1R and H4R) in allergic airway inflammation. Here, we show that histamine is necessary to generate IL-4-driven eosinophilic inflammation, as histamine deficient mice cannot generate eosinophilic lung inflammation in response to intratracheal IL-4 and exogenous histamine restores responsiveness. This is histamine 2 receptor (H2R) dependent since H2R KO mice fail to respond to IL-4,...

  19. Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Yang Xu

    Full Text Available BACKGROUND: Acute respiratory distress syndrome (ARDS is a severe and life-threatening acute lung injury (ALI that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK-MAPK pathway, in lipopolysaccharide (LPS-induced acute lung inflammation. METHODS: Wild-type (WT mice and Spred-2(-/- mice were exposed to intratracheal LPS (50 µg in 50 µL PBS to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/- mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. RESULTS: LPS-induced acute lung inflammation was significantly exacerbated in Spred-2(-/- mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2(-/- mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. CONCLUSIONS: The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls

  20. Development of a house dust mite model of mixed allergic airway inflammation and analysis of allergyprotective effects of Staphylococcus sciuri

    OpenAIRE

    Zhao, Min

    2012-01-01

    Allergic asthma is a chronic inflammatory disease of the airways based on a dysregulated immune response to innocuous antigens (allergens) with a predominance of Th2-driven activities. According to the hygiene hypothesis, neonatal and early childhood exposure to certain microbes and their products may protect them from the development of allergic responses due to a shift in the balance of T cell subpopulation activities. This conc...

  1. Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury

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    Duan Yingli

    2012-01-01

    Full Text Available Abstract Background Proline-rich tyrosine kinase 2 (Pyk2 is essential in neutrophil degranulation and chemotaxis in vitro. However, its effect on the process of lung inflammation and edema formation during LPS induced acute lung injury (ALI remains unknown. The goal of the present study was to determine the effect of inhibiting Pyk2 on LPS-induced acute lung inflammation and injury in vivo. Methods C57BL6 mice were given either 10 mg/kg LPS or saline intratracheally. Inhibition of Pyk2 was effected by intraperitoneal administration TAT-Pyk2-CT 1 h before challenge. Bronchoalveolar lavage analysis of cell counts, lung histology and protein concentration in BAL were analyzed at 18 h after LPS treatment. KC and MIP-2 concentrations in BAL were measured by a mouse cytokine multiplex kit. The static lung compliance was determined by pressure-volume curve using a computer-controlled small animal ventilator. The extravasated Evans blue concentration in lung homogenate was determined spectrophotometrically. Results Intratracheal instillation of LPS induced significant neutrophil infiltration into the lung interstitium and alveolar space, which was attenuated by pre-treatment with TAT-Pyk2-CT. TAT-Pyk2-CT pretreatment also attenuated 1 myeloperoxidase content in lung tissues, 2 vascular leakage as measured by Evans blue dye extravasation in the lungs and the increase in protein concentration in bronchoalveolar lavage, and 3 the decrease in lung compliance. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. By contrast, production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine in the bronchoalveolar lavage was not reduced by TAT-Pyk2-CT. Western blot analysis confirmed that tyrosine phosphorylation of Pyk2 in LPS-challenged lungs was reduced to control levels by TAT-Pyk2-CT pretreatment. Conclusions These results suggest that Pyk2 plays an important role in the development of acute lung injury in mice and

  2. Inhibition of Phosphodiesterase-4 during Pneumococcal Pneumonia Reduces Inflammation and Lung Injury in Mice.

    Science.gov (United States)

    Tavares, Luciana P; Garcia, Cristiana C; Vago, Juliana P; Queiroz-Junior, Celso M; Galvão, Izabela; David, Bruna A; Rachid, Milene A; Silva, Patrícia M R; Russo, Remo C; Teixeira, Mauro M; Sousa, Lirlândia P

    2016-07-01

    Pneumococcal pneumonia is a leading cause of mortality worldwide. The inflammatory response to bacteria is necessary to control infection, but it may also contribute to tissue damage. Phosphodiesterase-4 inhibitors, such as rolipram (ROL), effectively reduce inflammation. Here, we examined the impact of ROL in a pneumococcal pneumonia murine model. Mice were infected intranasally with 10(5)-10(6) CFU of Streptococcus pneumoniae, treated with ROL in a prophylactic or therapeutic schedule in combination, or not, with the antibiotic ceftriaxone. Inflammation and bacteria counts were assessed, and ex vivo phagocytosis assays were performed. ROL treatment during S. pneumoniae infection decreased neutrophil recruitment into lungs and airways and reduced lung injury. Prophylactic ROL treatment also decreased cytokine levels in the airways. Although modulation of inflammation by ROL ameliorated pneumonia, bacteria burden was not reduced. On the other hand, antibiotic therapy reduced bacteria without reducing neutrophil infiltration, cytokine level, or lung injury. Combined ROL and ceftriaxone treatment decreased lethality rates and was more efficient in reducing inflammation, by increasing proresolving protein annexin A1 (AnxA1) expression, and bacterial burden by enhancing phagocytosis. Lack of AnxA1 increased inflammation and lethality induced by pneumococcal infection. These data show that immunomodulatory effects of phosphodiesterase-4 inhibitors are useful during severe pneumococcal pneumonia and suggest their potential benefit as adjunctive therapy during infectious diseases. PMID:26677751

  3. Lung Neutrophilia in Myeloperoxidase Deficient Mice during the Course of Acute Pulmonary Inflammation

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    Silvie Kremserova

    2016-01-01

    Full Text Available Systemic inflammation accompanying diseases such as sepsis affects primarily lungs and induces their failure. This remains the most common cause of sepsis induced mortality. While neutrophils play a key role in pulmonary failure, the mechanisms remain incompletely characterized. We report that myeloperoxidase (MPO, abundant enzyme in neutrophil granules, modulates the course of acute pulmonary inflammatory responses induced by intranasal application of lipopolysaccharide. MPO deficient mice had significantly increased numbers of airway infiltrated neutrophils compared to wild-type mice during the whole course of lung inflammation. This was accompanied by higher levels of RANTES in bronchoalveolar lavage fluid from the MPO deficient mice. Other markers of lung injury and inflammation, which contribute to recruitment of neutrophils into the inflamed lungs, including total protein and other selected proinflammatory cytokines did not significantly differ in bronchoalveolar lavage fluid from the wild-type and the MPO deficient mice. Interestingly, MPO deficient neutrophils revealed a decreased rate of cell death characterized by phosphatidylserine surface expression. Collectively, the importance of MPO in regulation of pulmonary inflammation, independent of its putative microbicidal functions, can be potentially linked to MPO ability to modulate the life span of neutrophils and to affect accumulation of chemotactic factors at the inflammatory site.

  4. Lung Neutrophilia in Myeloperoxidase Deficient Mice during the Course of Acute Pulmonary Inflammation.

    Science.gov (United States)

    Kremserova, Silvie; Perecko, Tomas; Soucek, Karel; Klinke, Anna; Baldus, Stephan; Eiserich, Jason P; Kubala, Lukas

    2016-01-01

    Systemic inflammation accompanying diseases such as sepsis affects primarily lungs and induces their failure. This remains the most common cause of sepsis induced mortality. While neutrophils play a key role in pulmonary failure, the mechanisms remain incompletely characterized. We report that myeloperoxidase (MPO), abundant enzyme in neutrophil granules, modulates the course of acute pulmonary inflammatory responses induced by intranasal application of lipopolysaccharide. MPO deficient mice had significantly increased numbers of airway infiltrated neutrophils compared to wild-type mice during the whole course of lung inflammation. This was accompanied by higher levels of RANTES in bronchoalveolar lavage fluid from the MPO deficient mice. Other markers of lung injury and inflammation, which contribute to recruitment of neutrophils into the inflamed lungs, including total protein and other selected proinflammatory cytokines did not significantly differ in bronchoalveolar lavage fluid from the wild-type and the MPO deficient mice. Interestingly, MPO deficient neutrophils revealed a decreased rate of cell death characterized by phosphatidylserine surface expression. Collectively, the importance of MPO in regulation of pulmonary inflammation, independent of its putative microbicidal functions, can be potentially linked to MPO ability to modulate the life span of neutrophils and to affect accumulation of chemotactic factors at the inflammatory site. PMID:26998194

  5. Attenuation of Acute Lung Inflammation and Injury by Whole Body Cooling in a Rat Heatstroke Model

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    Hsi-Hsing Yang

    2009-01-01

    Full Text Available Whole body cooling is the current therapy of choice for heatstroke because the therapeutic agents are not available. In this study, we assessed the effects of whole body cooling on several indices of acute lung inflammation and injury which might occur during heatstroke. Anesthetized rats were randomized into the following groups and given (a no treatment or (b whole body cooling immediately after onset of heatstroke. As compared with the normothermic controls, the untreated heatstroke rats had higher levels of pleural exudates volume and polymorphonuclear cell numbers, lung myloperoxidase activity and inducible nitric oxide synthase expression, histologic lung injury score, and bronchoalveolar proinflammatory cytokines and glutamate, and PaCO2. In contrast, the values of mean arterial pressure, heart rate, PaO2, pH, and blood HCO3− were all significantly lower during heatstroke. The acute lung inflammation and injury and electrolyte imbalance that occurred during heatstroke were significantly reduced by whole body cooling. In conclusion, we identified heat-induced acute lung inflammation and injury and electrolyte imbalance could be ameliorated by whole body cooling.

  6. Blunted HPA axis responsiveness to stress in atopic patients is associated with the acuity and severeness of allergic inflammation.

    Science.gov (United States)

    Buske-Kirschbaum, A; Ebrecht, M; Hellhammer, D H

    2010-11-01

    Previously we could demonstrate attenuated responsiveness of the hypothalamus-pituitary-adrenal (HPA) axis to stress in patients with chronic allergic inflammatory disease (i.e., atopic dermatitis, allergic asthma). The present study was designed to investigate HPA axis function in an acute manifestation of allergy. Patients with seasonal allergic rhinitis (SAR; n = 20) and non-atopic controls (n = 20) were exposed to a standardized laboratory stressor ('Trier Social Stress Test'; TSST). Cortisol responses to the TSST and cortisol awakening responses (CAR) were measured in SAR subjects while suffering from acute symptoms of SAR (pollen season), and during a non-active state of their disease (pollen-free season). To assess the acuity and severity of SAR, eosinophil and basophil numbers and SAR symptomatology were determined. Non-allergic control subjects were examined at identical times during the year. To control for possible sequence effects, a cross-over design was used. SAR patients showed significantly increased symptom severity (t = 9.4; presponses were found in SAR subjects during acute manifestation of the disease (pollen season) when compared to the pollen-free season (F(16,456) = 1.65; presponse to the stressor (r = .53; p.05). These findings support previous data of attenuated HPA axis responsiveness to stress in atopic conditions and further, suggest that HPA axis hyporesponsiveness in atopy may be linked to the severity of the allergic inflammatory process. PMID:20633637

  7. Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation

    OpenAIRE

    Schreiber, Taylor H; Wolf, Dietlinde; Tsai, Matthew S.; Chirinos, Jackie; Deyev, Vadim V.; Gonzalez, Louis; Malek, Thomas R.; Levy, Robert B.; Podack, Eckhard R.

    2010-01-01

    TNF receptor superfamily member 25 (TNFRSF25; also known as DR3, and referred to herein as TNFR25) is constitutively and highly expressed by CD4+FoxP3+ Tregs. However, its function on these cells has not been determined. Here we used a TNFR25-specific agonistic monoclonal antibody, 4C12, to study the effects of TNFR25 signaling on Tregs in vivo in mice. Signaling through TNFR25 induced rapid and selective expansion of preexisting Tregs in vivo such that they became 30%–35% of all CD4+ T cells...

  8. Nano Titanium Dioxide Particles Promote Allergic Sensitization and Lung Inflammation in Mice

    OpenAIRE

    Larsen, Søren T; Roursgaard, Martin; Jensen, Keld A; Nielsen, Gunnar D

    2010-01-01

    The purpose of this study was to investigate whether photocatalytic TiO2 nanoparticles have adjuvant effect, when administered in combination with ovalbumin (OVA) in mice. Mice were immunized via intraperitoneal injections of OVA, OVA + TiO2 or OVA + Al(OH)3 and challenged with aerosols of OVA. At the end of the study, serum was analysed for content of OVA-specific IgE, IgG1 and IgG2a antibodies, and the bronchoalveolar lavage fluid (BALF) was analysed for content of inflammatory cells and le...

  9. Inhibition of protein kinase C delta attenuates allergic airway inflammation through suppression of PI3K/Akt/mTOR/HIF-1 alpha/VEGF pathway.

    Directory of Open Access Journals (Sweden)

    Yun Ho Choi

    Full Text Available Vascular endothelial growth factor (VEGF is supposed to contribute to the pathogenesis of allergic airway disease. VEGF expression is regulated by a variety of stimuli such as nitric oxide, growth factors, and hypoxia-inducible factor-1 alpha (HIF-1α. Recently, inhibition of the mammalian target of rapamycin (mTOR has been shown to alleviate cardinal asthmatic features, including airway hyperresponsiveness, eosinophilic inflammation, and increased vascular permeability in asthma models. Based on these observations, we have investigated whether mTOR is associated with HIF-1α-mediated VEGF expression in allergic asthma. In studies with the mTOR inhibitor rapamycin, we have elucidated the stimulatory role of a mTOR-HIF-1α-VEGF axis in allergic response. Next, the mechanisms by which mTOR is activated to modulate this response have been evaluated. mTOR is known to be regulated by phosphoinositide 3-kinase (PI3K/Akt or protein kinase C-delta (PKC δ in various cell types. Consistent with these, our results have revealed that suppression of PKC δ by rottlerin leads to the inhibition of PI3K/Akt activity and the subsequent blockade of a mTOR-HIF-1α-VEGF module, thereby attenuating typical asthmatic attack in a murine model. Thus, the present data indicate that PKC δ is necessary for the modulation of the PI3K/Akt/mTOR signaling cascade, resulting in a tight regulation of HIF-1α activity and VEGF expression. In conclusion, PKC δ may represent a valuable target for innovative therapeutic treatment of allergic airway disease.

  10. Level of Fatty Acid Binding Protein 5 (FABP5 Is Increased in Sputum of Allergic Asthmatics and Links to Airway Remodeling and Inflammation.

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    Hille Suojalehto

    Full Text Available The inflammatory processes in the upper and lower airways in allergic rhinitis and asthma are similar. Induced sputum and nasal lavage fluid provide a non-invasive way to examine proteins involved in airway inflammation in these conditions.We conducted proteomic analyses of sputum and nasal lavage fluid samples to reveal differences in protein abundances and compositions between the asthma and rhinitis patients and to investigate potential underlying mechanisms.Induced sputum and nasal lavage fluid samples were collected from 172 subjects with 1 allergic rhinitis, 2 asthma combined with allergic rhinitis, 3 nonallergic rhinitis and 4 healthy controls. Proteome changes in 21 sputum samples were analysed with two-dimensional difference gel electrophoresis (2D-DIGE, and the found differentially regulated proteins identified with mass spectrometry. Immunological validation of identified proteins in the sputum and nasal lavage fluid samples was performed with Western blot and ELISA.Altogether 31 different proteins were identified in the sputum proteome analysis, most of these were found also in the nasal lavage fluid. Fatty acid binding protein 5 (FABP5 was up-regulated in the sputum of asthmatics. Immunological validation in the whole study population confirmed the higher abundance levels of FABP5 in asthmatic subjects in both the sputum and nasal lavage fluid samples. In addition, the vascular endothelial growth factor (VEGF level was increased in the nasal lavage fluid of asthmatics and there were positive correlations between FABP5 and VEGF levels (r=0.660, p<0.001 and concentrations of FABP5 and cysteinyl leukotriene (CysLT (r=0.535, p<0.001 in the nasal lavage fluid.FABP5 may contribute to the airway remodeling and inflammation in asthma by fine-tuning the levels of CysLTs, which induce VEGF production.

  11. Interleukin 6 But Not T Helper 2 Cytokines Promotes Lung Carcinogenesis

    OpenAIRE

    Perez, Cesar Ochoa; Mirabolfathinejad, Seyedeh Golsar; Venado, Ana Ruiz; Evans, Scott E.; Gagea, Mihai; Evans, Christopher M.; Dickey, Burton F.; Moghaddam, Seyed Javad

    2010-01-01

    Several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer compared to smokers without COPD. We have shown a causal role for COPD-like airway inflammation in lung cancer promotion in the CCSPCre/LSL–K-rasG12D mouse model (CC-LR). In contrast, existing epidemiologic data do not suggest any definite association between allergic airway inflammation and lung cancer. To test thi...

  12. Cutting edge: histamine is required for IL-4-driven eosinophilic allergic responses.

    Science.gov (United States)

    Swartzendruber, Julie A; Byrne, Adam J; Bryce, Paul J

    2012-01-15

    Histamine is an important allergic mediator, and studies have defined roles for both histamine 1 and 4 receptors in allergic airway inflammation. In this study, we show that histamine is necessary to generate IL-4-driven eosinophilic inflammation, as histamine-deficient mice cannot generate eosinophilic lung inflammation in response to intratracheal IL-4 and exogenous histamine restores responsiveness. This is histamine 2 receptor (H2R) dependent because H2R knockout mice fail to respond to IL-4, and a H2R agonist restores inflammation in histidine decarboxylase knockout. Furthermore, alveolar epithelial cells require H2R to produce CCL24, an eosinophil recruitment factor, whereas H2R blockade reduces CCL24 production from wild-type cells. In an allergic inflammation model, H2R knockout mice show significantly reduced eosinophilic inflammation and CCL24 expression. These data demonstrate a previously unidentified role for H2R in allergic inflammation and establishes a synergy between endogenous histamine and IL-4 that supports eosinophilic recruitment to the lung. PMID:22156496

  13. Histamine is required for IL-4-driven eosinophilic allergic responses1

    Science.gov (United States)

    Swartzendruber, Julie A.; Byrne, Adam J.; Bryce, Paul J.

    2011-01-01

    Histamine is an important allergic mediator and studies have defined roles for both histamine 1 and 4 receptors (H1R and H4R) in allergic airway inflammation. Here, we show that histamine is necessary to generate IL-4-driven eosinophilic inflammation, as histamine deficient mice cannot generate eosinophilic lung inflammation in response to intratracheal IL-4 and exogenous histamine restores responsiveness. This is histamine 2 receptor (H2R) dependent since H2R KO mice fail to respond to IL-4, and a H2R agonist restores inflammation in HDC KO. Furthermore, alveolar epithelial cells require H2R in order to produce CCL24, an eosinophil recruitment factor, while H2R blockade reduces CCL24 production from WT cells. In an allergic inflammation model, H2R KO mice show significantly reduced eosinophilic inflammation and CCL24 expression. These data demonstrate a previously unidentified role for H2R in allergic inflammation and establishes a synergy between endogenous histamine and IL-4 that supports eosinophilic recruitment to the lung. PMID:22156496

  14. A biologically inspired lung-on-a-chip device for the study of protein-induced lung inflammation.

    Science.gov (United States)

    Punde, Tushar H; Wu, Wen-Hao; Lien, Pei-Chun; Chang, Ya-Ling; Kuo, Ping-Hsueh; Chang, Margaret Dah-Tsyr; Lee, Kang-Yun; Huang, Chien-Da; Kuo, Han-Pin; Chan, Yao-Fei; Shih, Po-Chen; Liu, Cheng-Hsien

    2015-02-01

    This study reports a biomimetic microsystem that reconstitutes the lung microenvironment for monitoring the role of eosinophil cationic protein (ECP) in lung inflammation. ECP induces the airway epithelial cell expression of CXCL-12, which in turn stimulates the migration of fibrocytes towards the epithelium. This two-layered microfluidic system provides a feasible platform for perfusion culture, and was used in this study to reveal that the CXCL12-CXCR4 axis mediates ECP induced fibrocyte extravasation in lung inflammation. This 'lung-on-a-chip' microdevice serves as a dynamic transwell system by introducing a flow that can reconstitute the blood vessel-tissue interface for in vitro assays, enhancing pre-clinical studies. We made an attempt to develop a new microfluidic model which could not only simulate the transwell for studying cell migration, but could also study the migration in the presence of a flow mimicking the physiological conditions in the body. As blood vessels are the integral part of our body, this model gives an opportunity to study more realistic in vitro models of organs where the blood vessel i.e. flow based migration is involved. PMID:25486073

  15. Two Faces of Vitamin E in the Lung

    OpenAIRE

    Cook-Mills, Joan M.; Abdala-Valencia, Hiam; Hartert, Tina

    2013-01-01

    Asthma and allergic lung disease occur as complex environmental and genetic interactions. Clinical studies of asthma indicate a number of protective dietary factors, such as vitamin E, on asthma risk. However, these studies have had seemingly conflicting outcomes. In this perspective, we discuss opposing regulatory effects of tocopherol isoforms of vitamin E, mechanisms for tocopherol isoform regulation of allergic lung inflammation, association of vitamin E isoforms with outcomes in clinical...

  16. Genomic instability in quartz dust exposed rat lungs: Is inflammation responsible?

    Science.gov (United States)

    Albrecht, C.; Knaapen, A. M.; Cakmak Demircigil, G.; Coskun, Erdem; van Schooten, F. J.; Borm, P. J. A.; Schins, R. P. F.

    2009-02-01

    Exposure to quartz dusts has been associated with lung cancer and fibrosis. Although the responsible mechanisms are not completely understood, progressive inflammation with associated induction of persistent oxidative stress has been discussed as a key event for these diseases. Previously we have evaluated the kinetics of pulmonary inflammation in the rat model following a single intratracheal instillation of 2mg DQ12 quartz, either in its native form or upon its surface modification with polyvinylpyridine-N-oxide or aluminium lactate. This model has been applied now to evaluate the role of inflammation in the kinetics of induction of DNA damage and response at 3, 7, 28, and 90 days after treatment. Bronchoalveolar lavage (BAL) cell counts and differentials as well as BAL fluid myeloperoxidase activity were used as markers of inflammation. Whole lung homogenate was investigated to determine the induction of the oxidative and pre-mutagenic DNA lesion 8-hydroxy-2-deoxy-guanosine (8-OHdG) by HPLC/ECD, while mRNA and protein expression of oxidative stress and DNA damage response genes including hemeoxygenase-1 (HO-1) and apurinic/apyrimidinic endonuclease (APE/Ref-1) were evaluated using Western blotting and real time PCR. Isolated lung epithelial cells from the treated rats were used for DNA strand breakage analysis using the alkaline comet assay as well as for micronucleus scoring in May-Gruenwald-Giemsa stained cytospin preparations. In the rats that were treated with quartz, no increased 8-OHdG levels were observed, despite the presence of a marked and persistent inflammation. However, DNA strand breakage in the lung epithelial cells of the quartz treated rats was significantly enhanced at 3 days, but not at 28 days. Moreover, significantly enhanced micronucleus frequencies were observed for all four time points investigated. In the animals that were treated with the PVNO modified quartz, micronuclei scores did not differ from controls, while in those treated with

  17. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice

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    Izziki Mohamed

    2009-01-01

    Full Text Available Abstract Background Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH. Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6. Methods To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/- and wild-type (IL-6+/+ mice exposed to hypoxia for 2 weeks. Results Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines. Conclusion These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice.

  18. Social Stress Enhances Allergen-Induced Airway Inflammation in Mice and Inhibits Corticosteroid Responsiveness of Cytokine Production

    OpenAIRE

    Bailey, Michael; Kierstein, Sonja; Sharma, Satish; Spaits, Matthew; Kinsey, Steven G.; Tliba, Omar; Amrani, Yassine; John F Sheridan; Panettieri, Reynold A.; Haczku, Angela

    2009-01-01

    Chronic psychosocial stress exacerbates asthma but the underlying mechanisms remain poorly understood. We hypothesized that psychosocial stress aggravates allergic airway inflammation by altering innate immune cell function. The effects of stress on airway inflammation, lung function and glucocorticoid responsiveness were studied in a novel in vivo murine model of combined social disruption stress and allergic sensitization. The effects of corticosterone were assessed on cytokine profile and ...

  19. Myeloid-specific Fos-related antigen-1 regulates cigarette smoke-induced lung inflammation, not emphysema, in mice.

    Science.gov (United States)

    Vaz, Michelle; Rajasekaran, Subbiah; Potteti, Haranatha R; Reddy, Sekhar P

    2015-07-01

    Heightened lung inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)-induced macrophage recruitment and activation, accompanied by abnormal secretion of a number of inflammatory cytokines and matrix metalloproteinases, play a major role in the pathophysiology of COPD. The Fos-related antigen-1 (Fra-1) transcription factor differentially regulates several cellular processes that are implicated in COPD, such as inflammation and immune responses, cell proliferation and death, and extracellular remodeling. Although CS stimulates Fra-1 expression in the lung, the precise role of this transcription factor in the regulation of CS-induced lung inflammation in vivo is poorly understood. Here, we report that myeloid-specific Fra-1 signaling is important for CS-induced lung macrophagic inflammatory response. In response to chronic CS exposure, mice with Fra-1 specifically deleted in myeloid cells showed reduced levels of CS-induced lung macrophagic inflammation, accompanied by decreased expression levels of proinflammatory cytokines compared with their wild-type counterparts. Consistent with this result, bone marrow-derived Fra-1-null macrophages treated with CS showed decreased levels of proinflammatory mediators and matrix metalloproteinases. Interestingly, deletion of Fra-1 in myeloid cells did not affect the severity of emphysema. We propose that Fra-1 plays a key role in promoting chronic CS-induced lung macrophagic inflammation in vivo, and that targeting this transcription factor may be useful in dampening persistent lung inflammation in patients with COPD. PMID:25489966

  20. Familial idiopathic pulmonary fibrosis. Evidence of lung inflammation in unaffected family members

    International Nuclear Information System (INIS)

    We evaluated 17 clinically unaffected members of three families with an autosomal dominant form of idiopathic pulmonary fibrosis for evidence of alveolar inflammation. Each person in the study was examined by gallium-67 scanning for a general estimate of pulmonary inflammation, and by bronchoalveolar lavage for characterization of the types of recovered cells and their state of activation. Eight of the 17 subjects had evidence of alveolar inflammation on the lavage studies. Supporting data included increased numbers of neutrophils and activated macrophages that released one or more neutrophil chemoattractants, and growth factors for lung fibroblasts--findings similar to those observed in patients with overt idiopathic pulmonary fibrosis. Four of these eight also had a positive gallium scan; in all the other clinically unaffected subjects the scan was normal. During a follow-up of two to four years in seven of the eight subjects who had evidence of inflammation, no clinical evidence of pulmonary fibrosis has appeared. These results indicate that alveolar inflammation occurs in approximately half the clinically unaffected family members at risk of inheriting autosomal dominant idiopathic pulmonary fibrosis. Whether these persons with evidence of pulmonary inflammation but no fibrosis will proceed to have clinically evident pulmonary fibrosis is not yet known

  1. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis

    Science.gov (United States)

    Kaminski, Naftali; Allard, John D.; Pittet, Jean F.; Zuo, Fengrong; Griffiths, Mark J. D.; Morris, David; Huang, Xiaozhu; Sheppard, Dean; Heller, Renu A.

    2000-02-01

    The molecular mechanisms of pulmonary fibrosis are poorly understood. We have used oligonucleotide arrays to analyze the gene expression programs that underlie pulmonary fibrosis in response to bleomycin, a drug that causes lung inflammation and fibrosis, in two strains of susceptible mice (129 and C57BL/6). We then compared the gene expression patterns in these mice with 129 mice carrying a null mutation in the epithelial-restricted integrin 6 subunit (6/-), which develop inflammation but are protected from pulmonary fibrosis. Cluster analysis identified two distinct groups of genes involved in the inflammatory and fibrotic responses. Analysis of gene expression at multiple time points after bleomycin administration revealed sequential induction of subsets of genes that characterize each response. The availability of this comprehensive data set should accelerate the development of more effective strategies for intervention at the various stages in the development of fibrotic diseases of the lungs and other organs.

  2. Milano summer particulate matter (PM10 triggers lung inflammation and extra pulmonary adverse events in mice.

    Directory of Open Access Journals (Sweden)

    Francesca Farina

    Full Text Available Recent studies have suggested a link between particulate matter (PM exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases; accumulating evidences point to a new role for air pollution in CNS diseases. The purpose of our study is to investigate PM10sum effects on lungs and extra pulmonary tissues. Milano PM10sum has been intratracheally instilled into BALB/c mice. Broncho Alveolar Lavage fluid, lung parenchyma, heart and brain were screened for markers of inflammation (cell counts, cytokines, ET-1, HO-1, MPO, iNOS, cytotoxicity (LDH, ALP, Hsp70, Caspase8-p18, Caspase3-p17 for a putative pro-carcinogenic marker (Cyp1B1 and for TLR4 pathway activation. Brain was also investigated for CD68, TNF-α, GFAP. In blood, cell counts were performed while plasma was screened for endothelial activation (sP-selectin, ET-1 and for inflammation markers (TNF-α, MIP-2, IL-1β, MPO. Genes up-regulation (HMOX1, Cyp1B1, IL-1β, MIP-2, MPO and miR-21 have been investigated in lungs and blood. Inflammation in the respiratory tract of PM10sum-treated mice has been confirmed in BALf and lung parenchyma by increased PMNs percentage, increased ET-1, MPO and cytokines levels. A systemic spreading of lung inflammation in PM10sum-treated mice has been related to the increased blood total cell count and neutrophils percentage, as well as to increased blood MPO. The blood-endothelium interface activation has been confirmed by significant increases of plasma ET-1 and sP-selectin. Furthermore PM10sum induced heart endothelial activation and PAHs metabolism, proved by increased ET-1 and Cyp1B1 levels. Moreover, PM10sum causes an increase in brain HO-1 and ET-1. These results state the translocation of inflammation mediators, ultrafine particles, LPS, metals associated to PM10sum, from lungs to bloodstream, thus triggering a systemic reaction, mainly involving heart and brain. Our results provided additional insight into the toxicity

  3. Toxicogenomic analysis of susceptibility to inhaled urban particulate matter in mice with chronic lung inflammation

    OpenAIRE

    Yauk Carole L; Williams Andrew; Thomson Errol M; Vincent Renaud

    2009-01-01

    Abstract Background Individuals with chronic lung disease are at increased risk of adverse health effects from airborne particulate matter. Characterization of underlying pollutant-phenotype interactions may require comprehensive strategies. Here, a toxicogenomic approach was used to investigate how inflammation modifies the pulmonary response to urban particulate matter. Results Transgenic mice with constitutive pulmonary overexpression of tumour necrosis factor (TNF)-α under the control of ...

  4. Spred-2 Deficiency Exacerbates Lipopolysaccharide-Induced Acute Lung Inflammation in Mice

    OpenAIRE

    Yang Xu; Toshihiro Ito; Soichiro Fushimi; Sakuma Takahashi; Junya Itakura; Ryojiro Kimura; Miwa Sato; Megumi Mino; Akihiko Yoshimura; Akihiro Matsukawa

    2014-01-01

    BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spr...

  5. Neutrophil DNA contributes to the antielastase barrier during acute lung inflammation.

    Science.gov (United States)

    Balloy, Viviane; Sallenave, Jean-Michel; Crestani, Bruno; Dehoux, Monique; Chignard, Michel

    2003-06-01

    During acute lung inflammation, the airspaces are invaded by circulating neutrophils. These may then injure tissues through the release of elastase. Different natural specific inhibitors such as alpha1-proteinase inhibitor, secretory leukocyte proteinase inhibitor, and elafin are nonetheless able to counteract the enzymatic activity of elastase. The present study was undertaken to assess the role of these different inhibitors in the intrinsic antielastase barrier during lipopolysaccharide-induced lung inflammation in mice. Upon intranasal administration of lipopolysaccharide to mice, the antielastase activity recovered from bronchoalveolar lavage fluids (BALF) increases progressively up to 48 h (7-fold) and returns to the basal level within 72 h. By contrast, when the same experiments are performed with neutropenic mice (pretreatment with an antigranulocyte antibody, or vinblastine), the increase is almost totally absent. Ultrafiltration of BALF through 100 kD cutoff membranes shows that the activity remains in the retentate, thus ruling out a role for native alpha1-proteinase inhibitor, secretory leukocyte proteinase inhibitor, and elafin. Gel filtration and fraction analysis show that the material eluted with a Mr of 600 kD. Agarose gel electrophoresis and ethidium bromide staining reveal that the activity corresponds to the presence a large amount of DNA. Interestingly, DNase treatment of the active fraction suppresses the antielastase activity. Analysis of BALF from patients with acute lung inflammation shows the presence of DNA with antielastase activity. We therefore concluded that during acute lung inflammation, the recruitment of neutrophils in the airspaces accounts for the increased presence of DNA, which in turn contributes to the antielastase barrier. PMID:12600833

  6. Platelet activation and aggregation promote lung inflammation and influenza virus pathogenesis.

    OpenAIRE

    Le, Vuong Ba; Schneider, Jochen; Boergeling, Yvonne; Berri, Fatma; Ducatez, Mariette; GUERIN, Jean-Luc; Adrian, Iris; Errazuriz-Cerda, Elisabeth; frasquilho, sonia; Antunes, Laurent; Lina, Bruno; Bordet, Jean-Claude; Jandrot-Perrus, Martine; Ludwig, Stephan; Riteau, Beatrice

    2015-01-01

    RATIONALE: The hallmark of severe influenza virus infection is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and inflammatory responses is unknown. OBJECTIVES: To determine the role of platelets during influenza A virus infections and propose new therapeutics against influenza. METHODS: We used targeted gene deletion approaches and pharmacologic interventions to investigate the role of platelets during influenza v...

  7. Carbon nanotubes induce inflammation but decrease the production of reactive oxygen species in lung

    OpenAIRE

    Crouzier, D.; Follot, S.; Gentilhomme, E.; Flahaut, Emmanuel; Arnaud, R.; Dabouis, V.; Castellarin, C.; Debouzy, J.C.

    2010-01-01

    With the rapid spread of carbon nanotubes (CNTs) applications, the respiratory toxicity of these compounds has attracted the attention of many scientists. Several studies have reported that after lung administration, CNTs could induce granuloma, fibrosis, or inflammation. By comparison with the mechanisms involved with other toxic particles such as asbestos, this effect could be attributed to an increase of oxidative stress. The aim of the present work was to test this hypothesis in vivo. ...

  8. Heat Shock Protein 90 Inhibitors Prolong Survival, Attenuate Inflammation, and Reduce Lung Injury in Murine Sepsis

    OpenAIRE

    Chatterjee, Anuran; Dimitropoulou, Christiana; Drakopanayiotakis, Fotios; ANTONOVA, Galina; Snead, Connie; Cannon, Joseph; Venema, Richard C.; Catravas, John D.

    2007-01-01

    Rationale: Severe sepsis is the leading cause of death for patients in intensive care units. Patients with severe sepsis develop multiple organ failure, including acute lung injury (ALI), resulting from a deregulated inflammatory response. Inhibitors of the ubiquitous chaperone, heat shock protein 90 (Hsp90), block the activity of certain proinflammatory mediators in vitro. We hypothesized that Hsp90 inhibitors may ameliorate the inflammation and ALI associated with severe sepsis.

  9. The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis.

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    Ajit A Kulkarni

    Full Text Available Pulmonary Fibrosis (PF is a devastating progressive disease in which normal lung structure and function is compromised by scarring. Lung fibrosis can be caused by thoracic radiation, injury from chemotherapy and systemic diseases such as rheumatoid arthritis that involve inflammatory responses. CDDO-Me (Methyl 2-cyano-3,12-dioxooleana-1,9(11dien-28-oate, Bardoxolone methyl is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties as shown by our in vitro studies. Based on this evidence, we hypothesized that CDDO-Me would reduce lung inflammation, fibrosis and lung function impairment in a bleomycin model of lung injury and fibrosis. To test this hypothesis, mice received bleomycin via oropharyngeal aspiration (OA on day zero and CDDO-Me during the inflammatory phase from days -1 to 9 every other day. Bronchoalveolar lavage fluid (BALF and lung tissue were harvested on day 7 to evaluate inflammation, while fibrosis and lung function were evaluated on day 21. On day 7, CDDO-Me reduced total BALF protein by 50%, alveolar macrophage infiltration by 40%, neutrophil infiltration by 90% (p≤0.01, inhibited production of the inflammatory cytokines KC and IL-6 by over 90% (p≤0.001, and excess production of the pro-fibrotic cytokine TGFβ by 50%. CDDO-Me also inhibited α-smooth muscle actin and fibronectin mRNA by 50% (p≤0.05. On day 21, CDDO-Me treatment reduced histological fibrosis, collagen deposition and αSMA production. Lung function was significantly improved at day 21 by treatment with CDDO-Me, as demonstrated by respiratory rate and dynamic compliance. These new findings reveal that CDDO-Me exhibits potent anti-fibrotic and anti-inflammatory properties in vivo. CDDO-Me is a potential new class of drugs to arrest inflammation and ameliorate fibrosis in patients who are predisposed to lung injury and fibrosis incited by cancer treatments (e.g. chemotherapy and radiation and by systemic autoimmune diseases.

  10. Versican in inflammation and tissue remodeling: the impact on lung disorders.

    Science.gov (United States)

    Andersson-Sjöland, Annika; Hallgren, Oskar; Rolandsson, Sara; Weitoft, Maria; Tykesson, Emil; Larsson-Callerfelt, Anna-Karin; Rydell-Törmänen, Kristina; Bjermer, Leif; Malmström, Anders; Karlsson, Jenny C; Westergren-Thorsson, Gunilla

    2015-03-01

    Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure comprises four different types of the core protein with attached glycosaminoglycans (GAGs) that can be sulfated to various extents and has the capacity to regulate differentiation of different cell types, migration, cell adhesion, proliferation, tissue stabilization and inflammation. Versican's regulatory properties are of importance during both homeostasis and changes that lead to disease progression. The GAGs that are attached to the core protein are of the chondroitin sulfate/dermatan sulfate type and are known to be important in inflammation through interactions with cytokines and growth factors. For a more complex understanding of versican, it is of importance to study the tissue niche, where the wound healing process in both healthy and diseased conditions take place. In previous studies, our group has identified changes in the amount of the multifaceted versican in chronic lung disorders such as asthma, chronic obstructive pulmonary disease, and bronchiolitis obliterans syndrome, which could be a result of pathologic, transforming growth factor β driven, on-going remodeling processes. Reversely, the context of versican in its niche is of great importance since versican has been reported to have a beneficial role in other contexts, e.g. emphysema. Here we explore the vast mechanisms of versican in healthy lung and in lung disorders. PMID:25371494

  11. The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis.

    Directory of Open Access Journals (Sweden)

    Abdulaleem Alnajar

    Full Text Available Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2 is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

  12. The LIM-Only Protein FHL2 Attenuates Lung Inflammation during Bleomycin-Induced Fibrosis

    Science.gov (United States)

    Schied, Tanja; Chiquet-Ehrismann, Ruth; Loser, Karin; Vogl, Thomas; Ludwig, Stephan; Wixler, Viktor

    2013-01-01

    Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2) is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages. PMID:24260575

  13. Melatonin reduces acute lung inflammation, edema,and hemorrhage in heatstroke rats

    Institute of Scientific and Technical Information of China (English)

    Wen-shiann WU; Ming-ting CHOU; Chien-ming CHAO; Chen-kuei CHANG; Mao-tsun LIN; Ching-ping CHANG

    2012-01-01

    Aim:To assess the therapeutic effect of melatonin on heat-induced acute lung inflammation and injury in rats.Methods:Heatstroke was induced by exposing anesthetized rats to heat stress (36 ℃,100 min).Rats were treated with vehicle or melatonin (0.2,1,5 mg/kg) by intravenous administration 100 min after the initiatioin of heatstroke and were allowed to recover at room temperature (26 ℃).The acute lung injury was quantified by morphological examination and by determination of the volume of pleural exudates,the number of polymorphonuclear (PMN) cells,and the myeloperoxidase (MPO) activity.The concentrations of tumor necrosis factor,interleukin (IL)-1β,IL-6,and IL-10 in bronchoalveolar fluid (BALF) were measured by ELISA.Nitric oxide (NO)level was determined by Griess method.The levels of glutamate and lactate-to-pyruvate ratio were analyzed by CMA600 microdialysis analyzer.The concentrations of hydroxyl radicals were measured by a procedure based on the hydroxylation of sodium salicylates leading to the production of 2,3-dihydroxybenzoic acid (DHBA).Results:Melatonin (1 and 5 mg/kg ) significantly (i) prolonged the survival time of heartstroke rats (117 and 186 min vs 59 min); (ii)attenuated heatstroke-induced hyperthermia and hypotension; (iii) attenuated acute lung injury,including edema,neutrophil infiltration,and hemorrhage scores; (iv) down-regulated exudate volume,BALF PMN cell number,and MPO activity; (v) decreased the BALF levels of lung inflammation response cytokines like TNF-alpha,interleukin (IL)-1β,and IL-6 but further increased the level of an anti-inflammatory cytokine IL-10; (vi) reduced BALF levels of glutamate,lactate-to-pyruvate ratio,NO,2,3-DHBA,and lactate dehydrogenase.Conclusion:Melatonin may improve the outcome of heatstroke in rats by attenuating acute lung inflammation and injury.

  14. Inhibitors of inflammation and endogenous surfactant pool size as modulators of lung injury with initiation of ventilation in preterm sheep

    OpenAIRE

    Polglase Graeme R; Nitsos Ilias; Pillow J Jane; Kallapur Suhas G; Hillman Noah H; Ikegami Machiko; Jobe Alan H

    2010-01-01

    Abstract Background Increased pro-inflammatory cytokines in tracheal aspirates correlate with the development of BPD in preterm infants. Ventilation of preterm lambs increases pro-inflammatory cytokines and causes lung inflammation. Objective We tested the hypothesis that selective inhibitors of pro-inflammatory signaling would decrease lung inflammation induced by ventilation in preterm newborn lambs. We also examined if the variability in injury response was explained by variations in the e...

  15. A Novel Synthetic Mycolic Acid Inhibits Bronchial Hyperresponsiveness and Allergic Inflammation in a Mouse Model of Asthma

    OpenAIRE

    KIM, YOUNG-JOON; Kim, Ha-Jung; Jeong, Se Kyoo; Lee, Seung-Hwa; Kang, Mi-Jin; Yu, Ho-Sung; Jung, Young-Ho; Seo, Ju-Hee; Kim, Byoung-Ju; Yu, Jinho; Park, Seoung-Ju; Lee, Yong-Chul; Hong, Soo-Jong

    2013-01-01

    Purpose Recognition of microbes is important to trigger the innate immune system. Mycolic acid (MA) is a component of the cell walls of mycobacteria such as Mycobacterium bovis Bacillus Calmette-Guerin. MA has immunogenic properties, which may modulate the innate and adaptive immune response. This study aimed to investigate whether a novel synthetic MA (sMA) inhibits allergic inflammatory responses in a mouse model of asthma. Methods BALB/c mice were injected intraperitoneally with sMA follow...

  16. Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses SEB-Induced Lung Inflammation

    Directory of Open Access Journals (Sweden)

    Olga N. Uchakina

    2013-10-01

    Full Text Available Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB, can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS. To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU on staphylococcal enterotoxin B (SEB induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB.

  17. Relationship between body composition, inflammation and lung function in overweight and obese asthma

    Directory of Open Access Journals (Sweden)

    Scott Hayley A

    2012-02-01

    Full Text Available Abstract Background The obese-asthma phenotype is not well defined. The aim of this study was to examine both mechanical and inflammatory influences, by comparing lung function with body composition and airway inflammation in overweight and obese asthma. Methods Overweight and obese (BMI 28-40 kg/m2 adults with asthma (n = 44 completed lung function assessment and underwent full-body dual energy x-ray absorptiometry. Venous blood samples and induced sputum were analysed for inflammatory markers. Results In females, android and thoracic fat tissue and total body lean tissue were inversely correlated with expiratory reserve volume (ERV. Conversely in males, fat tissue was not correlated with lung function, however there was a positive association between android and thoracic lean tissue and ERV. Lower body (gynoid and leg lean tissue was positively associated with sputum %neutrophils in females, while leptin was positively associated with android and thoracic fat tissue in males. Conclusions This study suggests that both body composition and inflammation independently affect lung function, with distinct differences between males and females. Lean tissue exacerbates the obese-asthma phenotype in females and the mechanism responsible for this finding warrants further investigation.

  18. Systemic Inflammation and Lung Function Impairment in Morbidly Obese Subjects with the Metabolic Syndrome

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    Astrid van Huisstede

    2013-01-01

    Full Text Available Background. Obesity and asthma are associated. There is a relationship between lung function impairment and the metabolic syndrome. Whether this relationship also exists in the morbidly obese patients is still unknown. Hypothesis. Low-grade systemic inflammation associated with the metabolic syndrome causes inflammation in the lungs and, hence, lung function impairment. Methods. This is cross-sectional study of morbidly obese patients undergoing preoperative screening for bariatric surgery. Metabolic syndrome was assessed according to the revised NCEP-ATP III criteria. Results. A total of 452 patients were included. Patients with the metabolic syndrome (n=293 had significantly higher blood monocyte (mean 5.3 versus 4.9, P=0.044 and eosinophil percentages (median 1.0 versus 0.8, P=0.002, while the total leukocyte count did not differ between the groups. The FEV1/FVC ratio was significantly lower in patients with the metabolic syndrome (76.7% versus 78.2%, P=0.032. Blood eosinophils were associated with FEV1/FVC ratio (adj. B −0.113, P=0.018. Conclusion. Although the difference in FEV1/FVC ratio between the groups is relatively small, in this cross-sectional study, and its clinical relevance may be limited, these data indicate that the presence of the metabolic syndrome may influence lung function impairment, through the induction of relative eosinophilia.

  19. Selenium and vitamin E deficiencies do not enhance lung inflammation from cigarette smoke in the hamster

    Energy Technology Data Exchange (ETDEWEB)

    Niewoehner, D.E.; Peterson, F.J.; Hoidal, J.R.

    1983-02-01

    The early lung inflammatory response to cigarette smoke may be oxidant-mediated. We fed Syrian hamsters a diet deficient in selenium and vitamin E to determine whether impairment of the lung's antioxidant defenses might worsen inflammation induced by cigarette smoke. After 8 wk, cigarette-smoke-exposed animals had characteristic inflammatory lesions in the distal airways. Increased numbers of phagocytes, predominantly macrophages, were recovered by lavage and these cells exhibited enhanced oxidative metabolism. Animals fed the deficient diet had profound depletions of selenium and vitamin E, but no alterations in the histologic appearance of smoke-induced inflammatory lesions, in the numbers of phagocytes recruited, or in the oxidative metabolism of these phagocytes. These results suggest that selenium and vitamin E are unimportant in protecting against cigarette-smoke-induced lung injury.

  20. Stimulation of allergen-loaded macrophages by TLR9-ligand potentiates IL-10-mediated suppression of allergic airway inflammation in mice

    Directory of Open Access Journals (Sweden)

    Hofman Gerard A

    2004-11-01

    Full Text Available Abstract Background Previously, we demonstrated that OVA-loaded macrophages (OVA-Mφ partially suppress OVA-induced airway manifestations of asthma in BALB/c mice. In vitro studies showed that OVA-Mφ start to produce IL-10 upon interaction with allergen-specific T cells, which might mediate their immunosuppressive effects. Herein, we examined whether IL-10 is essential for the immunosuppressive effects of OVA-Mφ in vivo, and whether ex vivo stimulation of the IL-10 production by OVA-Mφ could enhance these effects. Methods Peritoneal Mφ were loaded with OVA and stimulated with LPS or immunostimulatory sequence oligodeoxynucleotide (ISS-ODN in vitro. The increase of IL-10 production was examined and, subsequently, ex vivo stimulated OVA-Mφ were used to treat (i.v. OVA-sensitized mice. To further explore whether Mφ-derived IL-10 mediates the immunosuppressive effects, Mφ isolated from IL-10-/- mice were used for treatment. Results We found that stimulation with LPS or ISS-ODN highly increased the IL-10 production by OVA-Mφ (2.5-fold and 4.5-fold increase, respectively. ISS-ODN stimulation of OVA-Mφ significantly potentiated the suppressive effects on allergic airway inflammation. Compared to sham-treatment, ISS-ODN-stimulated OVA-Mφ suppressed the airway eosinophilia by 85% (vs. 30% by unstimulated OVA-Mφ, IL-5 levels in bronchoalveolar lavage fluid by 80% (vs. 50% and serum OVA-specific IgE levels by 60% (vs. 30%. Importantly, IL-10-/-Mφ that were loaded with OVA and stimulated with ISS-ODN ex vivo, failed to suppress OVA-induced airway inflammation. Conclusions These results demonstrate that Mφ-derived IL-10 mediates anti-inflammatory responses in a mouse model of allergic asthma, which both can be potentiated by stimulation with ISS-ODN.

  1. Surfactant dysfunction and lung inflammation in the female mouse model of lymphangioleiomyomatosis.

    Science.gov (United States)

    Atochina-Vasserman, Elena N; Guo, Chang-Jiang; Abramova, Elena; Golden, Thea N; Sims, Michael; James, Melane L; Beers, Michael F; Gow, Andrew J; Krymskaya, Vera P

    2015-07-01

    Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease caused by mutations of the tumor suppressor genes, tuberous sclerosis complex (TSC) 1 or TSC2. LAM affects women almost exclusively, and it is characterized by neoplastic growth of atypical smooth muscle-like TSC2-null LAM cells in the pulmonary interstitium, cystic destruction of lung parenchyma, and progressive decline in lung function. In this study, we hypothesized that TSC2-null lesions promote a proinflammatory environment, which contributes to lung parenchyma destruction. Using a TSC2-null female murine LAM model, we demonstrate that TSC2-null lesions promote alveolar macrophage accumulation, recruitment of immature multinucleated cells, an increased induction of proinflammatory genes, nitric oxide (NO) synthase 2, IL-6, chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein 1 (MCP1), chemokine (C-X-C motif) ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and up-regulation of IL-6, KC, MCP-1, and transforming growth factor-β1 levels in bronchoalveolar lavage fluid. Bronchoalveolar lavage fluid also contained an increased level of surfactant protein (SP)-D, but not SP-A, significant reduction of SP-B levels, and a resultant increase in alveolar surface tension. Consistent with the growth of TSC2-null lesions, NO levels were also increased and, in turn, modified SP-D through S-nitrosylation, forming S-nitrosylated SP-D, a known consequence of lung inflammation. Progressive growth of TSC2-null lesions was accompanied by elevated levels of matrix metalloproteinase-3 and -9. This report demonstrates a link between growth of TSC2-null lesions and inflammation-induced surfactant dysfunction that might contribute to lung destruction in LAM. PMID:25474372

  2. Lung inflammation and immunity: report from the 12th ERS Lung Science Conference

    OpenAIRE

    Bruno Crestani; Marina Pretolani; Hamida Hammad

    2014-01-01

    The European Respiratory Society (ERS) seeks to alleviate suffering from respiratory diseases and promote lung health through research, dissemination of knowledge, and medical and public education. In support of this mission, the ERS organises the annual Lung Science Conference (LSC). This world-class research meeting brings together leading experts on topics that are of relevance to respiratory medicine. Furthermore, at the LSC, one of the main focuses is early-career physicians and scientis...

  3. The effects of cordycepin on ovalbumin-induced allergic inflammation by strengthening Treg response and suppressing Th17 responses in ovalbumin-sensitized mice.

    Science.gov (United States)

    Tianzhu, Zhang; Shihai, Yang; Juan, Du

    2015-01-01

    The aim of the current study was to use a mouse model of allergic asthma to investigate whether cordycepin has antiasthmatic effects, and if so, to determine the mechanism of these effects. A total of 50 mice were randomly assigned to five experimental groups: control, model, dexamethasone (Dex, 2 mg/kg), and cordycepin (20-40 mg/kg). Histological studies were evaluated by the hematoxylin and eosin staining, OVA-specific serum and BALF IgE levels and Treg/Th17 cytokines were evaluated by enzyme-linked immunosorbent assay, and RORγt and Foxp3 were evaluated by western blot. Our study demonstrated that cordycepin inhibited OVA-induced increases in eosinophil count; IL-17A levels were recovered and increased IL-10 levels in bronchoalveolar lavage fluid. Histological studies demonstrated that cordycepin substantially inhibited OVA-induced eosinophilia in lung tissue. Western blot study demonstrated that cordycepin increased Foxp3 and inhibited RORγt. These findings suggest that cordycepin may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma. PMID:25417131

  4. Cerium oxide nanoparticles protect rodent lungs from hypobaric hypoxia-induced oxidative stress and inflammation

    Directory of Open Access Journals (Sweden)

    Arya A

    2013-11-01

    intraperitoneal injections of low micromole concentration, we successfully localized the nanoceria in rodent lung without any inflammatory response. The lung-deposited nanoceria limited ROS formation, lipid peroxidation, and glutathione oxidation, and prevented oxidative protein modifications like nitration and carbonyl formation during hypobaric hypoxia. We also observed reduced lung inflammation in the nanoceria-injected lungs, supporting the anti-inflammatory properties of nanoceria. Conclusion: Cumulatively, these results suggest nanoceria deposit in lungs, confer protection by quenching noxious free radicals during hypobaric hypoxia, and do not evoke any inflammatory response. Keywords: nanoceria, high altitude, nanomedicine

  5. Titanium dioxide nanoparticles augment allergic airway inflammation and Socs3 expression via NF-κB pathway in murine model of asthma.

    Science.gov (United States)

    Mishra, Vani; Baranwal, Vikas; Mishra, Rohit K; Sharma, Shivesh; Paul, Bholanath; Pandey, Avinash C

    2016-06-01

    Titanium dioxide nanoparticles (nTiO2) previously considered to possess relatively low toxicity both in vitro and in vivo, although classified as possibly carcinogenic to humans. Also, their adjuvant potential has been reported to promote allergic sensitization and modulate immune responses. Previously, in OVA induced mouse model of asthma we found high expression of Socs3 and low expression of Stat3 and IL-6. However, a clear understanding regarding the signaling pathways associated with nTiO2 adjuvant effect in mouse model of asthma is lacking. In the present study we investigated the status of Stat3/IL-6 and Socs3 and their relationship with NF-κB, with nTiO2 as an adjuvant in mouse model of asthma. nTiO2 when administered with ovalbumin (OVA) during sensitization phase augmented airway hyper-responsiveness (AHR), biochemical markers of lung damage and a mixed Th2/Th1 dependent immune response. At the same time, we observed significant elevation in the levels of Stat3, Socs3, NF-κB, IL-6 and TNF-α. Furthermore, transient in vivo blocking of NF-κB by NF-κB p65 siRNA, downregulated the expression of Socs3, IL-6 and TNF-α. Our study, thus, shows that nTiO2 exacerbate the inflammatory responses in lungs of pre-sensitized allergic individuals and that these changes are regulated via NF-κB pathway. PMID:27057692

  6. Neutralization of TSLP Inhibits Airway Remodeling in a Murine Model of Allergic Asthma Induced by Chronic Exposure to House Dust Mite

    OpenAIRE

    Chen, Zhuang-Gui; Zhang, Tian-Tuo; Li, Hong-Tao; Chen, Fen-Hua; Zou, Xiao-Ling; Ji, Jing-Zhi; Chen, Hong

    2013-01-01

    Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. However, the initiating factor that links airway inflammation to remodeling is unknown. Thymic stromal lymphopoietin (TSLP), an epithelium-derived cytokine, can strongly activate lung dendritic cells (DCs) through the TSLP-TSLPR and OX40L-OX40 signaling pathways to promote Th2 differentiation. To determine whether TSLP is the underlying trigger of ai...

  7. Ability of recombinant human catalase to suppress inflammation of the murine lung induced by influenza A.

    Science.gov (United States)

    Shi, Xunlong; Shi, Zhihui; Huang, Hai; Zhu, Hongguang; Zhou, Pei; Zhu, Haiyan; Ju, Dianwen

    2014-06-01

    Influenza A virus pandemics and emerging antiviral resistance highlight the urgent need for novel generic pharmacological strategies that reduce both viral replication and inflammation of the lung. We have previously investigated the therapeutic efficacy of recombinant human catalase (rhCAT) against viral pneumonia in mice, but the protection mechanisms involved were not explored. In the present study, we have performed a more in-depth analysis covering survival, lung inflammation, immune cell responses, production of cytokines, and inflammation signaling pathways in mice. Male imprinting control region mice were infected intranasally with high pathogenicity (H1N1) influenza A virus followed by treatment with recombinant human catalase. The administration of rhCAT resulted in a significant reduction in inflammatory cell infiltration (e.g., macrophages and neutrophils), inflammatory cytokine levels (e.g., IL-2, IL-6, TNF-α, IFN-γ), the level of the intercellular adhesion molecule 1 chemokine and the mRNA levels of toll-like receptors TLR-4, TLR-7, and NF-κB, as well as partially maintaining the activity of the antioxidant enzymes system. These findings indicated that rhCAT might play a key protective role in viral pneumonia of mice via suppression of inflammatory immune responses. PMID:24385240

  8. Thioperamide induces CD4+ CD25+ Foxp3+ regulatory T lymphocytes in the lung mucosa of allergic mice through its action on dendritic cells

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    Geffner J

    2011-09-01

    Full Text Available Maria Marta Amaral1*, Carolina A Alvarez1*, Cecilia Langellotti2, Carolina Jancic1, Gabriela Salamone1, Jorge Geffner1, Mónica Vermeulen1,1Institute of Hematologic Research, National Academy of Medicine, Buenos Aires, Argentina; 2Institute of Virology, CICVyA, INTA, Castelar, Argentina *Authors contributed equally to this workBackground: Histamine is an important mediator in the development of allergic reactions. The biological effects of histamine are mediated through four histaminergic receptors. In recent years, an important role has been assigned to the proinflammatory functions of histamine regarding the H4 receptor. Previously, we have demonstrated that injection of immature dendritic cells treated with histamine into allergic mice promotes an increase in CD8+ Tc2 lymphocytes, which are involved in the worsening of allergy symptoms during the chronic phase of the disease. The aim of this study was to evaluate the role of the H3/H4 receptor antagonist, thioperamide, in allergy.Methods: Ovalbumin-allergized mice and nonallergized mice were injected with phosphate-buffered saline, dendritic cells, or thioperamide-treated dendritic cells. After treatment, the lungs of the mice were obtained and analyzed for changes in the populations of dendritic cells and T lymphocytes, as well as the expression of H and H4 receptors in mononuclear lung cells.Results: We found an increase in regulatory T cells in the lungs of allergic mice intratracheally injected with dendritic cells which had their H3/H4 receptors blocked with thioperamide. We also found an increase in the production of interleukin-10 by dendritic cells of the lung. Finally, we observed a decrease in serum levels of specific anti-IgE and a reduction of eosinophils in bronchoalveolar lavage from allergic mice.Conclusion: Thioperamide induces a significant improvement in symptoms of allergic reaction perhaps via induction of regulatory T lymphocytes. These findings may become relevant in the

  9. The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation.

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    Grabiec, Aleksander M; Hussell, Tracy

    2016-07-01

    Acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called 'efferocytosis'. Apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. Efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. Disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (DAMPS). To control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. However, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases Tyro3, Axl and MerTK (TAM), may delay or prevent inflammatory responses to subsequent infections. In this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections. PMID:26957481

  10. Effects of Liver × receptor agonist treatment on signal transduction pathways in acute lung inflammation

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    Bramanti Placido

    2010-02-01

    Full Text Available Abstract Background Liver × receptor α (LXRα and β (LXRβ are members of the nuclear receptor super family of ligand-activated transcription factors, a super family which includes the perhaps better known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. There is limited evidence that LXL activation may reduces acute lung inflammation. The aim of this study was to investigate the effects of T0901317, a potent LXR receptor ligand, in a mouse model of carrageenan-induced pleurisy. Methods Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx, tumor necrosis factor-α, (TNF-α and interleukin-1β (IL-1β. Furthermore, carrageenan induced the expression of iNOS, nitrotyrosine and PARP, as well as induced apoptosis (TUNEL staining and Bax and Bcl-2 expression in the lung tissues. Results Administration of T0901317, 30 min after the challenge with carrageenan, caused a significant reduction in a dose dependent manner of all the parameters of inflammation measured. Conclusions Thus, based on these findings we propose that LXR ligand such as T0901317, may be useful in the treatment of various inflammatory diseases.

  11. Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation.

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    Hsu, Daniel; Taylor, Patricia; Fletcher, Dave; van Heeckeren, Rolf; Eastman, Jean; van Heeckeren, Anna; Davis, Pamela; Chmiel, James F; Pearlman, Eric; Bonfield, Tracey L

    2016-09-01

    Cystic fibrosis (CF) is characterized by an excessive neutrophilic inflammatory response within the airway as a result of defective cystic fibrosis transmembrane receptor (CFTR) expression and function. Interleukin-17A induces airway neutrophilia and mucin production associated with Pseudomonas aeruginosa colonization, which is associated with the pathophysiology of cystic fibrosis. The objectives of this study were to use the preclinical murine model of cystic fibrosis lung infection and inflammation to investigate the role of IL-17 in CF lung pathophysiology and explore therapeutic intervention with a focus on IL-17. Cftr-deficient mice (CF mice) and wild-type mice (WT mice) infected with P. aeruginosa had robust IL-17 production early in the infection associated with a persistent elevated inflammatory response. Intratracheal administration of IL-17 provoked a neutrophilic response in the airways of WT and CF animals which was similar to that observed with P. aeruginosa infection. The neutralization of IL-17 prior to infection significantly improved the outcomes in the CF mice, suggesting that IL-17 may be a therapeutic target. We demonstrate in this report that the pathophysiological contribution of IL-17 may be due to the induction of chemokines from the epithelium which is augmented by a deficiency of Cftr and ongoing inflammation. These studies demonstrate the in vivo contribution of IL-17 in cystic fibrosis lung disease and the therapeutic validity of attenuating IL-17 activity in cystic fibrosis. PMID:27271746

  12. Basophils in inflammation.

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    Schwartz, Christian; Eberle, Joerg U; Voehringer, David

    2016-05-01

    Basophils are functionally closely related to mast cells. Both cell types express the high-affinity IgE receptor (FcεRI) and rapidly release preformed mediator from intracellular stores upon IgE-mediated activation. However, in contrast to mast cells basophils finish their maturation in the bone marrow and have a lifespan of only 2-3 days. Basophil numbers increase in response to IL-3 or TSLP and migrate into tissues to promote type 2 immune responses. Here we review recent advances regarding the pro- and anti-inflammatory functions of basophils in murine models and human allergic inflammation of the skin, lung and intestine. PMID:25959388

  13. Relationship between lung inflammation, changes in lung function and severity of exposure in victims of the Bhopal tragedy.

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    Vijayan, V K; Sankaran, K

    1996-10-01

    The world's worst chemical industrial disaster, which occurred at Bhopal on 2-3 December, 1984, resulted in considerable respiratory morbidity in the exposed population. Therefore, a study was planned to evaluate the relationship between lower respiratory tract inflammation, lung function and severity of exposure. Sixty patients exposed to methyl isocyanate and presenting with respiratory symptoms were studied using bronchoalveolar lavage (BAL) 1-7 yrs after the accident. Pulmonary function tests included forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). An index of severity of exposure was derived retrospectively on the basis of the acute symptoms in the victims themselves or the occurrence of death among their family members. Total lung inflammatory cells (p < 0.01) and absolute numbers of macrophages (p = 0.01) and lymphocytes (p < 0.05) increased as severity of exposure increased. FEV1/FVC % (p = 0.05) was also significantly lower as severity of exposure increased. Moderately exposed subjects had significantly lower FEV1/FVC % (p < 0.05) compared to those mildly exposed. In nonsmokers, BAL neutrophils, both percentage and absolute numbers, showed significant negative correlations with FEV1 % predicted (rs = -0.350, p < 0.05; and rs = -0.374, p < 0.01, respectively). Neutrophil percentage was negatively correlated with FEV1/FVC % (rs = -0.378; p < 0.01). Absolute lymphocytes had significant negative correlations with FVC % pred (rs = -0.318; p < 0.05). Macrophages had significant positive correlations with FVC % pred (rs = 0.322; p < 0.05) and FEV1 % pred (rs = 0.433; p < 0.01). Radiographic abnormalities (International Labour Organization (ILO) classification) were associated with decline in FEV1 % pred (p < 0.05). This study suggests that pulmonary function abnormalities occur in gas-exposed subjects as a consequence of an abnormal accumulation of lung inflammatory cells (lymphocytes and neutrophils), and that the intensity of lung

  14. Lung effector memory and activated CD4+ T cells display enhanced proliferation in SP-A-deficient mice during allergen-mediated inflammation

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    Pastva, Amy M.; Mukherjee, Sambuddho; Giamberardino, Charles; Hsia, Bethany; Lo, Bernice; Sempowski, Gregory D; Wright, Jo Rae

    2011-01-01

    Although many studies show that pulmonary Surfactant Protein A (SP-A) functions in innate immunity, fewer studies have addressed its role in adaptive immunity and allergic hypersensitivity. We hypothesized that SP-A modulates the phenotype and prevalence of dendritic cells (DCs) and CD4+ T cells to inhibit Th2-associated inflammatory indices associated with allergen-induced inflammation. In an ovalbumin (OVA) model of allergic hypersensitivity, SP-A deficient (SP-A−/−) mice had greater eosino...

  15. Airway oxidative stress causes vascular and hepatic inflammation via upregulation of IL-17A in a murine model of allergic asthma.

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    Al-Harbi, Naif O; Nadeem, Ahmed; Al-Harbi, Mohammed M; Ansari, Mushtaq A; AlSharari, Shakir D; Bahashwan, Saleh A; Attia, Sabry M; Al-Hosaini, Khaled A; Al Hoshani, Ali R; Ahmad, Sheikh F

    2016-05-01

    Oxidants are generated in asthmatic airways due to infiltration of inflammatory leukocytes and resident cells in the lung. Reactive oxygen species (ROS) such as hydrogen peroxide and superoxide radical may leak into systemic circulation when generated in uncontrolled manner and may impact vasculature. Our previous studies have shown an association between airway inflammation and systemic inflammation; however so far none has investigated the impact of airway oxidative inflammation on hepatic oxidative stress and Th1/Th2/Th17 cytokine markers in liver/vasculature in a murine model of asthma. Therefore, this study investigated the contribution of oxidative stress encountered in asthmatic airways in modulation of systemic/hepatic Th1/Th2/Th17 cytokines balance and hepatic oxidative stress. Mice were sensitized intraperitoneally with cockroach extract (CE) in the presence of aluminum hydroxide followed by several intranasal (i.n.) challenges with CE. Mice were then assessed for systemic/hepatic inflammation through assessment of Th1/Th2/Th17 cytokines and oxidative stress (iNOS, protein nitrotyrosine, lipid peroxides and myeloperoxidase activity). Challenge with CE led to increased Th2/Th17 cytokines in blood/liver and hepatic oxidative stress. However, only Th17 related pro-inflammatory markers were upregulated by hydrogen peroxide (H2O2) inhalation in vasculature and liver, whereas antioxidant treatment, N-acetyl cysteine (NAC) downregulated them. Hepatic oxidative stress was also upregulated by H2O2 inhalation, whereas NAC attenuated it. Therefore, our study shows that airway oxidative inflammation may contribute to systemic inflammation through upregulation of Th17 immune responses in blood/liver and hepatic oxidative stress. This might predispose these patients to increased risk for the development of cardiovascular disorders. PMID:26953647

  16. Angiopoietin-1 treatment reduces inflammation but does not prevent ventilator-induced lung injury.

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    Maria A Hegeman

    Full Text Available BACKGROUND: Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI. Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang-Tie2 system plays a role in the development of VILI. The present study was designed to examine the effects of mechanical ventilation on the Ang-Tie2 system in lung tissue. Moreover, we evaluated whether treatment with Ang-1, a Tie2 receptor agonist, protects against inflammation, vascular leakage and impaired gas exchange induced by mechanical ventilation. METHODS: Mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with either an inspiratory pressure of 10 cmH2O ('low' tidal volume ∼7.5 ml/kg; LVT or 18 cmH2O ('high' tidal volume ∼15 ml/kg; HVT. At initiation of HVT-ventilation, recombinant human Ang-1 was intravenously administered (1 or 4 µg per animal. Non-ventilated mice served as controls. RESULTS: HVT-ventilation influenced the Ang-Tie2 system in lungs of healthy mice since Ang-1, Ang-2 and Tie2 mRNA were decreased. Treatment with Ang-1 increased Akt-phosphorylation indicating Tie2 signaling. Ang-1 treatment reduced infiltration of granulocytes and expression of keratinocyte-derived chemokine (KC, macrophage inflammatory protein (MIP-2, monocyte chemotactic protein (MCP-1 and interleukin (IL-1β caused by HVT-ventilation. Importantly, Ang-1 treatment did not prevent vascular leakage and impaired gas exchange in HVT-ventilated mice despite inhibition of inflammation, vascular endothelial growth factor (VEGF and Ang-2 expression. CONCLUSIONS: Ang-1 treatment downregulates pulmonary inflammation, VEGF and Ang-2 expression but does not protect against vascular leakage and impaired gas exchange induced by HVT-ventilation.

  17. Safety, tolerability, and impact on allergic inflammation of autologous E.coli autovaccine in the treatment of house dust mite asthma - a prospective open clinical trial

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    Schulze Johannes

    2011-06-01

    Full Text Available Abstract Background Asthma is increasing worldwide and results from a complex immunological interaction between genetic susceptibility and environmental factors. Autovaccination with E. coli induces a strong TH-1 immune response, thus offering an option for the treatment of allergic diseases. Methods Prospective open trial on safety, tolerability, and impact on allergic inflammation of an autologous E.coli autovaccine in intermittent or mild persistent house dust mite asthma. Determination of exhaled nitric monoxide (eNO before and after bronchial mite challenge initially and after nine months of autovaccination. Results In nine subjects and a total of 306 injections, we observed 101 episodes of local erythema (33.3%; median of maximal diameter 2.5 cm, 95 episodes of local swelling (31.1%; median of maximal diameter 3 cm, and 27 episodes of local pain (8.8%. Four subjects reported itching at the injection site with a total of 30 episodes (9.8%. Median eNO increase after autovaccination was significantly smaller (from 27.3 to 33.8 ppb; p = 0.334 compared to initial values (from 32.6 to 42.2 ppb; p = 0.046 (p = 0.034. We observed no serious adverse events. All organ functions (inclusive electrocardiogramm and laboratory testing of the blood (clinical chemistry, hematology and the urine (screening test, Β-microglobuline were within normal limits. Vital signs undulated within the physiological variability. Conclusion The administration of autologous autovacine for the treatment of house dust mite asthma resulted in a reduction of the eNO increase upon bronchial mite challenge. In nine subjects and 306 injections, only a few mild local reactions and no systemic severe adverse events were observed. Trial registration EudraCT Nr. 2005-005534-12 ClinicalTrials.gov ID NCT00677209

  18. Systemic inflammation in young adults is associated with abnormal lung function in middle age.

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    Ravi Kalhan

    Full Text Available BACKGROUND: Systemic inflammation is associated with reduced lung function in both healthy individuals and those with chronic obstructive pulmonary disease (COPD. Whether systemic inflammation in healthy young adults is associated with future impairment in lung health is uncertain. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the association between plasma fibrinogen and C-reactive protein (CRP in young adults and lung function in the Coronary Artery Risk Development in Young Adults cohort study. Higher year 7 fibrinogen was associated with greater loss of forced vital capacity (FVC between years 5 and 20 (439 mL in quartile 4 vs. 398 mL in quartile 1, P<0.001 and forced expiratory volume in 1 second (FEV(1 (487 mL in quartile 4 vs. 446 mL in quartile 1, P<0.001 independent of cigarette smoking, body habitus, baseline lung function and demographic factors. Higher year 7 CRP was also associated with both greater loss of FVC (455 mL in quartile 4 vs. 390 mL in quartile 1, P<0.001 and FEV(1 (491 mL in quartile 4 vs. 442 mL in quartile 1, P = 0.001. Higher year 7 fibrinogen and CRP were associated with abnormal FVC at year 20 (odds ratio (OR per standard deviation 1.51 (95% confidence interval (CI: 1.30-1.75 for fibrinogen and 1.35 (95% CI: 1.14-1.59 for CRP. Higher year 5 fibrinogen was additionally associated with abnormal FEV(1. A positive interaction was observed between pack-years cigarette smoking and year 7 CRP for the COPD endpoint, and among participants with greater than 10 pack-years of cigarette exposure, year 7 CRP was associated with greater odds of COPD at year 20 (OR per standard deviation 1.53 (95% CI: 1.08-2.16. CONCLUSION/SIGNIFICANCE: Systemic inflammation in young adults is associated with abnormal lung function in middle age. In particular, elevated CRP may identify vulnerability to COPD among individuals who smoke. TRIAL REGISTRATION: ClinicalTrials.gov NCT00005130.

  19. Systemic interleukin-2 administration improves lung function and modulates chorioamnionitis-induced pulmonary inflammation in the ovine fetus.

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    Willems, Monique G M; Ophelders, Daan R M G; Nikiforou, Maria; Jellema, Reint K; Butz, Anke; Delhaas, Tammo; Kramer, Boris W; Wolfs, Tim G A M

    2016-01-01

    Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-induced chorioamnionitis resulted in pulmonary inflammation with increased effector T cells and decreased regulatory T cell (Treg) numbers. Because Tregs are crucial for immune regulation, we assessed the effects of interleukin (IL)-2-driven selective Treg expansion on the fetal lung in an ovine chorioamnionitis model. Instrumented fetuses received systemic prophylactic IL-2 treatment [118 days gestational age (dGA)] with or without subsequent exposure to intra-amniotic LPS (122 dGA). Following delivery at 129 dGA (term 147 dGA), pulmonary and systemic inflammation, morphological changes, lung gas volume, and phospholipid concentration were assessed. IL-2 pretreatment increased the FoxP3(+)/CD3(+) ratio, which was associated with reduced CD3-positive cells in the fetal lungs of LPS-exposed animals. Prophylactic IL-2 treatment did not prevent pulmonary accumulation of myeloperoxidase- and PU.1-positive cells or elevation of bronchoalveolar lavage fluid IL-8 and systemic IL-6 concentrations in LPS-exposed animals. Unexpectedly, IL-2 treatment improved fetal lung function of control lambs as indicated by increased disaturated phospholipids and improved lung gas volume. In conclusion, systemic IL-2 treatment in utero preferentially expanded Tregs and improved lung gas volume and disaturated phospholipids. These beneficial effects on lung function were maintained despite the moderate immunomodulatory effects of prophylactic IL-2 in the course of chorioamnionitis. PMID:26519206

  20. Type 2 innate lymphoid cells-new members of the "type 2 franchise" that mediate allergic airway inflammation.

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    Mjösberg, Jenny; Spits, Hergen

    2012-05-01

    Type 2 innate lymphoid cells (ILC2s) are members of an ILC family, which contains NK cells and Rorγt(+) ILCs, the latter including lymphoid tissue inducer (LTi) cells and ILCs producing IL-17 and IL-22. ILC2s are dedicated to the production of IL-5 and IL-13 and, as such, ILC2s provide an early and important source of type 2 cytokines critical for helminth expulsion in the gut. Several studies have also demonstrated a role for ILC2s in airway inflammation. In this issue of the European Journal of Immunology, Klein Wolterink et al. [Eur. J. Immunol. 2012. 42: 1106-1116] show that ILC2s are instrumental in several models of experimental asthma where they significantly contribute to production of IL-5 and IL-13, key cytokines in airway inflammation. This study sheds light over the relative contribution of ILC2s versus T helper type 2 cells (Th2) in type 2 mediated allergen-specific inflammation in the airways as discussed in this commentary. PMID:22539283

  1. Toxicogenomic analysis of susceptibility to inhaled urban particulate matter in mice with chronic lung inflammation

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    Yauk Carole L

    2009-03-01

    Full Text Available Abstract Background Individuals with chronic lung disease are at increased risk of adverse health effects from airborne particulate matter. Characterization of underlying pollutant-phenotype interactions may require comprehensive strategies. Here, a toxicogenomic approach was used to investigate how inflammation modifies the pulmonary response to urban particulate matter. Results Transgenic mice with constitutive pulmonary overexpression of tumour necrosis factor (TNF-α under the control of the surfactant protein C promoter and wildtype littermates (C57BL/6 background were exposed by inhalation for 4 h to particulate matter (0 or 42 mg/m3 EHC-6802 and euthanized 0 or 24 h post-exposure. The low alveolar dose of particles (16 μg did not provoke an inflammatory response in the lungs of wildtype mice, nor exacerbate the chronic inflammation in TNF animals. Real-time PCR confirmed particle-dependent increases of CYP1A1 (30–100%, endothelin-1 (20–40%, and metallothionein-II (20–40% mRNA in wildtype and TNF mice (p Conclusion Our data support the hypothesis that health effects of acute exposure to urban particles are dominated by activation of specific physiological response cascades rather than widespread changes in gene expression.

  2. Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease

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    Maria Galluzzo

    2015-01-01

    Full Text Available Purpose. Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF. Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3Kγ plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3Kγ on airway inflammation and structural lung damage in a mouse model of CF lung disease. Methods. βENaC overexpressing mice (βENaC-Tg were backcrossed with PI3Kγ-deficient (PI3KγKO mice. Tissue damage was assessed by histology and morphometry and inflammatory cell number was evaluated in bronchoalveolar lavage fluid (BALF. Furthermore, we assessed the effect of a specific PI3Kγ inhibitor (AS-605240 on inflammatory cell number in BALF. Results. Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of PI3KγKO/βENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3Kγ inhibitor AS-605240 decreased the number of neutrophils in BALF of βENaC-Tg mice, reproducing the effect observed with genetic deletion of the enzyme. Conclusions. These results demonstrate the biological efficacy of both genetic deletion and pharmacological inhibition of PI3Kγ in reducing chronic neutrophilic inflammation in CF-like lung disease in vivo.

  3. RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation

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    Suri SS

    2011-12-01

    Full Text Available Sarabjeet Singh Suri1, Steven Mills1, Gurpreet Kaur Aulakh1, Felaniaina Rakotondradany2, Hicham Fenniri2, Baljit Singh11Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon; 2National Institute for Nanotechnology and Department of Chemistry, Edmonton, CanadaAbstract: Rosette nanotubes (RNT are a novel class of self-assembled biocompatible nanotubes that offer a built-in strategy for engineering structure and function through covalent tagging of synthetic self-assembling modules (G∧C motif. In this report, the G∧C motif was tagged with peptide Arg-Gly-Asp-Ser-Lys (RGDSK-G∧C and amino acid Lys (K-G∧C which, upon co-assembly, generate RNTs featuring RGDSK and K on their surface in predefined molar ratios. These hybrid RNTs, referred to as Kx/RGDSKy-RNT, where x and y refer to the molar ratios of K-G∧C and RGDSK–G∧C, were designed to target neutrophil integrins. A mouse model was used to investigate the effects of intravenous Kx/RGDSKy-RNT on acute lipopolysaccharide (LPS-induced lung inflammation. Healthy male C57BL/6 mice were treated intranasally with Escherichia coli LPS 80 µg and/or intravenously with K90/RGDSK10-RNT. Here we provide the first evidence that intravenous administration of K90/RGDSK10-RNT aggravates the proinflammatory effect of LPS in the mouse. LPS and K90/RGDSK10-RNT treatment groups showed significantly increased infiltration of polymorphonuclear cells in bronchoalveolar lavage fluid at all time points compared with the saline control. The combined effect of LPS and K90/RGDSK10-RNT was more pronounced than LPS alone, as shown by a significant increase in the expression of interleukin-1ß, MCP-1, MIP-1, and KC-1 in the bronchoalveolar lavage fluid and myeloperoxidase activity in the lung tissues. We conclude that K90/RGDSK10-RNT promotes acute lung inflammation, and when used along with LPS, leads to exaggerated immune response in the lung.Keywords: RGD peptide, helical rosette

  4. The acute impact of a hematopoietic allograft on lung function and inflammation: a prospective observational study

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    Enocson Alexandra

    2013-01-01

    Full Text Available Abstract Background No studies have investigated the immediate impact of receiving an allogeneic hematopoietic stem cell transplant (HSCT on pulmonary inflammation or lung function. Methods Using a prospective study design, we quantified the changes in these outcome measures in eligible adult individuals in the first six months after receiving an allogeneic hematopoietic stem cell transplant. Results Between January 2007 and December 2008, 72 patients were eligible to participate in the cohort, and of these 68 (94% were included in the study. Compared to baseline, pulmonary inflammation as measured by exhaled nitric oxide increased after receiving a HSCT with the largest increment seen at three months (+6.0ppb, 95%CI: +0.4 to +11.5, and this was sustained at six months. Percent predicted forced expiratory volume in one second decreased over the same period, with the largest decrease observed at six weeks (−5.9%, 95% CI: -8.9 to −2.9, and this was also sustained over a six month period. Similar associations were observed for FVC. A larger increase in exhaled nitric oxide from baseline at six weeks and three months may be associated with decreased mortality (p=0.06, p=0.04 respectively. Conclusion Our data demonstrate that recipients of an allogeneic HSCT experience an increase in biomarkers of pulmonary inflammation and a decrease in lung function in the first six months after the procedure. If independently validated in other study populations, these observations could have potential as a prognostic biomarker for this patient group.

  5. Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9.

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    Zhang, Lemeng; Deng, Songyun; Zhao, Shuangping; Ai, Yuhang; Zhang, Lina; Pan, Pinhua; Su, Xiaoli; Tan, Hongyi; Wu, Dongdong

    2016-01-01

    The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1β, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1β, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner. PMID:27589725

  6. Inhibitors of inflammation and endogenous surfactant pool size as modulators of lung injury with initiation of ventilation in preterm sheep

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    Polglase Graeme R

    2010-10-01

    Full Text Available Abstract Background Increased pro-inflammatory cytokines in tracheal aspirates correlate with the development of BPD in preterm infants. Ventilation of preterm lambs increases pro-inflammatory cytokines and causes lung inflammation. Objective We tested the hypothesis that selective inhibitors of pro-inflammatory signaling would decrease lung inflammation induced by ventilation in preterm newborn lambs. We also examined if the variability in injury response was explained by variations in the endogenous surfactant pool size. Methods Date-mated preterm lambs (n = 28 were operatively delivered and mechanically ventilated to cause lung injury (tidal volume escalation to 15 mL/kg by 15 min at age. The lambs then were ventilated with 8 mL/kg tidal volume for 1 h 45 min. Groups of animals randomly received specific inhibitors for IL-8, IL-1, or NF-κB. Unventilated lambs (n = 7 were the controls. Bronchoalveolar lavage fluid (BALF and lung samples were used to quantify inflammation. Saturated phosphatidylcholine (Sat PC was measured in BALF fluid and the data were stratified based on a level of 5 μmol/kg (~8 mg/kg surfactant. Results The inhibitors did not decrease the cytokine levels or inflammatory response. The inflammation increased as Sat PC pool size in BALF decreased. Ventilated lambs with a Sat PC level > 5 μmol/kg had significantly decreased markers of injury and lung inflammation compared with those lambs with Conclusion Lung injury caused by high tidal volumes at birth were decreased when endogenous surfactant pool sizes were larger. Attempts to decrease inflammation by blocking IL-8, IL-1 or NF-κB were unsuccessful.

  7. Apical Localization of Zinc Transporter ZnT4 in Human Airway Epithelial Cells and Its Loss in a Murine Model of Allergic Airway Inflammation

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    Chiara Murgia

    2011-10-01

    Full Text Available The apical cytoplasm of airway epithelium (AE contains abundant labile zinc (Zn ions that are involved in the protection of AE from oxidants and inhaled noxious substances. A major question is how dietary Zn traffics to this compartment. In rat airways, in vivo selenite autometallographic (Se-AMG-electron microscopy revealed labile Zn-selenium nanocrystals in structures resembling secretory vesicles in the apical cytoplasm. This observation was consistent with the starry-sky Zinquin fluorescence staining of labile Zn ions confined to the same region. The vesicular Zn transporter ZnT4 was likewise prominent in both the apical and basal parts of the epithelium both in rodent and human AE, although the apical pools were more obvious. Expression of ZnT4 mRNA was unaffected by changes in the extracellular Zn concentration. However, levels increased 3-fold during growth of cells in air liquid interface cultures and decreased sharply in the presence of retinoic acid. When comparing nasal versus bronchial human AE cells, there were significant positive correlations between levels of ZnT4 from the same subject, suggesting that nasal brushings may allow monitoring of airway Zn transporter expression. Finally, there were marked losses of both basally-located ZnT4 protein and labile Zn in the bronchial epithelium of mice with allergic airway inflammation. This study is the first to describe co-localization of zinc vesicles with the specific zinc transporter ZnT4 in airway epithelium and loss of ZnT4 protein in inflamed airways. Direct evidence that ZnT4 regulates Zn levels in the epithelium still needs to be provided. We speculate that ZnT4 is an important regulator of zinc ion accumulation in secretory apical vesicles and that the loss of labile Zn and ZnT4 in airway inflammation contributes to AE vulnerability in diseases such as asthma.

  8. Hydrogen Sulfide Prevents and Partially Reverses Ozone-Induced Features of Lung Inflammation and Emphysema in Mice.

    Science.gov (United States)

    Li, Feng; Zhang, Pengyu; Zhang, Min; Liang, Li; Sun, Xiaoyuan; Li, Min; Tang, Yueqin; Bao, Aihua; Gong, Jicheng; Zhang, Junfeng; Adcock, Ian; Chung, Kian Fan; Zhou, Xin

    2016-07-01

    Hydrogen sulfide (H2S), a novel signaling gasotransmitter in the respiratory system, may have antiinflammatory properties in the lung. We examined the preventive and therapeutic effects of H2S on ozone-induced features of lung inflammation and emphysema. C57/BL6 mice were exposed to ozone or filtered air over 6 weeks. Sodium hydrogen sulfide (NaHS), an H2S donor, was administered to the mice either before ozone exposure (preventive effect) or after completion of 6 weeks of ozone exposure (therapeutic effect). The ozone-exposed mice developed emphysema, measured by micro-computed tomography and histology, airflow limitation, measured by the forced maneuver system, and increased lung inflammation with augmented IL-1β, IL-18, and matrix metalloproteinase-9 (MMP-9) gene expression. Ozone-induced changes were associated with increased Nod-like receptor pyrin domain containing 3 (NLRP3)-caspase-1 activation and p38 mitogen-activated protein kinase phosphorylation and decreased Akt phosphorylation. NaHS both prevented and reversed lung inflammation and emphysematous changes in alveolar space. In contrast, NaHS prevented, but did not reverse, ozone-induced airflow limitation and bronchial structural remodeling. In conclusion, NaHS administration prevented and partially reversed ozone-induced features of lung inflammation and emphysema via regulation of the NLRP3-caspase-1, p38 mitogen-activated protein kinase, and Akt pathways. PMID:26731380

  9. LPS-Induced Lung Inflammation in Marmoset Monkeys – An Acute Model for Anti-Inflammatory Drug Testing

    OpenAIRE

    Sophie Seehase; Hans-Dieter Lauenstein; Christina Schlumbohm; Simone Switalla; Vanessa Neuhaus; Christine Förster; Hans-Gerd Fieguth; Olaf Pfennig; Eberhard Fuchs; Franz-Josef Kaup; Martina Bleyer; Hohlfeld, Jens M.; Armin Braun; Katherina Sewald; Sascha Knauf

    2012-01-01

    Increasing incidence and substantial morbidity and mortality of respiratory diseases requires the development of new human-specific anti-inflammatory and disease-modifying therapeutics. Therefore, new predictive animal models that closely reflect human lung pathology are needed. In the current study, a tiered acute lipopolysaccharide (LPS)-induced inflammation model was established in marmoset monkeys (Callithrix jacchus) to reflect crucial features of inflammatory lung diseases. Firstly, in ...

  10. Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro.

    Science.gov (United States)

    Tao, Weiwei; Su, Qiang; Wang, Hanqin; Guo, Shen; Chen, Yanyan; Duan, Jinao; Wang, Shumin

    2015-07-01

    Platycodin D (PLD) is the major triterpene saponin in the root of Platycodon grandiflorum (Jacq.) with various pharmacological activities. The purpose of the present study was to evaluate the protective effects and possible mechanisms of PLD on acute lung injury (ALI) both in vivo and in vitro. In vivo, we used two ALI models, lipopolysaccharide (LPS)-induced ALI and bleomycin (BLE)-induced ALI to evaluate the protective effects and possible mechanisms of PLD. Female BALB/c mice were randomly divided into the following groups: control group, LPS group, LPS plus pre-treatment with dexamethasone (2 mg/kg) group, LPS plus pre-treatment with PLD groups (50 mg/kg, 100 mg/kg), LPS plus post-treatment with dexamethasone (2 mg/kg) group, LPS plus post-treatment with PLD groups (50 mg/kg, 100 mg/kg), BLE group, BLE plus pre-treatment with dexamethasone (2 mg/kg) group, BLE plus pre-treatment with PLD groups (50 mg/kg, 100 mg/kg), BLE plus post-treatment with dexamethasone (2 mg/kg) group, and BLE plus post-treatment with PLD groups (50 mg/kg, 100 mg/kg). PLD was orally administered before or after LPS or BLE challenge with mice. Mice were sacrificed, and lung tissues and bronchoalveolar fluid (BALF) were prepared for further analysis. Our results showed that PLD significantly decreased lung wet-to-dry weight ratio (lung W/D weight ratio), total leukocyte number and neutrophil percentage in the BALF, and myeloperoxidase (MPO) activity of lung in a dose-dependent manner. Besides, cytokine levels, including interleukin (IL)-6, tumor neurosis factor (TNF)-α were also found significantly inhibited in BALF. Furthermore, PLD effectively inhibited the expressions of nuclear factor κB (NF-κB), Caspase-3 and Bax in the lung tissues, as well as restored the expression of Bcl-2 in the lungs and improved the superoxide dismutase (SOD) activity in BALF. In vitro, we used LPS-challenged cell model to evaluate the protective effects and possible mechanisms of PLD. MLE-12 cells were

  11. Puerarin Attenuates Ovalbumin-Induced Lung Inflammation and Hemostatic Unbalance in Rat Asthma Model

    Directory of Open Access Journals (Sweden)

    Feng Dong

    2014-01-01

    Full Text Available Aim. We aimed to investigate and evaluate the preventive activity of puerarin on the ovalbumin-induced asthma rat model. Materials and Methods. Male Wistar rats were sensitized intraperitoneally on days 0, 7, and 14 and challenged to ovalbumin intratracheally on day 21. Groups of sensitized rats were treated randomly either with placebo, puerarin, dexamethasone, or puerarin combined with dexamethasone, from days 15 to 20. Inflammatory markers, including cell counts in bronchoalveolar lavage fluid (BALF, inflammatory cytokines, histopathology, and coagulation parameters, such as coagulation tests and the activity of coagulation factors, were analyzed. Results. Puerarin significantly inhibited the recruitment of inflammatory cells in BALF and lung tissue. At the same time, the release of IL-4, IL-10, and IFN-γ in serum and the expression of mRNAs in lung tissue homogenate were changed by puerarin. Administration of puerarin also effectively rectified the coagulation disorder in asthmatic rats, such as prothrombin time (PT (P<0.01, thrombin time (TT (P<0.05, fibrinogen (FIB (P<0.01,the activity of factor II (FII (P<0.01, the activity of factor V (FV (P<0.05, the activity of factor VII (FVII (P<0.05, the activity of factor X (FX (P<0.05, the activity of factor VIII (FVIII (P<0.01, the activity of factor IX (FIX (P<0.05, and the activity of factor XII (FXII (P<0.05. Conclusions. Our results provide a clue that puerarin was useful for the preventive of allergic airway disease in rodents.

  12. Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice

    Directory of Open Access Journals (Sweden)

    Ladefoged Ole

    2009-01-01

    Full Text Available Abstract Background The toxic and inflammatory potential of 5 different types of nanoparticles were studied in a sensitive model for pulmonary effects in apolipoprotein E knockout mice (ApoE-/-. We studied the effects instillation or inhalation Printex 90 of carbon black (CB and compared CB instillation in ApoE-/- and C57 mice. Three and 24 h after pulmonary exposure, inflammation was assessed by mRNA levels of cytokines in lung tissue, cell composition, genotoxicity, protein and lactate dehydrogenase activity in broncho-alveolar lavage (BAL fluid. Results Firstly, we found that intratracheal instillation of CB caused far more pulmonary toxicity in ApoE-/- mice than in C57 mice. Secondly, we showed that instillation of CB was more toxic than inhalation of a presumed similar dose with respect to inflammation in the lungs of ApoE-/- mice. Thirdly, we compared effects of instillation in ApoE-/- mice of three carbonaceous particles; CB, fullerenes C60 (C60 and single walled carbon nanotubes (SWCNT as well as gold particles and quantum dots (QDs. Characterization of the instillation media revealed that all particles were delivered as agglomerates and aggregates. Significant increases in Il-6, Mip-2 and Mcp-1 mRNA were detected in lung tissue, 3 h and 24 h following instillation of SWCNT, CB and QDs. DNA damage in BAL cells, the fraction of neutrophils in BAL cells and protein in BAL fluid increased statistically significantly. Gold and C60 particles caused much weaker inflammatory responses. Conclusion Our data suggest that ApoE-/- model is sensitive for evaluating particle induced inflammation. Overall QDs had greatest effects followed by CB and SWCNT with C60 and gold being least inflammatory and DNA-damaging. However the gold was used at a much lower mass dose than the other particles. The strong effects of QDs were likely due to Cd release. The surface area of the instilled dose correlated well the inflammatory response for low toxicity particles.

  13. Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model.

    Science.gov (United States)

    Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao; Karpe, Pinakin Arun; Malek, Vajir; Patel, Deep; Tikoo, Kulbhushan

    2016-09-01

    Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2weeks. 48h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocyte count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers. PMID:27343405

  14. Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

    Energy Technology Data Exchange (ETDEWEB)

    Schneider, Brent C. [Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC 20037 (United States); Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037 (United States); Constant, Stephanie L. [Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC 20037 (United States); Patierno, Steven R. [Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037 (United States); GW Cancer Institute, The George Washington University, Washington, DC 20037 (United States); Jurjus, Rosalyn A. [Department of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20037 (United States); Ceryak, Susan M., E-mail: phmsmc@gwumc.edu [Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037 (United States)

    2012-02-15

    Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory response in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. -- Highlights: ► Allergic asthma correlated with exposure to certain inhaled particulate chromates. ► Direct causal association between Cr(VI) and allergic asthma not established. ► Cr exacerbated pathology and airway hyperresponsiveness in an OVA-challenged mouse. ► Particulate Cr

  15. Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

    International Nuclear Information System (INIS)

    Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory response in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. -- Highlights: ► Allergic asthma correlated with exposure to certain inhaled particulate chromates. ► Direct causal association between Cr(VI) and allergic asthma not established. ► Cr exacerbated pathology and airway hyperresponsiveness in an OVA-challenged mouse. ► Particulate Cr

  16. Inducible nitric oxide synthase inhibition attenuates physical stress-induced lung hyper-responsiveness and oxidative stress in animals with lung inflammation.

    Science.gov (United States)

    Marques, Ricardo Henrique; Reis, Fabiana G; Starling, Claudia M; Cabido, Claudia; de Almeida-Reis, Rafael; Dohlnikoff, Marisa; Prado, Carla M; Leick, Edna A; Martins, Mílton A; Tibério, Iolanda F L C

    2012-01-01

    Mechanisms involved in stress-induced asthmatic alterations have been poorly characterised. We assessed whether inducible nitric oxide synthase (iNOS) inhibition modulates the stress-amplified lung parenchyma responsiveness, oxidative stress and extracellular matrix remodelling that was previously increased by chronic lung inflammation. Guinea pigs were subjected to 7 exposures to ovalbumin (1-5 mg/ml) or saline (OVA and SAL groups) over 4 weeks. To induce behavioural stress, animals were subjected to a forced swimming protocol (5 times/week, over 2 weeks; SAL-Stress and OVA-Stress groups) 24 h after the 4th inhalation. 1400W (iNOS-specific inhibitor) was administered intraperitoneally in the last 4 days of the protocol (SAL-1400W, OVA-1400W, SAL-Stress+1400W and OVA-Stress+1400W groups). Seventy-two hours after the last inhalation, animals were anaesthetised and exsanguinated, and adrenal glands were removed. Lung tissue resistance and elastance were evaluated by oscillatory mechanics and submitted for histopathological evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, which were reduced by 1400W treatment. Behavioural stress in sensitised animals amplified the resistance and elastance responses after antigen challenge, numbers of eosinophils and iNOS+ cells, actin content and 8-iso-PGF2α density in the distal lung compared to the OVA group. 1400W treatment in ovalbumin-exposed and stressed animals reduced lung mechanics, iNOS+ cell numbers and 8-iso-PGF2α density compared to sensitised and stressed animals that received vehicle treatment. We concluded that stress amplifies the distal lung constriction, eosinophilic inflammation, iNOS expression, actin content and oxidative stress previously induced by chronic lung inflammation. iNOS-derived NO contributes to stress-augmented lung tissue functional alterations in this animal model and is at least partially due to activation of the oxidative stress pathway. PMID:22262048

  17. Th17 can regulate silica-induced lung inflammation through an IL-1β-dependent mechanism

    OpenAIRE

    Song, Laiyu; Weng, Dong; Dai, Wujing; Tang, Wen; Chen, Shi; Li, Chao; Chen, Ying; Liu, Fangwei; Chen, Jie

    2014-01-01

    Silicosis is an occupational lung disease caused by the inhalation of silica dust and characterized by lung inflammation and fibrosis. Interleukin (IL)-1β is induced by silica and functions as the key pro-inflammatory cytokine in this process. The Th17 response, which is induced by IL-1β, has been reported very important in chronic human lung inflammatory diseases. To elucidate the underlying mechanisms of IL-1β and IL-17 in silicosis, we used anakinra and an anti-IL-17 monoclonal antibody (m...

  18. Occurrence of hypermutable Pseudomonas aeruginosa in cystic fibrosis patients is associated with the oxidative stress caused by chronic lung inflammation

    DEFF Research Database (Denmark)

    Ciofu, Oana; Riis, Bente; Pressler, Tacjana; Poulsen, Henrik Enghusen; Høiby, Niels

    2005-01-01

    Oxidative stress caused by chronic lung inflammation in patients with cystic fibrosis (CF) and chronic lung infection with Pseudomonas aeruginosa is characterized by the reactive oxygen species (ROS) liberated by polymorphonuclear leukocytes (PMNs). We formulated the hypothesis that oxidation of....../patient) collected from the 1st and up to the 25th year of their chronic lung infection. The level of oxidized guanine moiety 8-oxo-2'-deoxyguanosine (8-oxodG), which is a frequently investigated DNA oxidative lesion, was measured. Hypermutable P. aeruginosa isolates were found in the sputum bacterial population of...

  19. Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice

    DEFF Research Database (Denmark)

    Raun Jacobsen, Nicklas; Møller, Peter; Alstrup Jensen, Keld;

    2009-01-01

    of three carbonaceous particles; CB, fullerenes C-60 (C-60) and single walled carbon nanotubes (SWCNT) as well as gold particles and quantum dots (QDs). Characterization of the instillation media revealed that all particles were delivered as agglomerates and aggregates. Significant increases in Il-6......, Mip-2 and Mcp-1 mRNA were detected in lung tissue, 3 h and 24 h following instillation of SWCNT, CB and QDs. DNA damage in BAL cells, the fraction of neutrophils in BAL cells and protein in BAL fluid increased statistically significantly. Gold and C-60 particles caused much weaker inflammatory...... responses. Conclusion: Our data suggest that ApoE(-/-) model is sensitive for evaluating particle induced inflammation. Overall QDs had greatest effects followed by CB and SWCNT with C-60 and gold being least inflammatory and DNA-damaging. However the gold was used at a much lower mass dose than the other...

  20. HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression

    Directory of Open Access Journals (Sweden)

    Frincke James M

    2010-10-01

    Full Text Available Abstract Background 17α-Ethynyl-5-androsten-3β, 7β, 17β-triol (HE3286 is a synthetic derivative of an endogenous steroid androstenetriol (β-AET, a metabolite of the abundant adrenal steroid deyhdroepiandrosterone (DHEA, with broad anti-inflammatory activities. We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact. Methods and Results In mice, oral treatment with HE3286 (40 mg/kg significantly (p in vivo (ovalbumin immunization. When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups. Conclusions HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.

  1. Broncho-Vaxom attenuates allergic airway inflammation by restoring GSK3β-related T regulatory cell insufficiency.

    Directory of Open Access Journals (Sweden)

    Ran Fu

    Full Text Available BACKGROUND: Oral administration of bacterial extracts (eg, Broncho-Vaxom (BV has been proposed to attenuate asthma through modulating Treg cells. However, the underlying mechanism has not been fully characterized. This study sought to assess the effects of oral administration of BV on GSK-3β expression and Treg cells in ovalbumin (OVA-induced asthmatic mice models. METHOD: Asthmatic mice models were established with OVA challenge and treated with oral administration of BV. Next, infiltration of inflammatory cells including eosinophil and neutrophils, mucous metaplasia, levels of Th1/Th2/Treg-typed cytokines and expression of GSK3β and Foxp3 were examined in asthmatic mice models by histological analysis, Bio-Plex and western blot, respectively. Moreover, the frequencies of Treg cells were evaluated in cultured splenocytes by flow cytometry in the presence of BV or GSK3β siRNA interference. RESULTS: We found significant decrease of infiltrated inflammatory cells in bronchoalveolar lavage fluid (BALF in asthmatic mice models after oral administration of BV. Oral administration of BV was shown to significantly suppress mucus metaplasia, Th2-typed cytokine levels and GSK3β expression while increasing Foxp3 production in asthmatic mice models. Moreover, BV significantly enhanced GSK3β-related expansion of Treg cells in cultured spleen cells in vitro. CONCLUSION: Our findings provide evidence that oral administration of BV is capable of attenuating airway inflammation in asthmatic mice models, which may be associated with GSK3β-related expansion of Treg cells.

  2. Persistent lung inflammation and fibrosis in serum amyloid P component (APCs-/-) knockout mice.

    Science.gov (United States)

    Pilling, Darrell; Gomer, Richard H

    2014-01-01

    Fibrosing diseases, such as pulmonary fibrosis, cardiac fibrosis, myelofibrosis, liver fibrosis, and renal fibrosis are chronic and debilitating conditions and are an increasing burden for the healthcare system. Fibrosis involves the accumulation and differentiation of many immune cells, including macrophages and fibroblast-like cells called fibrocytes. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP also promotes the formation of immuno-regulatory Mreg macrophages. To elucidate the endogenous function of SAP, we used bleomycin aspiration to induce pulmonary inflammation and fibrosis in mice lacking SAP. Compared to wildtype C57BL/6 mice, we find that in Apcs-/- "SAP knock-out" mice, bleomycin induces a more persistent inflammatory response and increased fibrosis. In both C57BL/6 and Apcs-/- mice, injections of exogenous SAP reduce the accumulation of inflammatory macrophages and prevent fibrosis. The types of inflammatory cells present in the lungs following bleomycin-aspiration appear similar between C57BL/6 and Apcs-/- mice, suggesting that the initial immune response is normal in the Apcs-/- mice, and that a key endogenous function of SAP is to promote the resolution of inflammation and fibrosis. PMID:24695531

  3. Bee venom phospholipase A2 suppresses allergic airway inflammation in an ovalbumin-induced asthma model through the induction of regulatory T cells.

    Science.gov (United States)

    Park, Soojin; Baek, Hyunjung; Jung, Kyung-Hwa; Lee, Gihyun; Lee, Hyeonhoon; Kang, Geun-Hyung; Lee, Gyeseok; Bae, Hyunsu

    2015-12-01

    Bee venom (BV) is one of the alternative medicines that have been widely used in the treatment of chronic inflammatory diseases. We previously demonstrated that BV induces immune tolerance by increasing the population of regulatory T cells (Tregs) in immune disorders. However, the major component and how it regulates the immune response have not been elucidated. We investigated whether bee venom phospholipase A2 (bvPLA2) exerts protective effects that are mediated via Tregs in OVA-induced asthma model. bvPLA2 was administered by intraperitoneal injection into control and OVA-challenged mice. The Treg population, total and differential bronchoalveolar lavage fluid (BALF) cell count, Th2 cytokines, and lung histological features were assessed. Treg depletion was used to determine the involvement of Treg migration and the reduction of asthmatic symptoms. The CD206-dependence of bvPLA2-treated suppression of airway inflammation was evaluated in OVA-challenged CD206(-/-) mice. The bvPLA2 treatment induced the Tregs and reduced the infiltration of inflammatory cells into the lung in the OVA-challenged mice. Th2 cytokines in the bronchoalveolar lavage fluid (BALF) were reduced in bvPLA2-treated mice. Although bvPLA2 suppressed the number of inflammatory cells after OVA challenge, these effects were not observed in Treg-depleted mice. In addition, we investigated the involvement of CD206 in bvPLA2-mediated immune tolerance in OVA-induced asthma model. We observed a significant reduction in the levels of Th2 cytokines and inflammatory cells in the BALF of bvPLA2-treated OVA-induced mice but not in bvPLA2-treated OVA-induced CD206(-/-) mice. These results demonstrated that bvPLA2 can mitigate airway inflammation by the induction of Tregs in an OVA-induced asthma model. PMID:26734460

  4. Carbon nanoparticles induce ceramide- and lipid raft-dependent signalling in lung epithelial cells: a target for a preventive strategy against environmentally-induced lung inflammation

    Directory of Open Access Journals (Sweden)

    Peuschel Henrike

    2012-12-01

    Full Text Available Abstract Background Particulate air pollution in lung epithelial cells induces pathogenic endpoints like proliferation, apoptosis, and pro-inflammatory reactions. The activation of the epidermal growth factor receptor (EGFR is a key event responsible for signalling events involving mitogen activated protein kinases specific for these endpoints. The molecular events leading to receptor activation however are not well understood. These events are relevant for the toxicological evaluation of inhalable particles as well as for potential preventive strategies in situations when particulate air pollution cannot be avoided. The current study therefore had the objective to elucidate membrane-coupled events leading to EGFR activation and the subsequent signalling cascade in lung epithelial cells. Furthermore, we aimed to identify the molecular target of ectoine, a biophysical active substance which we described to prevent carbon nanoparticle-induced lung inflammation. Methods Membrane signalling events were investigated in isolated lipid rafts from lung epithelial cells with regard to lipid and protein content of the signalling platforms. Using positive and negative intervention approaches, lipid raft changes, subsequent signalling events, and lung inflammation were investigated in vitro in lung epithelial cells (RLE-6TN and in vivo in exposed animals. Results Carbon nanoparticle treatment specifically led to an accumulation of ceramides in lipid rafts. Detailed analyses demonstrated a causal link of ceramides and subsequent EGFR activation coupled with a loss of the receptor in the lipid raft fractions. In vitro and in vivo investigations demonstrate the relevance of these events for carbon nanoparticle-induced lung inflammation. Moreover, the compatible solute ectoine was able to prevent ceramide-mediated EGFR phosphorylation and subsequent signalling as well as lung inflammation in vivo. Conclusion The data identify a so far unknown event in pro

  5. Effect of short-term stainless steel welding fume inhalation exposure on lung inflammation, injury, and defense responses in rats

    International Nuclear Information System (INIS)

    Many welders have experienced bronchitis, metal fume fever, lung function changes, and an increase in the incidence of lung infection. Questions remain regarding the possible mechanisms associated with the potential pulmonary effects of welding fume exposure. The objective was to assess the early effects of stainless steel (SS) welding fume inhalation on lung injury, inflammation, and defense responses. Male Sprague-Dawley rats were exposed to gas metal arc-SS welding fume at a concentration of 15 or 40 mg/m3 x 3 h/day for 1, 3, or 10 days. The control group was exposed to filtered air. To assess lung defense responses, some animals were intratracheally inoculated with 5 x 104Listeria monocytogenes 1 day after the last exposure. Welding particles were collected during exposure, and elemental composition and particle size were determined. At 1, 4, 6, 11, 14, and 30 days after the final exposure, parameters of lung injury (lactate dehydrogenase and albumin) and inflammation (PMN influx) were measured in the bronchoalveolar lavage fluid. In addition, particle-induced effects on pulmonary clearance of bacteria and macrophage function were assessed. SS particles were composed of Fe, Cr, Mn, and Ni. Particle size distribution analysis indicated the mass median aerodynamic diameter of the generated fume to be 0.255 μm. Parameters of lung injury were significantly elevated at all time points post-exposure compared to controls except for 30 days. Interestingly, no significant difference in lung PMNs was observed between the SS and control groups at 1, 4, and 6 days post-exposure. After 6 days post-exposure, a dramatic increase in lung PMNs was observed in the SS group compared to air controls. Lung bacteria clearance and macrophage function were reduced and immune and inflammatory cytokines were altered in the SS group. In summary, short-term exposure of rats to SS welding fume caused significant lung damage and suppressed lung defense responses to bacterial infection, but

  6. Increasing Regulatory T Cells With Interleukin-2 and Interleukin-2 Antibody Complexes Attenuates Lung Inflammation and Heart Failure Progression.

    Science.gov (United States)

    Wang, Huan; Hou, Lei; Kwak, Dongmin; Fassett, John; Xu, Xin; Chen, Angela; Chen, Wei; Blazar, Bruce R; Xu, Yawei; Hall, Jennifer L; Ge, Jun-Bo; Bache, Robert J; Chen, Yingjie

    2016-07-01

    Congestive heart failure (CHF) is associated with an increase of leukocyte infiltration, proinflammatory cytokines, and fibrosis in the heart and lung. Regulatory T cells (Tregs, CD4(+)CD25(+)FoxP3(+)) suppress inflammatory responses in various clinical conditions. We postulated that expansion of Tregs attenuates CHF progression by reducing cardiac and lung inflammation. We investigated the effects of interleukin-2 (IL-2) plus IL-2 monoclonal antibody clone JES6-1 complexes (IL2/JES6-1) on induction of Tregs, transverse aortic constriction-induced cardiac and lung inflammation, and CHF progression in mice. We demonstrated that end-stage CHF caused a massive increase of lung macrophages and T cells, as well as relatively mild left ventricular (LV) leukocyte infiltration. Administration of IL2/JES6-1 caused an ≈6-fold increase of Tregs within CD4(+) T cells in the spleen, lung, and heart of mice. IL2/JES6-1 treatment of mice with existing transverse aortic constriction-induced LV failure markedly reduced lung and right ventricular weight and improved LV ejection fraction and LV end-diastolic pressure. Mechanistically, IL2/JES6-1 treatment significantly increased Tregs; suppressed CD4(+) T-cell accumulation; dramatically attenuated leukocyte infiltration, including decreasing CD45(+) cells, macrophages, CD8(+) T cells, and effector memory CD8(+); and reduced proinflammatory cytokine expressions and fibrosis in the lung of mice. Furthermore, IL2/JES6-1 administered before transverse aortic constriction attenuated the development of LV hypertrophy and dysfunction in mice. Our data indicate that increasing Tregs through administration of IL2/JES6-1 effectively attenuates pulmonary inflammation, right ventricular hypertrophy, and further LV dysfunction in mice with existing LV failure, suggesting that strategies to properly expand Tregs may be useful in reducing CHF progression. PMID:27160197

  7. Tobacco smoke exposure suppresses radiation-induced inflammation in the lung

    International Nuclear Information System (INIS)

    Previous studies on patients with breast cancer, who received postsurgical irradiation, displayed a markedly suppressed inflammatory response in the lung of smoking patients compared to nonsmokers. The aim of the present study was to investigate further the effect of exposure to tobacco smoke on the development of irradiation-induced pneumonitis in the rat. Four groups of animals were used: controls (C); those exposed to tobacco smoke (S); those irradiated but not exposed to smoke (RNS); and those irradiated and exposed to tobacco smoke (RS). The rats were exposed to a diluted main stream of cigarette smoke, at a concentration of about 0.4 mgxl-1, in a nose-only exposure system for 1 hxday-1, 5 daysxweek-1 for 10 weeks. Exposure to tobacco smoke started 3 weeks before irradiation. The basal one third of both lungs was exposed to a single radiation dose of 28 Gy (6 MeV photons). All animals were killed 7 weeks after irradiation. We compared findings in bronchoalveolar lavage (BAL) and tissue morphology. The alveolar tissue showed less inflammation in the RS-group than in the RNS-group. Most strikingly, mast cells were increased one hundredfold in the lung interstitium and thirty fold in the peribronchial area in the RNS-group, whereas no increase was found in the RS-group or in the controls. The alveolar septa of the RNS-group were thickened, with occurrence of inflammatory cells and mast cells, whereas the RS-group displayed no difference as compared to the non-irradiated, nonsmoking group (C). There was a marked discrepancy between the findings in BAL and tissue of the alveolar space or lung interstitium. In BAL, neutrophils, and to a lesser extent lymphocytes, were increased both in the RS- and RNS-group; however, with significantly higher numbers in the RNS-group. In contrast, the cells in the alveolar space and interstitium were dominated by mononuclear cells, mainly macrophages. Moreover, a more than twenty fold increase in total cells in the alveolar space

  8. No adjuvant effect of Bacillus thuringiensis-maize on allergic responses in mice.

    Directory of Open Access Journals (Sweden)

    Daniela Reiner

    Full Text Available Genetically modified (GM foods are evaluated carefully for their ability to induce allergic disease. However, few studies have tested the capacity of a GM food to act as an adjuvant, i.e. influencing allergic responses to other unrelated allergens at acute onset and in individuals with pre-existing allergy. We sought to evaluate the effect of short-term feeding of GM Bacillus thuringiensis (Bt-maize (MON810 on the initiation and relapse of allergic asthma in mice. BALB/c mice were provided a diet containing 33% GM or non-GM maize for up to 34 days either before ovalbumin (OVA-induced experimental allergic asthma or disease relapse in mice with pre-existing allergy. We observed that GM-maize feeding did not affect OVA-induced eosinophilic airway and lung inflammation, mucus hypersecretion or OVA-specific antibody production at initiation or relapse of allergic asthma. There was no adjuvant effect upon GM-maize consumption on the onset or severity of allergic responses in a mouse model of allergic asthma.

  9. Melatonin decreases the expression of inflammation and apoptosis markers in the lung of a senescence-accelerated mice model.

    Science.gov (United States)

    Puig, Ángela; Rancan, Lisa; Paredes, Sergio D; Carrasco, Adrián; Escames, Germaine; Vara, Elena; Tresguerres, Jesús A F

    2016-03-01

    Aging is associated with an increase in oxidative stress and inflammation. The aging lung is particularly affected since it is continuously exposed to environmental oxidants while antioxidant machinery weakens with age. Melatonin, a free radical scavenger, counteracts inflammation and apoptosis in healthy cells from several tissues. Its effects on the aging lung are, however, not yet fully understood. This study aimed to investigate the effect of chronic administration of melatonin on the expression of inflammation markers (TNF-α, IL-1β, NFκB2, HO-1) and apoptosis parameters (BAD, BAX, AIF) in the lung tissue of male senescence-accelerated prone mice (SAMP8). In addition, RNA oxidative damage, as the formation of 8-hydroxyguanosine (8-OHG), was also evaluated. Young and old animals, aged 2 and 10 months respectively, were divided into 4 groups: untreated young, untreated old, old mice treated with 1mg/kg/day melatonin, and old animals treated with 10mg/kg/day melatonin. Untreated young and old male senescence accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed. Lungs were collected and immediately frozen in liquid nitrogen. mRNA and protein expressions were measured by RT-PCR and Western blotting, respectively. Levels of 8-OHG were quantified by ELISA. Mean values were analyzed using ANOVA. Old nontreated SAMP8 animals showed increased (paging-derived inflammation (paging, the effect being counteracted with melatonin (pAging also caused a significant elevation (panimals treated with melatonin (paging lungs, exerting a protective effect on age-induced damage. PMID:26656745

  10. Mast cell stabilization alleviates acute lung injury after orthotopic autologous liver transplantation in rats by downregulating inflammation.

    Directory of Open Access Journals (Sweden)

    Ailan Zhang

    Full Text Available BACKGROUND: Acute lung injury (ALI is one of the most severe complications after orthotopic liver transplantation. Amplified inflammatory response after transplantation contributes to the process of ALI, but the mechanism underlying inflammation activation is not completely understood. We have demonstrated that mast cell stabilization attenuated inflammation and ALI in a rodent intestine ischemia/reperfusion model. We hypothesized that upregulation of inflammation triggered by mast cell activation may be involve in ALI after liver transplantation. METHODS: Adult male Sprague-Dawley rats received orthotopic autologous liver transplantation (OALT and were executed 4, 8, 16, and 24 h after OALT. The rats were pretreated with the mast cell stabilizers cromolyn sodium or ketotifen 15 min before OALT and executed 8 h after OALT. Lung tissues and arterial blood were collected to evaluate lung injury. β-hexosaminidase and mast cell tryptase levels were assessed to determine the activation of mast cells. Tumor necrosis factor α (TNF-α, interleukin (IL-1β and IL-6 in serum and lung tissue were analyzed by enzyme-linked immunosorbent assay. Nuclear factor-kappa B (NF-κB p65 translocation was assessed by Western blot. RESULTS: The rats that underwent OALT exhibited severe pulmonary damage with a high wet-to-dry ratio, low partial pressure of oxygen, and low precursor surfactant protein C levels, which corresponded to the significant elevation of pro-inflammatory cytokines, β-hexosaminidase, and tryptase levels in serum and lung tissues. The severity of ALI progressed and maximized 8 h after OALT. Mast cell stabilization significantly inhibited the activation of mast cells, downregulated pro-inflammatory cytokine levels and translocation of NF-κB, and attenuated OALT-induced ALI. CONCLUSIONS: Mast cell activation amplified inflammation and played an important role in the process of post-OALT related ALI.

  11. Impact of inflammation, emphysema, and smoking cessation on V/Q in mouse models of lung obstruction

    Science.gov (United States)

    2014-01-01

    Background Chronic obstructive pulmonary disease (COPD) is known to greatly affect ventilation (V) and perfusion (Q) of the lung through pathologies such as inflammation and emphysema. However, there is little direct evidence regarding how these pathologies contribute to the V/Q mismatch observed in COPD and models thereof. Also, little is known regarding how smoking cessation affects V/Q relationships after inflammation and airspace enlargement have become established. To this end, we have quantified V/Q on a per-voxel basis using single photon emission computed tomography (SPECT) in mouse models of COPD and lung obstruction. Methods Three distinct murine models were used to investigate the impact of different pathologies on V/Q, as measured by SPECT. Lipopolysaccharide (LPS) was used to produce neutrophilic inflammation, porcine pancreatic elastase (PPE) was used to produce emphysema, and long-term cigarette smoke (CS) exposure and cessation were used to investigate the combination of these pathologies. Results CS exposure resulted in an increase in mononuclear cells and neutrophils, an increase in airspace enlargement, and an increase in V/Q mismatching. The inflammation produced by LPS was more robust and predominantly neutrophilic, compared to that of cigarette smoke; nevertheless, inflammation alone caused V/Q mismatching similar to that seen with long-term CS exposure. The emphysematous lesions caused by PPE administration were also capable of causing V/Q mismatch in the absence of inflammation. Following CS cessation, inflammatory cell levels returned to those of controls and, similarly, V/Q measures returned to normal despite evidence of persistent mild airspace enlargement. Conclusions Both robust inflammation and extensive airspace enlargement, on their own, were capable of producing V/Q mismatch. As CS cessation resulted in a return of V/Q mismatching and inflammatory cell counts to control levels, lung inflammation is likely a major contributor to V

  12. Human umbilical cord mesenchymal stem cells reduce systemic inflammation and attenuate LPS-induced acute lung injury in rats

    Directory of Open Access Journals (Sweden)

    Li Jianjun

    2012-09-01

    Full Text Available Abstract Background Mesenchymal stem cells (MSCs possess potent immunomodulatory properties and simultaneously lack the ability to illicit immune responses. Hence, MSCs have emerged as a promising candidate for cellular therapeutics for inflammatory diseases. Within the context of this study, we investigated whether human umbilical cord-derived mesenchymal stem cells (UC-MSCs could ameliorate lipopolysaccharide- (LPS- induced acute lung injury (ALI in a rat model. Methods ALI was induced via injection of LPS. Rats were divided into three groups: (1 saline group(control, (2 LPS group, and (3 MSC + LPS group. The rats were sacrificed at 6, 24, and 48 hours after injection. Serum, bronchoalveolar lavage fluid (BALF, and lungs were collected for cytokine concentration measurements, assessment of lung injury, and histology. Results UC-MSCs increased survival rate and suppressed LPS-induced increase of serum concentrations of pro-inflammatory mediators TNF-α, IL-1β, and IL-6 without decreasing the level of anti-inflammatory cytokine IL-10. The MSC + LPS group exhibited significant improvements in lung inflammation, injury, edema, lung wet/dry ratio, protein concentration, and neutrophil counts in the BALF, as well as improved myeloperoxidase (MPO activity in the lung tissue. Furthermore, UC-MSCs decreased malondialdehyde (MDA production and increased Heme Oxygenase-1 (HO-1 protein production and activity in the lung tissue. Conclusion UC-MSCs noticeably increased the survival rate of rats suffering from LPS-induced lung injury and significantly reduced systemic and pulmonary inflammation. Promoting anti-inflammatory homeostasis and reducing oxidative stress might be the therapeutic basis of UC-MSCs.

  13. SHIP represses lung inflammation and inhibits mammary tumor metastasis in BALB/c mice

    Science.gov (United States)

    Hamilton, Melisa J.; Halvorsen, Elizabeth C.; LePard, Nancy E.; Bosiljcic, Momir; Ho, Victor W.; Lam, Vivian; Banáth, Judit

    2016-01-01

    SH2-containing-inositol-5′-phosphatase (SHIP) is a negative regulator of the phosphatidylinositol-3-kinase pathway in hematopoietic cells and limits the development of leukemias and lymphomas. The potential role of SHIP in solid tumor development and metastasis remains unknown. While SHIP restricts the aberrant development of myeloid cells in C57BL/6 mice, there are conflicting reports regarding the effect of SHIP deletion in BALB/c mice with important consequences for determining the influence of SHIP in different model tumor systems. We generated SHIP−/− BALB/c mice and challenged them with syngeneic non-metastatic 67NR or metastatic 4T1 mammary tumors. We demonstrate that SHIP restricts the development, alternative-activation, and immunosuppressive function of myeloid cells in tumor-free and tumor-bearing BALB/c mice. Tumor-free SHIP−/− BALB/c mice exhibited pulmonary inflammation, myeloid hyperplasia, and M2-polarized macrophages and this phenotype was greatly exacerbated by 4T1, but not 67NR, tumors. 4T1-bearing SHIP−/− mice rapidly lost weight and died from necrohemorrhagic inflammatory pulmonary disease, characterized by massive infiltration of pulmonary macrophages and myeloid-derived suppressor cells that were more M2-polarized and immunosuppressive than wild-type cells. Importantly, while SHIP loss did not affect primary tumor growth, 4T1-bearing SHIP−/− mice had 7.5-fold more metastatic tumor cells in their lungs than wild-type mice, consistent with the influence of immunosuppressive myeloid cells on metastatic growth. Our findings identify the hematopoietic cell-restricted protein SHIP as an intriguing target to influence the development of solid tumor metastases, and support development of SHIP agonists to prevent the accumulation of immunosuppressive myeloid cells and tumor metastases in the lungs to improve treatment of metastatic breast cancer. PMID:26683227

  14. Bilateral vagotomy or atropine pre-treatment reduces experimental diesel-soot induced lung inflammation

    International Nuclear Information System (INIS)

    To investigate the role of the vagus nerve in acute inflammatory and cardiorespiratory responses to diesel particulate (DP) in the rat airway, we measured changes in respiration, blood pressure and neutrophils in lungs of urethane anesthetized Wistar rats 6-h post-instillation of DP (500 μg) and studied the effect of mid-cervical vagotomy or atropine (1 mg kg-1) pre-treatment. In conscious rats, we investigated DP, with and without atropine pre-treatment. DP increased neutrophil level in BAL (bronchoalveolar lavage) fluid from intact anesthetized rats to 2.5 ± 0.7 x 106 cells (n = 8), compared with saline instillation (0.3 ± 0.1 x 106, n = 7; P 6 cells (n = 8; P 6 (n = 4; P 6, n = 4, was reduced by pre-treatment with atropine to 2.2 ± 1.2 x 106 cells, n = 3. Hyperventilation occurred 6 h after DP in anesthetized rats with intact vagi, but not in bilaterally vagotomized or atropine pre-treated animals and was abolished by vagotomy (P < 0.05, paired test). There were no significant differences in the other variables (mean blood pressure, heart rate and heart rate variability) measured before and 360 min after DP. In conclusion, DP activates a pro-inflammatory vago-vagal reflex which is reduced by atropine. Muscarinic ACh receptors in the rat lung are involved in DP-induced neutrophilia, and hence muscarinic antagonists may reduce airway and/or cardiovascular inflammation evoked by inhaled atmospheric DP in susceptible individuals

  15. Upper and lower airway pathology in young children with allergic- and non-allergic rhinitis

    DEFF Research Database (Denmark)

    Chawes, Bo

    2011-01-01

    symptom in both allergic- and non-allergic rhinitis, and eosinophilic inflammation is a hallmark of the allergic diseases. In paper I, we studied nasal eosinophilia and nasal airway patency assessed by acoustic rhinometry in children with allergic rhinitis, non-allergic rhinitis and healthy controls......Allergic- and non-allergic rhinitis are very common diseases in childhood in industrialized countries. Although these conditions are widely trivialized by both parents and physicians they induce a major impact on quality of life for the affected children and a substantial drainage of health care...... resources. Unfortunately, diagnostic specificity is hampered by nonspecific symptom history and lack of reliable diagnostic tests which may explain why the pathology behind such diagnoses is poorly understood. Improved understanding of the pathophysiology of allergic- and non-allergic rhinitis in young...

  16. Vagus Nerve through α7 nAChR Modulates Lung Infection and Inflammation: Models, Cells, and Signals

    Directory of Open Access Journals (Sweden)

    Haiya Wu

    2014-01-01

    Full Text Available Cholinergic anti-inflammatory pathway (CAP bridges immune and nervous systems and plays pleiotropic roles in modulating inflammation in animal models by targeting different immune, proinflammatory, epithelial, endothelial, stem, and progenitor cells and signaling pathways. Acute lung injury (ALI is a devastating inflammatory disease. It is pathogenically heterogeneous and involves many cells and signaling pathways. Here, we emphasized the research regarding the modulatory effects of CAP on animal models, cell population, and signaling pathways that involved in the pathogenesis of ALI. By comparing the differential effects of CAP on systemic and pulmonary inflammation, we postulated that a pulmonary parasympathetic inflammatory reflex is formed to sense and respond to pathogens in the lung. Work targeting the formation and function of pulmonary parasympathetic inflammatory reflex would extend our understanding of how vagus nerve senses, recognizes, and fights with pathogens and inflammatory responses.

  17. Mouse lung inflammation after instillation of particulate matter collected from a working dairy barn

    International Nuclear Information System (INIS)

    Coarse and fine particulate matter (PM2.5-10 and PM2.5, respectively) are regulated ambient air pollutants thought to have major adverse health effects in exposed humans. The role of endotoxin and other bioaerosol components in the toxicity of PM from ambient air is controversial. This study evaluated the inflammatory lung response in mice instilled intratracheally with PM2.5-10 and PM2.5 emitted from a working dairy barn, a source presumed to have elevated concentrations of endotoxin. PM2.5-10 was more pro-inflammatory on an equal weight basis than was PM2.5; both fractions elicited a predominantly neutrophilic response. The inflammatory response was reversible, with a peak response to PM2.5-10 observed at 24 h after instillation, and a return to control values by 72 h after instillation. The major active pro-inflammatory component in whole PM2.5-10, but not in whole PM2.5, is heat-labile, consistent with it being endotoxin. A heat treatment protocol for the gradual inactivation of biological materials in the PM fractions over a measurable time course was developed and optimized in this study using pure lipopolysaccharide (LPS) as a model system. The time course of heat inactivation of pure LPS and of endotoxin activity in PM2.5-10 as measured by Limulus bioassay is identical. The active material in both PM2.5-10 and PM2.5 remained in the insoluble fraction when the whole PM samples were extracted with physiological saline solution. Histological analysis of lung sections from mice instilled with PM2.5-10 or PM2.5 showed evidence of inflammation consistent with the cellular responses observed in lung lavage fluid. The major pro-inflammatory components present in endotoxin-rich PM were found in the insoluble fraction of PM2.5-10; however, in contrast with PM2.5-10 isolated from ambient air in the Central Valley of California, the active components in the insoluble fraction were heat-labile.

  18. Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study

    OpenAIRE

    Tuinman, Pieter R; Vlaar, Alexander P; Cornet, Alexander D.; Hofstra, Jorrit J.; Levi, Marcel; Meijers, Joost CM; Beishuizen, Albertus; Schultz, Marcus J; Groeneveld, AB Johan; Juffermans, Nicole P.

    2011-01-01

    Introduction Blood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but cause-and-effect relations remain unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulation occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI). Methods We performed a case control study in a mixed medical-surgical intensive care unit of a university...

  19. LPS-induced lung inflammation in marmoset monkeys - an acute model for anti-inflammatory drug testing.

    Directory of Open Access Journals (Sweden)

    Sophie Seehase

    Full Text Available Increasing incidence and substantial morbidity and mortality of respiratory diseases requires the development of new human-specific anti-inflammatory and disease-modifying therapeutics. Therefore, new predictive animal models that closely reflect human lung pathology are needed. In the current study, a tiered acute lipopolysaccharide (LPS-induced inflammation model was established in marmoset monkeys (Callithrix jacchus to reflect crucial features of inflammatory lung diseases. Firstly, in an ex vivo approach marmoset and, for the purposes of comparison, human precision-cut lung slices (PCLS were stimulated with LPS in the presence or absence of the phosphodiesterase-4 (PDE4 inhibitor roflumilast. Pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α and macrophage inflammatory protein-1 beta (MIP-1β were measured. The corticosteroid dexamethasone was used as treatment control. Secondly, in an in vivo approach marmosets were pre-treated with roflumilast or dexamethasone and unilaterally challenged with LPS. Ipsilateral bronchoalveolar lavage (BAL was conducted 18 hours after LPS challenge. BAL fluid was processed and analyzed for neutrophils, TNF-α, and MIP-1β. TNF-α release in marmoset PCLS correlated significantly with human PCLS. Roflumilast treatment significantly reduced TNF-α secretion ex vivo in both species, with comparable half maximal inhibitory concentration (IC(50. LPS instillation into marmoset lungs caused a profound inflammation as shown by neutrophilic influx and increased TNF-α and MIP-1β levels in BAL fluid. This inflammatory response was significantly suppressed by roflumilast and dexamethasone. The close similarity of marmoset and human lungs regarding LPS-induced inflammation and the significant anti-inflammatory effect of approved pharmaceuticals assess the suitability of marmoset monkeys to serve as a promising model for studying anti-inflammatory drugs.

  20. Enhanced allergic responsiveness after early childhood infection with respiratory viruses: Are long-lived alternatively activated macrophages the missing link?

    Science.gov (United States)

    Keegan, Achsah D; Shirey, Kari Ann; Bagdure, Dayanand; Blanco, Jorge; Viscardi, Rose M; Vogel, Stefanie N

    2016-07-01

    Early childhood infection with respiratory viruses, including human rhinovirus, respiratory syncytial virus (RSV) and influenza, is associated with an increased risk of allergic asthma and severe exacerbation of ongoing disease. Despite the long recognition of this relationship, the mechanism linking viral infection and later susceptibility to allergic lung inflammation is still poorly understood. We discuss the literature and provide new evidence demonstrating that these viruses induce the alternative activation of macrophages. Alternatively activated macrophages (AAM) induced by RSV or influenza infection persisted in the lungs of mice up to 90 days after initial viral infection. Several studies suggest that AAM contribute to allergic inflammatory responses, although their mechanism of action is unclear. In this commentary, we propose that virus-induced AAM provide a link between viral infection and enhanced responses to inhaled allergens. PMID:27178560

  1. Biodiesel versus diesel exposure: Enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung

    Energy Technology Data Exchange (ETDEWEB)

    Yanamala, Naveena, E-mail: wqu1@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Hatfield, Meghan K., E-mail: wla4@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Farcas, Mariana T., E-mail: woe7@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Schwegler-Berry, Diane [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Hummer, Jon A., E-mail: qzh3@cdc.gov [Office of Mine Safety and Health Research/NIOSH/CDC, Pittsburgh, PA 15236 (United States); Shurin, Michael R., E-mail: shurinmr@upmc.edu [Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA (United States); Birch, M. Eileen, E-mail: mib2@cdc.gov [NIOSH/CDC, 4676 Columbia Parkway, Cincinnati, OH 45226 (United States); Gutkin, Dmitriy W., E-mail: dwgutkin@hotmail.com [Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA (United States); Kisin, Elena, E-mail: edk8@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Kagan, Valerian E., E-mail: kagan@pitt.edu [Department of Environmental and Occupational Health, University of Pittsburgh, PA (United States); Bugarski, Aleksandar D., E-mail: zjl1@cdc.gov [Office of Mine Safety and Health Research/NIOSH/CDC, Pittsburgh, PA 15236 (United States); Shvedova, Anna A., E-mail: ats1@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Department Physiology and Pharmacology, WVU, Morgantown, WV 26505 (United States)

    2013-10-15

    The use of biodiesel (BD) or its blends with petroleum diesel (D) is considered to be a viable approach to reduce occupational and environmental exposures to particulate matter (PM). Due to its lower particulate mass emissions compared to D, use of BD is thought to alleviate adverse health effects. Considering BD fuel is mainly composed of unsaturated fatty acids, we hypothesize that BD exhaust particles could induce pronounced adverse outcomes, due to their ability to readily oxidize. The main objective of this study was to compare the effects of particles generated by engine fueled with neat BD and neat petroleum-based D. Biomarkers of tissue damage and inflammation were significantly elevated in lungs of mice exposed to BD particulates. Additionally, BD particulates caused a significant accumulation of oxidatively modified proteins and an increase in 4-hydroxynonenal. The up-regulation of inflammatory cytokines/chemokines/growth factors was higher in lungs upon BD particulate exposure. Histological evaluation of lung sections indicated presence of lymphocytic infiltrate and impaired clearance with prolonged retention of BD particulate in pigment laden macrophages. Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. - Highlights: • Exposure of mice to BDPM caused higher pulmonary toxicity compared to DPM. • Oxidative stress and inflammation were higher in BD vs to D exposed mice. • Inflammatory lymphocyte infiltrates were seen only in lungs of mice exposed to BD. • Ineffective clearance, prolonged PM retention was present only after BD exposure.

  2. Interleukin-10 plays a key role in the modulation of neutrophils recruitment and lung inflammation during infection by Streptococcus pneumoniae.

    Science.gov (United States)

    Peñaloza, Hernán F; Nieto, Pamela A; Muñoz-Durango, Natalia; Salazar-Echegarai, Francisco J; Torres, Javiera; Parga, María J; Alvarez-Lobos, Manuel; Riedel, Claudia A; Kalergis, Alexis M; Bueno, Susan M

    2015-09-01

    Streptococcus pneumoniae is a major aetiological agent of pneumonia worldwide, as well as otitis media, sinusitis, meningitis and sepsis. Recent reports have suggested that inflammation of lungs due to S. pneumoniae infection promotes bacterial dissemination and severe disease. However, the contribution of anti-inflammatory molecules to the pathogenesis of S. pneumoniae remains unknown. To elucidate whether the production of the anti-inflammatory cytokine interleukin-10 (IL-10) is beneficial or detrimental for the host during pneumococcal pneumonia, we performed S. pneumoniae infections in mice lacking IL-10 (IL-10(-/-) mice). The IL-10(-/-) mice showed increased mortality, higher expression of pro-inflammatory cytokines, and an exacerbated recruitment of neutrophils into the lungs after S. pneumoniae infection. However, IL-10(-/-) mice showed significantly lower bacterial loads in lungs, spleen, brain and blood, when compared with mice that produced this cytokine. Our results support the notion that production of IL-10 during S. pneumoniae infection modulates the expression of pro-inflammatory cytokines and the infiltration of neutrophils into the lungs. This feature of IL-10 is important to avoid excessive inflammation of tissues and to improve host survival, even though bacterial dissemination is less efficient in the absence of this cytokine. PMID:26032199

  3. Evidence for chronic inflammation as a component of the interstitial lung disease associated with progressive systemic sclerosis

    International Nuclear Information System (INIS)

    Progressive systemic sclerosis (PSS) is a generalized disorder characterized by fibrosis of many organs including the lung parenchyma. Unlike most other interstitial disorders, traditional concepts of the interstitial lung disease associated with PSS have held it to be a ''pure'' fibrotic disorder without a significant inflammatory component. To directly evaluate whether an active alveolitis is associated with this disorder, patients with chronic interstitial lung disease and PSS were studied by open lung biopsy, gallium-67 scanning, and bronchoalveolar lavage. Histologic evaluation of the biopsies demonstrated that the interstitial fibrosis of PSS is clearly associated with the presence of macrophages, lymphocytes, and polymorphonuclear leukocytes, both in the interstitium and on the alveolar epithelial surface. Gallium-67 scans were positive in 77% of the patients, showing diffuse, primarily lower zone uptake, suggestive of active inflammation. Consistent with the histologic findings, bronchoalveolar lavage studies demonstrated a mild increase in the proportions of neutrophils and eosinophils with occasional increased numbers of lymphocytes. Importantly, alveolar macrophages from patients with PSS showed increased release of fibronectin and alveolar-macrophage-derived growth factor, mediators that together stimulate lung fibroblasts to proliferate, thus suggesting at least one mechanism modulating the lung fibrosis of these patients

  4. Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice

    International Nuclear Information System (INIS)

    Silica exposure can cause lung inflammation and fibrosis, known as silicosis. Interleukin-17A (IL-17A) and Th17 cells play a pivotal role in controlling inflammatory diseases. However, the roles of IL-17A and Th17 cells in the progress of silica-induced inflammation and fibrosis are poorly understood. This study explored the effects of IL-17A on silica-induced inflammation and fibrosis. We used an anti-mouse IL-17A antibody to establish an IL-17A-neutralized mice model, and mice were exposed to silica to establish an experimental silicosis model. We showed that IL-17A neutralization delayed neutrophil accumulation and progression of silica-induced lung inflammation and fibrosis. IL-17A neutralization reduced the percentage of Th17 in CD4 + T cells, decreased IL-6 and IL-1β expression, and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A delayed silica-induced Th1/Th2 immune and autoimmune responses. These results suggest that IL-17A neutralization alleviates early stage silica-induced lung inflammation and delays progression of silica-induced lung inflammation and fibrosis. Neutralization of IL-17A suppressed Th17 cell development by decreasing IL-6 and/or IL-1β and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A also delayed the Th1/Th2 immune response during silica-induced lung inflammation and fibrosis. IL-17A may play a pivotal role in the early phase of silica-induced inflammation and may mediate the Th immune response to influence silica-induced lung inflammation and fibrosis in mice. - Highlights: • Neutralization of IL-17A alleviated silica-induced lung inflammation of early stage. • Neutralization of IL-17A decreased Th17 cells and increased Tregs. • IL-17A mediated the reciprocal relationship of Th17/Tregs by IL-6 and/or IL-1β. • Neutralization of IL-17A delayed silica-induced Th1/Th2 immune response. • Neutralization of IL-17A delayed silica-induced lung

  5. Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ying; Li, Cuiying [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Weng, Dong [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai (China); Song, Laiyu; Tang, Wen; Dai, Wujing; Yu, Ye; Liu, Fangwei; Zhao, Ming; Lu, Chunwei [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Chen, Jie, E-mail: chenjie@mail.cmu.edu.cn [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China)

    2014-02-15

    Silica exposure can cause lung inflammation and fibrosis, known as silicosis. Interleukin-17A (IL-17A) and Th17 cells play a pivotal role in controlling inflammatory diseases. However, the roles of IL-17A and Th17 cells in the progress of silica-induced inflammation and fibrosis are poorly understood. This study explored the effects of IL-17A on silica-induced inflammation and fibrosis. We used an anti-mouse IL-17A antibody to establish an IL-17A-neutralized mice model, and mice were exposed to silica to establish an experimental silicosis model. We showed that IL-17A neutralization delayed neutrophil accumulation and progression of silica-induced lung inflammation and fibrosis. IL-17A neutralization reduced the percentage of Th17 in CD4 + T cells, decreased IL-6 and IL-1β expression, and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A delayed silica-induced Th1/Th2 immune and autoimmune responses. These results suggest that IL-17A neutralization alleviates early stage silica-induced lung inflammation and delays progression of silica-induced lung inflammation and fibrosis. Neutralization of IL-17A suppressed Th17 cell development by decreasing IL-6 and/or IL-1β and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A also delayed the Th1/Th2 immune response during silica-induced lung inflammation and fibrosis. IL-17A may play a pivotal role in the early phase of silica-induced inflammation and may mediate the Th immune response to influence silica-induced lung inflammation and fibrosis in mice. - Highlights: • Neutralization of IL-17A alleviated silica-induced lung inflammation of early stage. • Neutralization of IL-17A decreased Th17 cells and increased Tregs. • IL-17A mediated the reciprocal relationship of Th17/Tregs by IL-6 and/or IL-1β. • Neutralization of IL-17A delayed silica-induced Th1/Th2 immune response. • Neutralization of IL-17A delayed silica-induced lung

  6. Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

    International Nuclear Information System (INIS)

    Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS −/− mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS −/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS −/− mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS −/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS −/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning. -- Highlights: ► Lung injury, inflammation and oxidative stress are induced by the model vesicant CEES ► RNS generated via iNOS are important in the CEES-induced pulmonary toxicity ► iNOS −/− mice are protected from CEES-induced lung toxicity and

  7. Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

    Energy Technology Data Exchange (ETDEWEB)

    Sunil, Vasanthi R., E-mail: sunilvr@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy Piscataway, NJ (United States); Shen, Jianliang; Patel-Vayas, Kinal; Gow, Andrew J. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy Piscataway, NJ (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy Piscataway, NJ (United States)

    2012-05-15

    Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS −/− mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS −/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS −/− mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS −/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS −/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning. -- Highlights: ► Lung injury, inflammation and oxidative stress are induced by the model vesicant CEES ► RNS generated via iNOS are important in the CEES-induced pulmonary toxicity ► iNOS −/− mice are protected from CEES-induced lung toxicity and

  8. Correlation of measurable serum markers of inflammation with lung levels following bilateral femur fracture in a rat model

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    Benjamin W Sears

    2010-08-01

    Full Text Available Benjamin W Sears1, Dustin Volkmer1, Sherri Yong2, Ryan D Himes1, Kristen Lauing1, Michele Morgan1, Michael D Stover1, John J Callaci11Department of Orthopaedics, 2Department of Pathology, Loyola University Medical Center, Maywood, IL, USAIntroduction: Evaluation of the systemic inflammatory status following major orthopedic trauma has become an important adjunct in basing post-injury clinical decisions. In the present study, we examined the correlation of serum and lung inflammatory marker levels following bilateral femur fracture.Materials and methods: 45 Sprague Dawley rats underwent sham operation or bilateral femoral intramedullary pinning and mid-diaphyseal closed fracture via blunt guillotine. Animals were euthanized at specific time points after injury. Serum and lung tissue were collected, and 24 inflammatory markers were analyzed by immunoassay. Lung histology was evaluated by a blinded pathologist.Results: Bilateral femur fracture significantly increased serum markers of inflammation including interleukin (IL-2, IL-6, IL-10, GM-CSF, KC/GRO, MCP-1, and WBC. Femur fracture ­significantly increased serum and lung levels of IL-1a and KC/GRO at 6 hours. Lung levels of IL-6 ­demonstrated a trend towards significance. Histologic changes in pulmonary tissue after fracture included pulmonary edema and bone elements including cellular hematopoietic cells, bone fragments and marrow emboli.Discussion and conclusion: Our results indicate that bilateral femur fracture with fixation in rats results in increases in serum markers of inflammation. Among the inflammatory markers measured, rise in the serum KC/GRO (CINC-1, a homolog to human IL-8, correlated with elevated levels of lung KC/GRO. Ultimately, analysis of serum levels of KC/GRO (CINC-1, or human IL-8, may be a useful adjunct to guide clinical decisions regarding surgical timing.Keywords: blunt trauma, injury, cytokine, IL-8, bone marrow emboli

  9. Role of CD14 in a mouse model of acute lung inflammation induced by different lipopolysaccharide chemotypes.

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    Adam A Anas

    Full Text Available BACKGROUND: Recognition of lipopolysaccharide (LPS is required for effective defense against invading gram-negative bacteria. Recently, in vitro studies revealed that CD14 is required for activation of the myeloid differentiation factor (MyD88-dependent Toll-like receptor (TLR4 signaling pathway by smooth (S-LPS, but not by rough (R-LPS. The present study investigated the role of CD14 in induction of lung inflammation in mice by these different LPS chemotypes. METHODOLOGY/RESULTS: Neutrophil accumulation and tumor necrosis factor (TNF release in bronchoalveolar lavage fluid were determined 6 hours after intranasal treatment of wild type (WT and CD14 knock-out (KO mice with different doses S-LPS or R-LPS. The contribution of CD14 to lung inflammation induced by S-LPS or R-LPS depended on the LPS dose. At low doses, S-LPS and R-LPS induced neutrophil influx in a CD14-dependent manner. Low dose S-LPS-induced cytokine release also depended on CD14. Strikingly, neutrophil influx and TNF release induced by high dose S-LPS or R-LPS was diminished in the presence of CD14. Intranasal administration of sCD14 to CD14 KO mice treated with S-LPS partially reversed the inflammatory response to the response observed in WT mice. CONCLUSIONS: In conclusion, CD14 modulates effects of both S-LPS and R-LPS within the lung in a similar way. Except for R-LPS-induced TNF release, S-LPS and R-LPS at low dose induced acute lung inflammation in a CD14-dependent manner, while the inflammatory response triggered by high dose S-LPS or R-LPS was diminished by CD14.

  10. Prevention of bleomycin-induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment.

    Science.gov (United States)

    Rosa, Arianna Carolina; Pini, Alessandro; Lucarini, Laura; Lanzi, Cecilia; Veglia, Eleonora; Thurmond, Robin L; Stark, Holger; Masini, Emanuela

    2014-11-01

    Pulmonary fibrosis, a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components, is a major therapeutic challenge for which new therapeutic strategies are warranted. Cyclooxygenase (COX) inhibitors have been previously utilized to reduce inflammation. Histamine H4 receptor (H4R), largely expressed in hematopoietic cells, has been identified as a novel target for inflammatory and immune disorders. The aim of this study was to evaluate the effect of JNJ7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine), a selective H4R antagonist, and naproxen, a well known nonsteroidal anti-inflammatory drug, and their combination in a murine model of bleomycin-induced fibrosis. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated by micro-osmotic pump with vehicle, JNJ7777120 (40 mg/kg b.wt.), naproxen (21 mg/kg b.wt.), or a combination of both. Airway resistance to inflation, an index of lung stiffness, was assessed, and lung specimens were processed for inflammation, oxidative stress, and fibrosis markers. Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing COX-2 and myeloperoxidase expression and activity and thiobarbituric acid-reactive substance and 8-hydroxy-2'-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-β, collagen deposition, relative goblet cell number, and smooth muscle layer thickness. Our results demonstrate that both JNJ7777120 and naproxen exert an anti-inflammatory and antifibrotic effect that is increased by their combination, which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis. PMID:25185215

  11. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    International Nuclear Information System (INIS)

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS+ and cyclooxygenase-2+) and alternatively activated profibrotic (YM-1+ and galectin-3+) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute lung injury induced by

  12. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Malaviya, Rama; Venosa, Alessandro [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Hall, LeRoy [Drug Safety Sciences, Johnson and Johnson, Raritan, NJ 08869 (United States); Gow, Andrew J. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sinko, Patrick J. [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2012-12-15

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute

  13. Suppression of basal and carbon nanotube-induced oxidative stress, inflammation and fibrosis in mouse lungs by Nrf2.

    Science.gov (United States)

    Dong, Jie; Ma, Qiang

    2016-08-01

    The lungs are susceptible to oxidative damage by inhaled pathogenic agents, including multi-walled carbon nanotubes (MWCNT). The nuclear factor erythroid 2-related factor 2 (Nrf2) has been implicated in regulating the body's defense against oxidative stress. Here, we analyzed the function of Nrf2 in the lungs. Under a basal condition, Nrf2 knockout (KO) mice showed apparent pulmonary infiltration of granulocytes, macrophages and B and T lymphocytes, and elevated deposition of collagen fibers. Exposure to MWCNT (XNRI MWNT-7, Mitsui, Tokyo, Japan) by pharyngeal aspiration elicited rapid inflammatory and fibrotic responses in a dose (0, 5, 20 and 40 μg) and time (1, 3, 7 and 14 d)-dependent manner. The responses reached peak levels on day 7 post-exposure to 40 μg MWCNT, evidenced by massive inflammatory infiltration and formation of inflammatory and fibrotic foci, which were more evident in Nrf2 KO than wild-type (WT) lungs. At the molecular level, Nrf2 protein was detected at a low level under a basal condition, and was dramatically increased by MWCNT in WT, but not Nrf2 KO, lungs. Activation of Nrf2 was inversely correlated with induced expression of fibrosis marker genes and profibrotic cytokines. Furthermore, the levels of ROS and oxidative stress were remarkably higher in Nrf2 KO than WT lungs under a physiological condition, and were dramatically increased by MWCNT, with the increase significantly more striking in KO lungs. The findings reveal that Nrf2 plays an important role in suppressing the basal and MWCNT-induced oxidant production, inflammation and fibrosis in the lungs, thereby protecting against MWCNT lung toxicity. PMID:26592091

  14. Ambient air pollution and allergic diseases in children

    Directory of Open Access Journals (Sweden)

    Byoung-Ju Kim

    2012-06-01

    Full Text Available The prevalence of allergic diseases has increased worldwide, a phenomenon that can be largely attributed to environmental effects. Among environmental factors, air pollution due to traffic is thought to be a major threat to childhood health. Residing near busy roadways is associated with increased asthma hospitalization, decreased lung function, and increased prevalence and severity of wheezing and allergic rhinitis. Recently, prospective cohort studies using more accurate measurements of individual exposure to air pollution have been conducted and have provided definitive evidence of the impact of air pollution on allergic diseases. Particulate matter and groundlevel ozone are the most frequent air pollutants that cause harmful effects, and the mechanisms underlying these effects may be related to oxidative stress. The reactive oxidative species produced in response to air pollutants can overwhelm the redox system and damage the cell wall, lipids, proteins, and DNA, leading to airway inflammation and hyper-reactivity. Pollutants may also cause harmful effects via epigenetic mechanisms, which control the expression of genes without changing the DNA sequence itself. These mechanisms are likely to be a target for the prevention of allergies. Further studies are necessary to identify children at risk and understand how these mechanisms regulate gene-environment interactions. This review provides an update of the current understanding on the impact of air pollution on allergic diseases in children and facilitates the integration of issues regarding air pollution and allergies into pediatric practices, with the goal of improving pediatric health.

  15. Platelets promote allergic asthma through the expression of CD154.

    Science.gov (United States)

    Tian, Jun; Zhu, Tianyi; Liu, Juan; Guo, Zhenhong; Cao, Xuetao

    2015-11-01

    Platelet activation is associated with multiple immune responses and the pathogenesis of various immune-related diseases. However, the exact role and the underlying mechanism of platelets in the progression of allergic asthma remain largely unclear. In this study, we demonstrate that during antigen sensitization, platelets can be activated by ovalbumin (OVA) aerosol via the upregulation of CD154 (CD40L) expression. Platelet transfer promoted allergic asthma progression by inducing more severe leukocyte infiltration and lung inflammation, elevated IgE production and strengthened T helper 2 (Th2) responses in asthma-induced mice. Accordingly, platelet depletion compromised allergic asthma progression. Cd154-deficient platelets failed to promote asthma development, indicating the requirement of CD154 for platelets to promote asthma progression. The mechanistic study showed that platelets inhibited the induction of Foxp3(+) regulatory T cells both in vivo and in vitro at least partially through CD154, providing an explanation for the increase of Th2 responses by platelet transfer. Our study reveals the previously unknown role of platelet CD154 in the promotion of asthma progression by polarizing Th2 responses and inhibiting regulatory T-cell generation and thus provides a potential clue for allergic disease interventions. PMID:25418472

  16. Treatment Evaluation with Mometasone Furoate, Alone or in Combination with Desloratadine/ Montelukast in Moderate Severe Allergic Rhinitis

    Directory of Open Access Journals (Sweden)

    Florincescu-Gheorghe Nona-Aura

    2014-06-01

    Full Text Available Introduction: Allergic rhinitis is one of the most common allergic diseases, characterized by the inflammation of the nasal mucosa. Eosinophils play a predominant pro-inflammatory role in allergic inflammation. This study assesses the effect of mometasone furoate alone or in combination with desloratadine/montelukast in patients with moderate-severe allergic rhinitis.

  17. Mesenchymal Stem Cell Attenuates Neutrophil-predominant Inflammation and Acute Lung Injury in an In Vivo Rat Model of Ventilator-induced Lung Injury

    Directory of Open Access Journals (Sweden)

    Tian-Shun Lai

    2015-01-01

    Full Text Available Background: Subsequent neutrophil (polymorphonuclear neutrophil [PMN]-predominant inflammatory response is a predominant feature of ventilator-induced lung injury (VILI, and mesenchymal stem cell (MSC can improve mice survival model of endotoxin-induced acute lung injury, reduce lung impairs, and enhance the repair of VILI. However, whether MSC could attenuate PMN-predominant inflammatory in the VILI is still unknown. This study aimed to test whether MSC intervention could attenuate the PMN-predominate inflammatory in the mechanical VILI. Methods: Sprague-Dawley rats were ventilated for 2 hours with large tidal volume (20 mL/kg. MSCs were given before or after ventilation. The inflammatory chemokines and gas exchange were observed and compared dynamically until 4 hours after ventilation, and pulmonary pathological change and activation of PMN were observed and compared 4 hours after ventilation. Results: Mechanical ventilation (MV caused significant lung injury reflected by increasing in PMN pulmonary sequestration, inflammatory chemokines (tumor necrosis factor-alpha, interleukin-6 and macrophage inflammatory protein 2 in the bronchoalveolar lavage fluid, and injury score of the lung tissue. These changes were accompanied with excessive PMN activation which reflected by increases in PMN elastase activity, production of radical oxygen series. MSC intervention especially pretreatment attenuated subsequent lung injury, systemic inflammation response and PMN pulmonary sequestration and excessive PMN activation initiated by injurious ventilation. Conclusions: MV causes profound lung injury and PMN-predominate inflammatory responses. The protection effect of MSC in the VILI rat model is related to the suppression of the PMN activation.

  18. Mesenchymal Stem Cell Attenuates Neutrophil-predominant Inflammation and Acute Lung Injury in an In Vivo Rat Model of Ventilator-induced Lung Injury

    Institute of Scientific and Technical Information of China (English)

    Tian-Shun Lai; Zhi-Hong Wang; Shao-Xi Cai

    2015-01-01

    Background:Subsequent neutrophil (polymorphonuclear neutrophil [PMN])-predominant inflammatory response is a predominant feature of ventilator-induced lung injury (VILI),and mesenchymal stem cell (MSC) can improve mice survival model of endotoxin-induced acute lung injury,reduce lung impairs,and enhance the repair of VILI.However,whether MSC could attenuate PMN-predominant inflammatory in the VILI is still unknown.This study aimed to test whether MSC intervention could attenuate the PMN-predominate inflammatory in the mechanical VILI.Methods:Sprague-Dawley rats were ventilated for 2 hours with large tidal volume (20 mL/kg).MSCs were given before or after ventilation.The inflammatory chemokines and gas exchange were observed and compared dynamically until 4 hours after ventilation,and pulmonary pathological change and activation of PMN were observed and compared 4 hours after ventilation.Results:Mechanical ventilation (MV) caused significant lung injury reflected by increasing in PMN pulmonary sequestration,inflammatory chemokines (tumor necrosis factor-alpha,interleukin-6 and macrophage inflammatory protein 2) in the bronchoalveolar lavage fluid,and injury score of the lung tissue.These changes were accompanied with excessive PMN activation which reflected by increases in PMN elastase activity,production of radical oxygen series.MSC intervention especially pretreatment attenuated subsequent lung injury,systemic inflammation response and PMN pulmonary sequestration and excessive PMN activation initiated by injurious ventilation.Conclusions:MV causes profound lung injury and PMN-predominate inflammatory responses.The protection effect of MSC in the VILI rat model is related to the suppression of the PMN activation.

  19. Uvaol attenuates pleuritis and eosinophilic inflammation in ovalbumin-induced allergy in mice.

    Science.gov (United States)

    Agra, Lais Costa; Lins, Marvin Paulo; da Silva Marques, Patrícia; Smaniotto, Salete; Bandeira de Melo, Christianne; Lagente, Vincent; Barreto, Emiliano

    2016-06-01

    Uvaol, a triterpene present in olives and virgin olive oil, has been shown to possess anti-inflammatory properties and antioxidant effects. However, until now, no studies have demonstrated its potential effects on allergic inflammation. The aim of this study was to evaluate the anti-inflammatory effects of uvaol in a mouse model of allergy characterized by eosinophil-dominant inflammation in actively sensitized mice. The anti-inflammatory effect of uvaol was analyzed in two murine models of allergic inflammation (pleurisy and asthma). In these models, Swiss mice were sensitized and challenged with ovalbumin (OVA). In the pleurisy model, the pleural eosinophilic inflammation and IL-5 concentrations were examined 24h after the OVA challenge, while in the asthma model were examined the airway inflammation via bronchoalveolar lavage (BAL) fluid cytology and lung histopathology analyses. Our results showed that uvaol decreased the accumulation of eosinophils and the concentration of IL-5 in pleural effluent. Uvaol also demonstrated important anti-inflammatory activity by inhibiting production of IL-5 and influx of leukocytes, mainly of eosinophils, in BAL fluid, but without interfering with levels of reactive oxygen species in leukocytes. Moreover, the eosinophil infiltration, mucus production, number of alveoli that collapsed, and IL-5 levels in the lung were clearly decreased by uvaol treatment. These findings indicate that uvaol can be a good candidate for the treatment of allergic inflammation by inhibiting eosinophil influx and IL-5 production in ovalbumin-induced allergy. PMID:27038519

  20. Innate cellular sources of interleukin-17A regulate macrophage accumulation in cigarette- smoke-induced lung inflammation in mice.

    Science.gov (United States)

    Bozinovski, Steven; Seow, Huei Jiunn; Chan, Sheau Pyng Jamie; Anthony, Desiree; McQualter, Jonathan; Hansen, Michelle; Jenkins, Brendan J; Anderson, Gary P; Vlahos, Ross

    2015-11-01

    Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD). Interleukin-17A (IL-17A) is a pivotal cytokine that regulates lung immunity and inflammation. The aim of the present study was to investigate how IL-17A regulates CS-induced lung inflammation in vivo. IL-17A knockout (KO) mice and neutralization of IL-17A in wild-type (WT) mice reduced macrophage and neutrophil recruitment and chemokine (C-C motif) ligand 2 (CCL2), CCL3 and matrix metalloproteinase (MMP)-12 mRNA expression in response to acute CS exposure. IL-17A expression was increased in non-obese diabetic (NOD) severe combined immunodeficiency SCID) mice with non-functional B- and T-cells over a 4-week CS exposure period, where macrophages accumulated to the same extent as in WT mice. Gene expression analysis by QPCR (quantitative real-time PCR) of isolated immune cell subsets detected increased levels of IL-17A transcript in macrophages, neutrophils and NK/NKT cells in the lungs of CS-exposed mice. In order to further explore the relative contribution of innate immune cellular sources, intracellular IL-17A staining was performed. In the present study, we demonstrate that CS exposure primes natural killer (NK), natural killer T (NKT) and γδ T-cells to produce more IL-17A protein and CS alone increased the frequency of IL17+ γδ T-cells in the lung, whereas IL-17A protein was not detected in macrophages and neutrophils. Our data suggest that activation of innate cellular sources of IL-17A is an essential mediator of macrophage accumulation in CS-exposed lungs. Targeting non-conventional T-cell sources of IL-17A may offer an alternative strategy to reduce pathogenic macrophages in COPD. PMID:26201093

  1. Effect of bone marrow derived mesenchymal stem cells on lung pathology and inflammation in ovalbumin-induced asthma in mouse

    Directory of Open Access Journals (Sweden)

    Maryam Mohammadian

    2016-01-01

    Full Text Available Objective(s:Bone marrow-derived mesenchymal stem cells (BMSCs have attracted significant interest to treat asthma and its complication. In this study, the effects of BMSCs on lung pathology and inflammation in an ovalbumin-induced asthma model in mouse were examined. Materials and Methods:BALB/c mice were divided into three groups: control group (animals were not sensitized, asthma group (animals were sensitized by ovalbumin, asthma+BMSC group (animals were sensitized by ovalbumin and treated with BMSCs. BMSCs were isolated and characterized and then labeled with Bromodeoxyuridine (BrdU. After that the cells transferred into asthmatic mice. Histopathological changes of the airways, BMSCs migration and total and differential white blood cell (WBC count in bronchoalveolar lavage (BAL fluid were evaluated. Results:A large number of BrdU-BMSCs were found in the lungs of mice treated with BMSCs. The histopathological changes, BAL total WBC counts and the percentage of neutrophils and eosinophils were increased in asthma group compared to the control group. Treatment with BMSCs significantly decreased airway pathological indices, inflammatory cell infiltration, and also goblet cell hyperplasia. Conclusion:The results of this study revealed that BMSCs therapy significantly suppressed the lung pathology and inflammation in the ovalbumin induced asthma model in mouse.

  2. Allergic sensitization

    DEFF Research Database (Denmark)

    van Ree, Ronald; Hummelshøj, Lone; Plantinga, Maud; Poulsen, Lars K.; Swindle, Emily

    2014-01-01

    Allergic sensitization is the outcome of a complex interplay between the allergen and the host in a given environmental context. The first barrier encountered by an allergen on its way to sensitization is the mucosal epithelial layer. Allergic inflammatory diseases are accompanied by increased...... play a dominant role, B cells switch to IgE-production, a process that is more effective at young age. IgE-producing plasma cells have been shown to be long-lived, hiding in the bone-marrow or inflammatory tissues where they cannot easily be targeted by therapeutic intervention. Allergic sensitization...

  3. Proteomic Analysis of Lung Tissue in a Rat Acute Lung Injury Model: Identification of PRDX1 as a Promoter of Inflammation

    Directory of Open Access Journals (Sweden)

    Dongdong Liu

    2014-01-01

    Full Text Available Acute respiratory distress syndrome (ARDS remains a high morbidity and mortality disease entity in critically ill patients, despite decades of numerous investigations into its pathogenesis. To obtain global protein expression changes in acute lung injury (ALI lung tissues, we employed a high-throughput proteomics method to identify key components which may be involved in the pathogenesis of ALI. In the present study, we analyzed lung tissue proteomes of Pseudomonas aeruginosa-induced ALI rats and identified eighteen proteins whose expression levels changed more than twofold as compared to normal controls. In particular, we found that PRDX1 expression in culture medium was elevated by a lipopolysaccharide (LPS challenge in airway epithelial cells in vitro. Furthermore, overexpression of PRDX1 increased the expression of proinflammatory cytokines interleukin-6 (IL-6, interleukin-8 (IL-8, and tumor necrosis factor-α (TNF-α, whereas knockdown of PRDX1 led to downregulated expression of cytokines induced by LPS. In conclusion, our findings provide a global alteration in the proteome of lung tissues in the ALI rat model and indicate that PRDX1 may play a critical role in the pathogenesis of ARDS by promoting inflammation and represent a novel strategy for the development of new therapies against ALI.

  4. Pulmonary CD103 expression regulates airway inflammation in asthma.

    Science.gov (United States)

    Bernatchez, Emilie; Gold, Matthew J; Langlois, Anick; Lemay, Anne-Marie; Brassard, Julyanne; Flamand, Nicolas; Marsolais, David; McNagny, Kelly M; Blanchet, Marie-Renee

    2015-04-15

    Although CD103(+) cells recently emerged as key regulatory cells in the gut, the role of CD103 ubiquitous expression in the lung and development of allergic airway disease has never been studied. To answer this important question, we evaluated the response of Cd103(-/-) mice in two separate well-described mouse models of asthma (ovalbumin and house dust mite extract). Pulmonary inflammation was assessed by analysis of bronchoalveolar lavage content, histology, and cytokine response. CD103 expression was analyzed on lung dendritic cells and T cell subsets by flow cytometry. Cd103(-/-) mice exposed to antigens developed exacerbated lung inflammation, characterized by increased eosinophilic infiltration, severe tissue inflammation, and altered cytokine response. In wild-type mice exposed to house dust mite, CD103(+) dendritic cells are increased in the lung and an important subset of CD4(+) T cells, CD8(+) T cells, and T regulatory cells express CD103. Importantly, Cd103(-/-) mice presented a deficiency in the resolution phase of inflammation, which supports an important role for this molecule in the control of inflammation severity. These results suggest an important role for CD103 in the control of airway inflammation in asthma. PMID:25681437

  5. Long-term activation of TLR3 by Poly(I:C induces inflammation and impairs lung function in mice

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    Alexopoulou Lena

    2009-06-01

    Full Text Available Abstract Background The immune mechanisms associated with infection-induced disease exacerbations in asthma and COPD are not fully understood. Toll-like receptor (TLR 3 has an important role in recognition of double-stranded viral RNA, which leads to the production of various inflammatory mediators. Thus, an understanding of TLR3 activation should provide insight into the mechanisms underlying virus-induced exacerbations of pulmonary diseases. Methods TLR3 knock-out (KO mice and C57B6 (WT mice were intranasally administered repeated doses of the synthetic double stranded RNA analog poly(I:C. Results There was a significant increase in total cells, especially neutrophils, in BALF samples from poly(I:C-treated mice. In addition, IL-6, CXCL10, JE, KC, mGCSF, CCL3, CCL5, and TNFα were up regulated. Histological analyses of the lungs revealed a cellular infiltrate in the interstitium and epithelial cell hypertrophy in small bronchioles. Associated with the pro-inflammatory effects of poly(I:C, the mice exhibited significant impairment of lung function both at baseline and in response to methacholine challenge as measured by whole body plethysmography and an invasive measure of airway resistance. Importantly, TLR3 KO mice were protected from poly(I:C-induced changes in lung function at baseline, which correlated with milder inflammation in the lung, and significantly reduced epithelial cell hypertrophy. Conclusion These findings demonstrate that TLR3 activation by poly(I:C modulates the local inflammatory response in the lung and suggest a critical role of TLR3 activation in driving lung function impairment. Thus, TLR3 activation may be one mechanism through which viral infections contribute toward exacerbation of respiratory disease.

  6. Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury

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    Boersma Hester

    2009-04-01

    Full Text Available Abstract Background Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD, a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome. Methods Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50–150 mg/kg body weight/day; injected subcutaneously and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue. Results Prophylactic treatment with an optimal dose of sildenafil (2 × 50 mg/kg/day significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH. Conclusion Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary

  7. Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: Direct impact on OPCs differentiation failure.

    Science.gov (United States)

    Fernández, Mercedes; Baldassarro, Vito A; Sivilia, Sandra; Giardino, Luciana; Calzà, Laura

    2016-09-01

    Differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes is severely impaired by inflammatory cytokines and this could lead to remyelination failure in inflammatory/demyelinating diseases. Due to the role of thyroid hormone in the maturation of OPCs and developmental myelination, in this study we investigated (i) the possible occurrence of dysregulation of thyroid hormone signaling in the CNS tissue during experimental neuroinflammation; (ii) the possible impact of inflammatory cytokines on thyroid hormone signaling and OPCs differentiation in vitro. The disease model is the experimental allergic encephalomyelitis in female Dark-Agouti rats, whereas in vitro experiments were carried out in OPCs derived from neural stem cells. The main results are the following: (i) a strong upregulation of cytokine mRNA expression level was found in the spinal cord during experimental allergic encephalomyelitis; (ii) thyroid hormone signaling in the spinal cord (thyroid hormone receptors; deiodinase; thyroid hormone membrane transporter) is substantially downregulated, due to the upregulation of the thyroid hormone inactivating enzyme deiodinase 3 and the downregulation of thyroid hormone receptors, as investigated at mRNA expression level; (iii) when exposed to inflammatory cytokines, deiodinase 3 is upregulated in OPCs as well, and OPCs differentiation is blocked; (iv) deiodinase 3 inhibition by iopanoic acid recovers OPCs differentiation in the presence on inflammatory cytokines. These data suggest that cellular hypothyroidism occurs during experimental allergic encephalomyelitis, possibly impacting on thyroid hormone-dependent cellular processes, including maturation of OPCs into myelinating oligodendrocytes. GLIA 2016;64:1573-1589. PMID:27404574

  8. Interleukin-33 from Monocytes Recruited to the Lung Contributes to House Dust Mite-Induced Airway Inflammation in a Mouse Model.

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    Hiroki Tashiro

    Full Text Available Interleukin-33 (IL-33 activates group 2 innate lymphoid cells (ILC2, resulting in T-helper-2 inflammation in bronchial asthma. Airway epithelial cells were reported as sources of IL-33 during apoptosis and necrosis. However, IL-33 is known to be from sources other than airway epithelial cells such as leukocytes, and the mechanisms of IL-33 production and release are not fully understood. The aim of this study was to clarify the role of IL-33 production by monocytes in airway inflammation.BALB/c mice were sensitized and challenged with a house dust mite (HDM preparation. Airway inflammation was assessed by quantifying inflammatory cells in bronchoalveolar lavage (BAL fluid, and IL-25, IL-33, and thymic stromal lymphopoietin (TSLP levels in lung. Immunohistochemistry for IL-33 in lung sections was also performed. Ly6c, CD11b, and CD11c expression was examined by flow cytometry. Clodronate liposomes were used in the HDM-airway inflammation model to deplete circulating monocytes.The IL-33, but not IL-25 or TSLP, level in lung homogenates was markedly increased in HDM mice compared to control mice. IL-33-positive cells in the lungs were identified using immunohistochemistry and were increased in areas surrounding bronchi and vasculature. Furthermore, IL-33 levels were increased in mononuclear cells derived from lungs of HDM mice compared to controls. The expression of Ly6c in mononuclear cells was significantly higher in HDM mice than in controls. Treatment with clodronate liposomes led to inhibition of not only inflammatory cells in BAL fluid, airway hyper reactivity and Th2 cytokines in lung, but also IL-33 in lung.IL-33 from monocytes recruited to the lung may contribute to the pathogenesis of HDM-induced airway inflammation.

  9. Interleukin-33 from Monocytes Recruited to the Lung Contributes to House Dust Mite-Induced Airway Inflammation in a Mouse Model

    Science.gov (United States)

    Tashiro, Hiroki; Takahashi, Koichiro; Hayashi, Shinichiro; Kato, Go; Kurata, Keigo; Kimura, Shinya; Sueoka-Aragane, Naoko

    2016-01-01

    Background Interleukin-33 (IL-33) activates group 2 innate lymphoid cells (ILC2), resulting in T-helper-2 inflammation in bronchial asthma. Airway epithelial cells were reported as sources of IL-33 during apoptosis and necrosis. However, IL-33 is known to be from sources other than airway epithelial cells such as leukocytes, and the mechanisms of IL-33 production and release are not fully understood. The aim of this study was to clarify the role of IL-33 production by monocytes in airway inflammation. Methods BALB/c mice were sensitized and challenged with a house dust mite (HDM) preparation. Airway inflammation was assessed by quantifying inflammatory cells in bronchoalveolar lavage (BAL) fluid, and IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) levels in lung. Immunohistochemistry for IL-33 in lung sections was also performed. Ly6c, CD11b, and CD11c expression was examined by flow cytometry. Clodronate liposomes were used in the HDM-airway inflammation model to deplete circulating monocytes. Results The IL-33, but not IL-25 or TSLP, level in lung homogenates was markedly increased in HDM mice compared to control mice. IL-33-positive cells in the lungs were identified using immunohistochemistry and were increased in areas surrounding bronchi and vasculature. Furthermore, IL-33 levels were increased in mononuclear cells derived from lungs of HDM mice compared to controls. The expression of Ly6c in mononuclear cells was significantly higher in HDM mice than in controls. Treatment with clodronate liposomes led to inhibition of not only inflammatory cells in BAL fluid, airway hyper reactivity and Th2 cytokines in lung, but also IL-33 in lung. Conclusion IL-33 from monocytes recruited to the lung may contribute to the pathogenesis of HDM-induced airway inflammation. PMID:27310495

  10. Allergic skin diseases : Studies on mechanisms in experimental atopic dermatitis and allergic contact dermatitis

    OpenAIRE

    LehtimÀki, Sari

    2012-01-01

    Atopic dermatitis (AD) is an allergic skin disease, characterized by relapsing eczema, dry skin and chronic skin inflammation. A large proportion of AD patients develop other allergies or asthma later in life. Allergic contact dermatitis (ACD) in turn, is one of the leading occupational diseases worldwide. Therefore, allergic skin diseases not only impair the quality of life of patients but also cause a great economical burden for the society. This thesis investigates some of the mechanisms b...

  11. Nebulized anticoagulants limit pulmonary coagulopathy, but not inflammation, in a model of experimental lung injury

    NARCIS (Netherlands)

    Hofstra, Jorrit J; Vlaar, Alexander P; Cornet, Alexander D; Dixon, Barry; Roelofs, Joris J; Choi, Goda; van der Poll, Tom; Levi, Marcel; Schultz, Marcus J

    2010-01-01

    BACKGROUND: Pulmonary coagulopathy may contribute to an adverse outcome in lung injury. We assessed the effects of local anticoagulant therapy on bronchoalveolar and systemic haemostasis in a rat model of endotoxemia-induced lung injury. METHODS: Male Sprague-Dawley rats were intravenously challenge

  12. Nebulized Anticoagulants Limit Pulmonary Coagulopathy, But Not Inflammation, in a Model of Experimental Lung Injury

    NARCIS (Netherlands)

    J.J. Hofstra; A.P. Vlaar; A.D. Cornet; B. Dixon; J.J. Roelofs; G. Choi; T. van der Poll; M. Levi; M.J. Schultz

    2010-01-01

    Background: Pulmonary coagulopathy may contribute to an adverse outcome in lung injury. We assessed the effects of local anticoagulant therapy on bronchoalveolar and systemic haemostasis in a rat model of endotoxemia-induced lung injury. Methods: Male Sprague-Dawley rats were intravenously challenge

  13. Uncontrolled airway inflammation in lung disease represents a defect in counter-regulatory signaling

    OpenAIRE

    Planaguma, Anna; Levy, Bruce D.

    2008-01-01

    Counter-regulatory lipid mediators are generated during airway inflammation to promote resolution. Defects in the production of these lipid mediators have now been associated with several diseases of persistent airway inflammation. Lipoxins are the lead members of this class of anti-inflammatory and proresolving chemical mediators. Recently, several new families of fatty acid-derived counter-regulatory mediators have been discovered, including the resolvins and protectins. Diminished formatio...

  14. Blockade of Wnt/β-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses

    Directory of Open Access Journals (Sweden)

    Wujing Dai

    2016-01-01

    Full Text Available CD4+ T cells play an important role in regulating silica-induced inflammation and fibrosis. Recent studies showed that Wnt/β-catenin pathway could modulate the function and the differentiation of CD4+ T cells. Therefore, Wnt/β-catenin pathway may participate in the development and progress of silicosis. To investigate the role of Wnt/β-catenin pathway, we used lentivirus expressing β-catenin shRNA to block the Wnt/β-catenin pathway by intratracheal instillation to the mice model of silicosis. Treatment of lentivirus could significantly aggravate the silica-induced lung inflammation and attenuated the fibrosis at the late stage. By analyzing CD4+ T cells, we found that blockade of Wnt/β-catenin pathway suppressed regulatory T cells (Tregs. Reciprocally, enhanced Th17 response was responsible for the further accumulation of neutrophils and production of proinflammatory cytokines. In addition, blockade of Wnt/β-catenin pathway delayed the Th1/Th2 polarization by inhibiting Tregs and Th2 response. These results indicated that Wnt/β-catenin pathway could regulate Tregs to modulate Th immune response, which finally altered the pathological character of silicosis. Our study suggested that Wnt/β-catenin pathway might be a potential target to treat the silica-induced inflammation and fibrosis.

  15. Inhibition of NF-κB Expression and Allergen-induced Airway Inflammation in a Mouse Allergic Asthma Model by Andrographolide

    OpenAIRE

    Li, Jing; Luo, Li; Wang, Xiaoyun; Liao, Bin; Li, Guoping

    2009-01-01

    Andrographolide from traditional Chinese herbal medicines previously showed it possesses a strong anti-inflammatory activity. In present study, we investigated whether Andrographolide could inhibit allergen-induced airway inflammation and airways hyper-responsiveness and explored the mechanism of Andrographolide on allergen-induced airway inflammation and airways hyper-responsiveness. After sensitized and challenged by ovalbumin, the BALB/c mice were administered intraperitoneally with Androg...

  16. In vivo hydroquinone exposure alters circulating neutrophil activities and impairs LPS-induced lung inflammation in mice.

    Science.gov (United States)

    Ribeiro, André Luiz Teroso; Shimada, Ana Lúcia Borges; Hebeda, Cristina Bichels; de Oliveira, Tiago Franco; de Melo Loureiro, Ana Paula; Filho, Walter Dos Reis Pereira; Santos, Alcinéa Meigikos Dos Anjos; de Lima, Wothan Tavares; Farsky, Sandra Helena Poliselli

    2011-10-01

    Hydroquinone (HQ) is an environmental contaminant which causes immune toxicity. In this study, the effects of exposure to low doses of HQ on neutrophil mobilization into the LPS-inflamed lung were investigated. Male Swiss mice were exposed to aerosolized vehicle (control) or 12.5, 25 or 50ppm HQ (1h/day for 5 days). One hour later, oxidative burst, cell cycle, DNA fragmentation and adhesion molecules expressions in circulating neutrophils were determined by flow cytometry, and plasma malondialdehyde (MDA) levels were measured by HPLC. Also, 1h later the last exposures, inflammation was induced by LPS inhalation (0.1mg/ml/10min) and 3h later, the numbers of leukocytes in peripheral blood and in the bronchoalveolar lavage fluid (BALF) were determined using a Neubauer chamber and stained smears; adhesion molecules expressed on lung microvessel endothelial cells were quantified by immunohistochemistry; myeloperoxidase (MPO) activity was measured in the lung tissue by colorimetric assay; and cytokines in the BALF were determined by ELISA. In vivo HQ exposure augmented plasma MDA levels and oxidative activity of neutrophils, but did not cause alterations in cell cycle and DNA fragmentation. Under these conditions, the number of circulating leukocytes was not altered, but HQ exposure reduced LPS-induced neutrophil migration into the alveolar space, as these cells remained in the lung tissue. The impaired neutrophil migration into BALF may not be dependent on reduced cytokines secretions in the BALF and lung endothelial adhesion molecules expressions. However, HQ exposure increased the expression of β(2) and β(3) integrins and platelet-endothelial cell adhesion molecule-1 (PECAM-1) in neutrophils, which were not further enhanced by fMLP in vitro stimulation, indicating that HQ exposure activates circulating neutrophils, impairing further stimulatory responses. Therefore, it has been shown, for the first time, that neutrophils are target of lower levels of in vivo HQ

  17. The Glutathione Synthesis Gene Gclm Modulates Amphiphilic Polymer-Coated CdSe/ZnS Quantum Dot–Induced Lung Inflammation in Mice

    OpenAIRE

    Lisa A McConnachie; Dianne Botta; White, Collin C.; Chad S Weldy; Hui-Wen Wilkerson; Jianbo Yu; Russell Dills; Xiaozhong Yu; Griffith, William C.; Faustman, Elaine M; Farin, Federico M.; Gill, Sean E.; Parks, William C.; Xiaoge Hu; Xiaohu Gao

    2013-01-01

    Quantum dots (QDs) are unique semi-conductor fluorescent nanoparticles with potential uses in a variety of biomedical applications. However, concerns exist regarding their potential toxicity, specifically their capacity to induce oxidative stress and inflammation. In this study we synthesized CdSe/ZnS core/shell QDs with a tri-n-octylphosphine oxide, poly(maleic anhydride-alt-1-tetradecene) (TOPO-PMAT) coating and assessed their effects on lung inflammation in mice. Previously published in vi...

  18. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    Energy Technology Data Exchange (ETDEWEB)

    Salama, Samir A., E-mail: salama.3@buckeyemail.osu.edu [High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11751 (Egypt); Department of Pharmacology and GTMR Unit, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); Omar, Hany A. [Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514 (Egypt); Maghrabi, Ibrahim A. [Department of Clinical Pharmacy, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); AlSaeed, Mohammed S. [Department of Surgery, College of Medicine, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); EL-Tarras, Adel E. [High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia)

    2014-01-01

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  19. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    International Nuclear Information System (INIS)

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  20. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury.

    Science.gov (United States)

    Balakrishna, Shrilatha; Song, Weifeng; Achanta, Satyanarayana; Doran, Stephen F; Liu, Boyi; Kaelberer, Melanie M; Yu, Zhihong; Sui, Aiwei; Cheung, Mui; Leishman, Emma; Eidam, Hilary S; Ye, Guosen; Willette, Robert N; Thorneloe, Kevin S; Bradshaw, Heather B; Matalon, Sadis; Jordt, Sven-Eric

    2014-07-15

    The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function. PMID:24838754

  1. Alcohol Exposure Alters Mouse Lung Inflammation in Response to Inhaled Dust

    Directory of Open Access Journals (Sweden)

    Jill A. Poole

    2012-07-01

    Full Text Available Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE collected from a CAFO results in the activation of protein kinase C (PKC, elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6, and the development of significant lung pathology. Because alcohol blocks airway epithelial cell release of IL-6 in vitro, we hypothesized that alcohol exposure would alter mouse lung inflammatory responses to HDE. To test this hypothesis, C57BL/6 mice were fed 20% alcohol or water ad libitum for 6 weeks and treated with 12.5% HDE by intranasal inhalation method daily during the final three weeks. Bronchoalveolar lavage fluid (BALF, tracheas and lungs were collected. HDE stimulated a 2–4 fold increase in lung and tracheal PKCε (epsilon activity in mice, but no such increase in PKCε activity was observed in dust-exposed mice fed alcohol. Similarly, alcohol-fed mice demonstrated significantly less IL-6 in lung lavage in response to dust than that observed in control mice instilled with HDE. TNFα levels were also inhibited in the alcohol and HDE-exposed mouse lung tissue as compared to the HDE only exposed group. HDE-induced lung inflammatory aggregates clearly present in the tissue from HDE only exposed animals were not visually detectable in the HDE/alcohol co-exposure group. Statistically significant weight reductions and 20% mortality were also observed in the mice co-exposed to HDE and alcohol. These data suggest that alcohol exposure depresses the ability

  2. Inflammation and lung maturation from stretch injury in preterm fetal sheep

    OpenAIRE

    Hillman, Noah H.; Graeme R Polglase; Jane Pillow, J.; Saito, Masatoshi; Suhas G Kallapur; Alan H Jobe

    2010-01-01

    Mechanical ventilation is a risk factor for the development of bronchopulmonary dysplasia in premature infants. Fifteen minutes of high tidal volume (Vt) ventilation induces inflammatory cytokine expression in small airways and lung parenchyma within 3 h. Our objective was to describe the temporal progression of cytokine and maturation responses to lung injury in fetal sheep exposed to a defined 15-min stretch injury. After maternal anesthesia and hysterotomy, 129-day gestation fetal lambs (n...

  3. Chlamydia pneumoniae infection induced allergic airway sensitization is controlled by regulatory T-cells and plasmacytoid dendritic cells.

    Science.gov (United States)

    Crother, Timothy R; Schröder, Nicolas W J; Karlin, Justin; Chen, Shuang; Shimada, Kenichi; Slepenkin, Anatoly; Alsabeh, Randa; Peterson, Ellena; Arditi, Moshe

    2011-01-01

    Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs. PMID:21695198

  4. Chlamydia pneumoniae infection induced allergic airway sensitization is controlled by regulatory T-cells and plasmacytoid dendritic cells.

    Directory of Open Access Journals (Sweden)

    Timothy R Crother

    Full Text Available Chlamydia pneumoniae (CP is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate, but not a high dose (severe CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n. with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs.

  5. A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha.

    Science.gov (United States)

    Lee, Kyung Sun; Kim, So Ri; Park, Hee Sun; Park, Seoung Ju; Min, Kyung Hoon; Lee, Ka Young; Choe, Yeong Hun; Hong, Sang Hyun; Han, Hyo Jin; Lee, Young Rae; Kim, Jong Suk; Atlas, Daphne; Lee, Yong Chul

    2007-12-31

    Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-kappaB and hypoxia-inducible factor-1alpha (HIF-1alpha) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-kappaB and HIF-1alpha as well as reducing ROS generation in allergic airway disease. PMID:18160846

  6. Investigation of airway inflammation and asthma by repeated bronchoalveolar lavage combined with measurements of airway and lung tissue mechanics in individual rats.

    OpenAIRE

    dr Bánfi Andrea

    2011-01-01

    Acute and chronic airway inflammations are the main pathogenetic features of numerous pulmonary diseases. There are several methods studying the pathomechanisms of inflammatory respiratory diseases. To asses the severity of lung diseases, the bronchoalveolar lavage (BAL) and lung function tests are the most current diagnostic methods in the experimental and human pulmonology. However, repetition of BAL procedures and assessments of respiratory mechanic parameters in small rodents (mice and ra...

  7. The natural compound nujiangexanthone A suppresses mast cell activation and allergic asthma.

    Science.gov (United States)

    Lu, Yue; Cai, Shuangfan; Nie, Jia; Li, Yangyang; Shi, Guochao; Hao, Jimin; Fu, Wenwei; Tan, Hongsheng; Chen, Shilin; Li, Bin; Xu, Hongxi

    2016-01-15

    Mast cells play an important role in allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. The genus Garcinia of the family Guttiferae is well known as a prolific source of polycyclic polyprenylated acylphloroglucinols and bioactive prenylated xanthones, which exhibit various biological activities including antibacterial, antifungal, anti-inflammatory, antioxidant, and cytotoxic effects. Nujiangexanthone A (N7) is a novel compound isolated from the leaves of Garcinia nujiangensis. In this paper, we sought to determine the anti-allergic and anti-inflammation activity of N7 in vivo and its mechanism in vitro. We found N7 suppressed IgE/Ag induced mast cell activiation, including degranulation and production of cytokines and eicosanoids, through inhibiting Src kinase activity and Syk dependent pathways. N7 inhibited histamine release, prostaglandin D2 and leukotriene C4 generation in mast cell dependent passive cutaneous anaphylaxis animal model. We also found N7 inhibited the IL-4, IL-5, IL-13 and IgE levels in ovalbumin-induced asthma model. Histological studies demonstrated that N7 substantially inhibited OVA-induced cellular infiltration and increased mucus production in the lung tissue. Our study reveals the anti-allergic function of N7, thereby suggesting the utility of this compound as a possible novel agent for preventing mast cell-related immediate and delayed allergic diseases. PMID:26571438

  8. Proallergic cytokines and group 2 innate lymphoid cells in allergic nasal diseases

    Directory of Open Access Journals (Sweden)

    Kazufumi Matsushita

    2015-07-01

    Full Text Available Recent advances in our understanding of proallergic cytokines and group 2 innate lymphoid cells (ILC2s indicate their critical roles in type 2 immunity-mediated disorders. Proallergic cytokines, interleukin (IL-25, IL-33, and thymic stromal lymphopoietin, are released from epithelial cells in inflamed tissues and drive type 2 inflammation by acting on innate and acquired immune systems. ILC2s are an innate immune population that responds to proallergic cytokines by producing type 2 cytokines. In line with allergic disorders in the lung, skin, and intestine, emerging evidence suggests the involvement of proallergic cytokines and ILC2s in allergic nasal diseases such as chronic rhinosinusitis with polyps (CRSwNP, allergic fungal rhinosinusitis, and allergic rhinitis (AR. In CRSwNP patients, both proallergic cytokine levels and ILC2s frequency are increased in the nasal mucosa. Increased proallergic cytokine levels correlate with poorer disease outcomes in CRSwNP. Levels of nasal proallergic cytokines are also elevated in AR patients. In addition, animal studies demonstrate that cytokines are essential for the development of AR. It is becoming clear that the proallergic cytokine/ILC2s axis participates in allergic diseases by multiple mechanisms dependent upon the inflammatory context. Thus, a thorough understanding of these cytokines and ILC2s including their tissue- and disease-specific roles is essential for targeting the pathways to achieve therapeutic applications.

  9. Suppression of allergic airway inflammation in a mouse model of asthma by exogenous mesenchymal stem cells%外源性间充质干细胞减轻支气管哮喘小鼠气道炎症的研究

    Institute of Scientific and Technical Information of China (English)

    黄芸; 欧阳海峰; 吴朔; 王文雅; 吴昌归

    2010-01-01

    eosinophils. Concentration of IL-5, IL-9 in BALF were determined. To detect β-hexosaminidase activity.The paraffin embedded sections of lung tissue were stained with HE and the lung pathological changes were observed. Results ①Airway inflammation were significantly reduced by exogenous MSC. ②Administration of exogenous MSC significantly reduced airway cellular infiltrates. ③Mast cell degranulation were significantly reduced by exogenous MSC. ④Administration of exogenous MSC reversed the Th2 Bias.Conclusions Exogenous MSC reduced airway inflammation of allergic asthmatic mice through the reversion of Th2 Bias.

  10. Therapeutic effect of ent-kaur-16-en-19-oic acid on neutrophilic lung inflammation and sepsis is mediated by Nrf2.

    Science.gov (United States)

    Kim, Kyun Ha; Sadikot, Ruxana T; Joo, Myungsoo

    2016-06-01

    Kaurenoic acid (ent-kaur-16-en-19-oic acid: KA) is a key constituent found in the roots of Aralia continentalis Kitagawa (Araliaceae), a remedy to treat patients with inflammatory diseases in traditional Asian medicine. Since KA activates Nrf2, a key anti-inflammatory factor, at the cellular level, we explored a possible therapeutic usage of KA against neutrophilic inflammatory lung disease such as acute lung injury (ALI). Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) to C57BL/6 mice induced lung inflammation as in ALI. 2 h after i.p. LPS, intratracheal (i.t.) delivery of KA (0.3, 3, or 30 μg/kg body weight) improved lung structure and significantly suppressed neutrophil infiltrations to mouse lungs, with concomitant reduction of myeloperoxidase activity and of the expression of pro-inflammatory cytokine genes. While activating Nrf2 and expressing Nrf2-dependent genes in mouse lungs, KA did not significantly suppress neutrophil lung inflammation in Nrf2 KO mice. In a mouse model of sepsis, a major cause of ALI, single i.t. KA (3 μg/kg) 2 h after the onset of sepsis significantly decreased the mortality of mice. Together, these results suggest that KA has a therapeutic potential against inflammatory lung disease, the effect of which is associated with Nrf2 activation. PMID:27133718

  11. Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma.

    Directory of Open Access Journals (Sweden)

    Davina C M Simoes

    Full Text Available Mitochondrial glucocorticoid (mtGR and estrogen (mtER receptors participate in the coordination of the cell's energy requirement and in the mitochondrial oxidative phosphorylation enzyme (OXPHOS biosynthesis, affecting reactive oxygen species (ROS generation and induction of apoptosis. Although activation of mtGR and mtER is known to trigger anti-inflammatory signals, little information exists on the presence of these receptors in lung tissue and their role in respiratory physiology and disease. Using a mouse model of allergic airway inflammation disease and applying confocal microscopy, subcellular fractionation, and Western blot analysis we showed mitochondrial localization of GRα and ERβ in lung tissue. Allergic airway inflammation caused reduction in mtGRα, mtERβ, and OXPHOS enzyme biosynthesis in lung cells mitochondria and particularly in bronchial epithelial cells mitochondria, which was accompanied by decrease in lung mitochondrial mass and induction of apoptosis. Confirmation and validation of the reduction of the mitochondrial receptors in lung epithelial cells in human asthma was achieved by analyzing autopsies from fatal asthma cases. The presence of the mitochondrial GRα and ERβ in lung tissue cells and especially their reduction in bronchial epithelial cells during allergic airway inflammation suggests a crucial role of these receptors in the regulation of mitochondrial function in asthma, implicating their involvement in the pathophysiology of the disease.

  12. The cardiopulmonary continuum systemic inflammation as 'common soil' of heart and lung disease

    NARCIS (Netherlands)

    Ukena, Christian; Mahfoud, Felix; Kindermann, Michael; Kindermann, Ingrid; Bals, Robert; Voors, Adriaan A.; van Veldhuisen, Dirk J.; Boehm, Michael

    2010-01-01

    Coronary artery disease (CAD), chronic heart failure (CHF) or chronic obstructive pulmonary disease (COPD) occur commonly in the presence of each other and are associated with similar systemic inflammatory reactions. Inflammation plays a central role in the pathogenesis of these diseases. C-reactive

  13. Is Health-Related Quality of Life Associated with Upper and Lower Airway Inflammation in Asthmatics?

    Directory of Open Access Journals (Sweden)

    Nicola Scichilone

    2013-01-01

    Full Text Available Background. Allergic diseases impair health-related quality of life (HR-QoL. However, the relationship between airway inflammation and HR-QoL in patients with asthma and rhinitis has not been fully investigated. We explored whether the inflammation of upper and lower airways is associated with HR-QoL. Methods. Twenty-two mild allergic asthmatics with concomitant rhinitis (10 males, 38 ± 17 years were recruited. The Rhinasthma was used to identify HR-QoL, and the Asthma Control Test (ACT was used to assess asthma control. Subjects underwent lung function and exhaled nitric oxide (eNO test, collection of exhaled breath condensate (EBC, and nasal wash. Results. The Rhinasthma Global Summary score (GS was 25 ± 11. No relationships were found between GS and markers of nasal allergic inflammation (% eosinophils: , ; ECP: , or bronchial inflammation (pH of the EBC: , ; bronchial NO: , ; alveolar NO: , . The mean ACT score was 18. When subjects were divided into controlled (ACT ≥ 20 and uncontrolled (ACT < 20, the alveolar NO significantly correlated with GS in uncontrolled asthmatics (, . Conclusions. Upper and lower airways inflammation appears unrelated to HR-QoL associated with respiratory symptoms. These preliminary findings suggest that, in uncontrolled asthma, peripheral airway inflammation could be responsible for impaired HR-QoL.

  14. The effect of Nigella sativa extract on tracheal responsiveness and lung inflammation in ovalbumin-sensitized guinea pigs

    Directory of Open Access Journals (Sweden)

    Mohammad Hossein Boskabady

    2011-01-01

    Full Text Available OBJECTIVE: To examine the preventive effect of a hydro-ethanolic extract of Nigella sativa on the tracheal responsiveness and white blood cell count in the lung lavage fluid of sensitized guinea pigs. METHODS: Three groups of guinea pigs sensitized to intraperitoneally injected and inhaled ovalbumin were given drinking water alone (group S, drinking water containing a low concentration of N. sativa extract (group S+LNS or drinking water containing a high concentration of N. sativa extract (group S+HNS. The tracheal responses of control animals (group C and the three groups of sensitized guinea pigs (n = 7 for all groups to methacholine were measured by the assessment of the tracheal smooth muscle response to increasing concentrations of methacholine, and the effective concentration causing 50% of the maximum response (EC50 was determined. Tracheal responses to 0.1% ovalbumin and white blood cell counts in the lung lavage fluid were also examined. RESULTS: The tracheal response of the group S guinea pigs to both methacholine and ovalbumin was significantly higher than the response of the controls (p<0.01 for both cases. The tracheal responses of the S+LNS and S+HNS groups to both methacholine and ovalbumin were significantly decreased compared to those of the S group (p<0.05 to p<0.01. The total white blood cell and eosinophil counts in the lung lavage fluid of group S were significantly higher than those of group C (p<0.01. The white blood cell counts in both treated groups showed significant improvements (p<0.01 for both cases. CONCLUSIONS: These results demonstrate the preventive effect of the N. sativa extract on the tracheal response and lung inflammation in sensitized guinea pigs.

  15. [Allergic inflamation of the lower airways in patients with allergic rhinitis].

    Science.gov (United States)

    Stefanović, Lj; Balaban, J; Stosović, R; Mitrović, N; Djurasinović, M; Tanurdzić, S

    1994-01-01

    Reporting two of our cases we wanted to point to a great dilemma related to the final diagnosis. Recently, such cases have been more frewuently seen, since in all patients with allergic rhinitis conditions of the lower airways is examined before the administration of the specific immunotherapy. Therefore, we may see patients who are still free of pulmonary sings, despite of positive specific and/or non specific bronchoprovocative tests. The presented cases with evidenced allergic rhinitis are probably in the phase of development of allergic bronchial asthma, the phase of "allergic inflammation" of the lower airways, not clinically manifested yet. PMID:18173213

  16. Exosomes from bronchoalveolar fluid of tolerized mice prevent allergic reaction.

    Science.gov (United States)

    Prado, Noela; Marazuela, Eva G; Segura, Elodie; Fernández-García, Héctor; Villalba, Mayte; Théry, Clotilde; Rodríguez, Rosalía; Batanero, Eva

    2008-07-15

    Exosomes are nanovesicles originating from multivesicular bodies that are secreted by a variety of cell types. The dual capability of exosomes to promote immunity or to induce tolerance has prompted their clinical use as vehicles for vaccination against different human diseases. In the present study, the effect of allergen-specific exosomes from tolerized mice on the development of allergen-induced allergic response was determined using a mouse model. Mice were tolerized by respiratory exposure to the olive pollen allergen Ole e 1. Exosome-like vesicles were isolated from bronchoalveolar lavage fluid of the animals by the well-established filtration and ultracentrifugation procedure, characterized by electron microscopy, Western blot, and FACS analyses, and assessed in a prophylactic protocol. To this end, BALB/c mice were intranasally treated with tolerogenic exosomes or naive exosomes as control, 1 wk before sensitization/challenge to Ole e 1. Blood, lungs, and spleen were collected and analyzed for immune responses. Intranasal administration of tolerogenic exosomes inhibited the development of IgE response, Th2 cytokine production, and airway inflammation--cardinal features of allergy--and maintained specific long-term protection in vivo. This protective effect was associated with a concomitant increase in the expression of the regulatory cytokine TGF-beta. These observations demonstrate that exosomes can induce tolerance and protection against allergic sensitization in mice. Thus, exosome-based vaccines could represent an alternative to conventional therapy for allergic diseases in humans. PMID:18606707

  17. Anti-Allergic Properties of Curine, a Bisbenzylisoquinoline Alkaloid

    Directory of Open Access Journals (Sweden)

    Jaime Ribeiro-Filho

    2015-03-01

    Full Text Available Curine is a bisbenzylisoquinoline alkaloid isolated from Chondrodendron platyphyllum (Menispermaceae. Recent findings have shed light on the actions of curine in different models of allergy and inflammation. Here we review the properties and mechanisms of action of curine focusing on its anti-allergic effects. Curine pre-treatment significantly inhibited the scratching behavior, paw edema and systemic anaphylaxis induced by either ovalbumin (OVA in sensitized animals or compound 48/80, through mechanisms of mast cell stabilization and inhibition of mast cell activation to generate lipid mediators. In addition, oral administration of curine significantly inhibited eosinophil recruitment and activation, as well as, OVA-induced airway hyper-responsiveness in a mouse model of asthma, through inhibition of the production of IL-13 and eotaxin, and of Ca2+ influx. In conclusion, curine exhibit anti-allergic effects in models of lung, skin and systemic allergy in the absence of significant toxicity, and as such has the potential for anti-allergic drug development.

  18. Regulation of the development of asthmatic inflammation by in situ CD4(+)Foxp3 (+) T cells in a mouse model of late allergic asthma.

    Science.gov (United States)

    Nakashima, Tomomi; Hayashi, Toshiharu; Mizuno, Takuya

    2014-10-01

    CD4(+)Foxp3(+)T cells (Tregs) mediate homeostatic peripheral tolerance by suppressing helper T2 cells in allergy. However, the regulation of asthmatic inflammation by local (in situ) Tregs in asthma remains unclear. BALB/c mice sensitized and challenged with ovalbumin (OVA) (asthma group) developed asthmatic inflammation with eosinophils and lymphocytes, but not mast cells. The number of Tregs in the circulation, pulmonary lymph nodes (pLNs), and thymi significantly decreased in the asthma group compared to the control group without OVA sensitization and challenge in the effector phase. The development of asthmatic inflammation is inversely related to decreased Tregs with reduced mRNA expression such as interleukin (IL)-4, transforming growth factor-β1, and IL-10, but not interferon-γ, in pLNs. Moreover, M2 macrophages increased in the local site. The present study suggests that Tregs, at least in part, may regulate the development of asthmatic inflammation by cell-cell contact and regional cytokine productions. PMID:24854160

  19. PI3K-AKT Signaling via Nrf2 Protects against Hyperoxia-Induced Acute Lung Injury, but Promotes Inflammation Post-Injury Independent of Nrf2 in Mice.

    Directory of Open Access Journals (Sweden)

    Narsa M Reddy

    Full Text Available Lung epithelial and endothelial cell death accompanied by inflammation contributes to hyperoxia-induced acute lung injury (ALI. Impaired resolution of ALI can promote and/or perpetuate lung pathogenesis, including fibrosis. Previously, we have shown that the transcription factor Nrf2 induces cytoprotective gene expression and confers protection against hyperoxic lung injury, and that Nrf2-mediated signaling is also crucial for the restoration of lung homeostasis post-injury. Although we have reported that PI3K/AKT signaling is required for Nrf2 activation in lung epithelial cells, significance of the PI3K/AKT-Nrf2 crosstalk during hyperoxic lung injury and repair remains unclear. Thus, we evaluated this aspect using Nrf2 knockout (Nrf2(-/- and wild-type (Nrf2(+/+ mouse models. Here, we show that pharmacologic inhibition of PI3K/AKT signaling increased lung inflammation and alveolar permeability in Nrf2(+/+ mice, accompanied by decreased expression of Nrf2-target genes such as Nqo1 and Hmox1. PI3K/AKT inhibition dampened hyperoxia-stimulated Nqo1 and Hmox1 expression in lung epithelial cells and alveolar macrophages. Contrasting with its protective effects, PI3K/AKT inhibition suppressed lung inflammation in Nrf2(+/+ mice during post-injury. In Nrf2(-/- mice exposed to room-air, PI3K/AKT inhibition caused lung injury and inflammation, but it did not exaggerate hyperoxia-induced ALI. During post-injury, PI3K/AKT inhibition did not augment, but rather attenuated, lung inflammation in Nrf2(-/- mice. These results suggest that PI3K/AKT-Nrf2 signaling is required to dampen hyperoxia-induced lung injury and inflammation. Paradoxically, the PI3K/AKT pathway promotes lung inflammation, independent of Nrf2, during post-injury.

  20. Low-Level Laser Therapy Attenuates the Myeloperoxidase Activity and Inflammatory Mediator Generation in Lung Inflammation Induced By Gut Ischemia and Reperfusion: A Dose-Response Study

    OpenAIRE

    de Lima, Flávia Mafra; Aimbire, Flávio; Miranda, Humberto; Vieira, Rodolfo Paula; de Oliveira, Ana Paula Ligeiro; Albertini, Regiane

    2014-01-01

    Introduction: Intestinal ischemia and reperfusion (i-I/R) is an insult associated with acute respiratory distress syndrome (ARDS). Herein we evaluate the dose-response effect of low-level laser therapy (LLLT) on lung inflammation induced by i-I/R.

  1. Regulatory T Cells Contribute to the Inhibition of Radiation-Induced Acute Lung Inflammation via Bee Venom Phospholipase A₂ in Mice.

    Science.gov (United States)

    Shin, Dasom; Lee, Gihyun; Sohn, Sung-Hwa; Park, Soojin; Jung, Kyung-Hwa; Lee, Ji Min; Yang, Jieun; Cho, Jaeho; Bae, Hyunsu

    2016-01-01

    Bee venom has long been used to treat various inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Previously, we reported that bee venom phospholipase A₂ (bvPLA₂) has an anti-inflammatory effect through the induction of regulatory T cells. Radiotherapy is a common anti-cancer method, but often causes adverse effects, such as inflammation. This study was conducted to evaluate the protective effects of bvPLA₂ in radiation-induced acute lung inflammation. Mice were focally irradiated with 75 Gy of X-rays in the lung and administered bvPLA₂ six times after radiation. To evaluate the level of inflammation, the number of immune cells, mRNA level of inflammatory cytokine, and histological changes in the lung were measured. BvPLA₂ treatment reduced the accumulation of immune cells, such as macrophages, neutrophils, lymphocytes, and eosinophils. In addition, bvPLA₂ treatment decreased inflammasome-, chemokine-, cytokine- and fibrosis-related genes' mRNA expression. The histological results also demonstrated the attenuating effect of bvPLA₂ on radiation-induced lung inflammation. Furthermore, regulatory T cell depletion abolished the therapeutic effects of bvPLA₂ in radiation-induced pneumonitis, implicating the anti-inflammatory effects of bvPLA₂ are dependent upon regulatory T cells. These results support the therapeutic potential of bvPLA₂ in radiation pneumonitis and fibrosis treatments. PMID:27144583

  2. Angiopoietin-1 Treatment Reduces Inflammation but Does Not Prevent Ventilator-Induced Lung Injury

    NARCIS (Netherlands)

    M.A. Hegeman; M.P. Hennus; M. van Meurs; P.M. Cobelens; A. Kavelaars; N.J. Jansen; M.J. Schultz; A.J. van Vught; G. Molema; C.J. Heijnen

    2010-01-01

    Background: Loss of integrity of the epithelial and endothelial barriers is thought to be a prominent feature of ventilator-induced lung injury (VILI). Based on its function in vascular integrity, we hypothesize that the angiopoietin (Ang)-Tie2 system plays a role in the development of VILI. The pre

  3. Synergistic Effect of Anemia and Red Blood Cells Transfusion on Inflammation and Lung Injury

    OpenAIRE

    Anping Dong; Manjula Sunkara; Manikandan Panchatcharam; Abdel Salous; Samy Selim; Morris, Andrew J.; Smyth, Susan S.

    2012-01-01

    Anemia and resultant red blood cell transfusion may be associated with adverse long-term clinical outcomes. To investigate the mechanism(s) responsible, we profiled inflammatory biomarkers and circulating levels of the bioactive lysophospholipid mediator sphingosine-1-phosphate (S1P) in control and anemic mice with or without LPS-induced systemic inflammation. Acute anemia or lipopolysaccharide (LPS) challenge alone triggered an increase of circulating levels of the inflammatory markers IL-6 ...

  4. Nitric oxide and superoxide mediate diesel particle effects in cytokine-treated mice and murine lung epithelial cells — implications for susceptibility to traffic-related air pollution

    OpenAIRE

    Manzo Nicholas D; LaGier Adriana J; Slade Ralph; Ledbetter Allen D; Richards Judy H; Dye Janice A

    2012-01-01

    Abstract Background Epidemiologic studies associate childhood exposure to traffic-related air pollution with increased respiratory infections and asthmatic and allergic symptoms. The strongest associations between traffic exposure and negative health impacts are observed in individuals with respiratory inflammation. We hypothesized that interactions between nitric oxide (NO), increased during lung inflammatory responses, and reactive oxygen species (ROS), increased as a consequence of traffic...

  5. Effects of acteoside on lipopolysaccharide-induced inflammation in acute lung injury via regulation of NF-κB pathway in vivo and in vitro

    International Nuclear Information System (INIS)

    The purpose of the present study was to investigate the protective role of acteoside (AC) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). BalB/c mice intraperitoneally received AC (30, and 60 mg/kg) or dexamethasone (2 mg/kg) 2 h prior to or after intratracheal instillation of LPS. Treatment with AC significantly decreased lung wet-to-dry weight (W/D) ratio and lung myeloperoxidase (MPO) activity and ameliorated LPS-induced lung histopathological changes. In addition, AC increased super oxide dismutase (SOD) level and inhibited malondialdehyde (MDA) content, total cell and neutrophil infiltrations, and levels of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) in LPS-stimulated mice. Furthermore, we demonstrated that AC inhibited the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, inhibitor of nuclear factor kappa-B kinase-α (IKK-α) and inhibitor of nuclear factor kappa-B kinase-β (IKKβ) in LPS-induced inflammation in A549 cells. Our data suggested that LPS evoked the inflammatory response in lung epithelial cells A549. The experimental results indicated that the protective mechanism of AC might be attributed partly to the inhibition of proinflammatory cytokine production and NF-κB activation. - Highlights: • Acteoside inhibited inflammation in LPS-induced lung injury in mice. • Acteoside inhibited inflammation in lung epithelial cells A549. • Acteoside inhibited NF-kB activation in LPS-induced mice and lung epithelial cells A549

  6. Effects of acteoside on lipopolysaccharide-induced inflammation in acute lung injury via regulation of NF-κB pathway in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Jing, Wang; Chunhua, Ma, E-mail: machunhuabest@126.com; Shumin, Wang, E-mail: wangshuminch@126.com

    2015-06-01

    The purpose of the present study was to investigate the protective role of acteoside (AC) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). BalB/c mice intraperitoneally received AC (30, and 60 mg/kg) or dexamethasone (2 mg/kg) 2 h prior to or after intratracheal instillation of LPS. Treatment with AC significantly decreased lung wet-to-dry weight (W/D) ratio and lung myeloperoxidase (MPO) activity and ameliorated LPS-induced lung histopathological changes. In addition, AC increased super oxide dismutase (SOD) level and inhibited malondialdehyde (MDA) content, total cell and neutrophil infiltrations, and levels of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) in LPS-stimulated mice. Furthermore, we demonstrated that AC inhibited the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, inhibitor of nuclear factor kappa-B kinase-α (IKK-α) and inhibitor of nuclear factor kappa-B kinase-β (IKKβ) in LPS-induced inflammation in A549 cells. Our data suggested that LPS evoked the inflammatory response in lung epithelial cells A549. The experimental results indicated that the protective mechanism of AC might be attributed partly to the inhibition of proinflammatory cytokine production and NF-κB activation. - Highlights: • Acteoside inhibited inflammation in LPS-induced lung injury in mice. • Acteoside inhibited inflammation in lung epithelial cells A549. • Acteoside inhibited NF-kB activation in LPS-induced mice and lung epithelial cells A549.

  7. Role of Chemokines in Non-Small Cell Lung Cancer: Angiogenesis and Inflammation

    OpenAIRE

    Rivas-Fuentes, Selma; Salgado-Aguayo, Alfonso; Pertuz Belloso, Silvana; Gorocica Rosete, Patricia; Alvarado-Vásquez, Noé; Aquino-Jarquin, Guillermo

    2015-01-01

    Non-small cell lung cancer (NSCLC) is one of the most common types of aggressive cancer. The tumor tissue, which shows an active angiogenesis, is composed of neoplastic and stromal cells, and an abundant inflammatory infiltrate. Angiogenesis is important to support tumor growth, while infiltrating cells contribute to the tumor microenvironment through the secretion of growth factors, cytokines and chemokines, important molecules in the progression of the disease. Chemokines are important in d...

  8. Loss of red cell chemokine scavenging promotes transfusion-related lung inflammation

    OpenAIRE

    Mangalmurti, Nilam S.; Xiong, Zeyu; Hulver, Mei; Ranganathan, Mrunalini; Liu, Xiang Hong; Oriss, Timothy; Fitzpatrick, Meghan; Rubin, Marc; Triulzi, Darrell; Choi, Augustine; Lee, Janet S.

    2009-01-01

    Red cell transfusions are associated with the development of acute lung injury in the critically ill. Recent evidence suggests that storage induced alterations of the red blood cell (RBC) collectively termed the “storage lesion” may be linked with adverse biologic consequences. Using a 2-event model of systemic endotoxemia followed by a secondary challenge of RBC transfusion, we investigated whether purified RBC concentrates from syngeneic C57BL/6 mice altered inflammatory responses in murine...

  9. Beta-carotene metabolites enhance inflammation-induced oxidative DNA damage in lung epithelial cells.

    OpenAIRE

    van Helden, Yvonne G. J.; Keijer, Jaap; Knaapen, Ad M; Heil, Sandra G.; Briede, Jacob J.; Schooten, Frederik J.; Godschalk, Roger W. L.

    2009-01-01

    beta-Carotene (BC) intake has been shown to enhance lung cancer risk in smokers and asbestos-exposed subjects (according to the ATBC and CARET studies), but the mechanism behind this procarcinogenic effect of BC is unclear. Both smoking and asbestos exposure induce an influx of inflammatory neutrophils into the airways, which results in an increased production of reactive oxygen species and formation of promutagenic DNA lesions. Therefore, the aim of our study was to investigate the effects o...

  10. Dietary intake, lung function and airway inflammation in Mexico City school children exposed to air pollutants

    Directory of Open Access Journals (Sweden)

    Díaz-Sánchez David

    2009-12-01

    Full Text Available Abstract Introduction Air pollutant exposure has been associated with an increase in inflammatory markers and a decline in lung function in asthmatic children. Several studies suggest that dietary intake of fruits and vegetables might modify the adverse effect of air pollutants. Methods A total of 158 asthmatic children recruited at the Children's Hospital of Mexico and 50 non-asthmatic children were followed for 22 weeks. Pulmonary function was measured and nasal lavage collected and analyzed every 2 weeks. Dietary intake was evaluated using a 108-item food frequency questionnaire and a fruit and vegetable index (FVI and a Mediterranean diet index (MDI were constructed. The impact of these indices on lung function and interleukin-8 (IL-8 and their interaction with air pollutants were determined using mixed regression models with random intercept and random slope. Results FVI was inversely related to IL-8 levels in nasal lavage (p 1 (test for trend p 1 and FVC as was with MDI and ozone for FVC. No effect of diet was observed among healthy children. Conclusion Our results suggest that fruit and vegetable intake and close adherence to the Mediterranean diet have a beneficial effect on inflammatory response and lung function in asthmatic children living in Mexico City.

  11. Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury.

    Directory of Open Access Journals (Sweden)

    Leonardo C M Ávila

    Full Text Available Studies have reported that exposure to diesel exhaust particles (DEPs induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12, Swimming (30 min/day (n = 8, DEP (3 mg/mL-10 μL/mouse (n = 9 and DEP+Swimming (n = 8. The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF, measured the lung homogenate levels of IL-1β, TNF-α, IL-6, INF-ϫ, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH and the antioxidant enzymes catalase and glutathione peroxidase (GPx in the lung. Swimming sessions decreased the number of total cells (p<0.001, neutrophils and lymphocytes (p<0.001; p<0.05 in the BALF, as well as lung levels of IL-1β (p = 0.002, TNF-α (p = 0.003, IL-6 (p = 0.0001 and IFN-ϫ (p = 0.0001. However, the levels of IL-10 (p = 0.01 and IL-1ra (p = 0.0002 increased in the swimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001. Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and p<0.002. We concluded that in this experimental model, the high-intensity swimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung

  12. Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis.

    Science.gov (United States)

    Vannella, Kevin M; Ramalingam, Thirumalai R; Borthwick, Lee A; Barron, Luke; Hart, Kevin M; Thompson, Robert W; Kindrachuk, Kristen N; Cheever, Allen W; White, Sandra; Budelsky, Alison L; Comeau, Michael R; Smith, Dirk E; Wynn, Thomas A

    2016-05-01

    Thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and IL-33 are important initiators of type 2-associated mucosal inflammation and immunity. However, their role in the maintenance of progressive type 2 inflammation and fibrosis is much less clear. Using chronic models of helminth infection and allergic lung inflammation, we show that collective disruption of TSLP, IL-25, and IL-33 signaling suppresses chronic and progressive type 2 cytokine-driven inflammation and fibrosis. In a schistosome lung granuloma model or during chronic Schistosoma mansoni infection in the liver, individual ablation of TSLP, IL-25, or IL-33/ST2 had no impact on the development of IL-4/IL-13-dependent inflammation or fibrosis. However, significant reductions in granuloma-associated eosinophils, hepatic fibrosis, and IL-13-producing type 2 innate lymphoid cells (ILC2s) were observed when signaling of all three mediators was simultaneously disrupted. Combined blockade through monoclonal antibody (mAb) treatment also reduced IL-5 and IL-13 expression during primary and secondary granuloma formation in the lungs. In a model of chronic house dust mite-induced allergic lung inflammation, combined mAb treatment did not decrease established inflammation or fibrosis. TSLP/IL-33 double-knockout mice treated with anti-IL-25 mAb during priming, however, displayed decreased inflammation, mucus production, and lung remodeling in the chronic phase. Together, these studies reveal partially redundant roles for TSLP, IL-25, and IL-33 in the maintenance of type 2 pathology and suggest that in some settings, early combined targeting of these mediators is necessary to ameliorate progressive type 2-driven disease. PMID:27147589

  13. Up-regulation of the expression of S100A8 and S100A9 in lung adenocarcinoma and its correlation with inflammation and other clinical features

    Institute of Scientific and Technical Information of China (English)

    SU Yan-jun; XU Feng; YU Jin-pu; YUE Dong-sheng; REN Xiu-bao; WANG Chang-li

    2010-01-01

    Background S100A8 and S100A9 are two members of the S100 protein family characterized by the presence of two Ca2+-binding sites of the EF-hand type.Previous studies suggested that the whole S100 family displays significant functions in tumor growth, progression and invasion.This study aimed to determine the expression of the two indices of the family, S100A8 and S100A9, in lung cancer tissues and normal lung tissues and its correlation with clinical features.Methods A total of 60 cases with a variety of clinical data that were diagnosed with different histological subtypes of lung cancer were investigated.Semi-quantitative reverse transcriptase-PCR (Sq-Rt-PCR) and immunohistochemical staining of cancer, adjacent and peripheral lung tissues were executed to distinguish the expression patterns of S100A8and S100A9 and to further clarify their correlation with clinical features.Results Immunohistochemical staining of both proteins showed a significant up-regulation in lung cancer tissue (S100A8, S100A9, P<0.0001), and PCR revealed that the levels of S100A8 and S100A9 expression were significantly higher in lung cancer tissues (S100A8 P=0.002/0.004; S100A9 P=0.022/0.026).The higher expression was found to be correlated with the clinical characteristics of adenocarcinoma, inflammation and stage Ⅳ lesion.Conclusions S100A8, S100A9 up-regulation was found in the lung adenocarcinoma and end stage lung cancer tissue,the correlation of which with their higher expression in inflammatory lung tissues may indicate the collaborative effect of inflammation on the progression of cancer.

  14. Regulatory T Cells Contribute to the Inhibition of Radiation-Induced Acute Lung Inflammation via Bee Venom Phospholipase A2 in Mice

    OpenAIRE

    Dasom Shin; Gihyun Lee; Sung-Hwa Sohn; Soojin Park; Kyung-Hwa Jung; Ji Min Lee; Jieun Yang; Jaeho Cho; Hyunsu Bae

    2016-01-01

    Bee venom has long been used to treat various inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Previously, we reported that bee venom phospholipase A2 (bvPLA2) has an anti-inflammatory effect through the induction of regulatory T cells. Radiotherapy is a common anti-cancer method, but often causes adverse effects, such as inflammation. This study was conducted to evaluate the protective effects of bvPLA2 in radiation-induced acute lung inflammation. Mice were focall...

  15. Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

    OpenAIRE

    Martínez-González, Itziar; Cruz, Maria-Jesús; Moreno, Rafael; Morell, Ferran; Muñoz, Xavier; Aran, Josep M.

    2014-01-01

    Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2...

  16. A GM-CSF/IL-33 pathway facilitates allergic airway responses to sub-threshold house dust mite exposure.

    Science.gov (United States)

    Llop-Guevara, Alba; Chu, Derek K; Walker, Tina D; Goncharova, Susanna; Fattouh, Ramzi; Silver, Jonathan S; Moore, Cheryl Lynn; Xie, Juliana L; O'Byrne, Paul M; Coyle, Anthony J; Kolbeck, Roland; Humbles, Alison A; Stämpfli, Martin R; Jordana, Manel

    2014-01-01

    Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM), we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b(+) DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway. PMID:24551140

  17. A GM-CSF/IL-33 pathway facilitates allergic airway responses to sub-threshold house dust mite exposure.

    Directory of Open Access Journals (Sweden)

    Alba Llop-Guevara

    Full Text Available Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM, we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b(+ DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.

  18. Intrapulmonary administration of bone-marrow derived M1/M2 macrophages to enhance the resolution of LPS-induced lung inflammation: noninvasive monitoring using free-breathing MR and CT imaging protocols

    International Nuclear Information System (INIS)

    Alveolar macrophages, with their high functional plasticity, were reported to orchestrate the induction and resolution of inflammatory processes in chronic pulmonary diseases. Noninvasive imaging modalities that offer simultaneous monitoring of inflammation progression and tracking of macrophages subpopulations involved in the inflammatory cascade, can provide an ideal and specific diagnostic tool to visualize the action mechanism in its initial stages. Therefore, the purpose of the current study was to evaluate the role of M1 and M2 macrophages in the resolution of lipopolysaccharide (LPS)-induced lung inflammation and monitor this process using noninvasive free-breathing MRI and CT protocols. Bone-marrow derived macrophages were first polarized to M1 and M2 macrophages and then labeled with superparamagnetic iron oxide nanoparticles. BALB/c mice with lung inflammation received an intrapulmonary instillation of these ex vivo polarized M1 or M2 macrophages. The biodistribution of macrophages subpopulations and the subsequent resolution of lung inflammation were noninvasively monitored using MRI and micro-CT. Confirmatory immunohistochemistry analyses were performed on lung tissue sections using specific macrophage markers. As expected, large inflammatory areas noninvasively imaged using pulmonary MR and micro-CT were observed within the lungs following LPS challenge. Subsequent intrapulmonary administration of M1 and M2 macrophages resulted in a significant decrease in inflammation starting from 72 h. Confirmatory immunohistochemistry analyses established a progression of lung inflammation with LPS and its subsequent reduction with both macrophages subsets. An enhanced resolution of inflammation was observed with M2 macrophages compared to M1. The current study demonstrated that ex vivo polarized macrophages decreased LPS-induced lung inflammation. Noninvasive free-breathing MR and CT imaging protocols enabled efficient monitoring of progression and resolution of

  19. Rhinitis: Allergic and Non-Allergic

    OpenAIRE

    Ogrady, M.J.

    1987-01-01

    Rhinitis, or the “stuffy nose”, can be allergic or non-allergic in nature. Accurate diagnosis depends on a well-taken history and physical examination. Non-allergic rhinitis is characterized by absent elevation in allergen-specific IgE. Treatment is based, if possible, on the etiology. Surgical procedures on the turbinates are often needed to allow improvement. Allergic rhinitis is characterized by an increase in allergen-specific IgE. Treatment may involve environmental control, pharmocologi...

  20. Emphysema is associated with increased inflammation in lungs of atherosclerosis-prone mice by cigarette smoke: implications in comorbidities of COPD

    Directory of Open Access Journals (Sweden)

    Yao Hongwei

    2010-07-01

    Full Text Available Abstract Background Chronic obstructive pulmonary disease is associated with numerous vascular effects including endothelial dysfunction, arterial stiffness and atherogenesis. It is also known that a decline in lung function is associated with increased cardiovascular comorbidity in smokers. The mechanism of this cardiopulmonary dual risk by cigarette smoke (CS is not known. We studied the molecular mechanisms involved in development of emphysema in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/- mice in response to CS exposure. Methods Adult male and female wild-type (WT mice of genetic background C57BL/6J and ApoE-/- mice were exposed to CS, and lung inflammatory responses, oxidative stress (lipid peroxidation products, mechanical properties as well as airspace enlargement were assessed. Results and Discussion The lungs of ApoE-/- mice showed augmented inflammatory response and increased oxidative stress with development of distal airspace enlargement which was accompanied with decline in lung function. Interestingly, the levels and activities of matrix metalloproteinases (MMP-9 and MMP-12 were increased, whereas the level of eNOS was decreased in lungs of CS-exposed ApoE-/- mice as compared to air-exposed ApoE-/- mice or CS-exposed WT mice. Conclusion These findings suggest that CS causes premature emphysema and a decline of lung function in mice susceptible to cardiovascular abnormalities via abnormal lung inflammation, increased oxidative stress and alterations in levels of MMPs and eNOS.

  1. Hyperbaric oxygen preconditioning protects the lung against acute pancreatitis induced injury via attenuating inflammation and oxidative stress in a nitric oxide dependent manner.

    Science.gov (United States)

    Yu, Qi-Hong; Zhang, Pei-Xi; Liu, Ying; Liu, Wenwu; Yin, Na

    2016-09-01

    This study aimed to investigate the protective effects of hyperbaric oxygen preconditioning (HBO-PC) on acute pancreatitis AP associated acute lung injury (ALI) and the potential mechanisms. Rats were randomly divided into sham group, AP group, HBO-PC + AP group and HBO-PC + L-NAME group. Rats in HBO-PC + AP group received HBO-PC once daily for 3 days, and AP was introduced 24 h after last HBO-PC. In HBO-PC + L-NAME group, L-NAME (40 mg/kg) was intraperitoneally injected before each HBO-PC. At 24 h after AP, the blood lipase and amylase activities were measured; the lung and pancreas were harvested for pathological examination; the bronchoalveolar lavage fluid was collected for the detection of lactate dehydrogenase (LDH) and proteins; inflammatory factors, superoxide dismutase (SOD) activity and malonaldehyde content were measured in the lung and blood; the Nrf2, SOD-1 and haem oxygenase-1 (HO-1) protein expression was measured in the lung. The lung nitric oxide (NO) and NO synthase activity increased significantly after HBO-PC. HBO-PC was able to reduce blood lipase and amylase activities, improve lung and pancreatic pathology, decrease LDH and proteins in BALF, inhibit the production of inflammatory factors, reduce malonaldehyde content and increase SOD activity in the lung and blood as well as increase protein expression of Nrf2, SOD-1 and HO-1 in the lung. However, L-NAME before HBO-PC significantly attenuated protective effects of HBO-PC. HBO-PC is able to protect the lung against AP induced injury by attenuating inflammation and oxidative stress in the lung via a NO dependent manner. PMID:27453338

  2. Chitosan coating of copper nanoparticles reduces in vitro toxicity and increases inflammation in the lung

    International Nuclear Information System (INIS)

    Despite their potential for a variety of applications, copper nanoparticles induce very strong inflammatory responses and cellular toxicity following aerosolized delivery. Coating metallic nanoparticles with polysaccharides, such as biocompatible and antimicrobial chitosan, has the potential to reduce this toxicity. In this study, copper nanoparticles were coated with chitosan using a newly developed and facile method. The presence of coating was confirmed using x-ray photoelectron spectroscopy, rhodamine tagging of chitosan followed by confocal fluorescence imaging of coated particles and observed increases in particle size and zeta potential. Further physical and chemical characteristics were evaluated using dissolution and x-ray diffraction studies. The chitosan coating was shown to significantly reduce the toxicity of copper nanoparticles after 24 and 52 h and the generation of reactive oxygen species as assayed by DHE oxidation after 24 h in vitro. Conversely, inflammatory response, measured using the number of white blood cells, total protein, and cytokines/chemokines in the bronchoalveolar fluid of mice exposed to chitosan coated versus uncoated copper nanoparticles, was shown to increase, as was the concentration of copper ions. These results suggest that coating metal nanoparticles with mucoadhesive polysaccharides (e.g. chitosan) could increase their potential for use in controlled release of copper ions to cells, but will result in a higher inflammatory response if administered via the lung. (paper)

  3. Pulmonary Oxidative Stress, Inflammation and Cancer: Respirable Particulate Matter, Fibrous Dusts and Ozone as Major Causes of Lung Carcinogenesis through Reactive Oxygen Species Mechanisms

    Directory of Open Access Journals (Sweden)

    Spyridon Loridas

    2013-08-01

    Full Text Available Reactive oxygen or nitrogen species (ROS, RNS and oxidative stress in the respiratory system increase the production of mediators of pulmonary inflammation and initiate or promote mechanisms of carcinogenesis. The lungs are exposed daily to oxidants generated either endogenously or exogenously (air pollutants, cigarette smoke, etc.. Cells in aerobic organisms are protected against oxidative damage by enzymatic and non-enzymatic antioxidant systems. Recent epidemiologic investigations have shown associations between increased incidence of respiratory diseases and lung cancer from exposure to low levels of various forms of respirable fibers and particulate matter (PM, at occupational or urban air polluting environments. Lung cancer increases substantially for tobacco smokers due to the synergistic effects in the generation of ROS, leading to oxidative stress and inflammation with high DNA damage potential. Physical and chemical characteristics of particles (size, transition metal content, speciation, stable free radicals, etc. play an important role in oxidative stress. In turn, oxidative stress initiates the synthesis of mediators of pulmonary inflammation in lung epithelial cells and initiation of carcinogenic mechanisms. Inhalable quartz, metal powders, mineral asbestos fibers, ozone, soot from gasoline and diesel engines, tobacco smoke and PM from ambient air pollution (PM10 and PM2.5 are involved in various oxidative stress mechanisms. Pulmonary cancer initiation and promotion has been linked to a series of biochemical pathways of oxidative stress, DNA oxidative damage, macrophage stimulation, telomere shortening, modulation of gene expression and activation of transcription factors with important role in carcinogenesis. In this review we are presenting the role of ROS and oxidative stress in the production of mediators of pulmonary inflammation and mechanisms of carcinogenesis.

  4. Pulmonary Oxidative Stress, Inflammation and Cancer: Respirable Particulate Matter, Fibrous Dusts and Ozone as Major Causes of Lung Carcinogenesis through Reactive Oxygen Species Mechanisms

    OpenAIRE

    Spyridon Loridas; Konstantinos Fiotakis; Athanasios Valavanidis; Thomais Vlachogianni

    2013-01-01

    Reactive oxygen or nitrogen species (ROS, RNS) and oxidative stress in the respiratory system increase the production of mediators of pulmonary inflammation and initiate or promote mechanisms of carcinogenesis. The lungs are exposed daily to oxidants generated either endogenously or exogenously (air pollutants, cigarette smoke, etc.). Cells in aerobic organisms are protected against oxidative damage by enzymatic and non-enzymatic antioxidant systems. Recent epidemiologic investigations have s...

  5. The Correlation between Chitin and Acidic Mammalian Chitinase in Animal Models of Allergic Asthma

    Directory of Open Access Journals (Sweden)

    Chia-Rui Shen

    2015-11-01

    Full Text Available Asthma is the result of chronic inflammation of the airways which subsequently results in airway hyper-responsiveness and airflow obstruction. It has been shown that an elicited expression of acidic mammalian chitinase (AMCase may be involved in the pathogenesis of asthma. Our recent study has demonstrated that the specific suppression of elevated AMCase leads to reduced eosinophilia and Th2-mediated immune responses in an ovalbumin (OVA-sensitized mouse model of allergic asthma. In the current study, we show that the elicited expression of AMCase in the lung tissues of both ovalbumin- and Der P2-induced allergic asthma mouse models. The effects of allergic mediated molecules on AMCase expression were evaluated by utilizing promoter assay in the lung cells. In fact, the exposure of chitin, a polymerized sugar and the fundamental component of the major allergen mite and several of the inflammatory mediators, showed significant enhancement on AMCase expression. Such obtained results contribute to the basis of developing a promising therapeutic strategy for asthma by silencing AMCase expression.

  6. Regulatory T cells and regulation of allergic airway disease

    OpenAIRE

    Martin, Helen; Taube, Christian

    2012-01-01

    Diseases like asthma have dramatically increased in the last decades. The reasons for the rising prevalence are still controversially discussed. Besides the genetic predisposition a number of different causes are thought to affect the increase of allergies. These include the hygiene hypothesis as well as changes in intestinal microbiota. Allergic airway inflammation is driven by T cells but it has become clear that tolerance and also suppression of allergic inflammation are mediated by so cal...

  7. Phosphodiesterases Inhibition by Bacilli Calmette-Guérin Contributes to Decrease Asthma in Allergic Rats

    Directory of Open Access Journals (Sweden)

    Yajuan Wang

    2011-09-01

    Full Text Available Phosphodiesterases  (PDE  hydrolyse intracellular cAMP  and  cGMP  to  inactive  5’ monophosphates. Decreased level of cAMP is involved in the pathogenesis of asthma. We and others have shown that phosphodiesterases were upregulated in the lung of allergic rats, and Bacilli Calmette-Guérin (BCG induced the production of cAMP in vitro. However, it is unclear how BCG’s effect asthma and whether it is related to PDEs.In  this  study,  BCG  was  intraperitoneally  injected  into  male  Sprague-Dawley rats sensitized and later the rats were challenged with ovabumin/pertusis. The inflammation in lungs was measured. Airway hyperresponsiveness was determined using MedLab software after intravenous methacholine challenge. Furthermore,  cAMP level and adenylate cyclase activity in lungs were analyzed by ELISA, phosphodiesterases activities were analyzed by HPLC, while PDEs mRNA levels in lungs was analyzed by reverse transcription-polymerase chain  reaction.  Administration  of  BCG  significantly attenuated  allergen-induced  lung inflammatory response  and  hyper  responsiveness  as  compared  with  vehicle treatment. Furthermore,  the  levels of  cAMP in lungs were significantly increased in  BCG-treated allergic rats. Interestingly, administration of BCG decreased the activity of cAMP-PDE, but not adenylyl cyclase (AC, activity in lungs of animals. Furthermore, pretreatment with BCG significantly decreased the mRNA levels of PDE4A, 4C, 5 and 8, which were induced in lungs of allergic rats.BCG  administration  attenuated  airway inflammatory  response  and  bronchial  hyper responsiveness in rats, which are the most important symptoms in asthma. The decreased PDEs  mRNA  and  inhibited cAMP-PDE  activities by BCG  contribute,  at least in part, prevention of allergen-induced airway inflammation and asthma in rats.

  8. Design and Synthesis of N-Arylphthalimides as Inhibitors of Glucocorticoid-Induced TNF Receptor-Related Protein, Proinflammatory Mediators, and Cytokines in Carrageenan-Induced Lung Inflammation.

    Science.gov (United States)

    Bhat, Mashooq A; Al-Omar, Mohamed A; Ansari, Mushtaq A; Zoheir, Khairy M A; Imam, Faisal; Attia, Sabry M; Bakheet, Saleh A; Nadeem, Ahmed; Korashy, Hesham M; Voronkov, Andrey; Berishvili, Vladimir; Ahmad, Sheikh F

    2015-11-25

    N-Arylphthalimides (1-10P) derived from thalidomide by insertion of hydrophobic groups were evaluated for anti-inflammatory activity, and (4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N'-[(4-ethoxyphenyl)methylidene]benzohydrazide 6P was identified as a promising anti-inflammatory agent. Further testing confirmed that compared with the control, 6P treatment resulted in a considerable decrease in CD4(+), NF-κB p65(+), TNF-α(+), IL-6(+), GITR(+), and IL-17(+) cell populations and an increase in the Foxp3(+), CD4(+)Foxp3(+), and IκBα(+) populations in whole blood and pleural fluid of a mouse model of lung inflammation. Moreover, treatment with compound 6P decreased the proteins associated with inflammation including TNF-α, IL-6, IL-17, GITR, NF-κB, COX-2, STAT-3, and iNOS and increased the anti-inflammatory mediators such as IL-10 and IL-4. Further, histopathological examination confirmed the potent anti-inflammatory effects of compound 6P. Thus, the N-arylphthalimide derivative 6P acts as a potent anti-inflammatory agent in the carrageenan-induced lung inflammation model, suggesting that this compound may be useful for the treatment of inflammation in a clinical setting. PMID:26456029

  9. Pathway focused protein profiling indicates differential function for IL-1B, -18 and VEGF during initiation and resolution of lung inflammation evoked by carbon nanoparticle exposure in mice

    Directory of Open Access Journals (Sweden)

    Hamelmann Eckard

    2009-12-01

    Full Text Available Abstract Background Carbonaceous nanoparticles possess an emerging source of human exposure due to the massive release of combustion products and the ongoing revolution in nanotechnology. Pulmonary inflammation caused by deposited nanoparticles is central for their adverse health effects. Epidemiological studies suggest that individuals with favourable lung physiology are at lower risk for particulate matter associated respiratory diseases probably due to efficient control of inflammation and repair process. Therefore we selected a mouse strain C3H/HeJ (C3 with robust lung physiology and exposed it to moderately toxic carbon nanoparticles (CNP to study the elicited pulmonary inflammation and its resolution. Methods 5 μg, 20 μg and 50 μg CNP were intratracheally (i.t. instilled in C3 mice to identify the optimal dose for subsequent time course studies. Pulmonary inflammation was assessed using histology, bronchoalveolar lavage (BAL analysis and by a panel of 62 protein markers. Results 1 day after instillation of CNP, C3 mice exhibited a typical dose response, with the lowest dose (5 μg representing the 'no effect level' as reflected by polymorphonuclear leucocyte (PMN, and BAL/lung concentrations of pro-inflammatory proteins. Histological analysis and BAL-protein concentration did not reveal any evidence of tissue injury in 20 μg CNP instilled animals. Accordingly time course assessment of the inflammatory response was performed after 3 and 7 days with this dose (20 μg. Compared to day 1, BAL PMN counts were significantly decreased at day 3 and completely returned to normal by day 7. We have identified protein markers related to the acute response and also to the time dependent response in lung and BAL. After complete resolution of PMN influx on day 7, we detected elevated concentrations of 20 markers that included IL1B, IL18, FGF2, EDN1, and VEGF in lung and/or BAL. Biological pathway analysis revealed these factors to be involved in a

  10. Neutralization of TSLP inhibits airway remodeling in a murine model of allergic asthma induced by chronic exposure to house dust mite.

    Directory of Open Access Journals (Sweden)

    Zhuang-Gui Chen

    Full Text Available Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. However, the initiating factor that links airway inflammation to remodeling is unknown. Thymic stromal lymphopoietin (TSLP, an epithelium-derived cytokine, can strongly activate lung dendritic cells (DCs through the TSLP-TSLPR and OX40L-OX40 signaling pathways to promote Th2 differentiation. To determine whether TSLP is the underlying trigger of airway remodeling in chronic allergen-induced asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM extracts for up to 5 consecutive weeks. We showed that repeated respiratory exposure to HDM caused significant airway eosinophilic inflammation, peribronchial collagen deposition, goblet cell hyperplasia, and airway hyperreactivity (AHR to methacholine. These effects were accompanied with a salient Th2 response that was characterized by the upregulation of Th2-typed cytokines, such as IL-4 and IL-13, as well as the transcription factor GATA-3. Moreover, the levels of TSLP and transforming growth factor beta 1 (TGF-β1 were also increased in the airway. We further demonstrated, using the chronic HDM-induced asthma model, that the inhibition of Th2 responses via neutralization of TSLP with an anti-TSLP mAb reversed airway inflammation, prevented structural alterations, and decreased AHR to methacholine and TGF-β1 level. These results suggest that TSLP plays a pivotal role in the initiation and persistence of airway inflammation and remodeling in the context of chronic allergic asthma.

  11. Applicability of rat precision-cut lung slices in evaluating nanomaterial cytotoxicity, apoptosis, oxidative stress, and inflammation

    International Nuclear Information System (INIS)

    The applicability of rat precision-cut lung slices (PCLuS) in detecting nanomaterial (NM) toxicity to the respiratory tract was investigated evaluating sixteen OECD reference NMs (TiO2, ZnO, CeO2, SiO2, Ag, multi-walled carbon nanotubes (MWCNTs)). Upon 24-hour test substance exposure, the PCLuS system was able to detect early events of NM toxicity: total protein, reduction in mitochondrial activity, caspase-3/-7 activation, glutathione depletion/increase, cytokine induction, and histopathological evaluation. Ion shedding NMS (ZnO and Ag) induced severe tissue destruction detected by the loss of total protein. Two anatase TiO2 NMs, CeO2 NMs, and two MWCNT caused significant (determined by trend analysis) cytotoxicity in the WST-1 assay. At non-cytotoxic concentrations, different TiO2 NMs and one MWCNT increased GSH levels, presumably a defense response to reactive oxygen species, and these substances further induced a variety of cytokines. One of the SiO2 NMs increased caspase-3/-7 activities at non-cytotoxic levels, and one rutile TiO2 only induced cytokines. Investigating these effects is, however, not sufficient to predict apical effects found in vivo. Reproducibility of test substance measurements was not fully satisfactory, especially in the GSH and cytokine assays. Effects were frequently observed in negative controls pointing to tissue slice vulnerability even though prepared and handled with utmost care. Comparisons of the effects observed in the PCLuS to in vivo effects reveal some concordances for the metal oxide NMs, but less so for the MWCNT. The highest effective dosages, however, exceeded those reported for rat short-term inhalation studies. To become applicable for NM testing, the PCLuS system requires test protocol optimization. - Highlights: • 16 OECD reference nanomaterials were tested in rat precision-cut lung slices. • Nanomaterial cytotoxicity, apoptose, oxidative stress, and inflammation were detected. • Investigating these early effects

  12. Applicability of rat precision-cut lung slices in evaluating nanomaterial cytotoxicity, apoptosis, oxidative stress, and inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Sauer, Ursula G. [Scientific Consultancy — Animal Welfare, Neubiberg (Germany); Vogel, Sandra [Experimental Toxicology and Ecology, BASF SE, Ludwigshafen (Germany); Product Stewardship Water Solutions, BASF SE, Ludwigshafen (Germany); Aumann, Alexandra; Hess, Annemarie; Kolle, Susanne N.; Ma-Hock, Lan [Experimental Toxicology and Ecology, BASF SE, Ludwigshafen (Germany); Wohlleben, Wendel [Experimental Toxicology and Ecology, BASF SE, Ludwigshafen (Germany); Material Physics, BASF SE, Ludwigshafen (Germany); Dammann, Martina; Strauss, Volker; Treumann, Silke; Gröters, Sibylle [Experimental Toxicology and Ecology, BASF SE, Ludwigshafen (Germany); Wiench, Karin [Product Safety, BASF SE, Ludwigshafen (Germany); Ravenzwaay, Bennard van [Experimental Toxicology and Ecology, BASF SE, Ludwigshafen (Germany); Landsiedel, Robert, E-mail: robert.landsiedel@basf.com [Experimental Toxicology and Ecology, BASF SE, Ludwigshafen (Germany)

    2014-04-01

    The applicability of rat precision-cut lung slices (PCLuS) in detecting nanomaterial (NM) toxicity to the respiratory tract was investigated evaluating sixteen OECD reference NMs (TiO{sub 2}, ZnO, CeO{sub 2}, SiO{sub 2}, Ag, multi-walled carbon nanotubes (MWCNTs)). Upon 24-hour test substance exposure, the PCLuS system was able to detect early events of NM toxicity: total protein, reduction in mitochondrial activity, caspase-3/-7 activation, glutathione depletion/increase, cytokine induction, and histopathological evaluation. Ion shedding NMS (ZnO and Ag) induced severe tissue destruction detected by the loss of total protein. Two anatase TiO{sub 2} NMs, CeO{sub 2} NMs, and two MWCNT caused significant (determined by trend analysis) cytotoxicity in the WST-1 assay. At non-cytotoxic concentrations, different TiO{sub 2} NMs and one MWCNT increased GSH levels, presumably a defense response to reactive oxygen species, and these substances further induced a variety of cytokines. One of the SiO{sub 2} NMs increased caspase-3/-7 activities at non-cytotoxic levels, and one rutile TiO{sub 2} only induced cytokines. Investigating these effects is, however, not sufficient to predict apical effects found in vivo. Reproducibility of test substance measurements was not fully satisfactory, especially in the GSH and cytokine assays. Effects were frequently observed in negative controls pointing to tissue slice vulnerability even though prepared and handled with utmost care. Comparisons of the effects observed in the PCLuS to in vivo effects reveal some concordances for the metal oxide NMs, but less so for the MWCNT. The highest effective dosages, however, exceeded those reported for rat short-term inhalation studies. To become applicable for NM testing, the PCLuS system requires test protocol optimization. - Highlights: • 16 OECD reference nanomaterials were tested in rat precision-cut lung slices. • Nanomaterial cytotoxicity, apoptose, oxidative stress, and inflammation were

  13. Indoleamine 2,3-dioxygenase expression in patients with allergic rhinitis: a case-control study

    OpenAIRE

    Luukkainen Annika; Karjalainen Jussi; Honkanen Teemu; Lehtonen Mikko; Paavonen Timo; Toppila-Salmi Sanna

    2011-01-01

    Abstract Background Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catalyzing enzyme. It has been suggested that it has a role in lower airway allergic inflammations, but its role in allergic rhinitis has not been investigated. Objective Our aim was to evaluate the expression of IDO in the nasal mucosa of allergic rhinitis patients allergic to birch pollen during peak exposure to birch pollen allergen and compare it to non-atopic patients. Methods IDO expression was immunohistochemically e...

  14. The Contribution of Allergen-Specific IgG to the Development of Th2-Mediated Airway Inflammation

    Directory of Open Access Journals (Sweden)

    Jesse W. Williams

    2012-01-01

    Full Text Available In both human asthmatics and animal models of allergy, allergen-specific IgG can contribute to Th2-mediated allergic inflammation. Mouse models have elucidated an important role for IgG and Fc-gamma receptor (FcγR signaling on antigen presenting cells (APC for the induction of airway inflammation. These studies suggest a positive feedback loop between IgG produced by the adaptive B cell response and FcγR signaling on innate immune cells. Studies of IgG and FcγRs in humans with asthma or allergic lung disease have been more controversial. Some reports have identified associations between allergen-specific IgG and severity of allergic responses, while other studies have found associations of IgG subclass IgG4 with allergic tolerance. In this paper, we review the literature to help define the nature of IgG and FcγR signaling on innate immune cells and how it contributes to the development of allergic immune responses.

  15. Effect of Retinoic Acid in a Mouse Model of Allergic Rhinitis

    OpenAIRE

    Son, Hye-Lim; Park, Hyang-Rim; Park, Yong-Jin; Kim, Soo-Whan

    2015-01-01

    Purpose All-trans retinoic acid (ATRA) modulates immune responses by affecting T cells. Several studies have revealed that allergic inflammation of the lower airways is negatively associated with the vitamin A concentration. However, the role of ATRA in allergic inflammation of the upper airways is unclear. We investigated the effects of ATRA in an allergic rhinitis mouse model. Methods BALB/c mice except control groups (CON group) were sensitized with and challenged intra-nasally with Dermat...

  16. Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases

    Directory of Open Access Journals (Sweden)

    Jun Miyata

    2015-01-01

    Full Text Available Omega-3 fatty acids, docosahexaenoic acid (DHA and eicosapentaenoic acid (EPA, are found naturally in fish oil and are commonly thought to be anti-inflammatory nutrients, with protective effects in inflammatory diseases including asthma and allergies. The mechanisms of these effects remain mostly unknown but are of great interest for their potential therapeutic applications. Large numbers of epidemiological and observational studies investigating the effect of fish intake or omega-3 fatty acid supplementation during pregnancy, lactation, infancy, childhood, and adulthood on asthmatic and allergic outcomes have been conducted. They mostly indicate protective effects and suggest a causal relationship between decreased intake of fish oil in modernized diets and an increasing number of individuals with asthma or other allergic diseases. Specialized pro-resolving mediators (SPM: protectins, resolvins, and maresins are generated from omega-3 fatty acids such as EPA and DHA via several enzymatic reactions. These mediators counter-regulate airway eosinophilic inflammation and promote the resolution of inflammation in vivo. Several reports have indicated that the biosynthesis of SPM is impaired, especially in severe asthma, which suggests that chronic inflammation in the lung might result from a resolution defect. This article focuses on the beneficial aspects of omega-3 fatty acids and offers recent insights into their bioactive metabolites including resolvins and protectins.

  17. Angiogenic activity of sera from interstitial lung disease patients in relation to pulmonary function

    OpenAIRE

    Zielonka, TM; Demkow, U; Radzikowska, E; Bialas, B; Filewska, M; Zycinska, K; Obrowski, MH; Kowalski, J; Wardyn, KA; Skopinska-Rozewska, E

    2010-01-01

    Objective Chronic inflammation and fibrosis are characteristic of interstitial lung diseases (ILD) and are accompanied by neovascularisation. The aim of this study was to examine the relationship between the angiogenic activity of sera from ILD patients and pulmonary function tests. Material and methods Serum samples were obtained from 225 ILD patients: 83 with sarcoidosis, 31 with idiopathic pulmonary fibrosis, 29 with extrinsic allergic alveolitis, 16 with collagen vascular diseases, 13 wit...

  18. Immunologic principles of allergic disease.

    Science.gov (United States)

    Averbeck, Marco; Gebhardt, Carl; Emmrich, Frank; Treudler, Regina; Simon, Jan C

    2007-11-01

    Allergy either results from a pathological excessive immune reaction, or from the defective induction of tolerance to otherwise harmless antigens. Allergic reactions are mounted by mechanisms of innate and adaptive immunity. The development of an allergic response can be divided in sensitization and elicitation phases. Immediate type allergic reactions (e.g. anaphylaxis, urticaria, rhinoconjunctivitis allergica, allergic asthma) are mediated by IgE antibodies which are produced by B cells stimulated by allergen-specific Th2 cells. Crosslinking of allergen-specific IgE on membrane surfaces of mast cells and basophilic granulocytes leads to release of soluble mediators which may cause systemic symptoms within minutes to hours. The following infiltration of eosinophilic granulocytes and Th2 cells directs chronic inflammation. Humoral cytotoxic immune reactions (e.g. drug induced cytopenia) are mediated by IgG and IgM antibodies which are directed against membrane associated antigens. IgG and IgM antibodies directed against soluble antigens elicit immune complex mediated cytotoxicity (e.g.drug induced vasculitis). Delayed type immune reactions (e.g.contact dermatitis) are based on the activation of antigen specific CD4(+) and CD8(+) T cells and need 24 h to 48 h to develop. Upon recurrent contact with identical antigens, recruitment of CD4(+) and CD8(+) T cells cause inflammation and cytotoxic induced apoptosis in target cells as well as cytokine mediated leukocyte infiltration. Subsequent immigration of CD4(+) Th2 cells provides anti-inflammatory mechanisms leading to resolution of the inflammatory response and tissue repair. PMID:17976144

  19. Elevated plasma levels of pigment epithelium-derived factor correlated with inflammation and lung function in COPD patients

    Directory of Open Access Journals (Sweden)

    Li X

    2015-03-01

    diagnose COPD patients and we also analyzed the correlation between PEDF and lung function.Results: First, we found that the expression of PEDF in cigarette smoke extract-treated cells increased 16.2-fold when compared with the control group. Next, we confirmed that 4 weeks’ exposure to cigarette smoke can upregulate PEDF levels in rat lung tissues. We also discovered that plasma PEDF in COPD patients was significantly increased when compared with either healthy nonsmoking or smoking subjects. Furthermore, circulating PEDF was correlated with inflammatory cytokine and blood neutrophil numbers, but it was reversely associated with a decline in forced expiratory volume in 1 second percent predicted.Conclusion: Our findings provide a novel link between PEDF and COPD. Elevated PEDF levels may be involved in promoting the development of COPD by performing proinflammatory functions. Keywords: chronic obstructive pulmonary disease, pigment epithelium-derived factor, cigarette smoke, inflammation

  20. Dysregulated cytokine expression by CD4+ T cells from post-septic mice modulates both Th1 and Th2-mediated granulomatous lung inflammation.

    Directory of Open Access Journals (Sweden)

    William F Carson

    Full Text Available Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells. In particular, CD4+ T lymphocytes can exhibit reduced proliferative capacity and improper cytokine responses following sepsis. To further investigate the cell-intrinsic defects of CD4+ T cells following sepsis, splenic CD4+ T cells from sham surgery and post-septic mice were transferred into lymphopenic mice. These recipient mice were then subjected to both TH1-(purified protein derivative and TH2-(Schistosoma mansoni egg antigen driven models of granulomatous lung inflammation. Post-septic CD4+ T cells mediated smaller TH1 and larger TH2 lung granulomas as compared to mice receiving CD4+ T cells from sham surgery donors. However, cytokine production by lymph node cells in antigen restimulation assays indicated increased pan-specific cytokine expression by post-septic CD4+ T cell recipient mice in both TH1 and TH2 granuloma models. These include increased production of T(H2 cytokines in TH1 inflammation, and increased production of T(H1 cytokines in TH2 inflammation. These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression.

  1. Increased Th2 cytokine secretion, eosinophilic airway inflammation, and airway hyperresponsiveness in neurturin-deficient mice.

    Science.gov (United States)

    Michel, Tatiana; Thérésine, Maud; Poli, Aurélie; Domingues, Olivia; Ammerlaan, Wim; Brons, Nicolaas H C; Hentges, François; Zimmer, Jacques

    2011-06-01

    Neurotrophins such as nerve growth factor and brain-derived neurotrophic factor have been described to be involved in the pathogenesis of asthma. Neurturin (NTN), another neurotrophin from the glial cell line-derived neurotrophic factor family, was shown to be produced by human immune cells: monocytes, B cells, and T cells. Furthermore, it was previously described that the secretion of inflammatory cytokines was dramatically stimulated in NTN knockout (NTN(-/-)) mice. NTN is structurally similar to TGF-β, a protective cytokine in airway inflammation. This study investigates the implication of NTN in a model of allergic airway inflammation using NTN(-/-) mice. The bronchial inflammatory response of OVA-sensitized NTN(-/-) mice was compared with wild-type mice. Airway inflammation, Th2 cytokines, and airway hyperresponsiveness (AHR) were examined. NTN(-/-) mice showed an increase of OVA-specific serum IgE and a pronounced worsening of inflammatory features. Eosinophil number and IL-4 and IL-5 concentration in the bronchoalveolar lavage fluid and lung tissue were increased. In parallel, Th2 cytokine secretion of lung draining lymph node cells was also augmented when stimulated by OVA in vitro. Furthermore, AHR was markedly enhanced in NTN(-/-) mice after sensitization and challenge when compared with wild-type mice. Administration of NTN before challenge with OVA partially rescues the phenotype of NTN(-/-) mice. These findings provide evidence for a dampening role of NTN on allergic inflammation and AHR in a murine model of asthma. PMID:21508262

  2. Bone marrow cell derived arginase I is the major source of allergen-induced lung arginase but is not required for airway hyperresponsiveness, remodeling and lung inflammatory responses in mice

    Directory of Open Access Journals (Sweden)

    Rothenberg Marc E

    2009-06-01

    Full Text Available Abstract Background Arginase is significantly upregulated in the lungs in murine models of asthma, as well as in human asthma, but its role in allergic airway inflammation has not been fully elucidated in mice. Results In order to test the hypothesis that arginase has a role in allergic airway inflammation we generated arginase I-deficient bone marrow (BM chimeric mice. Following transfer of arginase I-deficient BM into irradiated recipient mice, arginase I expr