dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses.

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Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-08-04

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma.

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

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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.

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

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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.

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

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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.

An ovine tracheal explant culture model for allergic airway inflammation

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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

The R213G polymorphism in SOD3 protects against allergic airway inflammation

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Gaurav, Rohit; Varasteh, Jason T; Weaver, Michael R

2017-01-01

) in bronchoalveolar lavage fluid and reduced type II innate lymphoid cells (ILC2s) in lungs. SOD mimetic (Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin) attenuated Alternaria-induced expression of IL-33 and IL-8 release in BEAS-2B cells. These results suggest that R213G SNP potentially benefits its carriers...... by resulting in high EC-SOD in airway-lining fluid, which ameliorates allergic airway inflammation by dampening the innate immune response, including IL-33/ST2-mediated changes in ILC2s....

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

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Hansen, Jitka S; Nørgaard, Asger W; Koponen, Ismo K; Sørli, Jorid B; Paidi, Maya D; Hansen, Søren W K; Clausen, Per Axel; Nielsen, Gunnar D; Wolkoff, Peder; Larsen, Søren Thor

2016-11-01

Inhalation of indoor air pollutants may cause airway irritation and inflammation and is suspected to worsen allergic reactions. Inflammation may be due to mucosal damage, upper (sensory) and lower (pulmonary) airway irritation due to activation of the trigeminal and vagal nerves, respectively, and to neurogenic inflammation. The terpene, d-limonene, is used as a fragrance in numerous consumer products. When limonene reacts with the pulmonary irritant ozone, a complex mixture of gas and particle phase products is formed, which causes sensory irritation. This study investigated whether limonene, ozone or the reaction mixture can exacerbate allergic lung inflammation and whether airway irritation is enhanced in allergic BALB/cJ mice. Naïve and allergic (ovalbumin sensitized) mice were exposed via inhalation for three consecutive days to clean air, ozone, limonene or an ozone-limonene reaction mixture. Sensory 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, it was found that limonene and the ozone-limonene reaction mixture reduced allergic inflammation possibly due to antioxidant properties. Ozone induced sensory irritation in both naïve and allergic mice. However, allergic but not naïve mice were protected from pulmonary irritation induced by ozone. This study 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.

Adam8 Limits the Development of Allergic Airway Inflammation in Mice

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Knolle, Martin D.; Nakajima, Takahiro; Hergrueter, Anja; Gupta, Kushagra; Polverino, Francesca; Craig, Vanessa J.; Fyfe, Susanne E.; Zahid, Muhammad; Permaul, Perdita; Cernadas, Manuela; Montano, Gilbert; Tesfaigzi, Yohannes; Sholl, Lynette; Kobzik, Lester; Israel, Elliot; Owen, Caroline A.

2013-01-01

To determine whether a disintegrin and a metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyper-responsiveness (AHR), we compared AAI and AHR in wild type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with ovalbumin (OVA) or house dust mite protein extract (HDM). OVA- and HDM-treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some TH2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8−/− macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma. PMID:23670189

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

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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.

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity.

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Everaere, Laetitia; Ait-Yahia, Saliha; Molendi-Coste, Olivier; Vorng, Han; Quemener, Sandrine; LeVu, Pauline; Fleury, Sebastien; Bouchaert, Emmanuel; Fan, Ying; Duez, Catherine; de Nadai, Patricia; Staels, Bart; Dombrowicz, David; Tsicopoulos, Anne

2016-11-01

Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and T H 2 and T H 17 pulmonary profiles. Notably, nonsensitized obese mice already exhibited increased lung ILC counts and tissue eosinophil infiltration compared with values in lean mice in the absence of AHR. The numbers of total and cytokine-expressing lung ILC2s and ILC3s further increased in HDM-challenged obese mice compared with those in HDM-challenged lean mice, and this was accompanied by high IL-33 and IL-1β levels and decreased ILC markers in visceral adipose tissue. Furthermore, depletion of ILCs with an anti-CD90 antibody, followed by T-cell reconstitution, led to a profound decrease in allergic airway inflammatory features in obese mice, including T H 2 and T H 17 infiltration. These results indicate that HFD-induced obesity might exacerbate allergic airway inflammation through mechanisms involving ILC2s and ILC3s. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

TIM-3 is not essential for development of airway inflammation induced by house dust mite antigens

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Yoshihisa Hiraishi

2016-10-01

Conclusions: Our findings indicate that, in mice, TIM-3 is not essential for development of HDM-induced acute or chronic allergic airway inflammation, although it appears to be involved in reduced lymphocyte recruitment during HDM-induced chronic allergic airway inflammation.

Methylene-tetrahydrofolate reductase contributes to allergic airway disease.

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Kenneth R Eyring

Full Text Available Environmental exposures strongly influence the development and progression of asthma. We have previously demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. There is conflicting evidence on the role of folate (one of the primary methyl donors in modifying allergic airway disease.We hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (Mthfr activity would reduce the allergic airway disease phenotype through epigenetic mechanisms.Allergic airway disease was induced in C57BL/6 and C57BL/6Mthfr-/- mice through house dust mite (HDM exposure. Airway inflammation and airway hyperresponsiveness (AHR were measured between the two groups. Gene expression and methylation profiles were generated for whole lung tissue. Disease and molecular outcomes were evaluated in C57BL/6 and C57BL/6Mthfr-/- mice supplemented with betaine.Loss of Mthfr alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6Mthfr-/- mice demonstrated significantly less airway hyperreactivity (AHR compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6Mthfr-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL cellularity, eosinophilia, and Il-4/Il-5 cytokine concentrations. Betaine supplementation reversed parts of the HDM-induced allergic airway disease that are modified by Mthfr loss. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6Mthfr-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations.Collectively, these findings indicate that the loss of folate as a methyl donor is a modifier of

Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses.

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De Grove, Katrien C; Provoost, Sharen; Hendriks, Rudi W; McKenzie, Andrew N J; Seys, Leen J M; Kumar, Smitha; Maes, Tania; Brusselle, Guy G; Joos, Guy F

2017-01-01

Although the prominent role of T H 2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. We sought to investigate the relative contribution of ILC2 and adaptive T H 2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Wild-type, Gata-3 +/nlslacZ (Gata-3-haploinsufficient), RAR-related orphan receptor α (RORα) fl/fl IL7R Cre (ILC2-deficient), and recombination-activating gene (Rag) 2 -/- mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and T H 2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and T H 2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and T H 2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2 -/- mice. These data indicate that dysregulation of ILC2s and T H 2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure. Copyright © 2016 American

Maternal immune response to helminth infection during pregnancy determines offspring susceptibility to allergic airway inflammation.

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Straubinger, Kathrin; Paul, Sabine; Prazeres da Costa, Olivia; Ritter, Manuel; Buch, Thorsten; Busch, Dirk H; Layland, Laura E; Prazeres da Costa, Clarissa U

2014-12-01

Schistosomiasis, a chronic helminth infection, elicits distinct immune responses within the host, ranging from an initial TH1 and subsequent TH2 phase to a regulatory state, and is associated with dampened allergic reactions within the host. We sought to evaluate whether non-transplacental helminth infection during pregnancy alters the offspring's susceptibility to allergy. Ovalbumin-induced allergic airway inflammation was analyzed in offspring from Schistosoma mansoni-infected mothers mated during the TH1, TH2, or regulatory phase of infection. Embryos derived from in vitro fertilized oocytes of acutely infected females were transferred into uninfected foster mice to determine the role of placental environment. The fetomaternal unit was further characterized by helminth-specific immune responses and microarray analyses. Eventually, IFN-γ-deficient mice were infected to evaluate the role of this predominant cytokine on the offspring's allergy phenotype. We demonstrate that offspring from schistosome-infected mothers that were mated in the TH1 and regulatory phases, but not the TH2 immune phase, are protected against the onset of allergic airway inflammation. Interestingly, these effects were associated with distinctly altered schistosome-specific cytokine and gene expression profiles within the fetomaternal interface. Furthermore, we identified that it is not the transfer of helminth antigens but rather maternally derived IFN-γ during the acute phase of infection that is essential for the progeny's protective immune phenotype. Overall, we present a novel immune phase-dependent coherency between the maternal immune responses during schistosomiasis and the progeny's predisposition to allergy. Therefore, we propose to include helminth-mediated transmaternal immune modulation into the expanded hygiene hypothesis. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease.

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Royce, Simon G; Dang, William; Ververis, Katherine; De Sampayo, Nishika; El-Osta, Assam; Tang, Mimi L K; Karagiannis, Tom C

2011-12-01

Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targeted optimally by existing anti-inflammatory drugs. Histone deacetylase inhibitors have a wide range of effects that may potentially abrogate aspects of remodeling. One such histone deacetylase inhibitor is valproic acid (2-propylvaleric acid). Valproic acid is used clinically as an anti-epileptic drug and is a potent inhibitor of class I histone deacetylases but also inhibits class II histone deacetylases. We used valproic acid as a molecular model of histone deacetylase inhibition in vivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness. Wild-type Balb/c mice with allergic airways disease were treated with valproic acid or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and examination of lung tissue sections. Remodeling was assessed by morphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmography measurement of airway resistance. Valproic acid treatment did not affect inflammation parameters; however, valproic acid treatment resulted in reduced epithelial thickness as compared to vehicle treated mice (p < 0.01), reduced subepithelial collagen deposition (p < 0.05) and attenuated airway hyperresponsiveness (p < 0.05 and p < 0.01 for the two highest doses of methacholine, respectively). These findings show that treatment with valproic acid can reduce structural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use of histone deacetylase inhibitors for the treatment of asthma.

Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthma

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Cormier Stephania A

2009-07-01

Full Text Available Abstract Background Atrial natriuretic peptide (ANP and its receptor, NPRA, have been extensively studied in terms of cardiovascular effects. We have found that the ANP-NPRA signaling pathway is also involved in airway allergic inflammation and asthma. ANP, a C-terminal peptide (amino acid 99–126 of pro-atrial natriuretic factor (proANF and a recombinant peptide, NP73-102 (amino acid 73–102 of proANF have been reported to induce bronchoprotective effects in a mouse model of allergic asthma. In this report, we evaluated the effects of vessel dilator (VD, another N-terminal natriuretic peptide covering amino acids 31–67 of proANF, on acute lung inflammation in a mouse model of allergic asthma. Methods A549 cells were transfected with pVD or the pVAX1 control plasmid and cells were collected 24 hrs after transfection to analyze the effect of VD on inactivation of the extracellular-signal regulated receptor kinase (ERK1/2 through western blot. Luciferase assay, western blot and RT-PCR were also performed to analyze the effect of VD on NPRA expression. For determination of VD's attenuation of lung inflammation, BALB/c mice were sensitized and challenged with ovalbumin and then treated intranasally with chitosan nanoparticles containing pVD. Parameters of airway inflammation, such as airway hyperreactivity, proinflammatory cytokine levels, eosinophil recruitment and lung histopathology were compared with control mice receiving nanoparticles containing pVAX1 control plasmid. Results pVD nanoparticles inactivated ERK1/2 and downregulated NPRA expression in vitro, and intranasal treatment with pVD nanoparticles protected mice from airway inflammation. Conclusion VD's modulation of airway inflammation may result from its inactivation of ERK1/2 and downregulation of NPRA expression. Chitosan nanoparticles containing pVD may be therapeutically effective in preventing allergic airway inflammation.

Expression of the protein serum amyloid A in response to Aspergillus fumigatus in murine models of allergic airway inflammation.

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Moran, Gabriel; Carcamo, Carolina; Concha, Margarita; Folch, Hugo

2015-01-01

Serum amyloid A (SAA) is an acute phase protein that is elevated in blood during inflammation. The role of this protein in allergic diseases of airways remains unclear. The objective of this study was to evaluate the SAA in blood, lung and bronchial cells in a murine model of bronchial hypersensitivity to Aspergillus fumigatus. To achieve this purpose, different groups of 5-month-old mice were housed in cages containing hay bedding that was contaminated with A. fumigatus and were kept in an isolation room for 16 days to allow for the induction of allergic airway inflammation. Subsequently, the mice were then exposed once again to Aspergillus spores at 0, 2, 8, 24 and 72 h, and they were bled to acquire serum and sacrificed to obtain bronchoalveolar lavage fluid (BALF) or lung tissues for analysis. SAA levels were measured in lung, serum and BALF by dot blot assay and RT-PCR (reverse transcription polymerase chain reaction). The results indicated that SAA protein levels increased in both serum and lung within 2-24h after mice were exposed to Aspergillus spores. Moreover, the SAA mRNA expression levels in the lungs and BALF cells demonstrated the same trend that was observed for the protein levels through the dot blot assay; in particular, SAA mRNA levels increased within the first hour after mice were exposed to A. fumigatus. In this allergic airway model, we conclude that A. fumigatus can induce an acute inflammatory response in the airways through the stimulation of the SAA protein, increasing its levels in serum, lung tissue and BALF samples during the early hours of exposure of mice that have been sensitised for this fungus. Copyright © 2012 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Effects of Ex Vivo y-Tocopherol on Airway Macrophage Function in Healthy and Mild Allergic Asthmatics

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Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate y-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-med...

Group 2 Innate Lymphoid Cells Exhibit a Dynamic Phenotype in Allergic Airway Inflammation

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Li, Bobby W. S.; Stadhouders, Ralph; de Bruijn, Marjolein J. W.; Lukkes, Melanie; Beerens, Dior M. J. M.; Brem, Maarten D.; KleinJan, Alex; Bergen, Ingrid; Vroman, Heleen; Kool, Mirjam; van IJcken, Wilfred F. J.; Rao, Tata Nageswara; Fehling, Hans Jörg; Hendriks, Rudi W.

2017-01-01

Group 2 innate lymphoid cells (ILC2) are implicated in allergic asthma as an early innate source of the type 2 cytokines IL-5 and IL-13. However, their induction in house dust mite (HDM)-mediated airway inflammation additionally requires T cell activation. It is currently unknown whether phenotypic differences exist between ILC2s that are activated in a T cell-dependent or T cell-independent fashion. Here, we compared ILC2s in IL-33- and HDM-driven airway inflammation. Using flow cytometry, we found that surface expression levels of various markers frequently used to identify ILC2s were dependent on their mode of activation, highly variable over time, and differed between tissue compartments, including bronchoalveolar lavage (BAL) fluid, lung, draining lymph nodes, and spleen. Whereas in vivo IL-33-activated BAL fluid ILC2s exhibited an almost uniform CD25+CD127+T1/ST2+ICOS+KLRG1+ phenotype, at a comparable time point after HDM exposure BAL fluid ILC2s had a very heterogeneous surface marker phenotype. A major fraction of HDM-activated ILC2s were CD25lowCD127+T1/ST2low ICOSlowKLRG1low, but nevertheless had the capacity to produce large amounts of type 2 cytokines. HDM-activated CD25low ILC2s in BAL fluid and lung rapidly reverted to CD25high ILC2s upon in vivo stimulation with IL-33. Genome-wide transcriptional profiling of BAL ILC2s revealed ~1,600 differentially expressed genes: HDM-stimulated ILC2s specifically expressed genes involved in the regulation of adaptive immunity through B and T cell interactions, whereas IL-33-stimulated ILC2s expressed high levels of proliferation-related and cytokine genes. In both airway inflammation models ILC2s were present in the lung submucosa close to epithelial cells, as identified by confocal microscopy. In chronic HDM-driven airway inflammation ILC2s were also found inside organized cellular infiltrates near T cells. Collectively, our findings show that ILC2s are phenotypically more heterogeneous than previously thought

Group 2 Innate Lymphoid Cells Exhibit a Dynamic Phenotype in Allergic Airway Inflammation

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Bobby W. S. Li

2017-12-01

Full Text Available Group 2 innate lymphoid cells (ILC2 are implicated in allergic asthma as an early innate source of the type 2 cytokines IL-5 and IL-13. However, their induction in house dust mite (HDM-mediated airway inflammation additionally requires T cell activation. It is currently unknown whether phenotypic differences exist between ILC2s that are activated in a T cell-dependent or T cell-independent fashion. Here, we compared ILC2s in IL-33- and HDM-driven airway inflammation. Using flow cytometry, we found that surface expression levels of various markers frequently used to identify ILC2s were dependent on their mode of activation, highly variable over time, and differed between tissue compartments, including bronchoalveolar lavage (BAL fluid, lung, draining lymph nodes, and spleen. Whereas in vivo IL-33-activated BAL fluid ILC2s exhibited an almost uniform CD25+CD127+T1/ST2+ICOS+KLRG1+ phenotype, at a comparable time point after HDM exposure BAL fluid ILC2s had a very heterogeneous surface marker phenotype. A major fraction of HDM-activated ILC2s were CD25lowCD127+T1/ST2low ICOSlowKLRG1low, but nevertheless had the capacity to produce large amounts of type 2 cytokines. HDM-activated CD25low ILC2s in BAL fluid and lung rapidly reverted to CD25high ILC2s upon in vivo stimulation with IL-33. Genome-wide transcriptional profiling of BAL ILC2s revealed ~1,600 differentially expressed genes: HDM-stimulated ILC2s specifically expressed genes involved in the regulation of adaptive immunity through B and T cell interactions, whereas IL-33-stimulated ILC2s expressed high levels of proliferation-related and cytokine genes. In both airway inflammation models ILC2s were present in the lung submucosa close to epithelial cells, as identified by confocal microscopy. In chronic HDM-driven airway inflammation ILC2s were also found inside organized cellular infiltrates near T cells. Collectively, our findings show that ILC2s are phenotypically more heterogeneous than

The Ethanol Extract of Osmanthus fragrans Flowers Reduces Oxidative Stress and Allergic Airway Inflammation in an Animal Model

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Chien-Ya Hung

2013-01-01

Full Text Available The Osmanthus fragrans flower, a popular herb in Eastern countries, contains several antioxidant compounds. Ben Cao Gang Mu, traditional Chinese medical literature, describes the usefulness of these flowers for phlegm and stasis reduction, arrest of dysentery with blood in the bowel, and stomachache and diarrhea treatment. However, modern evidence regarding the therapeutic efficacy of these flowers is limited. This study was aimed at assessing the antioxidative effects of the ethanol extract of O. fragrans flowers (OFE in vivo and evaluating its antioxidant maintenance and therapeutic effect on an allergic airway inflammation in mice. After OFE’s oral administration to mice, the values obtained in the oxygen radical absorbance capacity assay as well as the glutathione concentration in the lungs and spleens of mice increased while thiobarbituric acid reactive substances decreased significantly, indicating OFE’s significant in vivo antioxidant activity. OFE was also therapeutically efficacious in a mouse model of ovalbumin-induced allergic airway inflammation. Orally administered OFE suppressed ovalbumin-specific IgE production and inflammatory cell infiltration in the lung. Moreover, the antioxidative state of the mice improved. Thus, our findings confirm the ability of the O. fragrans flowers to reduce phlegm and suggest that OFE may be useful as an antiallergic agent.

Semaphorin 4C Protects against Allergic Inflammation: Requirement of Regulatory CD138+ Plasma Cells.

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Xue, Di; Kaufman, Gabriel N; Dembele, Marieme; Beland, Marianne; Massoud, Amir H; Mindt, Barbara C; Fiter, Ryan; Fixman, Elizabeth D; Martin, James G; Friedel, Roland H; Divangahi, Maziar; Fritz, Jörg H; Mazer, Bruce D

2017-01-01

The regulatory properties of B cells have been studied in autoimmune diseases; however, their role in allergic diseases is poorly understood. We demonstrate that Semaphorin 4C (Sema4C), an axonal guidance molecule, plays a crucial role in B cell regulatory function. Mice deficient in Sema4C exhibited increased airway inflammation after allergen exposure, with massive eosinophilic lung infiltrates and increased Th2 cytokines. This phenotype was reproduced by mixed bone marrow chimeric mice with Sema4C deficient only in B cells, indicating that B lymphocytes were the key cells affected by the absence of Sema4C expression in allergic inflammation. We determined that Sema4C-deficient CD19 + CD138 + cells exhibited decreased IL-10 and increased IL-4 expression in vivo and in vitro. Adoptive transfer of Sema4c -/- CD19 + CD138 + cells induced marked pulmonary inflammation, eosinophilia, and increased bronchoalveolar lavage fluid IL-4 and IL-5, whereas adoptive transfer of wild-type CD19 + CD138 + IL-10 + cells dramatically decreased allergic airway inflammation in wild-type and Sema4c -/- mice. This study identifies a novel pathway by which Th2-mediated immune responses are regulated. It highlights the importance of plasma cells as regulatory cells in allergic inflammation and suggests that CD138 + B cells contribute to cytokine balance and are important for maintenance of immune homeostasis in allergic airways disease. Furthermore, we demonstrate that Sema4C is critical for optimal regulatory cytokine production in CD138 + B cells. Copyright © 2016 by The American Association of Immunologists, Inc.

Myeloid differentiation-2 is a potential biomarker for the amplification process of allergic airway sensitization in mice

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Daisuke Koyama

2015-09-01

Conclusions: Our data suggest MD-2 is a critical regulator of the establishment of allergic airway sensitization to HDM in mice. Serum MD-2 may represent a potential biomarker for the amplification of allergic sensitization and allergic inflammation.

Estrogen signaling modulates allergic inflammation and contributes to sex differences in asthma.

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Aleksander eKeselman

2015-11-01

Full Text Available Asthma is a chronic airway inflammatory disease that afflicts approximately 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, potentially 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-4 and interleukin-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 estrogen receptor 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.

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

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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

Anti-inflammatory Potentials of Excretory/Secretory (ES and Somatic Products of Marshallagia marshalli on Allergic Airway Inflammation in BALB/c Mice

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Sima PARANDE SHIRVAN

2016-12-01

Full Text Available Background: Inverse relationship between helminths infection and immune-mediated diseases has inspired researchers to investigate therapeutic potential of helminths in allergic asthma. Helminth unique ability to induce immunoregulatory responses has already been documented in several experimental studies. This study was designed to investigate whether excretory/secretory (ES and somatic products of Marshallagia marshalli modulate the development of ovalbumin-induced airway inflammation in a mouse model.Methods: This study was carried out at the laboratories of Immunology and Parasitology of Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran during spring and summer 2015. Allergic airway inflammation was induced in mice by intraperitoneal (IP injection with ovalbumin (OVA. The effects of ES and somatic products of M. marshalli were analyzed by inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF, pathological changes and IgE response.Results: Treatment with ES and somatic products of M. marshalli decreased cellular infiltration into BALF when they were administered during sensitization with allergen. Pathological changes were decreased in helminth-treated group, as demonstrated by reduced inflammatory cell infiltration, goblet cell hyperplasia, epithelial lesion and smooth muscle hypertrophy. However, no significant differences were observed in IgE serum levels, cytokines and eosinophil counts between different groups.Conclusion: This study provides new insights into anti-inflammatory effects of ES and somatic products of M. marshalli, during the development of non-eosinophilic model of asthma. Further study is necessary to characterize immunomodulatory molecules derived from M. marshalli as a candidate for the treatment of airway inflammation.

The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation.

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Claudio, Estefania; Sønder, Søren Ulrik; Saret, Sun; Carvalho, Gabrielle; Ramalingam, Thirumalai R; Wynn, Thomas A; Chariot, Alain; Garcia-Perganeda, Antonio; Leonardi, Antonio; Paun, Andrea; Chen, Amy; Ren, Nina Y; Wang, Hongshan; Siebenlist, Ulrich

2009-02-01

IL-17 is the signature cytokine of recently discovered Th type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production, and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (also known as Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses that these two cytokines elicit. We identify CD11c(+) macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo.

Neutralization of TSLP inhibits airway remodeling in a murine model of allergic asthma induced by chronic exposure to house dust mite.

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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.

Is a high-fiber diet able to influence ovalbumin-induced allergic airway inflammation in a mouse model?

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Zhang, Zhiyu; Shi, Lei; Pang, Wenhui; Wang, Xiaoting; Li, Jianfeng; Wang, Haibo; Shi, Guanggang

2016-01-01

More recently, a large amount of experimental and clinical discovered that dietary- fiber intake would decrease the susceptibility to allergic airway disease (AAD) and respiratory inflammation. To investigate whether a fiber-intake supplement is able to influence the induction of AAD and to elucidate the interactive relationship. AAD model mice and control mice were raised on a fundamental diet with standard 4% fiber content, whereas other mice were fed a 10% fiber-content diet in the high fiber-content group, along with a 25% fiber-content diet instead in very-high fiber-content group. All experimental mice were sensitized and challenged with ovalbumin to induce allergic inflammation in both the upper and lower airways. Hallmarks of AAD were examined in terms of eosinophil infiltration and goblet cell metaplasia in subepithelial mucosa, T-helper type 1 (Th1) to Th2 skewing of the immune response. Furthermore, to elucidate the interrelations, we generated 16S ribosomal DNA from fecal samples and further validated the variation of colony composition in each group. The excessive high-fiber supplement induced a promoting effect rather than a suppressive effect, including a rise in nasal rubbing and sneezing, an increase in eosinophil inflammation and goblet cell metaplasia in subepithelial mucosa, and promoted Th2 skewing of the immune response as well as the production of serum levels of ovalbumin-specific immunoglobulin E. Moreover, overconsumption of dietary fiber greatly altered the construction of bacterial flora in the intestinal tract, including an increased proportion of Firmicutes, Actinobacteria, and Proteobacteria, and a decreased proportion of Bacteroidetes. Our work indicated that, instead of a protecting impact, excessive fiber intake preformed a negative influence on the induction of AAD. Therefore, we suspected that an excessive supplement of dietary fiber might not be an advisable method for the prevention and treatment of AADs.

A PAF receptor antagonist inhibits acute airway inflammation and late-phase responses but not chronic airway inflammation and hyperresponsiveness in a primate model of asthma

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R. H. Gundel

1992-01-01

Full Text Available We have examined the effects of a PAF receptor antagonist, WEB 2170, on several indices of acute and chronic airway inflammation and associated changes in lung function in a primate model of allergic asthma. A single oral administration WEB 2170 provided dose related inhibition of the release of leukotriene C4 (LTC4 and prostaglandin D2 (PGD2 recovered and quantified in bronchoalveolar lavage (BAL fluid obtained during the acute phase response to inhaled antigen. In addition, oral WEB 2170 treatment in dual responder primates blocked the acute influx of neutrophils into the airways as well as the associated late-phase airway obstruction occurring 6 h after antigen inhalation. In contrast, a multiple dosing regime with WEB 2170 (once a day for 7 consecutive days failed to reduce the chronic airway inflammation (eosinophilic and associated airway hyperresponsiveness to inhaled methacholine that is characteristic of dual responder monkeys. Thus, we conclude that the generation of PAF following antigen inhalation contributes to the development of lipid mediators, acute airway inflammation and associated late-phase airway obstruction in dual responder primates; however, PAF does not play a significant role in the maintenance of chronic airway inflammation and associated airway hyperresponsiveness in this primate model.

Bovine milk fat enriched in conjugated linoleic and vaccenic acids attenuates allergic airway disease in mice.

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Kanwar, R K; Macgibbon, A K; Black, P N; Kanwar, J R; Rowan, A; Vale, M; Krissansen, G W

2008-01-01

It has been argued that a reduction in the Western diet of anti-inflammatory unsaturated lipids, such as n-3 polyunsaturated fatty acids, has contributed to the increase in the frequency and severity of allergic diseases. We investigated whether feeding milk fat enriched in conjugated linoleic acid and vaccenic acids (VAs) ('enriched' milk fat), produced by supplementing the diet of pasture-fed cows with fish and sunflower oil, will prevent development of allergic airway responses. C57BL/6 mice were fed a control diet containing soybean oil and diets supplemented with milk lipids. They were sensitized by intraperitoneal injection of ovalbumin (OVA) on days 14 and 28, and challenged intranasally with OVA on day 42. Bronchoalveolar lavage fluid, lung tissues and serum samples were collected 6 days after the intranasal challenge. Feeding of enriched milk fat led to marked suppression of airway inflammation as evidenced by reductions in eosinophilia and lymphocytosis in the airways, compared with feeding of normal milk fat and control diet. Enriched milk fat significantly reduced circulating allergen-specific IgE and IgG1 levels, together with reductions in bronchoalveolar lavage fluid of IL-5 and CCL11. Treatment significantly inhibited changes in the airway including airway epithelial cell hypertrophy, goblet cell metaplasia and mucus hypersecretion. The two major components of enriched milk fat, cis-9, trans-11 conjugated linoleic acid and VA, inhibited airway inflammation when fed together to mice, whereas alone they were not effective. Milk fat enriched in conjugated linoleic and VAs suppresses inflammation and changes to the airways in an animal model of allergic airway disease.

Kalanchoe pinnata inhibits mast cell activation and prevents allergic airway disease.

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Cruz, E A; Reuter, S; Martin, H; Dehzad, N; Muzitano, M F; Costa, S S; Rossi-Bergmann, B; Buhl, R; Stassen, M; Taube, C

2012-01-15

Aqueous extract of Kalanchoe pinnata (Kp) have been found effective in models to reduce acute anaphylactic reactions. In the present study, we investigate the effect of Kp and the flavonoid quercetin (QE) and quercitrin (QI) on mast cell activation in vitro and in a model of allergic airway disease in vivo. Treatment with Kp and QE in vitro inhibited degranulation and cytokine production of bone marrow-derived mast cells following IgE/FcɛRI crosslinking, whereas treatment with QI had no effect. Similarly, in vivo treatment with Kp and QE decreased development of airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and production of IL-5, IL-13 and TNF. In contrast, treatment with QI had no effect on these parameters. These findings demonstrate that treatment with Kp or QE is effective in treatment of allergic airway disease, providing new insights to the immunomodulatory functions of this plant. Copyright © 2011 Elsevier GmbH. All rights reserved.

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

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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.

The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation1

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Claudio, Estefania; Sønder, Søren Ulrik; Saret, Sun; Carvalho, Gabrielle; Ramalingam, Thirumalai R; Wynn, Thomas A; Chariot, Alain; Garcia-Perganeda, Antonio; Leonardi, Antonio; Paun, Andrea; Chen, Amy; Ren, Nina Y.; Wang, Hongshan; Siebenlist, Ulrich

2008-01-01

IL-17 is the signature cytokine of recently discovered T helper type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (a.k.a. Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses these two cytokines elicit. We identify CD11c+ macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo. PMID:19155511

Virus-induced asthma attack: The importance of allergic inflammation in response to viral antigen in an animal model of asthma.

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Skappak, Christopher; Ilarraza, Ramses; Wu, Ying-Qi; Drake, Matthew G; Adamko, Darryl J

2017-01-01

Asthma exacerbation can be a life-threatening condition, and is most often triggered by common respiratory viruses. Poor asthma control and worsening of respiratory function is associated with increased airway inflammation, including eosinophilia. Prevention of asthma exacerbation relies on treatment with corticosteroids, which preferentially inhibit allergic inflammation like eosinophils. Human studies demonstrate that inactivated virus can trigger eosinophil activation in vitro through antigen presentation and memory CD4+ lymphocytes. We hypothesized that animals with immunologic memory to a respiratory virus would also develop airway hyperresponsiveness in response to a UV-inactivated form of the virus if they have pre-existing allergic airway inflammation. Guinea pigs were ovalbumin-sensitized, infected with live parainfluenza virus (PIV), aerosol-challenged with ovalbumin, and then re-inoculated 60 days later with live or UV-inactivated PIV. Some animals were either treated with dexamethasone prior to the second viral exposure. Lymphocytes were isolated from parabronchial lymph nodes to confirm immunologic memory to the virus. Airway reactivity was measured and inflammation was assessed using bronchoalveolar lavage and lung histology. The induction of viral immunologic memory was confirmed in infected animals. Allergen sensitized and challenged animals developed airway hyperreactivity with eosinophilic airway inflammation when re-exposed to UV-inactivated PIV, while non-sensitized animals did not. Airway hyperreactivity in the sensitized animals was inhibited by pre-treatment with dexamethasone. We suggest that the response of allergic inflammation to virus antigen is a significant factor causing asthma exacerbation. We propose that this is one mechanism explaining how corticosteroids prevent virus-induced asthma attack.

Motorcycle exhaust particles induce airway inflammation and airway hyperresponsiveness in BALB/C mice.

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Lee, Chen-Chen; Liao, Jiunn-Wang; Kang, Jaw-Jou

2004-06-01

A number of large studies have reported that environmental pollutants from fossil fuel combustion can cause deleterious effects to the immune system, resulting in an allergic reaction leading to respiratory tract damage. In this study, we investigated the effect of motorcycle exhaust particles (MEP), a major pollutant in the Taiwan urban area, on airway inflammation and airway hyperresponsiveness in laboratory animals. BALB/c mice were instilled intratracheally (i.t.) with 1.2 mg/kg and 12 mg/kg of MEP, which was collected from two-stroke motorcycle engines. The mice were exposed 3 times i.t. with MEP, and various parameters for airway inflammation and hyperresponsiveness were sequentially analyzed. We found that MEP would induce airway and pulmonary inflammation characterized by infiltration of eosinophils, neutrophils, lymphocytes, and macrophages in bronchoalveolar lavage fluid (BALF) and inflammatory cell infiltration in lung. In addition, MEP treatment enhanced BALF interleukin-4 (IL-4), IL-5, and interferon-gamma (IFN-gamma) cytokine levels and serum IgE production. Bronchial response measured by unrestrained plethysmography with methacholine challenge showed that MEP treatment induced airway hyperresponsiveness (AHR) in BALB/c mice. The chemical components in MEP were further fractionated with organic solvents, and we found that the benzene-extracted fraction exerts a similar biological effect as seen with MEP, including airway inflammation, increased BALF IL-4, serum IgE production, and induction of AHR. In conclusion, we present evidence showing that the filter-trapped particles emitted from the unleaded-gasoline-fueled two-stroke motorcycle engine may induce proinflammatory and proallergic response profiles in the absence of exposure to allergen.

The plant extract Isatis tinctoria L. extract (ITE) inhibits allergen-induced airway inflammation and hyperreactivity in mice.

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Brattström, A; Schapowal, A; Kamal, M A; Maillet, I; Ryffel, B; Moser, R

2010-07-01

The herbal Isatis tinctoria extract (ITE) inhibits the inducible isoform of cyclooxygenase (COX-2) as well as lipoxygenase (5-LOX) and therefore possesses anti-inflammatory properties. The extract might also be useful in allergic airway diseases which are characterized by chronic inflammation. ITE obtained from leaves by supercritical carbon dioxide extraction was investigated in ovalbumin (OVA) immunised BALB/c mice given intranasally together with antigen challenge in the murine model of allergic airway disease (asthma) with the analysis of the inflammatory and immune parameters in the lung. ITE given with the antigen challenge inhibited in a dose related manner the allergic response. ITE diminished airway hyperresponsiveness (AHR) and eosinophil recruitment into the bronchoalveolar lavage (BAL) fluid upon allergen challenge, but had no effect in the saline control mice. Eosinophil recruitment was further assessed in the lung by eosinophil peroxidase (EPO) activity at a dose of 30 microg ITE per mouse. Microscopic investigations revealed less inflammation, eosinophil recruitment and mucus hyperproduction in the lung in a dose related manner. Diminution of AHR and inflammation was associated with reduced IL-4, IL-5, and RANTES production in the BAL fluid at the 30 microg ITE dose, while OVA specific IgE and eotaxin serum levels remained unchanged. ITE, which has been reported inhibiting COX-2 and 5-LOX, reduced allergic airway inflammation and AHR by inhibiting the production of the Th2 cytokines IL-4 and IL-5, and RANTES. (c) 2009 Elsevier GmbH. All rights reserved.

Prolonged ozone exposure in an allergic airway disease model: Adaptation of airway responsiveness and airway remodeling

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Park Chang-Soo

2006-02-01

Full Text Available Abstract Background Short-term exposure to high concentrations of ozone has been shown to increase airway hyper-responsiveness (AHR. Because the changes in AHR and airway inflammation and structure after chronic ozone exposure need to be determined, the goal of this study was to investigate these effects in a murine model of allergic airway disease. Methods We exposed BALB/c mice to 2 ppm ozone for 4, 8, and 12 weeks. We measured the enhanced pause (Penh to methacholine and performed cell differentials in bronchoalveolar lavage fluid. We quantified the levels of IL-4 and IFN-γ in the supernatants of the bronchoalveolar lavage fluids using enzyme immunoassays, and examined the airway architecture under light and electron microscopy. Results The groups exposed to ozone for 4, 8, and 12 weeks demonstrated decreased Penh at methacholine concentrations of 12.5, 25, and 50 mg/ml, with a dose-response curve to the right of that for the filtered-air group. Neutrophils and eosinophils increased in the group exposed to ozone for 4 weeks compared to those in the filtered-air group. The ratio of IL-4 to INF-γ increased significantly after exposure to ozone for 8 and 12 weeks compared to the ratio for the filtered-air group. The numbers of goblet cells, myofibroblasts, and smooth muscle cells showed time-dependent increases in lung tissue sections from the groups exposed to ozone for 4, 8, and 12 weeks. Conclusion These findings demonstrate that the increase in AHR associated with the allergic airway does not persist during chronic ozone exposure, indicating that airway remodeling and adaptation following repeated exposure to air pollutants can provide protection against AHR.

House dust mite allergic airway inflammation facilitates neosensitization to inhaled allergen in mice

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van Rijt, L. S.; Logiantara, A.; Utsch, L.; Canbaz, D.; Boon, L.; van Ree, R.

2012-01-01

Background The mechanism by which many monosensitized allergic individuals progress to polysensitization over time remains to be elucidated. Mouse models have contributed greatly to the understanding of sensitization to inhaled allergens in healthy airways but hardly any studies have addressed

Regulation of allergic airway inflammation by adoptive transfer of CD4+ T cells preferentially producing IL-10.

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Matsuda, Masaya; Doi, Kana; Tsutsumi, Tatsuya; Fujii, Shinya; Kishima, Maki; Nishimura, Kazuma; Kuroda, Ikue; Tanahashi, Yu; Yuasa, Rino; Kinjo, Toshihiko; Kuramoto, Nobuyuki; Mizutani, Nobuaki; Nabe, Takeshi

2017-10-05

Anti-inflammatory pharmacotherapy for asthma has mainly depended on the inhalation of glucocorticoids, which non-specifically suppress immune responses. If the anti-inflammatory cytokine interleukin (IL)-10 can be induced by a specific antigen, asthmatic airway inflammation could be suppressed when individuals are exposed to the antigen. The purpose of this study was to develop cellular immunotherapeutics for atopic diseases using IL-10-producing CD4 + T cells. Spleen cells isolated from ovalbumin (OVA)-sensitized mice were cultured with the antigen, OVA and growth factors, IL-21, IL-27 and TGF-β for 7 days. After the 7-day culture, the CD4 + T cells were purified using a murine CD4 magnetic beads system. When the induced CD4 + T cells were stimulated by OVA in the presence of antigen-presenting cells, IL-10 was preferentially produced in vitro. When CD4 + T cells were adoptively transferred to OVA-sensitized mice followed by intratracheal OVA challenges, IL-10 was preferentially produced in the serum and bronchoalveolar lavage fluid in vivo. IL-10 production coincided with the inhibition of eosinophilic airway inflammation and epithelial mucus plugging. Most of the IL-10-producing CD4 + T cells were negative for Foxp3 and GATA-3, transcription factors of naturally occurring regulatory T cells and Th2 cells, respectively, but double positive for LAG-3 and CD49b, surface markers of inducible regulatory T cells, Tr1 cells. Collectively, most of the induced IL-10-producing CD4 + T cells could be Tr1 cells, which respond to the antigen to produce IL-10, and effectively suppressed allergic airway inflammation. The induced Tr1 cells may be useful for antigen-specific cellular immunotherapy for atopic diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma.

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Foster, Paul S; Maltby, Steven; Rosenberg, Helene F; Tay, Hock L; Hogan, Simon P; Collison, Adam M; Yang, Ming; Kaiko, Gerard E; Hansbro, Philip M; Kumar, Rakesh K; Mattes, Joerg

2017-07-01

In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4 + T-helper type-2 lymphocytes (T H 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical T H 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of T H 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote T H 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of T H 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The who, where, and when of IgE in allergic airway disease.

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Dullaers, Melissa; De Bruyne, Ruth; Ramadani, Faruk; Gould, Hannah J; Gevaert, Philippe; Lambrecht, Bart N

2012-03-01

Allergic asthma and allergic rhinitis/conjunctivitis are characterized by a T(H)2-dominated immune response associated with increased serum IgE levels in response to inhaled allergens. Because IgE is a key player in the induction and maintenance of allergic inflammation, it represents a prime target for therapeutic intervention. However, our understanding of IgE biology remains fragmentary. This article puts together our current knowledge on IgE in allergic airway diseases with a special focus on the identity of IgE-secreting cells ("who"), their location ("where"), and the circumstances in which they are induced ("when"). We further consider the therapeutic implications of the insights gained. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Toll-like receptor-2 agonist-allergen coupling efficiently redirects Th2 cell responses and inhibits allergic airway eosinophilia.

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Krishnaswamy, Jayendra Kumar; Jirmo, Adan Chari; Baru, Abdul Mannan; Ebensen, Thomas; Guzmán, Carlos A; Sparwasser, Tim; Behrens, Georg M N

2012-12-01

Toll-like receptor (TLR) agonists beneficially modulate allergic airway inflammation. However, the efficiency of TLR agonists varies considerably, and their exact cellular mechanisms (especially of TLR 2/6 agonists) are incompletely understood. We investigated at a cellular level whether the administration of the pharmacologically improved TLR2/6 agonist S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxy polyethylene glycol (BPP) conjugated to antigenic peptide (BPP-OVA) could divert an existing Th2 response and influence airway eosinophilia. The effects of BPP-OVA on airway inflammation were assessed in a classic murine sensitization/challenge model and an adoptive transfer model, which involved the adoptive transfer of in vitro differentiated ovalbumin (OVA)-specific Th2 cells. Functional T-cell stimulation by lung dendritic cells (DCs) was determined both in vitro and in vivo, combined with a cytokine secretion analysis. A single mucosal application of BPP-OVA efficiently delivered antigen, led to TLR2-mediated DC activation, and resulted in OVA-specific T-cell proliferation via lung DCs in vivo. In alternative models of allergic airway disease, a single administration of BPP-OVA before OVA challenge (but not BPP alone) significantly reduced airway eosinophilia, most likely through altered antigen-specific T-cell stimulation via DCs. Analyses of adoptively transferred Th2-biased cells after BPP-OVA administration in vivo suggested that BPP-OVA guides antigen-specific Th2 cells to produce significantly higher amounts of IFN-γ upon allergen challenge. In conclusion, our data show for the first time that a single mucosal administration of a TLR 2/6 agonist-allergen conjugate can provoke IFN-γ responses in Th2-biased cells and alleviate allergic airway inflammation.

Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-β.

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Ogawa, Hirohisa; Ledford, Julie G; Mukherjee, Sambuddho; Aono, Yoshinori; Nishioka, Yasuhiko; Lee, James J; Izumi, Keisuke; Hollingsworth, John W

2014-11-29

Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease. C57BL/6 wild-type (WT) and SP-D-/- mice (C57BL/6 background) were chronically challenged with house dust mite antigen (Dermatophagoides pteronyssinus, Dp). Studies with SP-D rescue and neutralization of TGF-β were conducted. Lung histopathology and the concentrations of collagen, growth factors, and cytokines present in the airspace and lung tissue were determined. Cultured eosinophils were stimulated by Dp in presence or absence of SP-D. Dp-challenged SP-D-/- mice demonstrate increased sub-epithelial fibrosis, collagen production, eosinophil infiltration, TGF-β1, and IL-13 production, when compared to Dp-challenged WT mice. By immunohistology, we detected an increase in TGF-β1 and IL-13 positive eosinophils in SP-D-/- mice. Purified eosinophils stimulated with Dp produced TGF-β1 and IL-13, which was prevented by co-incubation with SP-D. Additionally, treatment of Dp challenged SP-D-/- mice with exogenous SP-D was able to rescue the phenotypes observed in SP-D-/- mice and neutralization of TGF-β1 reduced sub-epithelial fibrosis in Dp-challenged SP-D-/- mice. These data support a protective role for SP-D in the pathogenesis of sub-epithelial fibrosis in a mouse model of allergic inflammation through regulation of eosinophil-derived TGF-β.

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

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Hirose, Koichi; Wakashin, Hidefumi; Oki, Mie; Kagami, Shin-ichiro; Suto, Akira; Ikeda, Kei; Watanabe, Norihiko; Iwamoto, Itsuo; Furuichi, Yasuhiro; Nakajima, Hiroshi

2008-01-01

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

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

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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.

Effect of the anti-IL-17 antibody on allergic inflammation in an obesity-related asthma model.

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Liang, Lin; Hur, Jung; Kang, Ji Young; Rhee, Chin Kook; Kim, Young Kyoon; Lee, Sook Young

2018-04-19

The co-occurrence of obesity aggravates asthma symptoms. Diet-induced obesity increases helper T cell (TH) 17 cell differentiation in adipose tissue and the spleen. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pravastatin can potentially be used to treat asthma in obese patients by inhibiting interleukin 17 (IL-17) expression. This study investigated the combined effects of pravastatin and anti-IL-17 antibody treatment on allergic inflammation in a mouse model of obesity-related asthma. High-fat diet (HFD)-induced obesity was induced in C57BL/6 mice with or without ovalbumin (OVA) sensitization and challenge. Mice were administered the anti-IL-17 antibody, pravastatin, or both, and pathophysiological and immunological responses were analyzed. HFD exacerbated allergic airway inflammation in the bronchoalveolar lavage fluid of HFD-OVA mice as compared to OVA mice. Blockading of the IL-17 in the HFD-OVA mice decreased airway hyper-responsiveness (AHR) and airway inflammation compared to the HFD-OVA mice. Moreover, the administration of the anti-IL-17 antibody decreased the leptin/adiponectin ratio in the HFD-OVA but not the OVA mice. Co-administration of pravastatin and anti-IL-17 inhibited airway inflammation and AHR, decreased goblet cell numbers, and increased adipokine levels in obese asthmatic mice. These results suggest that the IL-17-leptin/adiponectin axis plays a key role in airway inflammation in obesity-related asthma. Our findings suggest a potential new treatment for IL-17 as a target that may benefit obesity-related asthma patients who respond poorly to typical asthma medications.

Enhancement of antigen-induced eosinophilic inflammation in the airways of mast-cell deficient mice by diesel exhaust particles

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Ichinose, Takamichi; Takano, Hirohisa; Miyabara, Yuichi; Sadakaneo, Kaori; Sagai, Masaru; Shibamoto, Takayuki

2002-01-01

The present study was conducted to clarify the involvement of mast cells in the exacerbating effect of diesel exhaust particles (DEP) toward allergic airway inflammation and airway hyperresponsiveness (AHR). Airway inflammation by the infiltration of cosinophils with goblet cell proliferation and AHR, as well as by the production of antigen-specific IgG1 and IgE, in plasma were examined using mast cell-deficient mice (W/W v ) and normal mice (W/W + ). Both groups of mice received ovalbumin (OVA) or OVA+DEP intratracheally. The eosinophilic airway inflammation and goblet cell proliferation promoted by OVA were significantly greater in W/W + than in W/W v . A similar result was observed in AHR, but was not significant among both groups of mice. DEP enhanced OVA induced-allergic airway inflammation, goblet cell proliferation, and development of AHR in W/W v , but not in W/W + . DEP decreased production of antigen-specific IgG1 and IgE in both groups of mice. Mast cells were observed in the submucosal layer of the main bronchus in W/W v . The number of mast cells was significantly decreased by OVA treatment. The results indicate that mast cells are not necessary to enhance airway damage and development of AHR in W/W v by DEP. However, mast cells may be required for the OVA-induced cosinophilic inflammation, airway damage with goblet cell proliferation, and AHR in W/W +

Local Effect of Neurotrophin-3 in Neuronal Inflammation of Allergic Rhinitis: Preliminary Report.

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İsmi, Onur; Özcan, Cengiz; Karabacak, Tuba; Polat, Gürbüz; Vayisoğlu, Yusuf; Güçlütürk, Taylan; Görür, Kemal

2015-10-01

Allergic rhinitis is a common inflammatory nasal mucosal disease characterized by sneezing, watery nasal discharge, nasal obstruction and itching. Although allergen-specific antibodies play a main role in the allergic airway inflammation, neuronal inflammation may also contribute to the symptoms of allergic rhinitis. Neuronal inflammation is primarily caused by the stimulation of sensory nerve endings with histamine. It has been shown that neurotrophins may also have a role in allergic reactions and neuronal inflammation. Nerve growth factor, neurotrophin 3 (NT-3), neurotrophin 4/5 and brain-derived neurotrophic factor are members of the neurotrophin family. Although nerve growth factor and brain-derived neurotrophic factor are well studied in allergic rhinitis patients, the exact role of Neurotrophin-3 is not known. To investigate the possible roles of neurotrophin-3 in allergic rhinitis patients. Case-control study. Neurotrophin-3 levels were studied in the inferior turbinate and serum samples of 20 allergic rhinitis and 13 control patients. Neurotrophin-3 staining of nasal tissues was evaluated by immunohistochemistry and ELISA was used for the determination of serum Neurotrophin-3 levels. Neurotrophin-3 staining scores were statistically higher in the study group than in the control patients (p=0.001). Regarding serum Neurotrophin-3 levels, no statistically significant difference could be determined between allergic rhinitis and control patients (p=0.156). When comparing the serum NT-3 levels with tissue staining scores, there were no statistically significant differences in the allergic rhinitis and control groups (p=0.254 for allergic rhinitis and p=0.624 for control groups). We suggest that Neurotrophin-3 might affect the nasal mucosa locally without being released into the systemic circulation in allergic rhinitis patients.

Vaccination against IL-33 Inhibits Airway Hyperresponsiveness and Inflammation in a House Dust Mite Model of Asthma.

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Ying Lei

Full Text Available In several clinical and experimental studies IL-33 and its receptor have been found to play important roles in the development of asthma and allergic airway inflammation. We evaluated the effects of vaccination against IL-33 in a mouse model of airway inflammation induced by house dust mite (HDM allergen. Balb/c mice received the IL-33 vaccine subcutaneously, followed by intranasal administration of HDM for up to six weeks. Vaccination against IL-33 induced high titers of specific anti-IL-33 IgG antibodies that inhibited HDM-induced airway hyperresponsiveness (AHR in the conducting airways and tissue damping. The vaccination also attenuated the HDM-induced elevation in the numbers of eosinophils in bronchoalveolar lavage fluid (BALF and suppressed the accumulation of inflammatory cells in the airways. Furthermore, the levels of IL-17A, IL-25, IL-33 and TSLP in lung tissue homogenates were reduced by vaccination against IL-33. These observations demonstrate that vaccination against IL-33 inhibits HDM-induced development of AHR, airway inflammation and production of inflammatory cytokines. The results also indicate an important role of IL-33 in the regulation of AHR of the distal lung compartments. Thus, administration of such a vaccine is potentially an effective therapeutic tool for treating allergic asthma.

Aspergillus antigen induces robust Th2 cytokine production, inflammation, airway hyperreactivity and fibrosis in the absence of MCP-1 or CCR2

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Charo Israel F

2004-09-01

Full Text Available Abstract Background Asthma is characterized by type 2 T-helper cell (Th2 inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2 and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma. Methods To test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response. Results We found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines. Conclusion We conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2.

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

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Karasuyama Hajime

2011-04-01

allergic airway inflammation via FcγRIIB on DCs.

Differential expression and function of breast regression protein 39 (BRP-39 in murine models of subacute cigarette smoke exposure and allergic airway inflammation

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Coyle Anthony J

2011-04-01

Full Text Available Abstract Background While the presence of the chitinase-like molecule YKL40 has been reported in COPD and asthma, its relevance to inflammatory processes elicited by cigarette smoke and common environmental allergens, such as house dust mite (HDM, is not well understood. The objective of the current study was to assess expression and function of BRP-39, the murine equivalent of YKL40 in a murine model of cigarette smoke-induced inflammation and contrast expression and function to a model of HDM-induced allergic airway inflammation. Methods CD1, C57BL/6, and BALB/c mice were room air- or cigarette smoke-exposed for 4 days in a whole-body exposure system. In separate experiments, BALB/c mice were challenged with HDM extract once a day for 10 days. BRP-39 was assessed by ELISA and immunohistochemistry. IL-13, IL-1R1, IL-18, and BRP-39 knock out (KO mice were utilized to assess the mechanism and relevance of BRP-39 in cigarette smoke- and HDM-induced airway inflammation. Results Cigarette smoke exposure elicited a robust induction of BRP-39 but not the catalytically active chitinase, AMCase, in lung epithelial cells and alveolar macrophages of all mouse strains tested. Both BRP-39 and AMCase were increased in lung tissue after HDM exposure. Examining smoke-exposed IL-1R1, IL-18, and IL-13 deficient mice, BRP-39 induction was found to be IL-1 and not IL-18 or IL-13 dependent, while induction of BRP-39 by HDM was independent of IL-1 and IL-13. Despite the importance of BRP-39 in cellular inflammation in HDM-induced airway inflammation, BRP-39 was found to be redundant for cigarette smoke-induced airway inflammation and the adjuvant properties of cigarette smoke. Conclusions These data highlight the contrast between the importance of BRP-39 in HDM- and cigarette smoke-induced inflammation. While functionally important in HDM-induced inflammation, BRP-39 is a biomarker of cigarette smoke induced inflammation which is the byproduct of an IL-1

Impact of Aspergillus fumigatus in allergic airway diseases

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Chaudhary Neelkamal

2011-06-01

Full Text Available Abstract For decades, fungi have been recognized as associated with asthma and other reactive airway diseases. In contrast to type I-mediated allergies caused by pollen, fungi cause a large number of allergic diseases such as allergic bronchopulmonary mycoses, rhinitis, allergic sinusitis and hypersensitivity pneumonitis. Amongst the fungi, Aspergillus fumigatus is the most prevalent cause of severe pulmonary allergic disease, including allergic bronchopulmonary aspergillosis (ABPA, known to be associated with chronic lung injury and deterioration in pulmonary function in people with chronic asthma and cystic fibrosis (CF. The goal of this review is to discuss new understandings of host-pathogen interactions in the genesis of allergic airway diseases caused by A. fumigatus. Host and pathogen related factors that participate in triggering the inflammatory cycle leading to pulmonary exacerbations in ABPA are discussed.

Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles

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Gustafsson, Åsa, E-mail: asa.gustafsson@foi.se [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Dept of Public Health and Clinical Medicine, Umeå University (Sweden); Bergström, Ulrika [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Dept of Organismal Biology, Uppsala University, SE-751 Uppsala (Sweden); Ågren, Lina [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Österlund, Lars [Dept of Engineering Sciences, The Ångström Laboratory, Uppsala University, SE-751 Uppsala (Sweden); Sandström, Thomas [Dept of Public Health and Clinical Medicine, Umeå University (Sweden); Bucht, Anders [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Dept of Public Health and Clinical Medicine, Umeå University (Sweden)

2015-10-01

The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials. - Highlights: • Hematite NPs induce differential responses in airways of healthy and allergic mice. • Hematite induced an airway inflammation in healthy mice. • Hematite induced cellular reduction in the alveolus and lymph nodes of allergic mice. • Cell death is possible due to extensive pro-oxidative environment in allergic mice. • It is important to include sensitive individuals when valuing health effects of NPs.

Propofol Attenuates Airway Inflammation in a Mast Cell-Dependent Mouse Model of Allergic Asthma by Inhibiting the Toll-like Receptor 4/Reactive Oxygen Species/Nuclear Factor κB Signaling Pathway.

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Li, Hong-Yi; Meng, Jing-Xia; Liu, Zhen; Liu, Xiao-Wen; Huang, Yu-Guang; Zhao, Jing

2018-06-01

Propofol, an intravenous anesthetic agent widely used in clinical practice, is the preferred anesthetic for asthmatic patients. This study was designed to determine the protective effect and underlying mechanisms of propofol on airway inflammation in a mast cell-dependent mouse model of allergic asthma. Mice were sensitized by ovalbumin (OVA) without alum and challenged with OVA three times. Propofol was given intraperitoneally 0.5 h prior to OVA challenge. The inflammatory cell count and production of cytokines in the bronchoalveolar lavage fluid (BALF) were detected. The changes of lung histology and key molecules of the toll-like receptor 4 (TLR4)/reactive oxygen species (ROS)/NF-κB signaling pathway were also measured. The results showed that propofol significantly decreased the number of eosinophils and the levels of IL-4, IL-5, IL-6, IL-13, and TNF-α in BALF. Furthermore, propofol significantly attenuated airway inflammation, as characterized by fewer infiltrating inflammatory cells and decreased mucus production and goblet cell hyperplasia. Meanwhile, the expression of TLR4, and its downstream signaling adaptor molecules--myeloid differentiation factor 88 (MyD88) and NF-κB, were inhibited by propofol. The hydrogen peroxide and methane dicarboxylic aldehyde levels were decreased by propofol, and the superoxide dismutase activity was increased in propofol treatment group. These findings indicate that propofol may attenuate airway inflammation by inhibiting the TLR4/MyD88/ROS/NF-κB signaling pathway in a mast cell-dependent mouse model of allergic asthma.

Inhibitory Effect of Pycnogenol® on Airway Inflammation in Ovalbumin-Induced Allergic Rhinitis

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Ceren Günel

2016-12-01

Full Text Available Background: The supplement Pycnogenol® (PYC has been used for the treatment of several chronic diseases including allergic rhinitis (AR. However, the in vivo effects on allergic inflammation have not been identified to date. Aims: To investigate the treatment results of PYC on allergic inflammation in a rat model of allergic rhinitis. Study Design: Animal experimentation. Methods: Allergic rhinitis was stimulated in 42 rats by intraperitoneal sensitization and intranasal challenge with Ovalbumin. The animals were divided into six subgroups: healthy controls, AR group, AR group treated with corticosteroid (dexamethasone 1 mg/kg; CS+AR, healthy rats group that were given only PYC of 10 mg/kg (PYC10, AR group treated with PYC of 3mg/kg (PYC3+AR, and AR group treated with PYC of 10 mg/kg (PYC10+AR. Interferon-γ (IFN-γ, interleukin-4 (IL-4, interleukin-10 (IL-10, and OVA-specific immunoglobulin E (Ig-E levels of serum were measured. Histopathological changes in nasal mucosa and expression of tumor necrosis factor-α (TNF-α and IL-1β were evaluated. Results: The levels of the IL-4 were significantly decreased in the PYC3+AR, PYC10+AR and CS+AR groups compared with the AR group (p=0.002, p<0.001, p=0.006. The production of the IFN-γ was significantly decreased in the PYC3+AR and PYC10+AR groups compared with the AR group (p=0.013, p=0.001. The administration of PYC to allergic rats suppressed the elevated IL-10 production, especially in the PYC3+AR group (p=0.006. Mucosal edema was significantly decreased respectively after treatment at dose 3 mg/kg and 10 mg/kg PYC (both, p<0.001. The mucosal expression of TNF-α has significantly decreased in the PYC3+AR and PYC10+AR groups (p=0.005, p<0.001, while the IL-1β expression significantly decreased in the CS+AR, PYC3+AR, and PYC10+AR groups (p<0.001, p=0.003, p=0.001. Conclusion: PYC has multiple suppressive effects on allergic response. Thus, PYC may be used as a supplementary agent in allergic

Inhibition of NF-κB Expression and Allergen-induced Airway Inflammation in a Mouse Allergic Asthma Model by Andrographolide

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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...

NEUROTROPHIN MEDIATION OF ALLERGIC AIRWAYS RESPONSES TO INHALED DIESEL PARTICLES IN MICE

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Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airway hyper-responsiveness. Diesel exhaust particulates (DEP) associated with the combustion of diesel fuel exacerbate many of these allergic airways respons...

Role of the adiponectin binding protein, T-cadherin (Cdh13, in allergic airways responses in mice.

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Alison S Williams

Full Text Available Adiponectin is an adipose derived hormone that declines in obesity. We have previously shown that exogenous administration of adiponectin reduces allergic airways responses in mice. T-cadherin (T-cad; Cdh13 is a binding protein for the high molecular weight isoforms of adiponectin. To determine whether the beneficial effects of adiponectin on allergic airways responses require T-cad, we sensitized wildtype (WT, T-cadherin deficient (T-cad(-/- and adiponectin and T-cad bideficient mice to ovalbumin (OVA and challenged the mice with aerosolized OVA or PBS. Compared to WT, T-cad(-/- mice were protected against OVA-induced airway hyperresponsiveness, increases in BAL inflammatory cells, and induction of IL-13, IL-17, and eotaxin expression. Histological analysis of the lungs of OVA-challenged T-cad(-/- versus WT mice indicated reduced inflammation around the airways, and reduced mucous cell hyperplasia. Combined adiponectin and T-cad deficiency reversed the effects of T-cad deficiency alone, indicating that the observed effects of T-cad deficiency require adiponectin. Compared to WT, serum adiponectin was markedly increased in T-cad(-/- mice, likely because adiponectin that is normally sequestered by endothelial T-cad remains free in the circulation. In conclusion, T-cad does not mediate the protective effects of adiponectin. Instead, mice lacking T-cad have reduced allergic airways disease, likely because elevated serum adiponectin levels act on other adiponectin signaling pathways.

Association and management of eosinophilic inflammation in upper and lower airways

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Mitsuhiro Okano

2015-04-01

Full Text Available This review discussed the contribution of eosinophilic upper airway inflammation includes allergic rhinitis (AR and chronic rhinosinusitis (CRS to the pathophysiology and course of asthma, the representative counterpart in the lower airway. The presence of concomitant AR can affect the severity of asthma in patients who have both diseases; however, it is still debatable whether the presence of asthma affects the severity of AR. Hypersensitivity, obstruction and/or inflammation in the lower airway can be detected in patients with AR without awareness or diagnosis of asthma, and AR is known as a risk factor for the new onset of wheeze and asthma both in children and adults. Allergen immunotherapy, pharmacotherapy and surgery for AR can contribute to asthma control; however, a clear preventive effect on the new onset of asthma has been demonstrated only for immunotherapy. Pathological similarities such as epithelial shedding are also seen between asthma and CRS, especially eosinophilic CRS. Abnormal sinus findings on computed tomography are seen in the majority of asthmatic patients, and asthmatic patients with CRS show a significant impairment in Quality of Life (QOL and pulmonary function as compared to those without CRS. Conversely, lower airway inflammation and dysfunction are seen in non-asthmatic patients with CRS. Treatments for CRS that include pharmacotherapy such as anti-leukotrienes, surgery, and aspirin desensitization show a beneficial effect on concomitant asthma. Acting as a gatekeeper of the united airways, the control of inflammation in the nose is crucial for improvement of the QOL of patients with co-existing AR/CRS and asthma.

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.

Citrus tachibana Leaves Ethanol Extract Alleviates Airway Inflammation by the Modulation of Th1/Th2 Imbalance via Inhibiting NF-κB Signaling and Histamine Secretion in a Mouse Model of Allergic Asthma.

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Bui, Thi Tho; Piao, Chun Hua; Kim, Soo Mi; Song, Chang Ho; Shin, Hee Soon; Lee, Chang-Hyun; Chai, Ok Hee

2017-07-01

Asthma is a chronic inflammatory disease of bronchial airway, which is characterized by chronic airway inflammation, airway edema, goblet cell hyperplasia, the aberrant production of the Th2 cytokines, and eosinophil infiltration in the lungs. In this study, the therapeutic effect and the underlying mechanism of Citrus tachibana leaves ethanol extract (CTLE) in the ovalbumin (OVA)-induced allergic asthma and compound 48/80-induced anaphylaxis were investigated. Oral administration of CTLE inhibited OVA-induced asthmatic response by reducing airway inflammation, OVA-specific IgE and IgG1 levels, and increasing OVA-specific IgG2a levels. CTLE restored Th1/Th2 balance through an increase in Th2 cytokines tumor necrosis factor-α, interleukin (IL)-4, and IL-6 and decreases in Th1 cytokines interferon-γ and IL-12. Furthermore, CTLE inhibited the total level of NF-κB and the phosphorylation of IκB-α and NF-κB by OVA. In addition, CTLE dose-dependently inhibited compound 48/80-induced anaphylaxis via blocking histamine secretion from mast cells. The anti-inflammatory mechanism of CTLE may involve the modulation of Th1/Th2 imbalance via inhibiting the NF-κB signaling and histamine secretion. Taken together, we suggest that CTLE could be used as a therapeutic agent for patients with Th2-mediated or histamine-mediated allergic asthma.

Rhinosinusitis and the lower airways

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Hellings, Peter W.; Hens, Greet

2009-01-01

The interaction between upper and lower airway disease has been recognized for centuries, with recent studies showing a direct link between upper and airway inflammation in allergic patients. The mechanisms underlying the interaction between nasal and bronchial inflammation have primarily been

Role of macrophage migration inhibitory factor (MIF in allergic and endotoxin-induced airway inflammation in mice

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M. Korsgren

2000-01-01

Full Text Available Macrophage migration inhibitory factor (MIF has recently been forwarded as a critical regulator of inflammatory conditions, and it has been hypothesized that MIF may have a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD. Hence, we examined effects of MIF immunoneutralization on the development of allergen-induced eosinophilic inflammation as well as on lipopolysaccaride (LPS-induced neutrophilic inflammation in lungs of mice. Anti-MIF serum validated with respect to MIF neutralizing capacity or normal rabbit serum (NRS was administered i.p. repeatedly during allergen aerosol exposure of ovalbumin (OVA-immunized mice in an established model of allergic asthma, or once before instillation of a minimal dose of LPS into the airways of mice, a tentative model of COPD. Anti-MIF treatment did not affect the induced lung tissue eosinophilia or the cellular composition of bronchoalveolar lavage fluid (BALF in the asthma model. Likewise, anti-MIF treatment did not affect the LPS-induced neutrophilia in lung tissue, BALF, or blood, nor did it reduce BALF levels of tumor necrosis factor-α (TNF-α and macrophage inflammatory protein–1 α (MIP–1 α. The present data suggest that MIF is not critically important for allergen-induced eosinophilic, and LPS-induced neutrophilic responses in lungs of mice. These findings do not support a role of MIF inhibition in the treatment of inflammatory respiratory diseases.

Artemisia argyi attenuates airway inflammation in ovalbumin-induced asthmatic animals.

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Shin, Na-Rae; Ryu, Hyung-Won; Ko, Je-Won; Park, Sung-Hyeuk; Yuk, Heung-Joo; Kim, Ha-Jung; Kim, Jong-Choon; Jeong, Seong-Hun; Shin, In-Sik

2017-09-14

Artemisia argyi is a traditional herbal medicine in Korea and commonly called as mugwort. It is traditionally used as food source and tea to control abdominal pain, dysmenorrhea, uterine hemorrhage, and inflammation. We investigated the effects of A. argyi (TOTAL) and dehydromatricarin A (DA), its active component on ovalbumin (OVA)-induced allergic asthma. The animals were sensitized on day 0 and 14 by intraperitoneal injection of OVA with aluminum hydroxide. On day 21, 22 and 23 after the initial sensitization, the animals received an airway challenge with OVA for 1h using an ultrasonic nebulizer. TOTAL (50 and 100mg/kg) or DA (10 and 20mg/kg) were administered to mice by oral gavage once daily from day 18-23. Airway hyperresponsiveness (AHR) was measured 24h after final OVA challenge. TOTAL and DA treated animals reduced inflammatory cell counts, cytokines and AHR in asthmatic animals, which was accompanied with inflammatory cell accumulation and mucus hypersecretion. Furthermore, TOTAL and DA significantly declined Erk phosphorylation and the expression of MMP-9 in asthmatic animals. In conclusion, we indicate that Total and DA suppress allergic inflammatory responses caused by OVA challenge. It was considered that A. argyi has a potential for treating allergic asthma. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Counterbalancing of TH2-driven allergic airway inflammation by IL-12 does not require IL-10.

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Tournoy, K G; Kips, J C; Pauwels, R A

2001-03-01

Asthma is characterized by allergen-induced airway inflammation orchestrated by TH2 cells. The TH1-promoting cytokine IL-12 is capable of inhibiting the TH2-driven allergen-induced airway changes in mice and is therefore regarded as an interesting strategy for treating asthma. The antiallergic effects of IL-12 are only partially dependent of IFN-gamma. Because IL-12 is a potent inducer of the anti-inflammatory cytokine IL-10, the aim of the present study was to investigate in vivo whether the antiallergic effects of IL-12 are mediated through IL-10. C57BL/6J-IL-10 knock-out (IL-10(-/-)) mice were sensitized intraperitoneally to ovalbumin (OVA) and subsequently exposed from day 14 to day 21 to aerosolized OVA (1%). IL-12 was administered intraperitoneally during sensitization, subsequent OVA exposure, or both. IL-12 inhibited the OVA-induced airway eosinophilia, despite the absence of IL-10. Moreover, a shift from a TH2 inflammatory pattern toward a TH1 reaction was observed, with concomitant pronounced mononuclear peribronchial inflammation after IL-12 treatment. Allergen-specific IgE synthesis was completely suppressed only when IL-12 was administered along with the allergen sensitization. Furthermore, treating the animals with IL-12 at the time of the secondary allergen challenge resulted not only in a significant suppression of the airway responsiveness but also in an important IFN-gamma-associated toxicity. These results indicate that IL-12 is able to inhibit allergen-induced airway changes, even in the absence of IL-10. In addition, our results raise concerns regarding the redirection of TH2 inflammation by TH1-inducing therapies because treatment with IL-12 resulted not only in a disappearance of the TH2 inflammation but also in a TH1-driven inflammatory pulmonary pathology.

Self-assembling nanoparticles containing dexamethasone as a novel therapy in allergic airways inflammation.

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Nicholas J Kenyon

Full Text Available Nanocarriers can deliver a wide variety of drugs, target them to sites of interest, and protect them from degradation and inactivation by the body. They have the capacity to improve drug action and decrease undesirable systemic effects. We have previously developed a well-defined non-toxic PEG-dendritic block telodendrimer for successful delivery of chemotherapeutics agents and, in these studies, we apply this technology for therapeutic development in asthma. In these proof-of-concept experiments, we hypothesized that dexamethasone contained in self-assembling nanoparticles (Dex-NP and delivered systemically would target the lung and decrease allergic lung inflammation and airways hyper-responsiveness to a greater degree than equivalent doses of dexamethasone (Dex alone. We found that ovalbumin (Ova-exposed mice treated with Dex-NP had significantly fewer total cells (2.78 ± 0.44 × 10(5 (n = 18 vs. 5.98 ± 1.3 × 10(5 (n = 13, P<0.05 and eosinophils (1.09 ± 0.28 × 10(5 (n = 18 vs. 2.94 ± 0.6 × 10(5 (n = 12, p<0.05 in the lung lavage than Ova-exposed mice alone. Also, lower levels of the inflammatory cytokines IL-4 (3.43 ± 1.2 (n = 11 vs. 8.56 ± 2.1 (n = 8 pg/ml, p<0.05 and MCP-1 (13.1 ± 3.6 (n = 8 vs. 28.8 ± 8.7 (n = 10 pg/ml, p<0.05 were found in lungs of the Dex-NP compared to control, and they were not lower in the Dex alone group. In addition, respiratory system resistance was lower in the Dex-NP compared to the other Ova-exposed groups suggesting a better therapeutic effect on airways hyperresponsiveness. Taken together, these findings from early-stage drug development studies suggest that the encapsulation and protection of anti-inflammatory agents such as corticosteroids in nanoparticle formulations can improve efficacy. Further development of novel drugs in nanoparticles is warranted to explore potential treatments for chronic inflammatory diseases such as asthma.

Neuropsychiatry phenotype in asthma: Psychological stress-induced alterations of the neuroendocrine-immune system in allergic airway inflammation

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Isao Ohno

2017-09-01

Full Text Available Since the recognition of asthma as a syndrome with complex pathophysiological signs and symptoms, recent research has sought to classify asthma phenotypes based on its clinical and molecular pathological features. Psychological stress was first recognized as a potential immune system modulator of asthma at the end of the 19th century. The activation of the central nervous system (CNS upon exposure to psychological stress is integral for the initiation of signal transduction processes. The stress hormones, including glucocorticoids, epinephrine, and norepinephrine, which are secreted following CNS activation, are involved in the immunological alterations involved in psychological stress-induced asthma exacerbation. The mechanisms underlying this process may involve a pathological series of events from the brain to the lungs, which is attracting attention as a conceptually advanced phenotype in asthma pathogenesis. This review presents insights into the critical role of psychological stress in the development and exacerbation of allergic asthma, with a special focus on our own data that emphasizes on the continuity from the central sensing of psychological stress to enhanced eosinophilic airway inflammation.

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.

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Levy, Bruce D; Lukacs, Nicholas W; Berlin, Aaron A; Schmidt, Birgitta; Guilford, William J; Serhan, Charles N; Parkinson, John F

2007-12-01

Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A4 (LXA4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA4 analog (ATLa) and a 3-oxa-15-epi-LXA4 analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At 50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA4 analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs' therapeutic potential as new agonists for the resolution of inflammation.

Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice

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Sun, Daqing [Department of Respiration, Xi’an Children’s Hospital, Xi’an 710003 (China); Wang, Jing [Department of Neonatology, Xi’an Children’s Hospital, Xi’an 710003 (China); Yang, Niandi [Outpatient Department, School of Aerospace Engineering, Air Force Engineering University, Xi’an 710038 (China); Ma, Haixin, E-mail: drhaixinma@163.com [Department of Quality Control, Xi’an Children’s Hospital, Xi’an 710003 (China)

2016-08-12

Matrine has been demonstrated to attenuate allergic airway inflammation. Elevated suppressor of cytokine signaling 3 (SOCS3) was correlated with the severity of asthma. The aim of this study was to investigate the effect of matrine on SOCS3 expression in airway inflammation. In this study, we found that matrine significantly inhibited OVA-induced AHR, inflammatory cell infiltration, goblet cell differentiation, and mucous production in a dose-dependent manner in mice. Matrine also abrogated the level of interleukin (IL)-4 and IL-13, but enhanced interferon (IFN)-γ expression, both in BALF and in lung homogenates. Furthermore, matrine impeded TNF-α-induced the expression of IL-6 and adhesion molecules in airway epithelial cells (BEAS-2B and MLE-12). Additionally, we found that matrine inhibited SOCS3 expression, both in asthmatic mice and TNF-α-stimulated epithelial cells via suppression of the NF-κB signaling pathway by using pcDNA3.1-SOCS3 plasmid, SOCS3 siRNA, or nuclear factor kappa-B (NF-κB) inhibitor PDTC. Conclusions: Matrine suppresses airway inflammation by downregulating SOCS3 expression via inhibition of NF-κB signaling in airway epithelial cells and asthmatic mice. - Highlights: • Matrine attenuates asthmatic symptoms and regulates Th1/Th2 balance in vivo. • Matrine suppresses inflammation responses in vitro. • Matrine decreases SOCS3 expression both in vivo and in vitro. • Matrine inhibits SOCS3 expression by suppressing NF-κB signaling.

March1 E3 Ubiquitin Ligase Modulates Features of Allergic Asthma in an Ovalbumin-Induced Mouse Model of Lung Inflammation

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Osama A. Kishta

2018-01-01

Full Text Available Membrane-associated RING-CH-1 (March1 is a member of the March family of E3 ubiquitin ligases. March1 downregulates cell surface expression of MHC II and CD86 by targeting them to lysosomal degradation. Given the key roles of MHC class II and CD86 in T cell activation and to get further insights into the development of allergic inflammation, we asked whether March1 deficiency exacerbates or attenuates features of allergic asthma in mice. Herein, we used an acute model of allergy to compare the asthmatic phenotype of March1-deficient and -sufficient mice immunized with ovalbumin (OVA and later challenged by intranasal instillation of OVA in the lungs. We found that eosinophilic inflammation in airways and lung tissue was similar between WT and March1−/− allergic mice, whereas neutrophilic inflammation was significant only in March1−/− mice. Airway hyperresponsiveness as well as levels of IFN-γ, IL-13, IL-6, and IL-10 was lower in the lungs of asthmatic March1−/− mice compared to WT, whereas lung levels of TNF-α, IL-4, and IL-5 were not significantly different. Interestingly, in the serum, levels of total and ova-specific IgE were reduced in March1-deficient mice as compared to WT mice. Taken together, our results demonstrate a role of March1 E3 ubiquitin ligase in modulating allergic responses.

Effects of mycobacteria major secretion protein, Ag85B, on allergic inflammation in the lung.

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Yusuke Tsujimura

Full Text Available Many epidemiological studies have suggested that the recent increase in prevalence and severity of allergic diseases such as asthma is inversely correlated with Mycobacterium bovis bacillus Calmette Guerin (BCG vaccination. However, the underlying mechanisms by which mycobacterial components suppress allergic diseases are not yet fully understood. Here we showed the inhibitory mechanisms for development of allergic airway inflammation by using highly purified recombinant Ag85B (rAg85B, which is one of the major protein antigens secreted from M. tuberculosis. Ag85B is thought to be a single immunogenic protein that can elicit a strong Th1-type immune response in hosts infected with mycobacteria, including individuals vaccinated with BCG. Administration of rAg85B showed a strong inhibitory effect on the development of allergic airway inflammation with induction of Th1-response and IL-17and IL-22 production. Both cytokines induced by rAg85B were involved in the induction of Th17-related cytokine-production innate immune cells in the lung. Administration of neutralizing antibodies to IL-17 or IL-22 in rAg85B-treated mice revealed that IL-17 induced the infiltration of neutrophils in BAL fluid and that allergen-induced bronchial eosinophilia was inhibited by IL-22. Furthermore, enhancement of the expression of genes associated with tissue homeostasis and wound healing was observed in bronchial tissues after rAg85B administration in a Th17-related cytokine dependent manner. The results of this study provide evidence for the potential usefulness of rAg85B as a novel approach for anti-allergic effect and tissue repair other than the role as a conventional TB vaccine.

Reduced immune responses in chimeric mice engrafted with bone marrow cells from mice with airways inflammation.

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Scott, Naomi M; Ng, Royce L X; McGonigle, Terence A; Gorman, Shelley; Hart, Prue H

2015-11-01

During respiratory inflammation, it is generally assumed that dendritic cells differentiating from the bone marrow are immunogenic rather than immunoregulatory. Using chimeric mice, the outcomes of airways inflammation on bone marrow progenitor cells were studied. Immune responses were analyzed in chimeric mice engrafted for >16 weeks with bone marrow cells from mice with experimental allergic airways disease (EAAD). Responses to sensitization and challenge with the allergen causing inflammation in the bone marrow-donor mice were significantly reduced in the chimeric mice engrafted with bone marrow cells from mice with EAAD (EAAD-chimeric). Responses to intranasal LPS and topical fluorescein isothiocyanate (non-specific challenges) were significantly attenuated. Fewer activated dendritic cells from the airways and skin of the EAAD-chimeric mice could be tracked to the draining lymph nodes, and may contribute to the significantly reduced antigen/chemical-induced hypertrophy in the draining nodes, and the reduced immune responses to sensitizing allergens. Dendritic cells differentiating in vitro from the bone marrow of >16 weeks reconstituted EAAD-chimeric mice retained an ability to poorly prime immune responses when transferred into naïve mice. Dendritic cells developing from bone marrow progenitors during airways inflammation are altered such that daughter cells have reduced antigen priming capabilities.

Sulfatide-activated type II NKT cells prevent allergic airway inflammation by inhibiting type I NKT cell function in a mouse model of asthma.

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Zhang, Guqin; Nie, Hanxiang; Yang, Jiong; Ding, Xuhong; Huang, Yi; Yu, Hongying; Li, Ruyou; Yuan, Zhuqing; Hu, Suping

2011-12-01

Asthma is a common chronic inflammatory disease involving many different cell types. Recently, type I natural killer T (NKT) cells have been demonstrated to play a crucial role in the development of asthma. However, the roles of type II NKT cells in asthma have not been investigated before. Interestingly, type I and type II NKT cells have been shown to have opposing roles in antitumor immunity, antiparasite immunity, and autoimmunity. We hypothesized that sulfatide-activated type II NKT cells could prevent allergic airway inflammation by inhibiting type I NKT cell function in asthma. Strikingly, in our mouse model, activation of type II NKT cells by sulfatide administration and adoptive transfer of sulfatide-activated type II NKT cells result in reduced-inflammation cell infiltration in the lung and bronchoalveolar lavage fluid, decreased levels of IL-4 and IL-5 in the BALF; and decreased serum levels of ovalbumin-specific IgE and IgG1. Furthermore, it is found that the activation of sulfatide-reactive type II NKT cells leads to the functional inactivation of type I NKT cells, including the proliferation and cytokine secretion. Our data reveal that type II NKT cells activated by glycolipids, such as sulfatide, may serve as a novel approach to treat allergic diseases and other disorders characterized by inappropriate type I NKT cell activation.

Suppression of Th17-polarized airway inflammation by rapamycin.

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Joean, Oana; Hueber, Anja; Feller, Felix; Jirmo, Adan Chari; Lochner, Matthias; Dittrich, Anna-Maria; Albrecht, Melanie

2017-11-10

Because Th17-polarized airway inflammation correlates with poor control in bronchial asthma and is a feature of numerous other difficult-to-treat inflammatory lung diseases, new therapeutic approaches for this type of airway inflammation are necessary. We assessed different licensed anti-inflammatory agents with known or expected efficacy against Th17-polarization in mouse models of Th17-dependent airway inflammation. Upon intravenous transfer of in vitro derived Th17 cells and intranasal challenge with the corresponding antigen, we established acute and chronic murine models of Th17-polarised airway inflammation. Consecutively, we assessed the efficacy of methylprednisolone, roflumilast, azithromycin, AM80 and rapamycin against acute or chronic Th17-dependent airway inflammation. Quantifiers for Th17-associated inflammation comprised: bronchoalveolar lavage (BAL) differential cell counts, allergen-specific cytokine and immunoglobulin secretion, as well as flow cytometric phenotyping of pulmonary inflammatory cells. Only rapamycin proved effective against acute Th17-dependent airway inflammation, accompanied by increased plasmacytoid dendritic cells (pDCs) and reduced neutrophils as well as reduced CXCL-1 levels in BAL. Chronic Th17-dependent airway inflammation was unaltered by rapamycin treatment. None of the other agents showed efficacy in our models. Our results demonstrate that Th17-dependent airway inflammation is difficult to treat with known agents. However, we identify rapamycin as an agent with inhibitory potential against acute Th17-polarized airway inflammation.

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

International Nuclear Information System (INIS)

Ribeiro-Filho, Jaime; Calheiros, Andrea Surrage; Vieira-de-Abreu, Adriana; Moraes de Carvalho, Katharinne Ingrid; Silva Mendes, Diego da; Melo, Christianne Bandeira; Martins, Marco Aurélio; Silva Dias, Celidarque da; Piuvezam, Márcia Regina

2013-01-01

Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effects of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca ++ influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs. - Highlights: • Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum. • Curine inhibits eosinophil influx and activation and airway hyper-responsiveness. • Curine

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

Energy Technology Data Exchange (ETDEWEB)

Ribeiro-Filho, Jaime [Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Laboratório de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, João Pessoa, Paraíba (Brazil); Calheiros, Andrea Surrage; Vieira-de-Abreu, Adriana [Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Moraes de Carvalho, Katharinne Ingrid [Laboratório de Inflamação, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Silva Mendes, Diego da [Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Melo, Christianne Bandeira [Laboratório de Inflamação, Instituto Biofisica Carlos Chagas Filho, UFRJ, Rio de Janeiro (Brazil); Martins, Marco Aurélio [Laboratório de Inflamação, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Silva Dias, Celidarque da [Laboratório de Fitoquímica, Departamento de Ciências Farmacêuticas, UFPB, João Pessoa, Paraíba (Brazil); Piuvezam, Márcia Regina, E-mail: mrpiuvezam@ltf.ufpb.br [Laboratório de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, João Pessoa, Paraíba (Brazil); and others

2013-11-15

Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effects of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca{sup ++} influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs. - Highlights: • Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum. • Curine inhibits eosinophil influx and activation and airway hyper-responsiveness. • Curine

Preventative effect of an herbal preparation (HemoHIM) on development of airway inflammation in mice via modulation of Th1/2 cells differentiation.

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Kim, Jong-Jin; Cho, Hyun Wook; Park, Hae-Ran; Jung, Uhee; Jo, Sung-Kee; Yee, Sung-Tae

2013-01-01

HemoHIM, an herbal preparation of three edible herbs (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia japonica Miyabe) is known to increase the Th1 immune response as well as reduce the allergic response in human mast cells. Here, our goal was to determine whether or not HemoHIM could induce Th1 cell differentiation as well as inhibit the development of airway inflammation. To study Th1/Th2 cell differentiation, naive CD4(+) T cells isolated from C57BL/6 mouse spleens were cultured with or without HemoHIM. To examine airway inflammation, C57BL/6 mice were fed HemoHIM for 4 weeks before sensitization and provocation with ovalbumin (OVA). In an in vitro experiment, naive CD4(+) T cells displayed increased Th1 (IFN-γ(+) cell) as well as decreased Th2 (IL-4(+) cell) differentiation in a HemoHIM concentration-dependent manner. Furthermore, in an airway inflammation mice model, eosinophil numbers in BALF, serum levels of OVA-specific IgE and IgG1, and cytokine (IL-4, IL-5, and IL-13) levels in BALF and the supernatant of splenocytes all decreased upon HemoHIM (100 mg/kg body weight) pretreatment (4 weeks). These results show that HemoHIM attenuated allergic airway inflammation in the mouse model through regulation of the Th1/Th2 balance.

Preventative effect of an herbal preparation (HemoHIM on development of airway inflammation in mice via modulation of Th1/2 cells differentiation.

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Jong-Jin Kim

Full Text Available HemoHIM, an herbal preparation of three edible herbs (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia japonica Miyabe is known to increase the Th1 immune response as well as reduce the allergic response in human mast cells. Here, our goal was to determine whether or not HemoHIM could induce Th1 cell differentiation as well as inhibit the development of airway inflammation. To study Th1/Th2 cell differentiation, naive CD4(+ T cells isolated from C57BL/6 mouse spleens were cultured with or without HemoHIM. To examine airway inflammation, C57BL/6 mice were fed HemoHIM for 4 weeks before sensitization and provocation with ovalbumin (OVA. In an in vitro experiment, naive CD4(+ T cells displayed increased Th1 (IFN-γ(+ cell as well as decreased Th2 (IL-4(+ cell differentiation in a HemoHIM concentration-dependent manner. Furthermore, in an airway inflammation mice model, eosinophil numbers in BALF, serum levels of OVA-specific IgE and IgG1, and cytokine (IL-4, IL-5, and IL-13 levels in BALF and the supernatant of splenocytes all decreased upon HemoHIM (100 mg/kg body weight pretreatment (4 weeks. These results show that HemoHIM attenuated allergic airway inflammation in the mouse model through regulation of the Th1/Th2 balance.

Synthetic Nanoparticles That Promote Tumor Necrosis Factor Receptor 2 Expressing Regulatory T Cells in the Lung and Resistance to Allergic Airways Inflammation

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Rohimah Mohamud

2017-12-01

Full Text Available Synthetic glycine coated 50 nm polystyrene nanoparticles (NP (PS50G, unlike ambient NP, do not promote pulmonary inflammation, but instead, render lungs resistant to the development of allergic airway inflammation. In this study, we show that PS50G modulate the frequency and phenotype of regulatory T cells (Treg in the lung, specifically increasing the proportion of tumor necrosis factor 2 (TNFR2 expressing Treg. Mice pre-exposed to PS50G, which were sensitized and then challenged with an allergen a month later, preferentially expanded TNFR2+Foxp3+ Treg, which further expressed enhanced levels of latency associated peptide and cytotoxic T-lymphocyte associated molecule-4. Moreover, PS50G-induced CD103+ dendritic cell activation in the lung was associated with the proliferative expansion of TNFR2+Foxp3+ Treg. These findings provide the first evidence that engineered NP can promote the selective expansion of maximally suppressing TNFR2+Foxp3+ Treg and further suggest a novel mechanism by which NP may promote healthy lung homeostasis.

Chronic respiratory aeroallergen exposure in mice induces epithelial-mesenchymal transition in the large airways.

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Jill R Johnson

Full Text Available Chronic allergic asthma is characterized by Th2-polarized inflammation and leads to airway remodeling and fibrosis but the mechanisms involved are not clear. To determine whether epithelial-mesenchymal transition contributes to airway remodeling in asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM extract for up to 15 consecutive weeks. We report that respiratory exposure to HDM led to significant airway inflammation and thickening of the smooth muscle layer in the wall of the large airways. Transforming growth factor beta-1 (TGF-β1 levels increased in mouse airways while epithelial cells lost expression of E-cadherin and occludin and gained expression of the mesenchymal proteins vimentin, alpha-smooth muscle actin (α-SMA and pro-collagen I. We also observed increased expression and nuclear translocation of Snail1, a transcriptional repressor of E-cadherin and a potent inducer of EMT, in the airway epithelial cells of HDM-exposed mice. Furthermore, fate-mapping studies revealed migration of airway epithelial cells into the sub-epithelial regions of the airway wall. These results show the contribution of EMT to airway remodeling in chronic asthma-like inflammation and suggest that Th2-polarized airway inflammation can trigger invasion of epithelial cells into the subepithelial regions of the airway wall where they contribute to fibrosis, demonstrating a previously unknown plasticity of the airway epithelium in allergic airway disease.

Effect of heat-inactivated kefir-isolated Lactobacillus kefiranofaciens M1 on preventing an allergic airway response in mice.

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Hong, Wei-Sheng; Chen, Yen-Po; Dai, Ting-Yeu; Huang, I-Nung; Chen, Ming-Ju

2011-08-24

In this study, we assessed the anti-asthmatic effects of heat-inactivated Lactobacillus kefiranofaciens M1 (HI-M1) and its fermented milk using different feeding procedures and at various dosage levels. The possible mechanisms whereby HI-M1 has anti-allergic asthmatic effects were also evaluated. Ovalbumin (OVA)-allergic asthma mice that have been orally administrated the HI-M1 samples showed strong inhibition of production of T helper cell (Th) 2 cytokines, pro-inflammatory cytokines, and Th17 cytokines in splenocytes and bronchoalveolar fluid compared to control mice. An increase in regulatory T cell population in splenocytes in the allergic asthma mice after oral administration of H1-M1 was also observed. In addition, all of the features of the asthmatic phenotype, including specific IgE production, airway inflammation, and development of airway hyperresponsiveness, were depressed in a dose-dependent manner by treatment. These findings support the possibility that oral feeding of H1-M1 may be an effective way of alleviating asthmatic symptoms in humans.

Fisetin-treatment alleviates airway inflammation through inhbition of MyD88/NF-κB signaling pathway.

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Huang, Wei; Li, Ming-Li; Xia, Ming-Yue; Shao, Jian-Ying

2018-07-01

Asthma is a common chronic airway inflammation disease and is considered as a major public health problem. Fisetin (3,3',4',7-tetrahydroxyflavone) is a naturally occurring flavonoid abundantly found in different vegetables and fruits. Fisetin has been reported to exhibit various positive biological effects, including anti-proliferative, anticancer, anti-oxidative and neuroprotective effects. We evaluated the effects of fisetin on allergic asthma regulation in mice. Mice were first sensitized, then airway-challenged with ovalbumin (OVA). Whether fisetin treatment attenuated OVA-induced airway inflammation was examined via inflammation inhibition through MyD88-related NF-κB (p65) signaling pathway. Mice were divided into the control (Con), OVA-induced asthma (Mod), 40 (FL) and 50 (FH) mg/kg fisetin-treated OVA-induced asthma groups. Our results found that OVA-induced airway inflammation in mice caused a significant inflammatory response via the activation of MyD88 and NF-κB signaling pathways, leading to release of pro-inflammatory cytokines. In contrast, fisetin-treated mice after OVA induction inhibited activation of MyD88 and NF-κB signaling pathways, resulting in downregulation of pro-inflammatory cytokine secretion. Further, fisetin significantly ameliorated the airway hyperresponsiveness (AHR) towards methacholine (Mch). In addition, fisetin reduced the number of eosinophil, monocyte, neutrophil and total white blood cell in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. The serum and BALF samples obtained from the OVA-induced mice with fisetin showed lower levels of pro-inflammatory cytokines. The results of our study illustrated that fisetin may be a new promising candidate to inhibit airway inflammation response induced by OVA.

Early sensitisation and development of allergic airway disease - risk factors and predictors

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Halken, Susanne

2003-01-01

The development and phenotypic expression of allergic airway disease depends on a complex interaction between genetic and several environmental factors, such as exposure to food, inhalant allergens and non-specific adjuvant factors (e.g. tobacco smoke, air pollution and infections). The first...... development of allergic disease at birth. Early sensitisation, cow's milk allergy and atopic eczema are predictors for later development of allergic airway disease. Exposure to indoor allergens, especially house dust mite allergens, is a risk factor for sensitisation and development of asthma later...

Natural Killer Receptor 1 Dampens the Development of Allergic Eosinophilic Airway Inflammation.

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Shirin Elhaik Goldman

Full Text Available The function of NCR1 was studied in a model of experimental asthma, classified as a type 1 hypersensitivity reaction, in mice. IgE levels were significantly increased in the serum of OVA immunized NCR1 deficient (NCR1gfp/gfp mice in comparison to OVA immunized wild type (NCR1+/+ and adjuvant immunized mice. Histological analysis of OVA immunized NCR1gfp/gfp mice revealed no preservation of the lung structure and overwhelming peribronchial and perivascular granulocytes together with mononuclear cells infiltration. OVA immunized NCR+/+ mice demonstrated preserved lung structure and peribronchial and perivascular immune cell infiltration to a lower extent than that in NCR1gfp/gfp mice. Adjuvant immunized mice demonstrated lung structure preservation and no immune cell infiltration. OVA immunization caused an increase in PAS production independently of NCR1 presence. Bronchoalveolar lavage (BAL revealed NCR1 dependent decreased percentages of eosinophils and increased percentages of lymphocytes and macrophages following OVA immunization. In the OVA immunized NCR1gfp/gfp mice the protein levels of eosinophils' (CCL24 and Th2 CD4+ T-cells' chemoattractants (CCL17, and CCL24 in the BAL are increased in comparison with OVA immunized NCR+/+ mice. In the presence of NCR1, OVA immunization caused an increase in NK cells numbers and decreased NCR1 ligand expression on CD11c+GR1+ cells and decreased NCR1 mRNA expression in the BAL. OVA immunization resulted in significantly increased IL-13, IL-4 and CCL17 mRNA expression in NCR1+/+ and NCR1gfp/gfp mice. IL-17 and TNFα expression increased only in OVA-immunized NCR1+/+mice. IL-6 mRNA increased only in OVA immunized NCR1gfp/gfp mice. Collectively, it is demonstrated that NCR1 dampens allergic eosinophilic airway inflammation.

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. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Indoleamine 2,3-dioxygenase expression in patients with allergic rhinitis: a case-control study

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Luukkainen Annika

2011-12-01

Full Text Available 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 evaluated from nasal specimens obtained in- and off-season from otherwise healthy non-smoking volunteers both allergic to birch pollen (having mild or moderate allergic rhinoconjunctivitis and non-allergic controls. Results: The IDO expression levels were low in healthy controls and remained low also in patients allergic to birch pollen. There were no differences in the expression of IDO in- and off-season in either healthy or allergic subjects. Conclusions There is a controversy in the role of IDO in upper and lower airways during allergic airway disease. It seems that IDO is associated to allergic inflammations of the lower airways, but does not have a local role in the nasal cavity at least in mild or moderate forms of allergic rhinitis.

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

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Chawes, Bo

2011-01-01

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......, 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...

The combination of Bifidobacterium breve with non-digestible oligosaccharides suppresses airway inflammation in a murine model for chronic asthma.

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Sagar, Seil; Vos, Arjan P; Morgan, Mary E; Garssen, Johan; Georgiou, Niki A; Boon, Louis; Kraneveld, Aletta D; Folkerts, Gert

2014-04-01

Over the last decade, there has been a growing interest in the use of interventions that target the intestinal microbiota as a treatment approach for asthma. This study is aimed at exploring the therapeutic effects of long-term treatment with a combination of Bifidobacterium breve with non-digestible oligosaccharides on airway inflammation and remodeling. A murine ovalbumin-induced chronic asthma model was used. Pulmonary airway inflammation; mRNA expression of pattern recognition receptors, Th-specific cytokines and transcription factors in lung tissue; expression of Foxp3 in blood Th cells; in vitro T cell activation; mast cell degranulation; and airway remodeling were examined. The combination of B. breve with non-digestible oligosaccharides suppressed pulmonary airway inflammation; reduced T cell activation and mast cell degranulation; modulated expression of pattern recognition receptors, cytokines and transcription factors; and reduced airway remodeling. The treatment induced regulatory T cell responses, as shown by increased Il10 and Foxp3 transcription in lung tissue, and augmented Foxp3 protein expression in blood CD4+CD25+Foxp3+ T cells. This specific combination of beneficial bacteria with non-digestible oligosaccharides has strong anti-inflammatory properties, possibly via the induction of a regulatory T cell response, resulting in reduced airway remodeling and, therefore, may be beneficial in the treatment of chronic inflammation in allergic asthma. Copyright © 2014 Elsevier B.V. All rights reserved.

Clonorchis sinensis-derived total protein attenuates airway inflammation in murine asthma model by inducing regulatory T cells and modulating dendritic cell functions

International Nuclear Information System (INIS)

Jeong, Young-Il; Kim, Seung Hyun; Ju, Jung Won; Cho, Shin Hyeong; Lee, Won Ja; Park, Jin Wook; Park, Yeong-Min; Lee, Sang Eun

2011-01-01

Highlights: → Treatment with Clonorchis sinensis-derived total protein attenuates OVA-induced airway inflammation and AHR to methacholine. → Induction of CD4 + CD25 + Foxp3 + T cells and IL-10 along with suppression of splenocyte proliferation by C. sinensis-derived total protein. → C. sinensis-derived total protein interferes with the expression of co-stimulatory molecules in DCs. -- Abstract: Asthma is characterized by Th2-mediated inflammation, resulting in airway hyperresponsiveness (AHR) through airway remodeling. Recent epidemiological and experimental reports have suggested an inverse relationship between the development of allergy and helminth infections. Infection by Clonorchis sinensis, a liver fluke that resides in the bile duct of humans, is endemic predominantly in Asia including Korea and China. Using a murine model for asthma, we investigated the effects of C. sinensis-derived total protein (Cs-TP) on allergen-induced airway inflammation and the mechanism underlying the protective effects of Cs-TP administration on asthma. Treatment with Cs-TP attenuated OVA-induced airway inflammation and methacholine-induced AHR, as well as eosinophilia development, lymphocyte infiltration into the lung, and goblet cell metaplasia. This protective effect of Cs-TP is associated with markedly reduced OVA-specific IgE and Th1/Th2 cytokine production. Moreover, Cs-TP increased the number of CD4 + CD25 + Foxp3 + regulatory T (Treg) cells as well as their suppressive activity. In fact, proliferation of OVA-restimulated splenocytes was suppressed significantly. Cs-TP also inhibited the expression of such co-stimulatory molecules as CD80, CD86, and CD40 in LPS- or OVA-stimulated dendritic cells (DCs), suggesting that Cs-TP could interfere with the capacity of airway DCs to prime naive T cells. These data demonstrate the capacity of C. sinensis to ameliorate allergic asthma and broaden our understanding of the paradoxical relationship between the allergic immune

Picroside II Attenuates Airway Inflammation by Downregulating the Transcription Factor GATA3 and Th2-Related Cytokines in a Mouse Model of HDM-Induced Allergic Asthma.

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Jin Choi

Full Text Available Picroside II isolated from Pseudolysimachion rotundum var. subintegrum has been used as traditional medicine to treat inflammatory diseases. In this study, we assessed whether picroside II has inhibitory effects on airway inflammation in a mouse model of house dust mite (HDM-induced asthma. In the HDM-induced asthmatic model, picroside II significantly reduced inflammatory cell counts in the bronchoalveolar lavage fluid (BALF, the levels of total immunoglobulin (Ig E and HDM-specific IgE and IgG1 in serum, airway inflammation, and mucus hypersecretion in the lung tissues. ELISA analysis showed that picroside II down-regulated the levels of Th2-related cytokines (including IL-4, IL-5, and IL-13 and asthma-related mediators, but it up-regulated Th1-related cytokine, IFNγ in BALF. Picroside II also inhibited the expression of Th2 type cytokine genes and the transcription factor GATA3 in the lung tissues of HDM-induced mice. Finally, we demonstrated that picroside II significantly decreased the expression of GATA3 and Th2 cytokines in developing Th2 cells, consistent with in vivo results. Taken together, these results indicate that picroside II has protective effects on allergic asthma by reducing GATA3 expression and Th2 cytokine bias.

Regulation of nasal airway homeostasis and inflammation in mice by SHP-1 and Th2/Th1 signaling pathways.

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Seok Hyun Cho

Full Text Available Allergic rhinitis is a chronic inflammatory disease orchestrated by Th2 lymphocytes. Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1 is known to be a negative regulator in the IL-4α/STAT-6 signaling pathway of the lung. However, the role of SHP-1 enzyme and its functional relationship with Th2 and Th1 cytokines are not known in the nasal airway. In this study, we aimed to study the nasal inflammation as a result of SHP-1 deficiency in viable motheaten (mev mice and to investigate the molecular mechanisms involved. Cytology, histology, and expression of cytokines and chemokines were analyzed to define the nature of the nasal inflammation. Targeted gene depletion of Th1 (IFN-γ and Th2 (IL-4 and IL-13 cytokines was used to identify the critical pathways involved. Matrix metalloproteinases (MMPs were studied to demonstrate the clearance mechanism of recruited inflammatory cells into the nasal airway. We showed here that mev mice had a spontaneous allergic rhinitis-like inflammation with eosinophilia, mucus metaplasia, up-regulation of Th2 cytokines (IL-4 and IL-13, chemokines (eotaxin, and MMPs. All of these inflammatory mediators were clearly counter-regulated by Th2 and Th1 cytokines. Deletion of IFN-γ gene induced a strong Th2-skewed inflammation with transepithelial migration of the inflammatory cells. These findings suggest that SHP-1 enzyme and Th2/Th1 paradigm may play a critical role in the maintenance of nasal immune homeostasis and in the regulation of allergic rhinitis.

Gelam honey attenuates ovalbumin-induced airway inflammation in a mice model of allergic asthma

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Nur Salme Suhana Shamshuddin

2018-01-01

Full Text Available Allergic asthma is a chronic inflammatory disorder of the pulmonary airways. Gelam honey has been proven to possess anti-inflammatory property with great potential to treat an inflammatory condition. However, the effect of ingestion of Gelam honey on allergic asthma has never been studied. This study aimed to investigate the efficacy of Gelam honey on the histopathological changes in the lungs of a mice model of allergic asthma. Forty-two Balb/c mice were divided into seven groups: control, I, II, III, IV, V and VI group. All groups except the control were sensitized and challenged with ovalbumin. Mice in groups I, II, III, IV, and V were given honey at a dose of 10% (v/v, 40% (v/v and 80% (v/v, dexamethasone 3 mg/kg, and phosphate buffered saline (vehicle respectively, orally once a day for 5 days of the challenged period. Mice were sacrificed 24 h after the last OVA challenged and the lungs were evaluated for histopathological changes by light microscopy. All histopathological parameters such as epithelium thickness, the number of mast cell and mucus expression in Group III significantly improved when compared to Group VI except for subepithelial smooth muscle thickness (p < 0.05. In comparing Group III and IV, all the improvements in histopathological parameters were similar. Also, Gelam honey showed a significant (p < 0.05 reduction in inflammatory cell infiltration and beta-hexosaminidase level in bronchoalveolar lavage fluid. In conclusion, we demonstrated that administration of high concentration of Gelam honey alleviates the histopathological changes of mice model of allergic asthma.

Differential activation of airway eosinophils induces IL-13-mediated allergic Th2 pulmonary responses in mice.

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Jacobsen, E A; Doyle, A D; Colbert, D C; Zellner, K R; Protheroe, C A; LeSuer, W E; Lee, N A; Lee, J J

2015-09-01

Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Wild-type or cytokine-deficient (IL-13(-/-) or IL-4(-/-) ) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophil deficient mice, which induced no immune/inflammatory changes either in the lung or in the lung draining lymph nodes (LDLN), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLN. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4(+) T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4, and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4(+) T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13, whereas IL-4 expression by eosinophils had no significant role. The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Differential Activation of Airway Eosinophils Induces IL-13 Mediated Allergic Th2 Pulmonary Responses in Mice

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Jacobsen, EA; Doyle, AD; Colbert, DC; Zellner, KR; Protheroe, CA; LeSuer, WE; Lee, NA.; Lee, JJ

2015-01-01

Background Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Methods Wild type or cytokine deficient (IL-13−/− or IL-4−/−) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. Results In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophildeficient mice, which induced no immune/inflammatory changes either in the lung or lung draining lymph nodes (LDLNs), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLNs. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4+ T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4 and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4+ T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13 whereas IL-4 expression by eosinophils had no significant role. Conclusion The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. PMID:26009788

Peripherally Generated Foxp3+ Regulatory T Cells Mediate the Immunomodulatory Effects of IVIg in Allergic Airways Disease.

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Massoud, Amir H; Kaufman, Gabriel N; Xue, Di; Béland, Marianne; Dembele, Marieme; Piccirillo, Ciriaco A; Mourad, Walid; Mazer, Bruce D

2017-04-01

IVIg is widely used as an immunomodulatory therapy. We have recently demonstrated that IVIg protects against airway hyperresponsiveness (AHR) and inflammation in mouse models of allergic airways disease (AAD), associated with induction of Foxp3 + regulatory T cells (Treg). Using mice carrying a DTR/EGFP transgene under the control of the Foxp3 promoter (DEREG mice), we demonstrate in this study that IVIg generates a de novo population of peripheral Treg (pTreg) in the absence of endogenous Treg. IVIg-generated pTreg were sufficient for inhibition of OVA-induced AHR in an Ag-driven murine model of AAD. In the absence of endogenous Treg, IVIg failed to confer protection against AHR and airway inflammation. Adoptive transfer of purified IVIg-generated pTreg prior to Ag challenge effectively prevented airway inflammation and AHR in an Ag-specific manner. Microarray gene expression profiling of IVIg-generated pTreg revealed upregulation of genes associated with cell cycle, chromatin, cytoskeleton/motility, immunity, and apoptosis. These data demonstrate the importance of Treg in regulating AAD and show that IVIg-generated pTreg are necessary and sufficient for inhibition of allergen-induced AAD. The ability of IVIg to generate pure populations of highly Ag-specific pTreg represents a new avenue to study pTreg, the cross-talk between humoral and cellular immunity, and regulation of the inflammatory response to Ags. Copyright © 2017 by The American Association of Immunologists, Inc.

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

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Chawes, Bo Lk

2011-01-01

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...... children may contribute to the discovery of new mechanisms involved in pathogenesis and help direct future research to develop correctly timed preventive measures as well as adequate monitoring and treatment of children with rhinitis. Asthma is a common comorbidity in subjects with allergic rhinitis...... understood and there is a paucity of data objectivizing this association in young children. The aim of this thesis was to describe pathology in the upper and lower airways in young children from the COPSAC birth cohort with investigator-diagnosed allergic- and non-allergic rhinitis. Nasal congestion is a key...

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

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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.

Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

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Högberg Thomas

2007-02-01

Full Text Available Abstract Background Mast cell-derived prostaglandin D2 (PGD2, may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2, a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology. Methods Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. Results TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia. Conclusion This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.

Ligation of TLR7 on CD19(+) CD1d(hi) B cells suppresses allergic lung inflammation via regulatory T cells.

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Khan, Adnan R; Amu, Sylvie; Saunders, Sean P; Hams, Emily; Blackshields, Gordon; Leonard, Martin O; Weaver, Casey T; Sparwasser, Tim; Sheils, Orla; Fallon, Padraic G

2015-06-01

B cells have been described as having the capacity to regulate cellular immune responses and suppress inflammatory processes. One such regulatory B-cell population is defined as IL-10-producing CD19(+) CD1d(hi) cells. Previous work has identified an expansion of these cells in mice infected with the helminth, Schistosoma mansoni. Here, microarray analysis of CD19(+) CD1d(hi) B cells from mice infected with S. mansoni demonstrated significantly increased Tlr7 expression, while CD19(+) CD1d(hi) B cells from uninfected mice also demonstrated elevated Tlr7 expression. Using IL-10 reporter, Il10(-/-) and Tlr7(-/-) mice, we formally demonstrate that TLR7 ligation of CD19(+) CD1d(hi) B cells increases their capacity to produce IL-10. In a mouse model of allergic lung inflammation, the adoptive transfer of TLR7-elicited CD19(+) CD1d(hi) B cells reduced airway inflammation and associated airway hyperresponsiveness. Using DEREG mice to deplete FoxP3(+) T regulatory cells in allergen-sensitized mice, we show that that TLR7-elicited CD19(+) CD1d(hi) B cells suppress airway hyperresponsiveness via a T regulatory cell dependent mechanism. These studies identify that TLR7 stimulation leads to the expansion of IL-10-producing CD19(+) CD1d(hi) B cells, which can suppress allergic lung inflammation via T regulatory cells. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Modulation of neurotrophin and neurotrophin receptor expression in nasal mucosa after nasal allergen provocation in allergic rhinitis

NARCIS (Netherlands)

Raap, U.; Fokkens, W.; Bruder, M.; Hoogsteden, H.; Kapp, A.; Braunstahl, G.-J.

2008-01-01

BACKGROUND: Patients with allergic rhinitis (AR) feature both allergic airway inflammation and a hyperresponsiveness to nonspecific stimuli which is partly neuronally controlled. Still, it is unclear whether or not neurotrophins are involved in airway pathophysiology of AR and in nasobronchial

Airway, responsiveness and inflammation in adolescent elite swimmers

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Pedersen, Lise; Lund, T.K.; Barnes, P.J.

2008-01-01

Background: Whereas increased airway hyperresponsiveness (AHR) and airway inflammation are well documented in adult elite athletes, it remains uncertain whether the same airway changes are present in adolescents involved in elite sport. Objective: To investigate airway responsiveness and airway....... There was no difference in FeNO, cellular composition of sputum, airway reactivity, or prevalence of having AHR to methacholine and/or EVH between swimmers with and without respiratory symptoms. Conclusion: Adolescent elite swimmers do not have significant signs of airway damage after only a few years of intense training...... and competition. This leads us to believe that elite swimmers do not have particularly susceptible airways when they take up competitive swimming when young, but that they develop respiratory symptoms, airway inflammation, and AHR during their swimming careers Udgivelsesdato: 2008/8...

DIESEL PARTICLE INSTILLATION ENHANCES INFLAMMATORY AND NEUROTROPHIN RESPONSES IN THE LUNGS OF ALLERGIC BALB/C MICE

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Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airways resistance and inflammation. Antibody blockade of NGF attenuates airways resistance associated with the allergen-specific airways responses in mice. ...

Clonorchis sinensis-derived total protein attenuates airway inflammation in murine asthma model by inducing regulatory T cells and modulating dendritic cell functions

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Jeong, Young-Il [Div. of Malaria and Parasitic Diseases, Korea Centers for Disease Control and Prevention, Osong (Korea, Republic of); Kim, Seung Hyun [Div. of AIDS, National Institute of Health, Korea Centers for Disease Control and Prevention, Osong (Korea, Republic of); Ju, Jung Won; Cho, Shin Hyeong; Lee, Won Ja [Div. of Malaria and Parasitic Diseases, Korea Centers for Disease Control and Prevention, Osong (Korea, Republic of); Park, Jin Wook; Park, Yeong-Min [Dept. of Microbiology and Immunology, College of Medicine, Pusan National University, Yang-San (Korea, Republic of); Lee, Sang Eun, E-mail: ondalgl@cdc.go.kr [Div. of Malaria and Parasitic Diseases, Korea Centers for Disease Control and Prevention, Osong (Korea, Republic of)

2011-04-22

Highlights: {yields} Treatment with Clonorchis sinensis-derived total protein attenuates OVA-induced airway inflammation and AHR to methacholine. {yields} Induction of CD4{sup +}CD25{sup +}Foxp3{sup +} T cells and IL-10 along with suppression of splenocyte proliferation by C. sinensis-derived total protein. {yields} C. sinensis-derived total protein interferes with the expression of co-stimulatory molecules in DCs. -- Abstract: Asthma is characterized by Th2-mediated inflammation, resulting in airway hyperresponsiveness (AHR) through airway remodeling. Recent epidemiological and experimental reports have suggested an inverse relationship between the development of allergy and helminth infections. Infection by Clonorchis sinensis, a liver fluke that resides in the bile duct of humans, is endemic predominantly in Asia including Korea and China. Using a murine model for asthma, we investigated the effects of C. sinensis-derived total protein (Cs-TP) on allergen-induced airway inflammation and the mechanism underlying the protective effects of Cs-TP administration on asthma. Treatment with Cs-TP attenuated OVA-induced airway inflammation and methacholine-induced AHR, as well as eosinophilia development, lymphocyte infiltration into the lung, and goblet cell metaplasia. This protective effect of Cs-TP is associated with markedly reduced OVA-specific IgE and Th1/Th2 cytokine production. Moreover, Cs-TP increased the number of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T (Treg) cells as well as their suppressive activity. In fact, proliferation of OVA-restimulated splenocytes was suppressed significantly. Cs-TP also inhibited the expression of such co-stimulatory molecules as CD80, CD86, and CD40 in LPS- or OVA-stimulated dendritic cells (DCs), suggesting that Cs-TP could interfere with the capacity of airway DCs to prime naive T cells. These data demonstrate the capacity of C. sinensis to ameliorate allergic asthma and broaden our understanding of the paradoxical

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.

Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome

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Sverrild, Asger; Kiilerich, Pia; Brejnrod, Asker Daniel

2017-01-01

BACKGROUND: Asthmatic patients have higher microbiome diversity and an altered composition, with more Proteobacteria and less Bacteroidetes compared with healthy control subjects. Studies comparing airway inflammation and the airway microbiome are sparse, especially in subjects not receiving anti......-inflammatory treatment. OBJECTIVE: We sought to describe the relationship between the airway microbiome and patterns of airway inflammation in steroid-free patients with asthma and healthy control subjects. METHODS: Bronchoalveolar lavage fluid was collected from 23 steroid-free nonsmoking patients with asthma and 10...... and AHR to mannitol but not airway neutrophilia. The overall composition of the airway microbiome of asthmatic patients with the lowest levels of eosinophils but not asthmatic patients with the highest levels of eosinophils deviated significantly from that of healthy subjects. Asthmatic patients...

Mangifera indica L. extract (Vimang) and mangiferin reduce the airway inflammation and Th2 cytokines in murine model of allergic asthma.

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Rivera, Dagmar García; Hernández, Ivones; Merino, Nelson; Luque, Yilian; Álvarez, Alina; Martín, Yanet; Amador, Aylin; Nuevas, Lauro; Delgado, René

2011-10-01

The aim was to study the effects of Mangifera indica extract and its major component mangiferin on lung inflammation response and Th2 cytokine production using a murine experimental model of allergic asthma. BALB/c mice were intraperitoneally sensitized with 10 µg of ovoalbumin (OVA) adsorbed on aluminium hydroxide on days 0, 7 and 14. Seven days after the last injection, the mice were challenged with 2% aerosolized OVA inhalation for 30 min beginning on day 21 and continuing until day 24. To evaluate the protective effect, mice were orally treated with M. indica extract (50, 100 or 250 mg/kg) or mangiferin (50 mg/kg) from days 0 to 24. Anti-OVA immunoglobulin E, interleukin (IL)-4 and IL-5 were determined by ELISA and lungs were analysed by histology. M. indica extract and mangiferin produced a marked reduction of airway inflammation around vessels and bronchi, inhibition of IL-4 and IL-5 cytokines in bronchoalveolar lavage fluid and lymphocyte culture supernatant, IgE levels and lymphocyte proliferation. This is the first pre-clinical report of the anti-inflammatory properties of M. indica extract and mangiferin in experimental asthma and it could be an important part of pre-clinical requirement necessary for its use to complement the treatment of this complex disease. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Relationship between airway pathophysiology and airway inflammation in older asthmatics

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Porsbjerg, Celeste M; Gibson, Peter G; Pretto, Jeffrey J

2013-01-01

-dose ratio (%fall in forced expiratory volume in 1 s (FEV1 )/mg saline). Airway closure was assessed during bronchoconstriction percent change in forced vital capacity (FVC)/percent change in FEV1 (i.e. Closing Index). Airway inflammation was assessed by induced sputum and exhaled nitric oxide (eNO). RESULTS...

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

International Nuclear Information System (INIS)

Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao; Karpe, Pinakin Arun; Malek, Vajir; Patel, Deep; Tikoo, Kulbhushan

2016-01-01

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 2 weeks. 48 h 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. - Highlights: • Diminazene aceturate (DIZE), an ACE2 activator prevents ovalbumin-induced asthma. • DIZE acted by upregulating ACE2, downregulating ACE1, MAPKs, markers of inflammation, apoptosis. • DIZE reduced airway inflammation, fibrosis, right ventricular hypertrophy and

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

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Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao; Karpe, Pinakin Arun; Malek, Vajir; Patel, Deep; Tikoo, Kulbhushan, E-mail: tikoo.k@gmail.com

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 2 weeks. 48 h 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. - Highlights: • Diminazene aceturate (DIZE), an ACE2 activator prevents ovalbumin-induced asthma. • DIZE acted by upregulating ACE2, downregulating ACE1, MAPKs, markers of inflammation, apoptosis. • DIZE reduced airway inflammation, fibrosis, right ventricular hypertrophy and

The development of allergic inflammation in a murine house dust mite asthma model is suppressed by synbiotic mixtures of non-digestible oligosaccharides and Bifidobacterium breve M-16V.

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Verheijden, K A T; Willemsen, L E M; Braber, S; Leusink-Muis, T; Jeurink, P V; Garssen, J; Kraneveld, A D; Folkerts, G

2016-04-01

The incidence and severity of allergic asthma is rising, and novel strategies to prevent or treat this disease are needed. This study investigated the effects of different mixtures of non-digestible oligosaccharides combined with Bifidobacterium breve M-16V (BB) on the development of allergic airway inflammation in an animal model for house dust mite (HDM)-induced allergic asthma. BALB/c mice were sensitized intranasally (i.n.) with HDM and subsequently challenged (i.n.) with PBS or HDM while being fed diets containing different oligosaccharide mixtures in combination with BB or an isocaloric identical control diet. Bronchoalveolar lavage fluid (BALF) inflammatory cell influx, chemokine and cytokine concentrations in lung homogenates and supernatants of ex vivo HDM-restimulated lung cells were analyzed. The HDM-induced influx of eosinophils and lymphocytes was reduced by the diet containing the short-chain and long-chain fructo-oligosaccharides and BB (FFBB). In addition to the HDM-induced cell influx, concentrations of IL-33, CCL17, CCL22, IL-6, IL-13 and IL-5 were increased in supernatants of lung homogenates or BALF and IL-4, IFN-γ and IL-10 were increased in restimulated lung cell suspensions of HDM-allergic mice. The diet containing FFBB reduced IL-6, IFN-γ, IL-4 and IL-10 concentrations, whereas the combination of galacto-oligosaccharides and long-chain fructo-oligosaccharides with BB was less potent in this model. These findings show that synbiotic dietary supplementation can affect respiratory allergic inflammation induced by HDM. The combination of FFBB was most effective in the prevention of HDM-induced airway inflammation in mice.

Sleep apnea is associated with bronchial inflammation and continuous positive airway pressure-induced airway hyperresponsiveness.

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Devouassoux, Gilles; Lévy, Patrick; Rossini, Eliane; Pin, Isabelle; Fior-Gozlan, Michèle; Henry, Mireille; Seigneurin, Daniel; Pépin, Jean-Louis

2007-03-01

Obstructive sleep apnea syndrome (OSA) is associated with systemic and upper airway inflammation. Pharyngeal inflammation has a potential role in upper airway collapse, whereas systemic inflammation relates to cardiovascular morbidity. However, the presence of an inflammatory involvement of lower airway has been poorly investigated. The aim of the study was to demonstrate an inflammatory process at the bronchial level in patients with OSA and to analyze effects of continuous positive airway pressure (CPAP) application and humidification on bronchial mucosa. The study was conducted by using sequential induced sputum for cell analysis and IL-8 production, nitric oxide exhalation measurement, and methacholine challenge before and after CPAP. Bronchial neutrophilia and a high IL-8 concentration were observed in untreated OSA compared with controls (75% +/- 20% vs 43% +/- 12%, P Obstructive sleep apnea syndrome is associated with bronchial inflammation. Our data demonstrate CPAP effect on the development of AHR, possibly facilitated by the pre-existing inflammation. Both issues should be evaluated during long-term CPAP use. Results showing a spontaneous bronchial inflammation in OSA and the development of a CPAP-related AHR require a long-term follow-up to evaluate consequences on chronic bronchial obstruction.

BLOCKADE OF TRKA OR P75 NEUROTROPHIN RECEPTORS ATTENUATES DIESEL PARTICULATE-INDUCED ENHANCEMENT OF ALLERGIC AIRWAYS RESPONSES IN BALB/C MICE

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Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airway resistance. Exposure to diesel exhaust particles (DEP) associated with the combustion of diesel fuel exacerbates allergic airways responses. We tested t...

The effect of body weight on distal airway function and airway inflammation.

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van de Kant, Kim D G; Paredi, Paolo; Meah, Sally; Kalsi, Harpal S; Barnes, Peter J; Usmani, Omar S

Obesity is a global health problem that adversely influences the respiratory system. We assessed the effects of body mass index (BMI) on distal airway function and airway inflammation. Impulse oscillometry (IOS) as a measure of distal airway function, together with spirometry, were assessed in adults with a range of different BMIs. Airway inflammation was assessed with the fraction of exhaled nitric oxide (FeNO) and participants exhaled at various exhalation flows to determine alveolar and bronchial NO. In total 34 subjects were enrolled in the study; 19 subjects had a normal BMI (18.50-24.99), whilst 15 subjects were overweight (BMI 25.00-29.99), or obese (BMI ≥30). All subjects had normal spirometry. However, IOS measures of airway resistance (R) at 5Hz, 20Hz and frequency dependence (R 5-20 ) were elevated in overweight/obese individuals, compared to subjects with a normal BMI (median (interquartile range)); 5Hz: 0.41 (0.37, 0.45) vs. 0.32 (0.30, 0.37)kPa/l/s; 20Hz: 0.34 (0.30, 0.37) vs. 0.30 (0.26, 0.33)kPa/l/s; R 5-20 : 0.06 (0.04, 0.11) vs. 0.03 (0.01, 0.05)kPa/l/s; plimitation) and FeNO inflammatory measures, did not differ between groups (p>0.05). Being overweight has significant effects on distal and central airway function as determined by IOS, which is not detected by spirometry. Obesity does not influence airway inflammation as measured by FeNO. IOS is a reliable technique to identify airway abnormalities in the presence of normal spirometry in overweight people. Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Allergen-specific subcutaneous immunotherapy in allergic asthma : immunologic mechanisms and improvement

NARCIS (Netherlands)

Taher, Yousef A.; Henricks, Paul A. J.; van Oosterhout, Antoon J. M.

2010-01-01

Allergic asthma is a disease characterized by persistent allergen-driven airway inflammation, remodeling, and airway hyperresponsiveness. CD4(+) T-cells, especially T-helper type 2 cells, play a critical role in orchestrating the disease process through the release of the cytokines IL-4, IL-5, and

Absence of the common gamma chain (γ(c)), a critical component of the Type I IL-4 receptor, increases the severity of allergic lung inflammation.

Science.gov (United States)

Dasgupta, Preeta; Qi, Xiulan; Smith, Elizabeth P; Keegan, Achsah D

2013-01-01

The T(H)2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma pathogenesis: IL-4 regulates T(H)2 cell differentiation, while IL-13 regulates airway hyperreactivity and mucus production. Aside from controlling T(H)2 differentiation, the unique contribution of IL-4 signaling via the Type I receptor in airway inflammation remains unclear. Therefore, we analyzed responses in mice deficient in gamma c (γ(c)) to elucidate the role of the Type I IL-4 receptor. OVA primed CD4⁺ OT-II T cells were adoptively transferred into RAG2⁻/⁻ and γ(c)⁻/⁻ mice and allergic lung disease was induced. Both γ(c)⁻/⁻ and γcxRAG2⁻/⁻ mice developed increased pulmonary inflammation and eosinophilia upon OVA challenge, compared to RAG2⁻/⁻ mice. Characteristic AAM proteins FIZZ1 and YM1 were expressed in lung epithelial cells in both mouse strains, but greater numbers of FIZZ1+ or YM1+ airways were present in γ(c)⁻/⁻ mice. Absence of γc in macrophages, however, resulted in reduced YM1 expression. We observed higher T(H)2 cytokine levels in the BAL and an altered DC phenotype in the γ(c)⁻/⁻ recipient mice suggesting the potential for dysregulated T cell and dendritic cell (DC) activation in the γ(c)-deficient environment. These results demonstrate that in absence of the Type I IL-4R, the Type II R can mediate allergic responses in the presence of T(H)2 effectors. However, the Type I R regulates AAM protein expression in macrophages.

Components of Streptococcus pneumoniae suppress allergic airways disease and NKT cells by inducing regulatory T cells.

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Thorburn, Alison N; Foster, Paul S; Gibson, Peter G; Hansbro, Philip M

2012-05-01

Asthma is an allergic airways disease (AAD) caused by dysregulated immune responses and characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). NKT cells have been shown to contribute to AHR in some mouse models. Conversely, regulatory T cells (Tregs) control aberrant immune responses and maintain homeostasis. Recent evidence suggests that Streptococcus pneumoniae induces Tregs that have potential to be harnessed therapeutically for asthma. In this study, mouse models of AAD were used to identify the S. pneumoniae components that have suppressive properties, and the mechanisms underlying suppression were investigated. We tested the suppressive capacity of type-3-polysaccharide (T3P), isolated cell walls, pneumolysoid (Ply) and CpG. When coadministered, T3P + Ply suppressed the development of: eosinophilic inflammation, Th2 cytokine release, mucus hypersecretion, and AHR. Importantly, T3P + Ply also attenuated features of AAD when administered during established disease. We show that NKT cells contributed to the development of AAD and also were suppressed by T3P + Ply treatment. Furthermore, adoptive transfer of NKT cells induced AHR, which also could be reversed by T3P + Ply. T3P + Ply-induced Tregs were essential for the suppression of NKT cells and AAD, which was demonstrated by Treg depletion. Collectively, our results show that the S. pneumoniae components T3P + Ply suppress AAD through the induction of Tregs that blocked the activity of NKT cells. These data suggest that S. pneumoniae components may have potential as a therapeutic strategy for the suppression of allergic asthma through the induction of Tregs and suppression of NKT cells.

Obesity promotes prolonged ovalbumin-induced airway inflammation modulating T helper type 1 (Th1), Th2 and Th17 immune responses in BALB/c mice.

Science.gov (United States)

Silva, F M C; Oliveira, E E; Gouveia, A C C; Brugiolo, A S S; Alves, C C; Correa, J O A; Gameiro, J; Mattes, J; Teixeira, H C; Ferreira, A P

2017-07-01

Clinical and epidemiological studies indicate that obesity affects the development and phenotype of asthma by inducing inflammatory mechanisms in addition to eosinophilic inflammation. The aim of this study was to assess the effect of obesity on allergic airway inflammation and T helper type 2 (Th2) immune responses using an experimental model of asthma in BALB/c mice. Mice fed a high-fat diet (HFD) for 10 weeks were sensitized and challenged with ovalbumin (OVA), and analyses were performed at 24 and 48 h after the last OVA challenge. Obesity induced an increase of inducible nitric oxide synthase (iNOS)-expressing macrophages and neutrophils which peaked at 48 h after the last OVA challenge, and was associated with higher levels of interleukin (IL)-4, IL-9, IL-17A, leptin and interferon (IFN)-γ in the lungs. Higher goblet cell hyperplasia was associated with elevated mast cell influx into the lungs and trachea in the obese allergic mice. In contrast, early eosinophil influx and lower levels of IL-25, thymic stromal lymphopoietin (TSLP), CCL11 and OVA-specific immunoglobulin (IgE) were observed in the obese allergic mice in comparison to non-obese allergic mice. Moreover, obese mice showed higher numbers of mast cells regardless of OVA challenge. These results indicate that obesity affects allergic airway inflammation through mechanisms involving mast cell influx and the release of TSLP and IL-25, which favoured a delayed immune response with an exacerbated Th1, Th2 and Th17 profile. In this scenario, an intense mixed inflammatory granulocyte influx, classically activated macrophage accumulation and intense mucus production may contribute to a refractory therapeutic response and exacerbate asthma severity. © 2017 British Society for Immunology.

Trichuris suis ova therapy for allergic rhinitis

DEFF Research Database (Denmark)

Bager, Peter; Arnved, John; Rønborg, Steen

2010-01-01

Parasitic helminth infections can protect against allergic airway inflammation in experimental models and have been associated with a reduced risk of atopy and a reduced course of asthma in some observational studies. Although no clinical evidence exists to support the use of helminth therapy...... for allergic disease, the helminth Trichuris suis has demonstrated efficacy in treatment of inflammatory bowel disease....

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

15-lipoxygenase metabolites play an important role in the development of a T-helper type 1 allergic inflammation induced by double-stranded RNA.

Science.gov (United States)

Jeon, S G; Moon, H-G; Kim, Y-S; Choi, J-P; Shin, T-S; Hong, S-W; Tae, Y-M; Kim, S-H; Zhu, Z; Gho, Y S; Kim, Y-K

2009-06-01

We recently demonstrated that the T-helper type 1 (Th1) immune response plays an important role in the development of non-eosinophilic inflammation induced by airway exposure of an allergen plus double-stranded RNA (dsRNA). However, the role of lipoxygenase (LO) metabolites in the development of Th1 inflammation is poorly understood. To evaluate the role of LO metabolites in the development of Th1 inflammation induced by sensitization with an allergen plus dsRNA. A Th2-allergic inflammation mouse model was created by an intraperitoneal injection of lipopolysaccharide-depleted ovalbumin (OVA, 75 microg) and alum (2 mg) twice, and the Th1 model was created by intranasal application of OVA (75 microg) and synthetic dsRNA [10 microg of poly(I : C)] four times, followed by an intranasal challenge with 50 microg of OVA four times. The role of LO metabolites was evaluated using two approaches: a transgenic approach using 5-LO(-/-) and 15-LO(-/-) mice, and a pharmacological approach using inhibitors of cysteinyl leucotriene receptor-1 (cysLTR1), LTB4 receptor (BLT1), and 15-LO. We found that the Th1-allergic inflammation induced by OVA+dsRNA sensitization was similar between 5-LO(-/-) and wild-type (WT) control mice, although Th2 inflammation induced by sensitization with OVA+alum was reduced in the former group. In addition, dsRNA-induced Th1 allergic inflammation, which is associated with down-regulation of 15-hydroxyeicosateraenoic acids production, was not affected by treatment with cysLTR1 or BLT1 inhibitors, whereas it was significantly lower in 12/15-LO(-/-) mice compared with WT control mice. Moreover, dsRNA-induced allergic inflammation and the recruitment of T cells following an allergen challenge were significantly inhibited by treatment with a specific 15-LO inhibitor (PD146176). 15-LO metabolites appear to be important mediators in the development of Th1-allergic inflammation induced by sensitization with an allergen plus dsRNA. Our findings suggest that the

Neutralisation of interleukin-13 in mice prevents airway pathology caused by chronic exposure to house dust mite.

Directory of Open Access Journals (Sweden)

Kate L Tomlinson

Full Text Available BACKGROUND: Repeated exposure to inhaled allergen can cause airway inflammation, remodeling and dysfunction that manifests as the symptoms of allergic asthma. We have investigated the role of the cytokine interleukin-13 (IL-13 in the generation and persistence of airway cellular inflammation, bronchial remodeling and deterioration in airway function in a model of allergic asthma caused by chronic exposure to the aeroallergen House Dust Mite (HDM. METHODOLOGY/PRINCIPAL FINDINGS: Mice were exposed to HDM via the intranasal route for 4 consecutive days per week for up to 8 consecutive weeks. Mice were treated either prophylactically or therapeutically with a potent neutralising anti-IL-13 monoclonal antibody (mAb administered subcutaneously (s.c.. Airway cellular inflammation was assessed by flow cytometry, peribronchial collagen deposition by histocytochemistry and airway hyperreactivity (AHR by invasive measurement of lung resistance (R(L and dynamic compliance (C(dyn. Both prophylactic and therapeutic treatment with an anti-IL-13 mAb significantly inhibited (P<0.05 the generation and maintenance of chronic HDM-induced airway cellular inflammation, peribronchial collagen deposition, epithelial goblet cell upregulation. AHR to inhaled methacholine was reversed by prophylactic but not therapeutic treatment with anti-IL-13 mAb. Both prophylactic and therapeutic treatment with anti-IL-13 mAb significantly reversed (P<0.05 the increase in baseline R(L and the decrease in baseline C(dyn caused by chronic exposure to inhaled HDM. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that in a model of allergic lung disease driven by chronic exposure to a clinically relevant aeroallergen, IL-13 plays a significant role in the generation and persistence of airway inflammation, remodeling and dysfunction.

Pulmonary allergic reactions impair systemic vascular relaxation in ragweed sensitive mice.

Science.gov (United States)

Hazarika, Surovi; Van Scott, Michael R; Lust, Robert M; Wingard, Christopher J

2010-01-01

Asthma is often associated with cardiovascular complications, and recent observations in animal models indicate that induction of pulmonary allergic inflammation increases susceptibility of the myocardium to ischemia and reperfusion injury. In this study, we used a murine model of allergen sensitization in which aspiration of allergen induces pulmonary and systemic inflammation, to test the hypothesis that pulmonary exposure to allergen alters vascular relaxation responses. BALB/C mice were sensitized by intraperitoneal injection of ragweed and challenged by intratracheal instillation of allergen. Airway hyperreactivity and pulmonary inflammation were confirmed, and endothelium-dependent and -independent reactivity of thoracic aorta rings were evaluated. Ragweed sensitization and challenge induced airway hyperreactivity to methacholine and pulmonary inflammation, but did not affect constrictor responses of the aortic rings to phenylephrine and K+ depolarization. In contrast, maximal relaxation of aortic rings to acetylcholine and sodium nitroprusside decreased from 87.6±3.9% and 97.7±1.2% to 32±4% and 51±6%, respectively (p<0.05). The sensitivity to acetylcholine was likewise reduced (EC₅₀=0.26±0.05 μM vs. 1.09±0.16 μM, p<0.001). The results demonstrate that induction of allergic pulmonary inflammation in mice depresses endothelium-dependent and -independent vascular relaxation, which can contribute to cardiovascular complications associated with allergic inflammation. Copyright © 2010 Elsevier Inc. All rights reserved.

Protective effects of tiotropium bromide in the progression of airway smooth muscle remodeling

NARCIS (Netherlands)

Gosens, Reinout; Bos, I.S.; Zaagsma, Hans; Meurs, Herman

2005-01-01

Rationale: Recent findings have demonstrated that muscarinic M-3 receptor stimulation enhances airway smooth muscle proliferation to peptide growth factors in vitro. Because both peptide growth factor expression and acetylcholine release are known to be augmented in allergic airway inflammation, it

Overexpression of dimethylarginine dimethylaminohydrolase 1 attenuates airway inflammation in a mouse model of asthma.

Directory of Open Access Journals (Sweden)

Kayla G Kinker

Full Text Available Levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of nitric oxide synthase, are increased in lung, sputum, exhaled breath condensate and plasma samples from asthma patients. ADMA is metabolized primarily by dimethylarginine dimethylaminohydrolase 1 (DDAH1 and DDAH2. We determined the effect of DDAH1 overexpression on development of allergic inflammation in a mouse model of asthma. The expression of DDAH1 and DDAH2 in mouse lungs was determined by RT-quantitative PCR (qPCR. ADMA levels in bronchoalveolar lavage fluid (BALF and serum samples were determined by mass spectrometry. Wild type and DDAH1-transgenic mice were intratracheally challenged with PBS or house dust mite (HDM. Airway inflammation was assessed by bronchoalveolar lavage (BAL total and differential cell counts. The levels of IgE and IgG1 in BALF and serum samples were determined by ELISA. Gene expression in lungs was determined by RNA-Seq and RT-qPCR. Our data showed that the expression of DDAH1 and DDAH2 was decreased in the lungs of mice following HDM exposure, which correlated with increased ADMA levels in BALF and serum. Transgenic overexpression of DDAH1 resulted in decreased BAL total cell and eosinophil numbers following HDM exposure. Total IgE levels in BALF and serum were decreased in HDM-exposed DDAH1-transgenic mice compared to HDM-exposed wild type mice. RNA-Seq results showed downregulation of genes in the inducible nitric oxide synthase (iNOS signaling pathway in PBS-treated DDAH1-transgenic mice versus PBS-treated wild type mice and downregulation of genes in IL-13/FOXA2 signaling pathway in HDM-treated DDAH1-transgenic mice versus HDM-treated wild type mice. Our findings suggest that decreased expression of DDAH1 and DDAH2 in the lungs may contribute to allergic asthma and overexpression of DDAH1 attenuates allergen-induced airway inflammation through modulation of Th2 responses.

Airway inflammation in patients affected by obstructive sleep apnea syndrome.

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Salerno, F G; Carpagnano, E; Guido, P; Bonsignore, M R; Roberti, A; Aliani, M; Vignola, A M; Spanevello, A

2004-01-01

Obstructive sleep apnea syndrome (OSAS) has been shown to be associated to upper airway inflammation. The object of the present study was to establish the presence of bronchial inflammation in OSAS subjects. In 16 subjects affected by OSAS, and in 14 healthy volunteers, airway inflammation was detected by the cellular analysis of the induced sputum. OSAS patients, as compared to control subjects, showed a higher percentage of neutrophils (66.7+/-18.9 vs. 25.8+/-15.6) (Pbronchial inflammation characterized by a significant increase in neutrophils.

Bilirubin nanoparticles ameliorate allergic lung inflammation in a mouse model of asthma.

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Kim, Dong Eon; Lee, Yonghyun; Kim, MinGyo; Lee, Soyoung; Jon, Sangyong; Lee, Seung-Hyo

2017-09-01

Although asthma, a chronic inflammatory airway disease, is relatively well-managed by inhaled corticosteroids, the side effects associated with the long-term use of these agents precipitate the need for alternative therapeutic options based on differing modes of action. Bilirubin, a potent endogenous antioxidant, and anti-inflammatory molecule have been shown to ameliorate asthmatic symptoms; however, its clinical translation has been limited owing to its water insolubility and associated potential toxicity. Here we report the first application of bilirubin-based nanoparticles (BRNPs) as a nanomedicine for the treatment of allergic lung inflammatory disease. BRNPs were prepared directly from self-assembly of PEGylated bilirubin in aqueous solution and had a hydrodynamic diameter of ∼100 nm. Because allergen-specific type 2 T-helper (Th2) cells play a key role in the pathogenesis and progression of allergic asthma, the effects of BRNPs on Th2 immune responses were investigated both in vivo and in vitro. BRNPs after intravenous injection (i.v.) showed much higher serum concentration and a longer circulation time of bilirubin than the intraperitoneal injection (i.p.) of BRNPs or unconjugated bilirubin (UCB). The anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Compared with UCB, treatment with BRNPs suppressed the symptoms of experimental allergic asthma and dramatically ameliorated Th2-related allergic lung inflammation. Consistent with these results, BRNPs caused a reduction of Th2 cell populations and the expression of related cytokines by antibody-stimulated CD4 + T cells in vitro. Therefore, our results establish BRNPs as an important immunomodulatory agent that may be useful as a therapeutic for allergic lung inflammatory disease and other immune-mediated disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

IL-18 Does not Increase Allergic Airway Disease in Mice When Produced by BCG

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L. Amniai

2007-01-01

These data show that IL-18 did not increase allergic airway responses in the context of the mycobacterial infection, and suggest that BCG-IL-18 and BCG are able to prevent the development of local Th2 responses and therefore inhibit allergen-induced airway responses even after restimulation.

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c.

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Liu, Gang; Cooley, Marion A; Nair, Prema M; Donovan, Chantal; Hsu, Alan C; Jarnicki, Andrew G; Haw, Tatt Jhong; Hansbro, Nicole G; Ge, Qi; Brown, Alexandra C; Tay, Hock; Foster, Paul S; Wark, Peter A; Horvat, Jay C; Bourke, Jane E; Grainge, Chris L; Argraves, W Scott; Oliver, Brian G; Knight, Darryl A; Burgess, Janette K; Hansbro, Philip M

2017-12-01

Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c -/- ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c -/- mice with AAD also had reduced numbers of α-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3-positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show

Airway inflammation in chronic obstructive pulmonary disease (COPD): a true paradox.

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Eapen, Mathew Suji; Myers, Stephen; Walters, Eugene Haydn; Sohal, Sukhwinder Singh

2017-10-01

Chronic obstructive pulmonary disease (COPD) is primarily an airway condition, which mainly affects cigarette smokers and presents with shortness of breath that is progressive and poorly reversible. In COPD research, there has been a long held belief that airway disease progression is due to inflammation. Although this may be true in the airway lumen with innate immunity activated by the effect of smoke or secondary to infection, the accurate picture of inflammatory cells in the airway wall, where the pathophysiological COPD remodeling occurs, is uncertain and debatable. Areas covered: The current review provides a comprehensive literature survey of the changes in the main inflammatory cells in human COPD patients and focuses on contrarian views that affect the prevailing dogma on inflammation. The review also delves into the role of oxidative stress and inflammasomes in modulating the immune response in COPD. Further, the effects of inflammation in affecting the epithelium, fibroblasts, and airway remodeling are discussed. Expert commentary: Inflammation as a driving force for airway wall damage and remodelling in early COPD is at the very least 'oversimplified' and is likely to be misleading. This has serious implications for rational thinking about the illness, including pathogenesis and designing therapy.

Allergic Inflammation Leads to Neuropathic Pain via Glial Cell Activation.

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Yamasaki, Ryo; Fujii, Takayuki; Wang, Bing; Masaki, Katsuhisa; Kido, Mizuho A; Yoshida, Mari; Matsushita, Takuya; Kira, Jun-Ichi

2016-11-23

Allergic and atopic disorders have increased over the past few decades and have been associated with neuropsychiatric conditions, such as autism spectrum disorder and asthmatic amyotrophy. Myelitis presenting with neuropathic pain can occur in patients with atopic disorder; however, the relationship between allergic inflammation and neuropathic pain, and the underlying mechanism, remains to be established. We studied whether allergic inflammation affects the spinal nociceptive system. We found that mice with asthma, atopic dermatitis, or atopic diathesis had widespread and significantly more activated microglia and astroglia in the spinal cord than those without atopy, and displayed tactile allodynia. Microarray analysis of isolated microglia revealed a dysregulated phenotype showing upregulation of M1 macrophage markers and downregulation of M2 markers in atopic mice. Among the cell surface protein genes, endothelin receptor type B (EDNRB) was most upregulated. Immunohistochemical analysis revealed that EDNRB expression was enhanced in microglia and astroglia, whereas endothelin-1, an EDNRB ligand, was increased in serum, lungs, and epidermis of atopic mice. No EDNRA expression was found in the spinal cord. Expression of FBJ murine osteosarcoma viral oncogene homolog B was significantly higher in the dorsal horn neurons of asthma mice than nonatopic mice. The EDNRB antagonist BQ788 abolished glial and neural activation and allodynia. We found increased serum endothelin-1 in atopic patients with myelitis and neuropathic pain, and activation of spinal microglia and astroglia with EDNRB upregulation in an autopsied case. These results suggest that allergic inflammation induces diffuse glial activation, influencing the nociceptive system via the EDNRB pathway. The prevalence of allergic disorders has markedly increased over the past few decades. Allergic disorders are associated with neuropsychiatric conditions; however, the relationship between allergic inflammation

Inhibition of pan neurotrophin receptor p75 attenuates diesel particulate-induced enhancement of allergic airway responses in C57/B16J mice.

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Farraj, Aimen K; Haykal-Coates, Najwa; Ledbetter, Allen D; Evansky, Paul A; Gavett, Stephen H

2006-06-01

Recent investigations have linked neurotrophins, including nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF), to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance in allergic mice. Diesel exhaust particle (DEP) exposure has been linked to asthma exacerbation in many cities with vehicular traffic congestion. We tested the hypothesis that DEP-induced enhancement of the hallmark features of allergic airway disease in a murine model is dependent on the function of the pan neurotrophin receptor p75. Ovalbumin (OVA)-sensitized C57B1/6J mice were intranasally instilled with an antibody against the p75 receptor or saline alone 1 h before OVA challenge. The mice were then exposed nose-only to the PM2.5 fraction of SRM2975 DEP or air alone for 5 h beginning 1 h after OVA challenge. Two days later, air-exposed OVA-allergic mice developed a small but insignificant increase in methacholine-induced airflow obstruction relative to air-exposed, vehicle-sensitized mice. DEP-exposed OVA-allergic mice had a significantly greater degree of airway obstruction than all other groups. Instillation of anti-p75 significantly attenuated the DEP-induced increase in airway obstruction in OVA-allergic mice to levels similar to non-sensitized mice. The DEP-induced exacerbation of allergic airway responses may, in part, be mediated by neurotrophins.

Critical role of aldehydes in cigarette smoke-induced acute airway inflammation

NARCIS (Netherlands)

van der Toorn, Marco; Slebos, Dirk-Jan; de Bruin, Harold G.; Gras, Renee; Rezayat, Delaram; Jorge, Lucie; Sandra, Koen; van Oosterhout, Antoon J. M.

2013-01-01

Background: Cigarette smoking (CS) is the most important risk factor for COPD, which is associated with neutrophilic airway inflammation. We hypothesize, that highly reactive aldehydes are critical for CS-induced neutrophilic airway inflammation. Methods: BALB/c mice were exposed to CS, water

A study on the effects of herbal acupuncture with Liriopis Tuber extract on airway inflammation in the mouse induced with bronchial asthma

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Young-Whan Park

2001-02-01

Full Text Available Objectives: Herbal acupuncture has been administered with Liriopis Tuber extract on the point of BL 13 (Pyesu to treat bronchial asthma and a certain degree of clinical benefits have been observed but lacking scientific substantiation. Methods: The present report describes on Th1 cytokine (Interleukin-2, Interferon-gamma, Th2 cytokine, (Interleukin-4, Interleukin-5, and IL-12 in bronchoalveolar lavage fluid (ELISA. Five groups were devised to study the effects of herbal acupuncture with Liriopis Tuber extract at BL 13 (Pyesu for airway inflammation in the mouse model with bronchial asthma. Results shows that herbal acupuncture with Liriopis Tuber extract at BL 13 increased Th1 cytokine (Interleukin-2 in allergic sensitization and allergic challenge, and decreased Th2 cytokine (Interleukin-2, Interleukin-5 in allergic sensitization.

Cyclooxygenase-2 Regulates Th17 Cell Differentiation during Allergic Lung Inflammation

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Li, Hong; Bradbury, J. Alyce; Dackor, Ryan T.; Edin, Matthew L.; Graves, Joan P.; DeGraff, Laura M.; Wang, Ping Ming; Bortner, Carl D.; Maruoka, Shuichiro; Lih, Fred B.; Cook, Donald N.; Tomer, Kenneth B.; Jetten, Anton M.; Zeldin, Darryl C.

2011-01-01

Rationale: Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation.

Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

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Uller, Lena; Mathiesen, Jesper Mosolff; Alenmyr, Lisa

2007-01-01

BACKGROUND: Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells......, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist...... in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. RESULTS: TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other...

ADAM10 mediates the house dust mite-induced release of chemokine ligand CCL20 by airway epithelium

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Post, S.; Rozeveld, D.; Jonker, M. R.; Bischoff, R.; van Oosterhout, A. J.; Heijink, I. H.

2015-01-01

Background: House dust mite (HDM) acts on the airway epithelium to induce airway inflammation in asthma. We previously showed that the ability of HDM to induce allergic sensitization in mice is related to airway epithelial CCL20 secretion. Objective: As a disintegrin and metalloprotease (ADAM)s have

Role of IRE1α/XBP-1 in Cystic Fibrosis Airway Inflammation

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Carla M. P. Ribeiro

2017-01-01

Full Text Available Cystic fibrosis (CF pulmonary disease is characterized by chronic airway infection and inflammation. The infectious and inflamed CF airway environment impacts on the innate defense of airway epithelia and airway macrophages. The CF airway milieu induces an adaptation in these cells characterized by increased basal inflammation and a robust inflammatory response to inflammatory mediators. Recent studies have indicated that these responses depend on activation of the unfolded protein response (UPR. This review discusses the contribution of airway epithelia and airway macrophages to CF airway inflammatory responses and specifically highlights the functional importance of the UPR pathway mediated by IRE1/XBP-1 in these processes. These findings suggest that targeting the IRE1/XBP-1 UPR pathway may be a therapeutic strategy for CF airway disease.

Effect of the Velvet Antler of Formosan Sambar Deer (Cervus unicolor swinhoei on the Prevention of an Allergic Airway Response in Mice

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Ching-Yun Kuo

2012-01-01

Full Text Available Two mouse models were used to assay the antiallergic effects of the velvet antler (VA of Formosan sambar deer (Cervus unicolor swinhoei in this study. The results using the ovalbumin- (OVA- sensitized mouse model showed that the levels of total IgE and OVA-specific IgE were reduced after VA powder was administrated for 4 weeks. In addition, the ex vivo results indicated that the secretion of T helper cell 1 (Th1, regulatory T (Treg, and Th17 cytokines by splenocytes was significantly increased (P<0.05 when VA powder was administered to the mice. Furthermore, OVA-allergic asthma mice that have been orally administrated with VA powder showed a strong inhibition of Th2 cytokine and proinflammatory cytokine production in bronchoalveolar fluid compared to control mice. An increase in the regulatory T-cell population of splenocytes in the allergic asthma mice after oral administration of VA was also observed. All the features of the asthmatic phenotype, including airway inflammation and the development of airway hyperresponsiveness, were reduced by treatment with VA. These findings support the hypothesis that oral feeding of VA may be an effective way of alleviating asthmatic symptoms in humans.

INHIBITION OF PAN NEUROTROPHIN RECEPTOR P75 ATTENUATES DIESEL PARTICULATE-INDUCED ENHANCEMENT OF ALLERGIC AIRWAY RESPONSES IN C57/BL6J MICE

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Recent investigations have linked neurotrophins including nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF) to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance in allergic mice. Diesel exhaust particle...

Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation

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Sverrild, Asger; Bergqvist, Anders; Baines, Katherine J

2016-01-01

BACKGROUND: Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway...... tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell-associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol. METHODS: Airway hyperresponsiveness to inhaled mannitol was measured in 23 non......-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell-associated genes was measured by real-time PCR. RESULTS...

Protective Effects of Intratracheally-Administered Bee Venom Phospholipase A2 on Ovalbumin-Induced Allergic Asthma in Mice

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Kyung-Hwa Jung

2016-09-01

Full Text Available Asthma is a common chronic disease characterized by bronchial inflammation, reversible airway obstruction, and airway hyperresponsiveness (AHR. Current therapeutic options for the management of asthma include inhaled corticosteroids and β2 agonists, which elicit harmful side effects. In the present study, we examined the capacity of phospholipase A2 (PLA2, one of the major components of bee venom (BV, to reduce airway inflammation and improve lung function in an experimental model of asthma. Allergic asthma was induced in female BALB/c mice by intraperitoneal administration of ovalbumin (OVA on days 0 and 14, followed by intratracheal challenge with 1% OVA six times between days 22 and 30. The infiltration of immune cells, such as Th2 cytokines in the lungs, and the lung histology, were assessed in the OVA-challenged mice in the presence and absence of an intratracheal administration of bvPLA2. We showed that the intratracheal administration of bvPLA2 markedly suppressed the OVA-induced allergic airway inflammation by reducing AHR, overall area of inflammation, and goblet cell hyperplasia. Furthermore, the suppression was associated with a significant decrease in the production of Th2 cytokines, such as IL-4, IL-5, and IL-13, and a reduction in the number of total cells, including eosinophils, macrophages, and neutrophils in the airway.

Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma.

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de Castro, Ligia Lins; Xisto, Debora Gonçalves; Kitoko, Jamil Zola; Cruz, Fernanda Ferreira; Olsen, Priscilla Christina; Redondo, Patricia Albuquerque Garcia; Ferreira, Tatiana Paula Teixeira; Weiss, Daniel Jay; Martins, Marco Aurélio; Morales, Marcelo Marcos; Rocco, Patricia Rieken Macedo

2017-06-24

Asthma is a chronic inflammatory disease that can be difficult to treat due to its complex pathophysiology. Most current drugs focus on controlling the inflammatory process, but are unable to revert the changes of tissue remodeling. Human mesenchymal stromal cells (MSCs) are effective at reducing inflammation and tissue remodeling; nevertheless, no study has evaluated the therapeutic effects of extracellular vesicles (EVs) obtained from human adipose tissue-derived MSCs (AD-MSC) on established airway remodeling in experimental allergic asthma. C57BL/6 female mice were sensitized and challenged with ovalbumin (OVA). Control (CTRL) animals received saline solution using the same protocol. One day after the last challenge, each group received saline, 10 5 human AD-MSCs, or EVs (released by 10 5  AD-MSCs). Seven days after treatment, animals were anesthetized for lung function assessment and subsequently euthanized. Bronchoalveolar lavage fluid (BALF), lungs, thymus, and mediastinal lymph nodes were harvested for analysis of inflammation. Collagen fiber content of airways and lung parenchyma were also evaluated. In OVA animals, AD-MSCs and EVs acted differently on static lung elastance and on BALF regulatory T cells, CD3 + CD4 + T cells, and pro-inflammatory mediators (interleukin [IL]-4, IL-5, IL-13, and eotaxin), but similarly reduced eosinophils in lung tissue, collagen fiber content in airways and lung parenchyma, levels of transforming growth factor-β in lung tissue, and CD3 + CD4 + T cell counts in the thymus. No significant changes were observed in total cell count or percentage of CD3 + CD4 + T cells in the mediastinal lymph nodes. In this immunocompetent mouse model of allergic asthma, human AD-MSCs and EVs effectively reduced eosinophil counts in lung tissue and BALF and modulated airway remodeling, but their effects on T cells differed in lung and thymus. EVs may hold promise for asthma; however, further studies are required to elucidate the different

Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life

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Lee, Debbie C P; Walker, Simone A; Byrne, Adam J; Gregory, Lisa G; Buckley, James; Bush, Andrew; Shaheen, Seif O; Saglani, Sejal; Lloyd, Clare M

2015-01-01

Background Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model. Methods Pregnant mice were administered paracetamol or saline by oral gavage from the day of mating throughout pregnancy and/or lactation. Subsequently, their pups were exposed to intranasal HDM or saline from day 3 of life for up to 6 weeks. Assessments of airway hyper-responsiveness, inflammation and remodelling were made at weaning (3 weeks) and 6 weeks of age. Results Maternal paracetamol exposure either during pregnancy and/or lactation did not affect development of AAD in offspring at weaning or at 6 weeks. There were no effects of maternal paracetamol at any time point on airway remodelling or IgE levels. Conclusions Maternal paracetamol did not enhance HDM induced AAD in offspring. Our mechanistic data do not support the hypothesis that prenatal paracetamol exposure increases the risk of childhood asthma. PMID:25841236

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.

Inducing maternal inflammation promotes leptin production in offspring but does not improve allergic symptoms in a mouse model of allergic rhinitis

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Atsuko Imai

2017-06-01

Full Text Available Aims: The intrauterine environment is considered to affect immunological development in fetus, leading to an increased risk of developing allergy. In particular, maternal lipopolysaccharides (LPS administration might regulate the development of allergic disease in offspring. Several studies have shown that being obese relates to a higher prevalence of allergic diseases compared to normal weight. The present study explored the effects of inducing maternal inflammation with LPS before pregnancy on body weight, physical composition including body fat, adipokine production, and pathology of allergic rhinitis in offspring. Main methods: Female mice received a single intraperitoneal injection of LPS (2 μg/g BW. After 5 days of LPS administration, female mice were mated with males, and experimental allergic rhinitis was induced in female offspring. Immunization and nasal challenge with ovalbumin (OVA were performed at 7 and 8 weeks of age. Allergic rhinitis-like symptoms, OVA-specific IgE and adipokines in sera, body weight, fat pad weight, and cytokine production by splenocytes in these 9-week-old offspring. Key findings: Maternal LPS administration results in a significant increase in body weight, visceral fat accumulation, and serum leptin concentration, and the dominance of Th1 in Th balance. Nevertheless, there was no statistical difference in OVA-specific IgE titer and allergic-like symptoms between the groups. Significance: In conclusion, maternal LPS promoted leptin production and altered Th balance in mice offspring, but not improved allergic symptoms in a mouse model of allergic rhinitis. It might suggest that inflammation during pregnancy plays a role in the adipose tissue function which could diversely influence allergic inflammation in offspring. Keywords: Immunology, Metabolism, Nutrition, Health Sciences

The role of heparanase in pulmonary cell recruitment in response to an allergic but not non-allergic stimulus.

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Abigail Morris

Full Text Available Heparanase is an endo-β-glucuronidase that specifically cleaves heparan sulfate proteoglycans in the extracellular matrix. Expression of this enzyme is increased in several pathological conditions including inflammation. We have investigated the role of heparanase in pulmonary inflammation in the context of allergic and non-allergic pulmonary cell recruitment using heparanase knockout (Hpa-/- mice as a model. Following local delivery of LPS or zymosan, no significant difference was found in the recruitment of neutrophils to the lung between Hpa-/- and wild type (WT control. Similarly neutrophil recruitment was not inhibited in WT mice treated with a heparanase inhibitor. However, in allergic inflammatory models, Hpa-/- mice displayed a significantly reduced eosinophil (but not neutrophil recruitment to the airways and this was also associated with a reduction in allergen-induced bronchial hyperresponsiveness, indicating that heparanase expression is associated with allergic reactions. This was further demonstrated by pharmacological treatment with a heparanase inhibitor in the WT allergic mice. Examination of lung specimens from patients with different severity of chronic obstructive pulmonary disease (COPD found increased heparanase expression. Thus, it is established that heparanase contributes to allergen-induced eosinophil recruitment to the lung and could provide a novel therapeutic target for the development of anti-inflammatory drugs for the treatment of asthma and other allergic diseases.

Assessment of sensitization to insect aeroallergens among patients with allergic rhinitis in Yazd City, Iran.

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Mohammad Hassan Bemanian; Narges Alizadeh Korkinejad; Shima Shirkhoda; Mohammad Nabavi; Zahra Pourpak

2012-01-01

The  frequency of  allergic diseases such  as allergic rhinitis is considerable in general population. Insect aeroallergens are important allergens which can induce airway inflammation. The aim of this study was to determine the prevalence of sensitization to insect aeroallergens in allergic rhinitis patients in Yazd as a desert city in Iran.A cross-sectional study was undertaken on 95 allergic rhinitis patients who were referred to allergy clinic of Yazd city. Skin prick tests (SPT) by stand...

Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations.

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Edith T Zemanick

Full Text Available Pulmonary exacerbations (PEx, frequently associated with airway infection and inflammation, are the leading cause of morbidity in cystic fibrosis (CF. Molecular microbiologic approaches detect complex microbiota from CF airway samples taken during PEx. The relationship between airway microbiota, inflammation, and lung function during CF PEx is not well understood.To determine the relationships between airway microbiota, inflammation, and lung function in CF subjects treated for PEx.Expectorated sputum and blood were collected and lung function testing performed in CF subjects during early (0-3d. and late treatment (>7d. for PEx. Sputum was analyzed by culture, pyrosequencing of 16S rRNA amplicons, and quantitative PCR for total and specific bacteria. Sputum IL-8 and neutrophil elastase (NE; and circulating C-reactive protein (CRP were measured.Thirty-seven sputum samples were collected from 21 CF subjects. At early treatment, lower diversity was associated with high relative abundance (RA of Pseudomonas (r = -0.67, p<0.001, decreased FEV(1% predicted (r = 0.49, p = 0.03 and increased CRP (r = -0.58, p = 0.01. In contrast to Pseudomonas, obligate and facultative anaerobic genera were associated with less inflammation and higher FEV₁. With treatment, Pseudomonas RA and P. aeruginosa by qPCR decreased while anaerobic genera showed marked variability in response. Change in RA of Prevotella was associated with more variability in FEV₁ response to treatment than Pseudomonas or Staphylococcus.Anaerobes identified from sputum by sequencing are associated with less inflammation and higher lung function compared to Pseudomonas at early exacerbation. CF PEx treatment results in variable changes of anaerobic genera suggesting the need for larger studies particularly of patients without traditional CF pathogens.

Role of airway epithelial barrier dysfunction in pathogenesis of asthma.

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Gon, Yasuhiro; Hashimoto, Shu

2018-01-01

Bronchial asthma is characterized by persistent cough, increased sputum, and repeated wheezing. The pathophysiology underlying these symptoms is the hyper-responsiveness of the airway along with chronic airway inflammation. Repeated injury, repair, and regeneration of the airway epithelium following exposure to environmental factors and inflammation results in histological changes and functional abnormalities in the airway mucosal epithelium; such changes are believed to have a significant association with the pathophysiology of asthma. Damage to the barrier functions of the airway epithelium enhances mucosal permeability of foreign substances in the airway epithelium of patients with asthma. Thus, epithelial barrier fragility is closely involved in releasing epithelial cytokines (e.g., TSLP, IL-25, and IL-33) because of the activation of airway epithelial cells, dendritic cells, and innate group 2 innate lymphoid cells (ILC2). Functional abnormalities of the airway epithelial cells along with the activation of dendritic cells, Th2 cells, and ILC2 form a single immunopathological unit that is considered to cause allergic airway inflammation. Here we use the latest published literature to discuss the potential pathological mechanisms regarding the onset and progressive severity of asthma with regard to the disruption of the airway epithelial function. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

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

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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.

IL-18 Does not Increase Allergic Airway Disease in Mice When Produced by BCG

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Amniai, L.; Biet, F.; Marquillies, P.; Locht, C.; Pestel, J.; Tonnel, A.-B.; Duez, C.

2007-01-01

Whilst BCG inhibits allergic airway responses in murine models, IL-18 has adversary effects depending on its environment. We therefore constructed a BCG strain producing murine IL-18 (BCG-IL-18) and evaluated its efficiency to prevent an asthma-like reaction in mice. BALB/cByJ mice were sensitized (day (D) 1 and D10) by intraperitoneal injection of ovalbumin (OVA)-alum and primary (D20–22) and secondary (D62, 63) challenged with OVA aerosols. BCG or BCG-IL-18 were intraperitonealy administered 1 hour before each immunization (D1 and D10). BCG-IL-18 and BCG were shown to similarly inhibit the development of AHR, mucus production, eosinophil influx, and local Th2 cytokine production in BAL, both after the primary and secondary challenge. These data show that IL-18 did not increase allergic airway responses in the context of the mycobacterial infection, and suggest that BCG-IL-18 and BCG are able to prevent the development of local Th2 responses and therefore inhibit allergen-induced airway responses even after restimulation. PMID:18299704

Relationship between airway colonization, inflammation and exacerbation frequency in COPD.

Science.gov (United States)

Tumkaya, Munir; Atis, Sibel; Ozge, Cengiz; Delialioglu, Nuran; Polat, Gurbuz; Kanik, Arzu

2007-04-01

To evaluate bacterial colonization and the airway inflammatory response, and its relationship to the frequency of exacerbation in patients with stable chronic obstructive pulmonary disease (COPD). Quantitative bacteriologic cultures, neutrophil elastase, myeloperoxidase (MPO), tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-8 were measured in bronchoalveoler lavage (BAL) in 39 patients with stable COPD [19 with frequent exacerbation (> or = 3/year), and 20 with infrequent] and in 18 healthy controls (10 smokers and 8 non-smokers). BAL revealed the microorganisms with potential pathogenicity above the established threshold (> or = 10(3)cfu/ml) in 68.4% of patients with frequent exacerbation, 55% of infrequent exacerbation, 40% of smokers and 12.5% of non-smokers controls (P=0.05). BAL MPO, IL-8 and TNF-alpha levels were found to be significantly higher in COPD as compared to controls (P=0.001). However, only IL-8 level was significantly higher in COPD patients with frequent exacerbation as compared to infrequent (P=0.001). Airway bacterial load correlated with levels of airway inflammation markers in COPD (P<0.05). The bacterial load and airway inflammation contributes to each other in stable COPD. However, there is a link only between interleukine (IL)-8 and frequent exacerbations. Clearly, the relationship between bacterial colonization, airway inflammation and frequent exacerbations is of major importance in understanding of the COPD pathogenesis.

25-Hydroxyvitamin D, IL-31, and IL-33 in Children with Allergic Disease of the Airways

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Anna Bonanno

2014-01-01

Full Text Available Low vitamin D is involved in allergic asthma and rhinitis. IL-31 and IL-33 correlate with Th2-associated cytokines in allergic disease. We investigated whether low vitamin D is linked with circulating IL-31 and IL-33 in children with allergic disease of the airways. 25-Hydroxyvitamin D [25(OH Vit D], IL-31, and IL-33 plasma levels were measured in 28 controls (HC, 11 allergic rhinitis (AR patients, and 35 allergic asthma with rhinitis (AAR patients. We found significant lower levels of 25(OH Vit D in AR and in AAR than in HC. IL-31 and IL-33 plasma levels significantly increased in AAR than HC. IL-31 and IL-33 positively correlated in AR and AAR. 25(OH Vit D deficient AAR had higher levels of blood eosinophils, exacerbations, disease duration, and total IgE than patients with insufficient or sufficient 25(OH Vit D. In AAR 25(OH Vit D levels inversely correlated with total allergen sIgE score and total atopy index. IL-31 and IL-33 did not correlate with 25(OH Vit D in AR and AAR. In conclusion, low levels of 25(OH Vit D might represent a risk factor for the development of concomitant asthma and rhinitis in children with allergic disease of the airways independently of IL-31/IL-33 Th2 activity.

Allergic sensitization enhances the contribution of Rho-kinase to airway smooth muscle contraction

NARCIS (Netherlands)

Schaafsma, D.; Gosens, Reinout; Bos, I.S.T.; Meurs, Herman; Zaagsma, Hans; Nelemans, Herman

2004-01-01

1 Repeated allergen challenge has been shown to increase the role of Rho-kinase in airway smooth muscle (ASM) contraction. We considered the possibility that active allergic sensitization by itself, that is, without subsequent allergen exposure, could be sufficient to enhance Rho-kinase-mediated ASM

Pulmonary Stress Induced by Hyperthermia: Role of Airway Sensory Nerves

Science.gov (United States)

2016-01-01

Myers AC, Kajekar R, Undem BJ. Allergic inflammation-induced neuropeptide production in rapidly adapting afferent nerves in guinea pig airways. Am J...induced neuro- peptide production in rapidly adapting afferent nerves in guinea pig airways. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L775–L781...co-localization of transient receptor po- tential vanilloid (trpv)1 and sensory neuropeptides in the guinea - pig respiratory system. Neuroscience

Allergic Conjunctivitis-induced Retinal Inflammation Promotes Myopia Progression

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Chang-Ching Wei

2018-02-01

Full Text Available Myopia is a highly prevalent eye disease. There is limited information suggesting a relationship between myopia and inflammation. We found children with allergic conjunctivitis (AC had the highest adjusted odds ratio (1.75, 95% confidence interval [CI], 1.72–1.77 for myopia among the four allergic diseases. A cohort study was conducted and confirmed that children with AC had a higher incidence and subsequent risk of myopia (hazard ratio 2.35, 95%CI 2.29–2.40 compared to those without AC. Lower refractive error and longer axial length were observed in an AC animal model. Myopia progression was enhanced by tumor necrosis factor (TNF-α or interleukin (IL-6 administration, two cytokines secreted by mast cell degranulation. The TNF-α or IL-6 weakened the tight junction formed by corneal epithelial (CEP cells and inflammatory cytokines across the layer of CEP cells, which increased the levels of TNF-α, IL-6, and IL-8 secreted by retinal pigment epithelial cells. The expression levels of TNF-α, IL-6, IL-8, monocyte chemoattractant protein-1, and nuclear factor kappa B were up-regulated in eyes with AC, whereas IL-10 and the inhibitor of kappa B were down-regulated. In conclusion, the experimental findings in mice corroborate the epidemiological data showing that allergic inflammation influences the development of myopia.

Airway Inflammation in Chronic Rhinosinusitis with Nasal Polyps and Asthma: The United Airways Concept Further Supported

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Håkansson, Kåre; Bachert, Claus; Konge, Lars

2015-01-01

Background It has been established that patients with chronic rhinosinusitis with nasal polyps (CRSwNP) often have co-existing asthma. Objective We aimed to test two hypotheses: (i) upper and lower airway inflammation in CRSwNP is uniform in agreement with the united airways concept; and (ii) bro...

Effects of concentrated ambient particles on normal and hypersecretory airways in rats.

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Harkema, Jack R; Keeler, Gerald; Wagner, James; Morishita, Masako; Timm, Edward; Hotchkiss, Jon; Marsik, Frank; Dvonch, Timothy; Kaminski, Norbert; Barr, Edward

2004-08-01

Epidemiological studies have reported that elevated levels of particulate air pollution in urban communities are associated with increases in attacks of asthma based on evidence from hospital admissions and emergency department visits. Principal pathologic features of chronic airway diseases, like asthma, are airway inflammation and mucous hypersecretion with excessive amounts of luminal mucus and increased numbers of mucus-secreting cells in regions of the respiratory tract that normally have few or no mucous cells (ie, mucous cell metaplasia). The overall goal of the present project was to understand the adverse effects of urban air fine particulate matter (PM2.5; pollutants in the outdoor air of a local Detroit community with a high incidence of childhood asthma; (2) determine the effects of this community-based PM2.5 on the airway epithelium in normal rats and rats compromised with preexisting hypersecretory airway diseases (ie, animal models of human allergic airway disease--asthma and chronic bronchitis); and (3) identify the chemical or physical components of PM2.5 that are responsible for PM2.5 -induced airway inflammation and epithelial alterations in these animal models. Two animal models of airway disease were used to examine the effects of PM2.5 exposure on preexisting hypersecretory airways: neutrophilic airway inflammation induced by endotoxin challenge in F344 rats and eosinophilic airway inflammation induced by ovalbumin (OVA) challenge in BN rats. A mobile air monitoring and exposure laboratory equipped with inhalation exposure chambers for animal toxicology studies, air pollution monitors, and particulate collection devices was used in this investigation. The mobile laboratory was parked in a community in southwestern Detroit during the summer months when particulate air pollution is usually high (July and September 2000). We monitored the outdoor air pollution in this community daily, and exposed normal and compromised rats to concentrated PM2

Intervention effect and dose-dependent response of tanreqing injection on airway inflammation in lipopolysaccharide-induced rats.

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Dong, Shoujin; Zhong, Yunqing; Yang, Kun; Xiong, Xiaoling; Mao, Bing

2013-08-01

To assess the effect of Tanreqing injection on airway inflammation in rats. A rat model of airway inflammation was generated with lipopolysaccharide (LPS). Tanreqing injection was given by intratracheal instillation, and bronchoalveolar lavage fluid (BALF) from the right lung was collected. BALF total cell and neutrophil counts were then determined. In addition, BALF levels of inflammatory cytokines interleukin-13, cytokine-induced neutrophil chemoat-tractant-1, and tumor necrosis factor-alpha were measured using enzyme linked immunosorbent assay. The middle lobe of the right lung was stained with hematoxylin-eosin and histological changes examined. LPS increased airway inflammation, decreased BALF inflammatory cell count, inflammatory cytokine levels, and suppressed leukocyte influx of the lung. The LPS-induced airway inflammation peaked at 24 h, decreased beginning at 48 h, and had decreased markedly by 96 h. Tanreqing injection contains anti-inflammatory properties, and inhibits airway inflammation in a dose-dependent manner.

Transient receptor potential ankyrin 1 channel localized to non-neuronal airway cells promotes non-neurogenic inflammation

DEFF Research Database (Denmark)

Nassini, Romina; Pedretti, Pamela; Moretto, Nadia

2012-01-01

The transient receptor potential ankyrin 1 (TRPA1) channel, localized to airway sensory nerves, has been proposed to mediate airway inflammation evoked by allergen and cigarette smoke (CS) in rodents, via a neurogenic mechanism. However the limited clinical evidence for the role of neurogenic...... inflammation in asthma or chronic obstructive pulmonary disease raises an alternative possibility that airway inflammation is promoted by non-neuronal TRPA1.By using Real-Time PCR and calcium imaging, we found that cultured human airway cells, including fibroblasts, epithelial and smooth muscle cells express...... functional TRPA1 channels. By using immunohistochemistry, TRPA1 staining was observed in airway epithelial and smooth muscle cells in sections taken from human airways and lung, and from airways and lung of wild-type, but not TRPA1-deficient mice. In cultured human airway epithelial and smooth muscle cells...

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......E-receptor) on the cell surface. These mediators also contribute to the late and chronic stages of allergic inflammation. Thus, the IgE/antigen response has been a major focus in the development of new drugs targeting mast cells. The essential role that stem cell factor (SCF) and its receptor, Kit, play in mast cell...... remains an attractive target for such pharmacological intervention. Mast cells are major players in the early phase of the allergic response since they generate and release a variety of inflammatory mediators following antigen-dependent aggregation of IgE-bound FcepsilonRI (high affinity Ig...

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

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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.

Lung sound analysis helps localize airway inflammation in patients with bronchial asthma

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Shimoda T

2017-03-01

Full Text Available Terufumi Shimoda,1 Yasushi Obase,2 Yukio Nagasaka,3 Hiroshi Nakano,1 Akiko Ishimatsu,1 Reiko Kishikawa,1 Tomoaki Iwanaga1 1Clinical Research Center, Fukuoka National Hospital, Fukuoka, 2Second Department of Internal Medicine, School of Medicine, Nagasaki University, Nagasaki, 3Kyoto Respiratory Center, Otowa Hospital, Kyoto, Japan Purpose: Airway inflammation can be detected by lung sound analysis (LSA at a single point in the posterior lower lung field. We performed LSA at 7 points to examine whether the technique could identify the location of airway inflammation in patients with asthma. Patients and methods: Breath sounds were recorded at 7 points on the body surface of 22 asthmatic subjects. Inspiration sound pressure level (ISPL, expiration sound pressure level (ESPL, and the expiration-to-inspiration sound pressure ratio (E/I were calculated in 6 frequency bands. The data were analyzed for potential correlation with spirometry, airway hyperresponsiveness (PC20, and fractional exhaled nitric oxide (FeNO. Results: The E/I data in the frequency range of 100–400 Hz (E/I low frequency [LF], E/I mid frequency [MF] were better correlated with the spirometry, PC20, and FeNO values than were the ISPL or ESPL data. The left anterior chest and left posterior lower recording positions were associated with the best correlations (forced expiratory volume in 1 second/forced vital capacity: r=–0.55 and r=–0.58; logPC20: r=–0.46 and r=–0.45; and FeNO: r=0.42 and r=0.46, respectively. The majority of asthmatic subjects with FeNO ≥70 ppb exhibited high E/I MF levels in all lung fields (excluding the trachea and V50%pred <80%, suggesting inflammation throughout the airway. Asthmatic subjects with FeNO <70 ppb showed high or low E/I MF levels depending on the recording position, indicating uneven airway inflammation. Conclusion: E/I LF and E/I MF are more useful LSA parameters for evaluating airway inflammation in bronchial asthma; 7-point lung

Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

International Nuclear Information System (INIS)

Schneider, Brent C.; Constant, Stephanie L.; Patierno, Steven R.; Jurjus, Rosalyn A.; Ceryak, Susan M.

2012-01-01

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

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

Preventative Effect of an Herbal Preparation (HemoHIM) on Development of Airway Inflammation in Mice via Modulation of Th1/2 Cells Differentiation

OpenAIRE

Kim, Jong-Jin; Cho, Hyun Wook; Park, Hae-Ran; Jung, Uhee; Jo, Sung-Kee; Yee, Sung-Tae

2013-01-01

HemoHIM, an herbal preparation of three edible herbs (Angelica gigas Nakai, Cnidium officinale Makino, Paeonia japonica Miyabe) is known to increase the Th1 immune response as well as reduce the allergic response in human mast cells. Here, our goal was to determine whether or not HemoHIM could induce Th1 cell differentiation as well as inhibit the development of airway inflammation. To study Th1/Th2 cell differentiation, naive CD4(+) T cells isolated from C57BL/6 mouse spleens were cultured w...

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

Science.gov (United States)

Pishdadian, Abbas; Varasteh, Abdol-Reza; Sankian, Mojtaba

2012-01-01

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. PMID:23209480

Effects of Ex Vivo y-Tocopherol on Airway Macrophage ...

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Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate y-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from nonsmoking healthy (n = 6)and mild house dust mite-sensitive allergic asthmatics (n =6) were treated ex vivo with GT (300 uM) or saline (control). Phagocytosis of opsonized zymosan A bioparticles (Saccharomyces cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (p < 0.05) internalization of attached zymosan bioparticles and decreased (p < 0.05) macrophage expression of CD206,CD36 and CD86 in allergic asthmatics but not in corntrols. Overall, GT caused down regulation of both innate and adaptive immune response elements, and atopic status appears to be an important factor. Recent studies on the effects of the fat-soluble steriod hormone vitamins D and E suggest that dietary suplementation with these vitamins may be helpful for the prevention or in the treatment of inflammatory and immune-mediated diseases, including atopic asthma.

EFFECT OF SHORT TERM DIESEL EXHAUST EXPOSURE ON NASAL RESPONSES TO INFLUENZA IN ALLERGIC RHINITICS.

Science.gov (United States)

Introduction: Recently published data suggest that diesel exhaust (DE) has special impact on allergic inflammation, suppressing Th1 and augmenting Th2 responses to allergen via oxidant stress effects on airway cells. Exposures to particulate air pollutants including DE are also a...

Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats.

Science.gov (United States)

Wang, T; Liu, Y; Chen, L; Wang, X; Hu, X-R; Feng, Y-L; Liu, D-S; Xu, D; Duan, Y-P; Lin, J; Ou, X-M; Wen, F-Q

2009-05-01

Airway inflammation with mucus overproduction is a distinguishing pathophysiological feature of many chronic respiratory diseases. Phosphodiesterase (PDE) inhibitors have shown anti-inflammatory properties. In the present study, the effect of sildenafil, a potent inhibitor of PDE5 that selectively degrades cyclic guanosine 3',5'-monophosphate (cGMP), on acrolein-induced inflammation and mucus production in rat airways was examined. Rats were exposed to acrolein for 14 and 28 days. Sildenafil or distilled saline was administered intragastrically prior to acrolein exposure. Bronchoalveolar lavage fluid (BALF) was acquired for cell count and the detection of pro-inflammatory cytokine levels. Lung tissue was examined for cGMP content, nitric oxide (NO)-metabolite levels, histopathological lesion scores, goblet cell metaplasia and mucin production. The results suggested that sildenafil pretreatment reversed the significant decline of cGMP content in rat lungs induced by acrolein exposure, and suppressed the increase of lung NO metabolites, the BALF leukocyte influx and pro-inflammatory cytokine release. Moreover, sildenafil pretreatment reduced acrolein-induced Muc5ac mucin synthesis at both mRNA and protein levels, and attenuated airway inflammation, as well as epithelial hyperplasia and metaplasia. In conclusion, sildenafil could attenuate airway inflammation and mucus production in the rat model, possibly through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, and, thus, might have a therapeutic potential for chronic airway diseases.

Role of lysophosphatidic acid receptor LPA2 in the development of allergic airway inflammation in a murine model of asthma

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Chun Jerold

2009-11-01

Full Text Available Abstract Background Lysophosphatidic acid (LPA plays a critical role in airway inflammation through G protein-coupled LPA receptors (LPA1-3. We have demonstrated that LPA induced cytokine and lipid mediator release in human bronchial epithelial cells. Here we provide evidence for the role of LPA and LPA receptors in Th2-dominant airway inflammation. Methods Wild type, LPA1 heterozygous knockout mice (LPA1+/-, and LPA2 heterozygous knockout mice (LPA2+/- were sensitized with inactivated Schistosoma mansoni eggs and local antigenic challenge with Schistosoma mansoni soluble egg Ag (SEA in the lungs. Bronchoalveolar larvage (BAL fluids and lung tissues were collected for analysis of inflammatory responses. Further, tracheal epithelial cells were isolated and challenged with LPA. Results BAL fluids from Schistosoma mansoni egg-sensitized and challenged wild type mice (4 days of challenge showed increase of LPA level (~2.8 fold, compared to control mice. LPA2+/- mice, but not LPA1+/- mice, exposed to Schistosoma mansoni egg revealed significantly reduced cell numbers and eosinophils in BAL fluids, compared to challenged wild type mice. Both LPA2+/- and LPA1+/- mice showed decreases in bronchial goblet cells. LPA2+/- mice, but not LPA1+/- mice showed the decreases in prostaglandin E2 (PGE2 and LPA levels in BAL fluids after SEA challenge. The PGE2 production by LPA was reduced in isolated tracheal epithelial cells from LPA2+/- mice. These results suggest that LPA and LPA receptors are involved in Schistosoma mansoni egg-mediated inflammation and further studies are proposed to understand the role of LPA and LPA receptors in the inflammatory process.

Eicosapentaenoic Acid Enhances the Effects of Mesenchymal Stromal Cell Therapy in Experimental Allergic Asthma

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Soraia Carvalho Abreu

2018-05-01

Full Text Available Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF, thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D1 (RvD1, prostaglandin E2 (PGE2, interleukin (IL-10, and transforming growth factor (TGF-β1 by MSCs were evaluated in vitro. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes, and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD1, PGE2, IL-10, and TGF-β, modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel

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.

2013-01-01

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.—Liu, B., Escalera, J., Balakrishna, S., Fan, L., Caceres, A. I., Robinson, E., Sui, A., McKay, M. C., McAlexander, M. A., Herrick, C. A., Jordt, S. E. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. PMID:23722916

Role of IL-4 receptor α-positive CD4(+) T cells in chronic airway hyperresponsiveness.

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Kirstein, Frank; Nieuwenhuizen, Natalie E; Jayakumar, Jaisubash; Horsnell, William G C; Brombacher, Frank

2016-06-01

TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responses in vivo remain incompletely understood. This study defines the requirements for IL-4Rα-responsive CD4(+) T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease. Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4(+) T cell-specific IL-4Rα-deficient BALB/c mice (Lck(cre)IL-4Rα(-/lox)) and respective control mice in the presence or absence of IL-4 or IL-13. During acute allergic airway disease, IL-4 deficiency did not prevent the onset of TH2 immune responses and OVA-induced airway hyperresponsiveness or goblet cell hyperplasia, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. In contrast, deficiency of IL-13 prevented allergic asthma, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. Importantly, chronic allergic inflammation and airway hyperresponsiveness were dependent on IL-4Rα-responsive CD4(+) T cells. Deficiency in IL-4Rα-responsive CD4(+) T cells resulted in increased numbers of IL-17-producing T cells and, consequently, increased airway neutrophilia. IL-4-responsive T helper cells are dispensable for acute OVA-induced airway disease but crucial in maintaining chronic asthmatic pathology. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Eosinophils contribute to the resolution of lung-allergic responses following repeated allergen challenge.

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Takeda, Katsuyuki; Shiraishi, Yoshiki; Ashino, Shigeru; Han, Junyan; Jia, Yi; Wang, Meiqin; Lee, Nancy A; Lee, James J; Gelfand, Erwin W

2015-02-01

Eosinophils accumulate at the site of allergic inflammation and are critical effector cells in allergic diseases. Recent studies have also suggested a role for eosinophils in the resolution of inflammation. To determine the role of eosinophils in the resolution phase of the response to repeated allergen challenge. Eosinophil-deficient (PHIL) and wild-type (WT) littermates were sensitized and challenged to ovalbumin (OVA) 7 or 11 times. Airway inflammation, airway hyperresponsiveness (AHR) to inhaled methacholine, bronchoalveolar lavage (BAL) cytokine levels, and lung histology were monitored. Intracellular cytokine levels in BAL leukocytes were analyzed by flow cytometry. Groups of OVA-sensitized PHIL mice received bone marrow from WT or IL-10(-/-) donors 30 days before the OVA challenge. PHIL and WT mice developed similar levels of AHR and numbers of leukocytes and cytokine levels in BAL fluid after OVA sensitization and 7 airway challenges; no eosinophils were detected in the PHIL mice. Unlike WT mice, sensitized PHIL mice maintained AHR, lung inflammation, and increased levels of IL-4, IL-5, and IL-13 in BAL fluid after 11 challenges whereas IL-10 and TGF-β levels were decreased. Restoration of eosinophil numbers after injection of bone marrow from WT but not IL-10-deficient mice restored levels of IL-10 and TGF-β in BAL fluid as well as suppressed AHR and inflammation. Intracellular staining of BAL leukocytes revealed the capacity of eosinophils to produce IL-10. After repeated allergen challenge, eosinophils appeared not essential for the development of AHR and lung inflammation but contributed to the resolution of AHR and inflammation by producing IL-10. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Small airways dysfunction and neutrophilic inflammation in bronchial biopsies and BAL in COPD

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Lapperre, Thérèse S.; Willems, Luuk N. A.; Timens, Wim; Rabe, Klaus F.; Hiemstra, Pieter S.; Postma, Dirkje S.; Sterk, Peter J.

2007-01-01

BACKGROUND: The single-breath N(2) test (sbN(2)-test) is closely related to small airways pathology in resected lung specimens of smokers. We investigated whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, BAL,

Small airways dysfunction and neutrophilic inflammation in bronchial biopsies and BAL in COPD

NARCIS (Netherlands)

Lapperre, Therese S.; Willems, Luuk N. A.; Timens, Wim; Rabe, Klaus F.; Hiemstra, Pieter S.; Postma, Dirkje S.; Sterk, Peter J.

Background: The single-breath N-2 test (sbN(2)-test) is closely related to small airways pathology in resected lung specimens of smokers. We investigated whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, BAIL,

Elaeocarpusin Inhibits Mast Cell-Mediated Allergic Inflammation

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Min-Jong Kim

2018-06-01

Full Text Available Mast cells are major effector cells for allergic responses that act by releasing inflammatory mediators, such as histamine and pro-inflammatory cytokines. Accordingly, different strategies have been pursued to develop anti-allergic and anti-inflammatory candidates by regulating the function of mast cells. The purpose of this study was to determine the effectiveness of elaeocarpusin (EL on mast cell-mediated allergic inflammation. We isolated EL from Elaeocarpus sylvestris L. (Elaeocarpaceae, which is known to possess anti-inflammatory properties. For this study, various sources of mast cells and mouse anaphylaxis models were used. EL suppressed the induction of markers for mast cell degranulation, such as histamine and β-hexosaminidase, by reducing intracellular calcium levels. Expression of pro-inflammatory cytokines, such as tumor necrosis factor-α and IL-4, was significantly decreased in activated mast cells by EL. This inhibitory effect was related to inhibition of the phosphorylation of Fyn, Lyn, Syk, and Akt, and the nuclear translocation of nuclear factor-κB. To confirm the effect of EL in vivo, immunoglobulin E-mediated passive cutaneous anaphylaxis (PCA and ovalbumin-induced active systemic anaphylaxis (ASA models were induced. EL reduced the PCA reaction in a dose dependent manner. In addition, EL attenuated ASA reactions such as hypothemia, histamine release, and IgE production. Our results suggest that EL is a potential therapeutic candidate for allergic inflammatory diseases that acts via the inhibition of mast cell degranulation and expression of proinflammatory cytokines.

The role of chemokines and chemokine receptors in eosinophil activation during inflammatory allergic reactions

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Oliveira S.H.P.

2003-01-01

Full Text Available Chemokines are important chemotactic cytokines that play a fundamental role in the trafficking of leukocytes to sites of inflammation. They are also potent cell-activating factors, inducing cytokine and histamine release and free radical production, a fact that makes them particularly important in the pathogenesis of allergic inflammation. The action of chemokines is regulated at the level of agonist production and processing as well as at the level of receptor expression and coupling. Therefore, an analysis of the ligands must necessarily consider receptors. Eosinophils are target cells involved in the allergic inflammatory response since they are able to release a wide variety of mediators including CC and CXC chemokines and express their receptors. These mediators could damage the airway epithelial cells and might be important to stimulate other cells inducing an amplification of the allergic response. This review focuses on recently emerging data pertaining to the importance of chemokines and chemokine receptors in promoting eosinophil activation and migration during the allergic inflammatory process. The analysis of the function of eosinophils and their chemokine receptors during allergic inflammation might be a good approach to understanding the determinants of asthma severity and to developing novel therapies.

Noninvasive methods to measure airway inflammation: future considerations

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Magnussen, H.; Holz, O.; Sterk, P. J.; Hargreave, F. E.

2000-01-01

This last contribution to the series focuses on open questions regarding: 1) methodological issues; and 2) the potential clinical application of the noninvasive methods such as induced sputum and the analysis of exhaled air for the assessment of airway inflammation. In addition their potential

IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

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Toshifumi Tezuka

Full Text Available Plasminogen activator inhibitor (PAI-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp. IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.

IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

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Tezuka, Toshifumi; Ogawa, Hirohisa; Azuma, Masahiko; Goto, Hisatsugu; Uehara, Hisanori; Aono, Yoshinori; Hanibuchi, Masaki; Yamaguchi, Yoichi; Fujikawa, Tomoyuki; Itai, Akiko; Nishioka, Yasuhiko

2015-01-01

Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.

The TLR5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens

OpenAIRE

Wilson, Rhonda H.; Maruoka, Shuichiro; Whitehead, Gregory S.; Foley, Julie F.; Flake, Gordon P.; Sever, Michelle L.; Zeldin, Darryl C.; Kraft, Monica; Garantziotis, Stavros; Nakano, Hideki; Cook, Donald N.

2012-01-01

Allergic asthma is a complex disease characterized by eosinophilic pulmonary inflammation, mucus production and reversible airway obstruction 1 . Exposure to indoor allergens is a clear risk factor for asthma, but this disease is also associated with high household levels of total and Gram-negative bacteria 2 . The ability of bacterial products to act as adjuvants 3 suggests they might promote asthma by priming allergic sensitization to inhaled allergens. In support of this idea, house dust e...

Acrolein exposure suppresses antigen-induced pulmonary inflammation

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2013-01-01

Background Adverse health effects of tobacco smoke arise partly from its influence on innate and adaptive immune responses, leading to impaired innate immunity and host defense. The impact of smoking on allergic asthma remains unclear, with various reports demonstrating that cigarette smoke enhances asthma development but can also suppress allergic airway inflammation. Based on our previous findings that immunosuppressive effects of smoking may be largely attributed to one of its main reactive electrophiles, acrolein, we explored the impact of acrolein exposure in a mouse model of ovalbumin (OVA)-induced allergic asthma. Methods C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection with the adjuvant aluminum hydroxide on days 0 and 7, and challenged with aerosolized OVA on days 14–16. In some cases, mice were also exposed to 5 ppm acrolein vapor for 6 hrs/day on days 14–17. Lung tissues or brochoalveolar lavage fluids (BALF) were collected either 6 hrs after a single initial OVA challenge and/or acrolein exposure on day 14 or 48 hrs after the last OVA challenge, on day 18. Inflammatory cells and Th1/Th2 cytokine levels were measured in BALF, and lung tissue samples were collected for analysis of mucus and Th1/Th2 cytokine expression, determination of protein alkylation, cellular thiol status and transcription factor activity. Results Exposure to acrolein following OVA challenge of OVA-sensitized mice resulted in markedly attenuated allergic airway inflammation, demonstrated by decreased inflammatory cell infiltrates, mucus hyperplasia and Th2 cytokines. Acrolein exposure rapidly depleted lung tissue glutathione (GSH) levels, and induced activation of the Nrf2 pathway, indicated by accumulation of Nrf2, increased alkylation of Keap1, and induction of Nrf2-target genes such as HO-1. Additionally, analysis of inflammatory signaling pathways showed suppressed activation of NF-κB and marginally reduced activation of JNK in acrolein

An α4β1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice

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Kenyon, Nicholas J.; Liu, Ruiwu; O’Roark, Erin M.; Huang, Wenzhe; Peng, Li; Lam, Kit S.

2008-01-01

Inhibition of the α4 subunit of both the α4β1 and α4β7 integrins has shown promise in decreasing airway inflammation and airway hyperresponsiveness in various animal models. We hypothesized that a novel, high-affinity α4β1 antagonist (LLP2A) would decrease the migration of eosinophils to the lung and ameliorate the airway hyperresponsiveness in a mouse model of ovalbumin-induced airway inflammation. To test this hypothesis, we administered LLP2A, or scrambled LLP2A (a negative control), prior to exposure of sensitized BALB/c mice to ovalbumin aerosol. We can partially prevent, or reverse, the airway inflammatory response, but not airways hyperresponsiveness, by treatment of mice with LLP2A, a synthetic peptidomimetic α4β1 antagonist LLP2A. Specifically engineered, PEGylated (PEG) formulations of this antagonist further reduce the airway inflammatory response to ovalbumin lbumin, presumably by improving the circulating half-life of the drug. PMID:19103195

Airway function indicators and blood indicators in children with dust mite allergic rhinitis after sublingual immunotherapy

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Hua Xiang

2016-07-01

Full Text Available Objective: To evaluate the airway function indicators and blood indicators in children with dust mite allergic rhinitis after sublingual immunotherapy. Methods: A total of 68 children with dust mite allergic rhinitis treated in our hospital from November, 2012 to October, 2015 were selected as the research subjects and randomly divided into observation group 34 cases and control group 34 cases. The control group received clinical routine therapy for allergic rhinitis, the observation group received sublingual immunotherapy, and then differences in basic lung function indicator values, small airway function indicator values and levels of serum inflammatory factors as well as serum ECP, TARC, Eotaxin-2 and VCAM were compared between two groups after treatment. Results: The FVC, FEV1, PEF and FEV1/FVC values of the observation group after treatment were higher than those of the control group (P<0.05; the MMEF, MEF50% and MEF25% values of the observation group were higher than those of the control group, and the proportion of AHR was lower than that of the control group (P<0.05; the serum IL-4, IL-9, IL-12, IL-13 and IL-16 levels of the observation group after treatment were lower than those of the control group, and the IL-10 and IL-12 levels are higher than those of the control group (P<0.05; the serum ECP, TARC, Eotaxin-2 and VCAM levels of the observation group children after treatment were lower than those of the control group (P<0.05. Conclusions: Sublingual immunotherapy for children with dust mite allergic rhinitis can optimize the airway function, reduce the systemic inflammatory response and eventually improve the children’s overall state, and it’s has positive clinical significance.

The interplay between neuroendocrine activity and psychological stress-induced exacerbation of allergic asthma

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Tomomitsu Miyasaka

2018-01-01

Full Text Available Psychological stress is recognized as a key factor in the exacerbation of allergic asthma, whereby brain responses to stress act as immunomodulators for asthma. In particular, stress-induced enhanced type 2 T-helper (Th2-type lung inflammation is strongly associated with asthma pathogenesis. Psychological stress leads to eosinophilic airway inflammation through activation of the hypothalamic-pituitary-adrenal pathway and autonomic nervous system. This is followed by the secretion of stress hormones into the blood, including glucocorticoids, epinephrine, and norepinephrine, which enhance Th2 and type 17 T-helper (Th17-type asthma profiles in humans and rodents. Recent evidence has shown that a defect of the μ-opioid receptor in the brain along with a defect of the peripheral glucocorticoid receptor signaling completely disrupted stress-induced airway inflammation in mice. This suggests that the stress response facilitates events in the central nervous and endocrine systems, thus exacerbating asthma. In this review, we outline the recent findings on the interplay between stress and neuroendocrine activities followed by stress-induced enhanced Th2 and Th17 immune responses and attenuated regulatory T (Treg cell responses that are closely linked with asthma exacerbation. We will place a special focus on our own data that has emphasized the continuity from central sensing of psychological stress to enhanced eosinophilic airway inflammation. The mechanism that modulates psychological stress-induced exacerbation of allergic asthma through neuroendocrine activities is thought to involve a series of consecutive pathological events from the brain to the lung, which implies there to be a “neuropsychiatry phenotype” in asthma.

Oral fungal immunomodulatory protein-Flammulina velutipes has influence on pulmonary inflammatory process and potential treatment for allergic airway disease: A mouse model

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Po-Yu Chu

2017-06-01

Conclusion: Oral FIP-fve had an anti-inflammatory effect on the acute phase of the airway inflammatory process induced by HDM in the mouse model and might have a potentially therapeutic role for allergic airway diseases.

The TLR5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens

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Wilson, Rhonda H.; Maruoka, Shuichiro; Whitehead, Gregory S.; Foley, Julie F.; Flake, Gordon P.; Sever, Michelle L.; Zeldin, Darryl C.; Kraft, Monica; Garantziotis, Stavros; Nakano, Hideki; Cook, Donald N.

2012-01-01

Allergic asthma is a complex disease characterized by eosinophilic pulmonary inflammation, mucus production and reversible airway obstruction1. Exposure to indoor allergens is a clear risk factor for asthma, but this disease is also associated with high household levels of total and Gram-negative bacteria2. The ability of bacterial products to act as adjuvants3 suggests they might promote asthma by priming allergic sensitization to inhaled allergens. In support of this idea, house dust extracts (HDEs) can activate antigen presenting dendritic cells (DC) in vitro and promote allergic sensitization to inhaled innocuous proteinsin vivo4. It is unknown which microbial products provide most of the adjuvant activity in HDEs. A screen of microbial products for their adjuvant activity in the airway revealed that the bacterial protein, flagellin (FLA) stimulated strong allergic responses to an innocuous inhaled protein. Moreover, toll-like receptor (TLR)5, the mammalian receptor for FLA5,6, was required for priming strong allergic responses to natural indoor allergens present in HDEs. In addition, the incidence of human asthma was associated with high serum levels of FLA-specific antibodies. Together, these findings suggest that household FLA promotes the development of allergic asthma by TLR5-dependent priming of allergic responses to indoor allergens. PMID:23064463

Therapeutic potential of anti-IL-1β IgY in guinea pigs with allergic asthma induced by ovalbumin.

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Wei-xu, Hu; Qin, Xiang; Zhu, Wen; Yuan-yi, Chen; Li-feng, Zeng; Zhi-yong, Liu; Dan, He; Xiao-mu, Wu; Guo-zhu, Hu

2014-03-01

Interleukin-1 beta (IL-1β) plays pivotal roles in the progression of allergic airway inflammation. This study aims to determine whether the blockade of IL-1β can inhibit airway inflammation in guinea pigs with allergic asthma induced by the inhalation of aerosolized ovalbumin (OVA). Healthy guinea pigs treated with saline were used as normal controls (group C). The guinea pigs with allergic asthma induced by the inhalation of aerosolized OVA were randomly divided into three groups: (1) the M group containing negative control animals treated with saline; (2) the Z1 group containing animals treated by the inhalation of atomized 0.1% anti-IL-1β immunoglobulin yolk (IgY); and (3) the Z2 group containing positive control animals that were treated with budesonide. The inflammatory cells in the peripheral blood (PB) and bronchoalveolar lavage fluid (BALF) were evaluated using methylene blue and eosin staining. Cytokine concentrations were measured using an enzyme-linked immunosorbent assay. Pulmonary sections were examined using hematoxylin-eosin staining. Allergic inflammation and damage to the pulmonary tissues were decreased in the Z1 group compared to the M group. Eosinophils and neutrophils in the PB and BALF were significantly decreased in the Z1 group compared to the M group (Pguinea pigs with allergic asthma. The inhibitory activity may be due to the decrease in the numbers of eosinophils and neutrophils and the reduced levels of inflammatory cytokines and IgE in the PB and BALF. Copyright © 2013 Elsevier Ltd. All rights reserved.

Alveolar Macrophages Play a Key Role in Cockroach-Induced Allergic Inflammation via TNF-α Pathway

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Kim, Joo Young; Sohn, Jung Ho; Choi, Je-Min; Lee, Jae-Hyun; Hong, Chein-Soo; Lee, Joo-Shil; Park, Jung-Won

2012-01-01

The activity of the serine protease in the German cockroach allergen is important to the development of allergic disease. The protease-activated receptor (PAR)-2, which is expressed in numerous cell types in lung tissue, is known to mediate the cellular events caused by inhaled serine protease. Alveolar macrophages express PAR-2 and produce considerable amounts of tumor necrosis factor (TNF)-α. We determined whether the serine protease in German cockroach extract (GCE) enhances TNF-α production by alveolar macrophages through the PAR-2 pathway and whether the TNF-α production affects GCE-induced pulmonary inflammation. Effects of GCE on alveolar macrophages and TNF-α production were evaluated using in vitro MH-S and RAW264.6 cells and in vivo GCE-induced asthma models of BALB/c mice. GCE contained a large amount of serine protease. In the MH-S and RAW264.7 cells, GCE activated PAR-2 and thereby produced TNF-α. In the GCE-induced asthma model, intranasal administration of GCE increased airway hyperresponsiveness (AHR), inflammatory cell infiltration, productions of serum immunoglobulin E, interleukin (IL)-5, IL-13 and TNF-α production in alveolar macrophages. Blockade of serine proteases prevented the development of GCE induced allergic pathologies. TNF-α blockade also prevented the development of such asthma-like lesions. Depletion of alveolar macrophages reduced AHR and intracellular TNF-α level in pulmonary cell populations in the GCE-induced asthma model. These results suggest that serine protease from GCE affects asthma through an alveolar macrophage and TNF-α dependent manner, reflecting the close relation of innate and adaptive immune response in allergic asthma model. PMID:23094102

MODERN APPROACHES TO FRACTIONAL EXHALED NITRIC OXIDE AS A USEFUL BIOMARKER FOR ALLERGIC ASTHMA PHENOTYPING AND MANAGEMENT.

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Mgaloblishvili, N; Gotua, M

2017-12-01

Asthma is a pathologically heterogeneous disease, consisting of several phenotypes. Different types of airway inflammation are the cornerstone feature of this condition. Fraction of nitric oxide in exhaled air (FENO) has been proposed as a noninvasive, specific biomarker for eosinophilic airway inflammation and has been shown to be elevated in patients with allergic asthma phenotype. More recent studies indicate that FeNO identifies T-helper cell type 2 (Th2)-mediated airway inflammation with a high predictive value for identifying inhaled corticosteroid (ICS) responsive airway inflammation. Taking into account the accumulated evidence,it is possible to consider, that FeNO testing has an important role in the assessment of patients with suspected asthma and in the management of established asthmadiagnosis. In conjunction with symptom scores and lung function tests, FeNO measurement could provide a more useful and effective approach for asthma in terms of: (1) detecting the presence of Th2-mediated airway inflammation, (2) determining the likelihood of ICS responsive (and lack of course), (3) monitoring of airway inflammation to determine risk for future impairment or loss of asthma control during reduction/cessation of ICS treatment, (4) unmasking (otherwise unsuspected) non-adherence to corticosteroid therapy and (5) in severe asthma cases tailoring treatment with biological drugs. However, more work is still needed to address outstanding questions about its exact role in guiding asthma management and better define the use of FENO in different clinical settings.

The effect of omalizumab on small airway inflammation as measured by exhaled nitric oxide in moderate-to-severe asthmatic patients.

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Pasha, M Asghar; Jourd'heuil, David; Jourd'heuil, Francis; Mahon, Lori; Romero, Francisco; Feustel, Paul J; Evans, Mary; Smith, Thomas; Mitchell, Jesse; Gendapodi, Pradeep; Demeyere-Coursey, Kelly C; Townley, Robert G

2014-01-01

Measurement of fractional nitric oxide concentration in exhaled breath (FENO) is a simple, noninvasive method to evaluate eosinophilic airway inflammation. Nitric oxide (NO) arising from peripheral small airways/alveoli (alveolar NO concentration [CalvNO]) can be estimated using multiple flow rates and a two-compartment model of the airways and alveoli. Omalizumab, a monoclonal anti-IgE antibody, is approved for the treatment of allergic asthma and also has been shown to decrease FENO levels. This study investigates the effects of omalizumab, when added to an inhaled corticosteroid (ICS) ± long-acting beta-adrenergic agonist (LABA) treatment, on peripheral small airway/alveolar inflammation reflected by FENO measurements at higher flow rates. We hypothesized that compared with placebo, omalizumab would decrease CalvNO levels in asthmatic patients on ICS ± LABA. Forty-two patients with moderate-to-severe asthma were randomly assigned 2:1 to either omalizumab (n = 29) or placebo treatment (n = 13) for 16 weeks. Selection criteria included moderate-to-severe asthmatic patients on an ICS ± LABA, positive skin test to one or more perennial allergen, screening FENO of >13 ppb, and a baseline IgE of 30-700 IU/mL. FENO measured at multiple flow rates was used to calculate CalvNO over the course of 16 weeks. FENO levels decrease with increasing flow rates (p < 0.05 repeated measures ANOVA) but no differences between the placebo and treatment groups in overall CalvNO levels or in the changes of CalvNO with time were found. Omalizumab did not lower the CalvNO, which could have been caused by the initial low CalvNO in this asthmatic population. The model used may not be completely sufficient and/or sensitive enough to detect small changes in CalvNO.

The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation.

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Lim, Hun Jai; Jin, Hong-Guang; Woo, Eun-Rhan; Lee, Sang Kook; Kim, Hyun Pyo

2013-08-26

The root barks of Morus alba have been used in traditional medicine as an anti-inflammatory drug, especially for treating lung inflammatory disorders. To find new alternative agents against airway inflammation and to establish the scientific rationale of the herbal medicine in clinical use, the root barks of Morus alba and its flavonoid constituents were examined for the first time for their pharmacological activity against lung inflammation. For in vivo evaluation, an animal model of lipopolysaccharide-induced airway inflammation in mice was used. An inhibitory action against the production of proinflammatory molecules in lung epithelial cells and lung macrophages was examined. Against lipopolysaccharide-induced airway inflammation, the ethanol extract of the root barks of Morus alba clearly inhibited bronchitis-like symptoms, as determined by TNF-α production, inflammatory cells infiltration and histological observation at 200-400mg/kg/day by oral administration. In addition, Morus alba and their major flavonoid constituents including kuwanone E, kuwanone G and norartocarpanone significantly inhibited IL-6 production in lung epithelial cells (A549) and NO production in lung macrophages (MH-S). Taken together, it is concluded that Morus alba and the major prenylated flavonoid constituents have a potential for new agents to control lung inflammation including bronchitis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Inhalation of rod-like carbon nanotubes causes unconventional allergic airway inflammation

OpenAIRE

Rydman, Elina M.; Ilves, Marit; Koivisto, Antti J.; Kinaret, Pia A. S.; Fortino, Vittorio; Savinko, Terhi S.; Lehto, Maili T.; Pulkkinen, Ville; Vippola, Minnamari; Hämeri, Kaarle J.; Matikainen, Sampsa; Wolff, Henrik; Savolainen, Kai M.; Greco, Dario; Alenius, Harri

2014-01-01

Background Carbon nanotubes (CNT) represent a great promise for technological and industrial development but serious concerns on their health effects have also emerged. Rod-shaped CNT are, in fact, able to induce asbestos-like pathogenicity in mice including granuloma formation in abdominal cavity and sub-pleural fibrosis. Exposure to CNT, especially in the occupational context, happens mainly by inhalation. However, little is known about the possible effects of CNT on pulmonary allergic dise...

Air Pollution and Allergic Airway Diseases: Social Determinantsand Sustainability in the Control and Prevention.

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Paramesh, H

2018-04-01

Air pollution, global warming and climate change are the major contributing factors in causing the increase prevalence of allergic airway diseases like asthma and allergic rhinitis and they will be the defining issues for health system in the twenty-first century. Asthma is an early onset non-communicable environmental disease with global epidemic and contributes a greatest psycho socio economic burden. Nearly 8 million global deaths are from air pollution. Over one billion population are the sufferers during 2015 and will increase to 4 billion by 2050. Air pollution not only triggers the asthma episodes but also changes the genetic pattern in initiating the disease process. Over the years our concept of management of allergic airway disease has changed from control of symptoms to prevention of the disease. To achieve this we need positive development on clean air policies with standard norms, tracking progress, monitoring and evaluation, partnership and conventions with local and global authorities. We do have challenges to overcome like rapid urbanization, lack of multisectorial policy making, lack of finance for research and development and lack of monitoring exposure to health burden from air pollution. We need to prioritize our strategy by sustainable, safe, human settlement, cities, sustainable energy, industrialization, and research. The measures to be adopted are highlighted in this review article. With effective measures by all stake holders we can reduce air pollution and prevent the global warming by 2030, along with 194 countries as adopted by WHO in May 2015.

The IL-17F/IL-17RC Axis Promotes Respiratory Allergy in the Proximal Airways

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Antonella De Luca

2017-08-01

Full Text Available The interleukin 17 (IL-17 cytokine and receptor family is central to antimicrobial resistance and inflammation in the lung. Mice lacking IL-17A, IL-17F, or the IL-17RA subunit were compared with wild-type mice for susceptibility to airway inflammation in models of infection and allergy. Signaling through IL-17RA was required for efficient microbial clearance and prevention of allergy; in the absence of IL-17RA, signaling through IL-17RC on epithelial cells, predominantly by IL-17F, significantly exacerbated lower airway Aspergillus or Pseudomonas infection and allergic airway inflammation. In contrast, following infection with the upper respiratory pathogen Staphylococcus aureus, the IL-17F/IL-17RC axis mediated protection. Thus, IL-17A and IL-17F exert distinct biological effects during pulmonary infection; the IL-17F/IL-17RC signaling axis has the potential to significantly worsen pathogen-associated inflammation of the lower respiratory tract in particular, and should be investigated further as a therapeutic target for treating pathological inflammation in the lung.

Probiotics as Additives on Therapy in Allergic Airway Diseases: A Systematic Review of Benefits and Risks

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Rashmi Ranjan Das

2013-01-01

Full Text Available Background. We conducted a systematic review to find out the role of probiotics in treatment of allergic airway diseases.  Methods. A comprehensive search of the major electronic databases was done till March 2013. Trials comparing the effect of probiotics versus placebo were included. A predefined set of outcome measures were assessed. Continuous data were expressed as standardized mean difference with 95% CI. Dichotomous data were expressed as odds ratio with 95% CI. P value < 0.05 was considered as significant. Results. A total of 12 studies were included. Probiotic intake was associated with a significantly improved quality of life score in patients with allergic rhinitis (SMD −1.9 (95% CI −3.62, −0.19; P = 0.03, though there was a high degree of heterogeneity. No improvement in quality of life score was noted in asthmatics. Probiotic intake also improved the following parameters: longer time free from episodes of asthma and rhinitis and decrease in the number of episodes of rhinitis per year. Adverse events were not significant. Conclusion. As the current evidence was generated from few trials with high degree of heterogeneity, routine use of probiotics as an additive on therapy in subjects with allergic airway diseases cannot be recommended.

Illicium verum Extract and Trans-Anethole Attenuate Ovalbumin-Induced Airway Inflammation via Enhancement of Foxp3+ Regulatory T Cells and Inhibition of Th2 Cytokines in Mice

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Yoon-Young Sung

2017-01-01

Full Text Available Illicium verum is used in traditional medicine to treat inflammation. The study investigates the effects of IVE and its component, trans-anethole (AET, on airway inflammation in ovalbumin- (OVA- induced asthmatic mice. Asthma was induced in BALB/c mice by systemic sensitization to OVA, followed by intratracheal, intraperitoneal, and aerosol allergen challenges. IVE and AET were orally administered for four weeks. We investigated the effects of treatment on airway hyperresponsiveness, IgE production, pulmonary eosinophilic infiltration, immune cell phenotypes, Th2 cytokine production in bronchoalveolar lavage, Th1/Th2 cytokine production in splenocytes, forkhead box protein 3 (Foxp3 expression, and lung histology. IVE and AET ameliorated OVA-driven airway hyperresponsiveness (p<0.01, pulmonary eosinophilic infiltration (p<0.05, mucus hypersecretion (p<0.01, and IL-4, IL-5, IL-13, and CCR3 production (p<0.05, as well as IgE levels (p<0.01. IVE and AET increased Foxp3 expression in lungs (p<0.05. IVE and AET reduced IL-4 and increased IFN-γ production in the supernatant of splenocyte cultures (p<0.05. Histological studies showed that IVE and AET inhibited eosinophilia and lymphocyte infiltration in lungs (p<0.01. These results indicate that IVE and AET exert antiasthmatic effects through upregulation of Foxp3+ regulatory T cells and inhibition of Th2 cytokines, suggesting that IVE may be a potential therapeutic agent for allergic lung inflammation.

Lung macrophages contribute to house dust mite driven airway remodeling via HIF-1α.

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Adam J Byrne

Full Text Available HIF-1α is a transcription factor that is activated during hypoxia and inflammation and is a key regulator of angiogenesis in vivo. During the development of asthma, peribronchial angiogenesis is induced in response to aeroallergens and is thought to be an important feature of sustained chronic allergic inflammation. Recently, elevated HIF-1α levels have been demonstrated in both the lung tissue and bronchoalveolar lavage of allergic patients, respectively. Therefore, we investigated the role of HIF-1α on the development of angiogenesis and inflammation following acute and chronic allergen exposure. Our data shows that intranasal exposure to house dust mite (HDM increases the expression of HIF-1α in the lung, whilst reducing the expression of the HIF-1α negative regulators, PHD1 and PHD3. Blockade of HIF-1α in vivo, significantly decreased allergic inflammation and eosinophilia induced by allergen, due to a reduction in the levels of IL-5 and Eotaxin-2. Importantly, HIF-1α blockade significantly decreased levels of VEGF-A and CXCL1 in the lungs, which in turn led to a profound decrease in the recruitment of endothelial progenitor cells and a reduction of peribronchial angiogenesis. Furthermore, HDM or IL-4 treatment of primary lung macrophages resulted in significant production of both VEGF-A and CXCL1; inhibition of HIF-1α activity abrogated the production of these factors via an up-regulation of PHD1 and PHD3. These findings suggest that novel strategies to reduce the expression and activation of HIF-1α in lung macrophages may be used to attenuate allergen-induced airway inflammation and angiogenesis through the modulation of VEGF-A and CXCL1 expression.This study provides new insights into the role of HIF-1α in the development of peribronchial angiogenesis and inflammation in a murine model of allergic airway disease. These findings indicate that strategies to reduce activation of macrophage derived HIF-1α may be used as a target to

Dorsal Vagal Complex Modulates Neurogenic Airway Inflammation in a Guinea Pig Model With Esophageal Perfusion of HCl

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Zhe Chen

2018-05-01

Full Text Available Neurogenic airway inflammation in chronic cough and bronchial asthma related to gastroesophageal reflux (GER is involved in the esophageal–bronchial reflex, but it is unclear whether this reflex is mediated by central neurons. This study aimed to investigate the regulatory effects of the dorsal vagal complex (DVC on airway inflammation induced by the esophageal perfusion of hydrochloric acid (HCl following the microinjection of nuclei in the DVC in guinea pigs. Airway inflammation was evaluated by measuring the extravasation of Evans blue dye (EBD and substance P (SP expression in the airway. Neuronal activity was indicated by Fos expression in the DVC. The neural pathways from the lower esophagus to the DVC and the DVC to the airway were identified using DiI tracing and pseudorabies virus Bartha (PRV-Bartha retrograde tracing, respectively. HCl perfusion significantly increased plasma extravasation, SP expression in the trachea, and the expression of SP and Fos in the medulla oblongata nuclei, including the nucleus of the solitary tract (NTS and the dorsal motor nucleus of the vagus (DMV. The microinjection of glutamic acid (Glu or exogenous SP to enhance neuronal activity in the DVC significantly potentiated plasma extravasation and SP release induced by intra-esophageal perfusion. The microinjection of γ-aminobutyric acid (GABA, lidocaine to inhibit neuronal activity or anti-SP serum in the DVC alleviated plasma extravasation and SP release. In conclusion, airway inflammation induced by the esophageal perfusion of HCl is regulated by DVC. This study provides new insight for the mechanism of airway neurogenic inflammation related to GER.

The Toll-like receptor 5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens.

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Wilson, Rhonda H; Maruoka, Shuichiro; Whitehead, Gregory S; Foley, Julie F; Flake, Gordon P; Sever, Michelle L; Zeldin, Darryl C; Kraft, Monica; Garantziotis, Stavros; Nakano, Hideki; Cook, Donald N

2012-11-01

Allergic asthma is a complex disease characterized by eosinophilic pulmonary inflammation, mucus production and reversible airway obstruction. Exposure to indoor allergens is a risk factor for asthma, but this disease is also associated with high household levels of total and particularly Gram-negative bacteria. The ability of bacterial products to act as adjuvants suggests they might promote asthma by priming allergic sensitization to inhaled allergens. In support of this idea, house dust extracts (HDEs) can activate antigen-presenting dendritic cells (DCs) in vitro and promote allergic sensitization to inhaled innocuous proteins in vivo. It is unknown which microbial products provide most of the adjuvant activity in HDEs. A screen for adjuvant activity of microbial products revealed that the bacterial protein flagellin (FLA) stimulated strong allergic airway responses to an innocuous inhaled protein, ovalbumin (OVA). Moreover, Toll-like receptor 5 (TLR5), the mammalian receptor for FLA, was required for priming strong allergic responses to natural indoor allergens present in HDEs. In addition, individuals with asthma have higher serum levels of FLA-specific antibodies as compared to nonasthmatic individuals. Together, these findings suggest that household FLA promotes the development of allergic asthma by TLR5-dependent priming of allergic responses to indoor allergens.

Differential effects of allergen challenge on large and small airway reactivity in mice.

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Chantal Donovan

Full Text Available The relative contributions of large and small airways to hyperresponsiveness in asthma have yet to be fully assessed. This study used a mouse model of chronic allergic airways disease to induce inflammation and remodelling and determine whether in vivo hyperresponsiveness to methacholine is consistent with in vitro reactivity of trachea and small airways. Balb/C mice were sensitised (days 0, 14 and challenged (3 times/week, 6 weeks with ovalbumin. Airway reactivity was compared with saline-challenged controls in vivo assessing whole lung resistance, and in vitro measuring the force of tracheal contraction and the magnitude/rate of small airway narrowing within lung slices. Increased airway inflammation, epithelial remodelling and fibrosis were evident following allergen challenge. In vivo hyperresponsiveness to methacholine was maintained in isolated trachea. In contrast, methacholine induced slower narrowing, with reduced potency in small airways compared to controls. In vitro incubation with IL-1/TNFα did not alter reactivity. The hyporesponsiveness to methacholine in small airways within lung slices following chronic ovalbumin challenge was unexpected, given hyperresponsiveness to the same agonist both in vivo and in vitro in tracheal preparations. This finding may reflect the altered interactions of small airways with surrounding parenchymal tissue after allergen challenge to oppose airway narrowing and closure.

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

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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....... CONCLUSION: Our results demonstrate the involvement of T(H)17-mediated immunopathology in human allergic contact dermatitis, including both innate and adaptive immune responses to contact allergens....

Increased mast cell density and airway responses to allergic and non-allergic stimuli in a sheep model of chronic asthma.

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Joanne Van der Velden

Full Text Available BACKGROUND: Increased mast cell (MC density and changes in their distribution in airway tissues is thought to contribute significantly to the pathophysiology of asthma. However, the time sequence for these changes and how they impact small airway function in asthma is not fully understood. The aim of the current study was to characterise temporal changes in airway MC density and correlate these changes with functional airway responses in sheep chronically challenged with house dust mite (HDM allergen. METHODOLOGY/PRINCIPAL FINDINGS: MC density was examined on lung tissue from four spatially separate lung segments of allergic sheep which received weekly challenges with HDM allergen for 0, 8, 16 or 24 weeks. Lung tissue was collected from each segment 7 days following the final challenge. The density of tryptase-positive and chymase-positive MCs (MC(T and MC(TC respectively was assessed by morphometric analysis of airway sections immunohistochemically stained with antibodies against MC tryptase and chymase. MC(T and MC(TC density was increased in small bronchi following 24 weeks of HDM challenges compared with controls (P<0.05. The MC(TC/MC(T ratio was significantly increased in HDM challenged sheep compared to controls (P<0.05. MC(T and MC(TC density was inversely correlated with allergen-induced increases in peripheral airway resistance after 24 weeks of allergen exposure (P<0.05. MC(T density was also negatively correlated with airway responsiveness after 24 challenges (P<0.01. CONCLUSIONS: MC(T and MC(TC density in the small airways correlates with better lung function in this sheep model of chronic asthma. Whether this finding indicates that under some conditions mast cells have protective activities in asthma, or that other explanations are to be considered requires further investigation.

Oxytetracycline Inhibits Mucus Secretion and Inflammation in Human Airway Epithelial Cells.

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Shah, Said Ahmad; Ishinaga, Hajime; Takeuchi, Kazuhiko

2017-01-01

Oxytetracycline is a broad-spectrum antibiotic, but its nonantibacterial effects in the human respiratory tract are unknown. In this study, the effects of oxytetracycline on mucus secretion and inflammation were examined by PCR and ELISA in the human airway epithelial cell line NCI-H292. Oxytetracycline (10 μg/mL) significantly inhibited TNF-α-induced MUC5AC gene expression and MUC5AC protein levels in NCI-H292 cells. It also downregulated IL-8 and IL-1β gene expression and IL-1β protein levels. Our findings demonstrated that oxytetracycline suppressed mucus production and inflammation in human respiratory epithelial cells, providing further evidence for the usefulness of oxytetracycline for human airway inflammatory diseases. © 2017 S. Karger AG, Basel.

Alterations of the murine gut microbiome in allergic airway disease are independent of surfactant protein D

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Barfod, Kenneth Klingenberg; Roggenbuck, Michael; Al-Shuweli, Suzan

2017-01-01

Background SP-D is an important host defense lectin in innate immunity and SP-D deficient mice show several abnormal immune effects and are susceptible to allergen-induced airway disease. At the same time, host microbiome interactions play an important role in the development of allergic airway...... disease, and alterations to gut microbiota have been linked to airway disease through the gut-lung axis. Currently, it is unknown if the genotype (Sftpd-/- or Sftpd+/+) of the standard SP-D mouse model can affect the host microbiota to such an degree that it would overcome the cohousing effect...... on microbiota and interfere with the interpretation of immunological data from the model. Generally, little is known about the effect of the SP-D protein in itself and in combination with airway disease on the microbiota. In this study, we tested the hypothesis that microbiome composition would change...

Bromodomain and Extra Terminal (BET Inhibitor Suppresses Macrophage-Driven Steroid-Resistant Exacerbations of Airway Hyper-Responsiveness and Inflammation.

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Thi Hiep Nguyen

Full Text Available Exacerbations of asthma are linked to significant decline in lung function and are often poorly controlled by corticosteroid treatment. Clinical investigations indicate that viral and bacterial infections play crucial roles in the onset of steroid-resistant inflammation and airways hyperresponsiveness (AHR that are hallmark features of exacerbations. We have previously shown that interferon γ (IFNγ and lipopolysaccharide (LPS cooperatively activate pulmonary macrophages and induce steroid-resistant airway inflammation and AHR in mouse models. Furthermore, we have established a mouse model of respiratory syncytial virus (RSV-induced exacerbation of asthma, which exhibits macrophage-dependent, steroid-resistant lung disease. Emerging evidence has demonstrated a key role for bromo- and extra-terminal (BET proteins in the regulation of inflammatory gene expression in macrophages. We hypothesised that BET proteins may be involved in the regulation of AHR and airway inflammation in our steroid-resistant exacerbation models.We investigated the effects of a BET inhibitor (I-BET-762 on the development of steroid-resistant AHR and airway inflammation in two mouse models. I-BET-762 administration decreased macrophage and neutrophil infiltration into the airways, and suppressed key inflammatory cytokines in both models. I-BET treatment also suppressed key inflammatory cytokines linked to the development of steroid-resistant inflammation such as monocyte chemoattractant protein 1 (MCP-1, keratinocyte-derived protein chemokine (KC, IFNγ, and interleukin 27 (IL-27. Attenuation of inflammation was associated with suppression of AHR.Our results suggest that BET proteins play an important role in the regulation of steroid-resistant exacerbations of airway inflammation and AHR. BET proteins may be potential targets for the development of future therapies to treat steroid-resistant inflammatory components of asthma.

Peculiarities of Airway Inflammation and Lipid Peroxidation in the Development of Hyperosmotic Airway Hyperresponsiveness in Patients with Asthma

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Alexey B. Pirogov

2016-12-01

Full Text Available The aim of our study was to evaluate the role of airway cellular inflammation and the lipid peroxidation level in the development of airway hyperresponsiveness (AHR to inhalation of hypertonic saline (IHS. Methods and Results: The study included the estimation of inflammatory-cellular composition, intracellular concentration of myeloperoxidase (MPO in induced sputum (IS, serum levels of lipid hydroperoxides (LHP, ceruloplasmin, and vitamin E in 29 patients with asthma and 12 healthy persons. AHR to IHS was assessed by spirometry after 3-min IHS via ultrasonic nebulizer. Patients with asthma had higher indices of leukocytes destruction and cytolysis intensity with the increased leukocyte count in IS. Maximum values of neutrophils cytolysis intensity and leukocytic MPO were found in IS of the patients with AHR to IHS. After the bronchial provocation, serum concentration of LHP was higher in these patients in comparison with the patients without the AHR and control groups. In addition, patients with asthma had lower level of antioxidants than healthy subjects. Conclusion: Marked inflammation involving MPO-activated leukocytes and intensive lipid peroxidation underlie the excessive airway response to IHS.

Dietary Compound Kaempferol Inhibits Airway Thickening Induced by Allergic Reaction in a Bovine Serum Albumin-Induced Model of Asthma.

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Shin, Daekeun; Park, Sin-Hye; Choi, Yean-Jung; Kim, Yun-Ho; Antika, Lucia Dwi; Habibah, Nurina Umy; Kang, Min-Kyung; Kang, Young-Hee

2015-12-16

Asthma is characterized by aberrant airways including epithelial thickening, goblet cell hyperplasia, and smooth muscle hypertrophy within the airway wall. The current study examined whether kaempferol inhibited mast cell degranulation and prostaglandin (PG) release leading to the development of aberrant airways, using an in vitro model of dinitrophenylated bovine serum albumin (DNP-BSA)-sensitized rat basophilic leukemia (RBL-2H3) mast cells and an in vivo model of BSA-challenged asthmatic mice. Nontoxic kaempferol at 10-20 μM suppressed β-hexosaminidase release and cyclooxygenase 2 (COX2)-mediated production of prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α) in sensitized mast cells. Oral administration of ≤20 mg/kg kaempferol blocked bovine serum albumin (BSA) inhalation-induced epithelial cell excrescence and smooth muscle hypertrophy by attenuating the induction of COX2 and the formation of PGD2 and PGF2α, together with reducing the anti-α-smooth muscle actin (α-SMA) expression in mouse airways. Kaempferol deterred the antigen-induced mast cell activation of cytosolic phospholipase A2 (cPLA2) responsive to protein kinase Cμ (PKCμ) and extracellular signal-regulated kinase (ERK). Furthermore, the antigen-challenged activation of Syk-phospholipase Cγ (PLCγ) pathway was dampened in kaempferol-supplemented mast cells. These results demonstrated that kaempferol inhibited airway wall thickening through disturbing Syk-PLCγ signaling and PKCμ-ERK-cPLA2-COX2 signaling in antigen-exposed mast cells. Thus, kaempferol may be a potent anti-allergic compound targeting allergic asthma typical of airway hyperplasia and hypertrophy.

Divergent effects of urban particulate air pollution on allergic airway responses in experimental asthma: a comparison of field exposure studies

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Wagner James G

2012-07-01

Full Text Available Abstract Background Increases in ambient particulate matter of aerodynamic diameter of 2.5 μm (PM2.5 are associated with asthma morbidity and mortality. The overall objective of this study was to test the hypothesis that PM2.5 derived from two distinct urban U.S. communities would induce variable responses to aggravate airway symptoms during experimental asthma. Methods We used a mobile laboratory to conduct community-based inhalation exposures to laboratory rats with ovalbumin-induced allergic airways disease. In Grand Rapids exposures were conducted within 60 m of a major roadway, whereas the Detroit was located in an industrial area more than 400 m from roadways. Immediately after nasal allergen challenge, Brown Norway rats were exposed by whole body inhalation to either concentrated air particles (CAPs or filtered air for 8 h (7:00 AM - 3:00 PM. Both ambient and concentrated PM2.5 was assessed for mass, size fractionation, and major component analyses, and trace element content. Sixteen hours after exposures, bronchoalveolar lavage fluid (BALF and lung lobes were collected and evaluated for airway inflammatory and mucus responses. Results Similar CAPs mass concentrations were generated in Detroit (542 μg/m3 and Grand Rapids (519 μg/m3. Exposure to CAPs at either site had no effects in lungs of non-allergic rats. In contrast, asthmatic rats had 200% increases in airway mucus and had more BALF neutrophils (250% increase, eosinophils (90%, and total protein (300% compared to controls. Exposure to Detroit CAPs enhanced all allergic inflammatory endpoints by 30-100%, whereas inhalation of Grand Rapids CAPs suppressed all allergic responses by 50%. Detroit CAPs were characterized by high sulfate, smaller sized particles and were derived from local combustion sources. Conversely Grand Rapids CAPs were derived primarily from motor vehicle sources. Conclusions Despite inhalation exposure to the same mass concentration of urban PM2

Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids

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Jonasson, Sofia, E-mail: sofia.jonasson@foi.se [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Wigenstam, Elisabeth [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå (Sweden); Koch, Bo [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Bucht, Anders [Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå (Sweden); Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå (Sweden)

2013-09-01

Chlorine (Cl{sub 2}) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl{sub 2}-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200 ppm Cl{sub 2} during 15 min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24 h or 14 days post-exposure. A single dose of the corticosteroid dexamethasone (10 or 100 mg/kg) was administered intraperitoneally 1, 3, 6, or 12 h following Cl{sub 2} exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6 h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1 h was dose-dependent; high-dose significantly reduced acute airway inflammation (100 mg/kg) but not treatment with the relatively low-dose (10 mg/kg). Both doses reduced AHR 14 days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl{sub 2} exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl{sub 2} exposure. - Highlights: • Inhalation of Cl{sub 2} may lead to a long-standing airway hyperresponsiveness. • The symptoms in Cl{sub 2}-exposed mice are similar to those described for RADS in humans. • Corticosteroids prevent delayed symptoms such as AHR in

Does Inhalation of Virgin Coconut Oil Accelerate Reversal of Airway Remodelling in an Allergic Model of Asthma?

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Sulaiman, S. A.

2017-01-01

Many studies have been done to evaluate the effect of various natural products in controlling asthma symptoms. Virgin coconut oil (VCO) is known to contain active compounds that have beneficial effects on human health and diseases. The objective of this study was to evaluate the effect of VCO inhalation on airway remodelling in a rabbit model of allergic asthma. The effects of VCO inhalation on infiltration of airway inflammatory cells, airway structures, goblet cell hyperplasia, and cell proliferation following ovalbumin induction were evaluated. Allergic asthma was induced by a combination of ovalbumin and alum injection and/or followed by ovalbumin inhalation. The effect of VCO inhalation was then evaluated via the rescue or the preventive route. Percentage of inflammatory cells infiltration, thickness of epithelium and mucosa regions, and the numbers of goblet and proliferative cells were reduced in the rescue group but not in preventive group. Analysis using a gas chromatography-mass spectrometry found that lauric acid and capric acid were among the most abundant fatty acids present in the sample. Significant improvement was observed in rescue route in alleviating the asthma symptoms, which indicates the VCO was able to relieve asthma-related symptoms more than preventing the onset of asthma. PMID:28660089

Does Inhalation of Virgin Coconut Oil Accelerate Reversal of Airway Remodelling in an Allergic Model of Asthma?

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N. A. Kamalaldin

2017-01-01

Full Text Available Many studies have been done to evaluate the effect of various natural products in controlling asthma symptoms. Virgin coconut oil (VCO is known to contain active compounds that have beneficial effects on human health and diseases. The objective of this study was to evaluate the effect of VCO inhalation on airway remodelling in a rabbit model of allergic asthma. The effects of VCO inhalation on infiltration of airway inflammatory cells, airway structures, goblet cell hyperplasia, and cell proliferation following ovalbumin induction were evaluated. Allergic asthma was induced by a combination of ovalbumin and alum injection and/or followed by ovalbumin inhalation. The effect of VCO inhalation was then evaluated via the rescue or the preventive route. Percentage of inflammatory cells infiltration, thickness of epithelium and mucosa regions, and the numbers of goblet and proliferative cells were reduced in the rescue group but not in preventive group. Analysis using a gas chromatography-mass spectrometry found that lauric acid and capric acid were among the most abundant fatty acids present in the sample. Significant improvement was observed in rescue route in alleviating the asthma symptoms, which indicates the VCO was able to relieve asthma-related symptoms more than preventing the onset of asthma.

Allergic Lung Inflammation Aggravates Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice

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Liu, Cong-Lin; Wang, Yi; Liao, Mengyang

2016-01-01

sensitization and challenge in mice led to the development of allergic lung inflammation (ALI). Subcutaneous infusion of angiotensin II into mice produced AAA. Simultaneous production of ALI in AAA mice doubled abdominal aortic diameter and increased macrophage and mast cell content, arterial media smooth...... and reduced lesion inflammation, plasma IgE, and bronchioalveolar inflammation. Pre-establishment of ALI also increased AAA lesion size, lesion accumulation of macrophages and mast cells, media smooth muscle cell loss, and plasma IgE, reduced plasma interleukin-5, interleukin-13, and transforming growth...... factor-β, and increased bronchioalveolar inflammation. Consequent production of ALI also doubled lesion size of pre-established AAA and increased lesion mast cell and T-cell accumulation, media smooth muscle cell loss, lesion cell proliferation and apoptosis, plasma IgE, and bronchioalveolar inflammation...

Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma.

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Green, Benjamin J; Wiriyachaiporn, Surasa; Grainge, Christopher; Rogers, Geraint B; Kehagia, Valia; Lau, Laurie; Carroll, Mary P; Bruce, Kenneth D; Howarth, Peter H

2014-01-01

Molecular microbiological analysis of airway samples in asthma has demonstrated an altered microbiome in comparison to healthy controls. Such changes may have relevance to treatment-resistant severe asthma, particularly those with neutrophilic airway inflammation, as bacteria might be anticipated to activate the innate immune response, a process that is poorly steroid responsive. An understanding of the relationship between airway bacterial presence and dominance in severe asthma may help direct alternative treatment approaches. We aimed to use a culture independent analysis strategy to describe the presence, dominance and abundance of bacterial taxa in induced sputum from treatment resistant severe asthmatics and correlate findings with clinical characteristics and airway inflammatory markers. Induced sputum was obtained from 28 stable treatment-resistant severe asthmatics. The samples were divided for supernatant IL-8 measurement, cytospin preparation for differential cell count and Terminal Restriction Fragment Length Polymorphism (T-RFLP) profiling for bacterial community analysis. In 17/28 patients, the dominant species within the airway bacterial community was Moraxella catarrhalis or a member of the Haemophilus or Streptococcus genera. Colonisation with these species was associated with longer asthma disease duration (mean (SD) 31.8 years (16.7) vs 15.6 years (8.0), p = 0.008), worse post-bronchodilator percent predicted FEV1 (68.0% (24.0) vs 85.5% (19.7), p = 0.025) and higher sputum neutrophil differential cell counts (median (IQR) 80% (67-83) vs 43% (29-67), p = 0.001). Total abundance of these organisms significantly and positively correlated with sputum IL-8 concentration and neutrophil count. Airway colonisation with potentially pathogenic micro-organisms in asthma is associated with more severe airways obstruction and neutrophilic airway inflammation. This altered colonisation may have a role in the development of an asthma phenotype that

No adjuvant effect of Bacillus thuringiensis-maize on allergic responses in mice.

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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.

Exposure to Particulate Hexavalent Chromium Exacerbates Allergic Asthma Pathology

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Schneider, Brent C.; Constant, Stephanie L.; Patierno, Steven R.; Jurjus, Rosalyn A.; Ceryak, Susan M.

2011-01-01

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. PMID:22178736

Mucociliary clearance, airway inflammation and nasal symptoms in urban motorcyclists

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Tereza C.S. Brant

2014-01-01

Full Text Available OBJECTIVES: There is evidence that outdoor workers exposed to high levels of air pollution exhibit airway inflammation and increased airway symptoms. We hypothesized that these workers would experience increased airway symptoms and decreased nasal mucociliary clearance associated with their exposure to air pollution. METHODS: In total, 25 non-smoking commercial motorcyclists, aged 18-44 years, were included in this study. These drivers work 8-12 hours per day, 5 days per week, driving on urban streets. Nasal mucociliary clearance was measured by the saccharine transit test; airway acidification was measured by assessing the pH of exhaled breath condensate; and airway symptoms were measured by the Sino-nasal Outcome Test-20 questionnaire. To assess personal air pollution exposure, the subjects used a passive-diffusion nitrogen dioxide (NO2 concentration-monitoring system during the 14 days before each assessment. The associations between NO2 and the airway outcomes were analyzed using the Mann-Whitney test and the Chi-Square test. Clinicaltrials.gov: NCT01976039. RESULTS: Compared with clearance in healthy adult males, mucociliary clearance was decreased in 32% of the motorcyclists. Additionally, 64% of the motorcyclists had airway acidification and 92% experienced airway symptoms. The median personal NO2 exposure level was 75 mg/m3 for these subjects and a significant association was observed between NO2 and impaired mucociliary clearance (p = 0.036. CONCLUSION: Non-smoking commercial motorcyclists exhibit increased airway symptoms and airway acidification as well as decreased nasal mucociliary clearance, all of which are significantly associated with the amount of exposure to air pollution.

Acute airway effects of airborne formaldehyde in sensitized and non-sensitized mice housed in a dry or humid environment

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Larsen, Søren Thor, E-mail: stl@nrcwe.dk; Wolkoff, Peder, E-mail: pwo@nrcwe.dk; Hammer, Maria, E-mail: mha@nrcwe.dk; Kofoed-Sørensen, Vivi, E-mail: vks@nrcwe.dk; Clausen, Per Axel, E-mail: pac@nrcwe.dk; Nielsen, Gunnar Damgård, E-mail: gdn@nrcwe.dk

2013-05-01

We investigated the role of air humidity and allergic sensitization on the acute airway response to inhaled formaldehyde (FA) vapor. Mice were sensitized to the immunogen ovalbumin (OVA) by three intraperitoneal injections followed by two aerosol challenges, giving rise to allergic airway inflammation. Control mice were sham sensitized by saline injections and challenged by saline aerosols. Once sensitized, the mice were housed at high (85–89%) or low (< 10%) relative humidity, respectively for 48 h prior to a 60-min exposure to either 0.4, 1.8 or about 5 ppm FA. Before, during and after exposure, breathing parameters were monitored. These included the specific markers of nose and lung irritations as well as the expiratory flow rate, the latter being a marker of airflow limitation. The sensory irritation response in the upper airways was not affected by allergic inflammation or changes in humidity. At high relative humidity, the OVA-sensitized mice had a decreased expiratory airflow rate compared to the saline control mice after exposure to approximately 5 ppm FA. This is in accordance with the observations that asthmatics are more sensitive than non-asthmatics to higher concentrations of airway irritants including FA. In the dry environment, the opposite trend was seen; here, the saline control mice had a significantly decreased expiratory airflow rate compared to OVA-sensitized mice when exposed to 1.8 and 4 ppm FA. We speculate that increased mucus production in the OVA-sensitized mice has increased the “scrubber effect” in the nose, consequently protecting the conducting and lower airways. - Highlights: ► Role of air humidity and allergy on sensitivity to an airway irritant was studied. ► In the humid environment, allergy amplified the effects of formaldehyde. ► In the dry environment, allergy reduced the effect of formaldehyde. ► Neither allergy nor humidity changed the formaldehyde-induced nasal irritation.

Acute airway effects of airborne formaldehyde in sensitized and non-sensitized mice housed in a dry or humid environment

International Nuclear Information System (INIS)

Larsen, Søren Thor; Wolkoff, Peder; Hammer, Maria; Kofoed-Sørensen, Vivi; Clausen, Per Axel; Nielsen, Gunnar Damgård

2013-01-01

We investigated the role of air humidity and allergic sensitization on the acute airway response to inhaled formaldehyde (FA) vapor. Mice were sensitized to the immunogen ovalbumin (OVA) by three intraperitoneal injections followed by two aerosol challenges, giving rise to allergic airway inflammation. Control mice were sham sensitized by saline injections and challenged by saline aerosols. Once sensitized, the mice were housed at high (85–89%) or low (< 10%) relative humidity, respectively for 48 h prior to a 60-min exposure to either 0.4, 1.8 or about 5 ppm FA. Before, during and after exposure, breathing parameters were monitored. These included the specific markers of nose and lung irritations as well as the expiratory flow rate, the latter being a marker of airflow limitation. The sensory irritation response in the upper airways was not affected by allergic inflammation or changes in humidity. At high relative humidity, the OVA-sensitized mice had a decreased expiratory airflow rate compared to the saline control mice after exposure to approximately 5 ppm FA. This is in accordance with the observations that asthmatics are more sensitive than non-asthmatics to higher concentrations of airway irritants including FA. In the dry environment, the opposite trend was seen; here, the saline control mice had a significantly decreased expiratory airflow rate compared to OVA-sensitized mice when exposed to 1.8 and 4 ppm FA. We speculate that increased mucus production in the OVA-sensitized mice has increased the “scrubber effect” in the nose, consequently protecting the conducting and lower airways. - Highlights: ► Role of air humidity and allergy on sensitivity to an airway irritant was studied. ► In the humid environment, allergy amplified the effects of formaldehyde. ► In the dry environment, allergy reduced the effect of formaldehyde. ► Neither allergy nor humidity changed the formaldehyde-induced nasal irritation

Anti-Allergic Properties of Curine, a Bisbenzylisoquinoline Alkaloid

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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.

The Correlation between Chitin and Acidic Mammalian Chitinase in Animal Models of Allergic Asthma

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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.

Morin Attenuates Ovalbumin-Induced Airway Inflammation by Modulating Oxidative Stress-Responsive MAPK Signaling

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Yuan Ma

2016-01-01

Full Text Available Asthma is one of the most common inflammatory diseases characterized by airway hyperresponsiveness, inflammation, and remodeling. Morin, an active ingredient obtained from Moraceae plants, has been demonstrated to have promising anti-inflammatory activities in a range of disorders. However, its impacts on pulmonary diseases, particularly on asthma, have not been clarified. This study was designed to investigate whether morin alleviates airway inflammation in chronic asthma with an emphasis on oxidative stress modulation. In vivo, ovalbumin- (OVA- sensitized mice were administered with morin or dexamethasone before challenge. Bronchoalveolar lavage fluid (BALF and lung tissues were obtained to perform cell counts, histological analysis, and enzyme-linked immunosorbent assay. In vitro, human bronchial epithelial cells (BECs were challenged by tumor necrosis factor alpha (TNF-α. The supernatant was collected for the detection of the proinflammatory proteins, and the cells were collected for reactive oxygen species (ROS/mitogen-activated protein kinase (MAPK evaluations. Severe inflammatory responses and remodeling were observed in the airways of the OVA-sensitized mice. Treatment with morin dramatically attenuated the extensive trafficking of inflammatory cells into the BALF and inhibited their infiltration around the respiratory tracts and vessels. Morin administration also significantly suppressed goblet cell hyperplasia and collagen deposition/fibrosis and dose-dependently inhibited the OVA-induced increases in IgE, TNF-α, interleukin- (IL- 4, IL-13, matrix metalloproteinase-9, and malondialdehyde. In human BECs challenged by TNF-α, the levels of proteins such as eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1, were consistently significantly decreased by morin. Western blotting and the 2′,7′-dichlorofluorescein assay revealed that the increases in intracellular ROS and MAPK phosphorylation were

An extract of Crataegus pinnatifida fruit attenuates airway inflammation by modulation of matrix metalloproteinase-9 in ovalbumin induced asthma.

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In Sik Shin

Full Text Available BACKGROUND: Crataegus pinnatifida (Chinese hawthorn has long been used as a herbal medicine in Asia and Europe. It has been used for the treatment of various cardiovascular diseases such as myocardial weakness, tachycardia, hypertension and arteriosclerosis. In this study, we investigated the anti-inflammatory effects of Crataegus pinnatifida ethanolic extracts (CPEE on Th2-type cytokines, eosinophil infiltration, expression of matrix metalloproteinase (MMP-9, and other factors, using an ovalbumin (OVA-induced murine asthma model. METHODS/PRINCIPAL FINDING: Airways of OVA-sensitized mice exposed to OVA challenge developed eosinophilia, mucus hypersecretion and increased cytokine levels. CPEE was applied 1 h prior to OVA challenge. Mice were administered CPEE orally at doses of 100 and 200 mg/kg once daily on days 18-23. Bronchoalveolar lavage fluid (BALF was collected 48 h after the final OVA challenge. Levels of interleukin (IL-4 and IL-5 in BALF were measured using enzyme-linked immunosorbent (ELISA assays. Lung tissue sections 4 µm in thickness were stained with Mayer's hematoxylin and eosin for assessment of cell infiltration and mucus production with PAS staining, in conjunction with ELISA, and Western blot analyses for the expression of MMP-9, intercellular adhesion molecule (ICAM-1 and vascular cell adhesion molecule (VCAM-1 protein expression. CPEE significantly decreased the Th2 cytokines including IL-4 and IL-5 levels, reduced the number of inflammatory cells in BALF and airway hyperresponsiveness, suppressed the infiltration of eosinophil-rich inflammatory cells and mucus hypersecretion and reduced the expression of ICAM-1, VCAM-1 and MMP-9 and the activity of MMP-9 in lung tissue of OVA-challenged mice. CONCLUSIONS: These results showed that CPEE can protect against allergic airway inflammation and can act as an MMP-9 modulator to induce a reduction in ICAM-1 and VCAM-1 expression. In conclusion, we strongly suggest the feasibility

Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2-positive dendritic cells in allergic asthma.

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Cho, Minkyoung; Lee, Jeong-Eun; Lim, Hoyong; Shin, Hyun-Woo; Khalmuratova, Roza; Choi, Garam; Kim, Hyuk Soon; Choi, Wahn Soo; Park, Young-Jun; Shim, Inbo; Kim, Byung-Seok; Kang, Chang-Yuil; Kim, Jae-Ouk; Tanaka, Shinya; Kubo, Masato; Chung, Yeonseok

2017-10-14

Inhaled protease allergens preferentially trigger T H 2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of T H 2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce T H 2-favorable DCs in the airway remains unclear. We sought to determine a subset of DCs responsible for T H 2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway. Mice were challenged intranasally with protease allergens or fibrinogen cleavage products (FCPs) to induce allergic airway inflammation. DCs isolated from mediastinal lymph nodes were analyzed for surface phenotype and T-cell stimulatory function. Anti-Thy1.2 and Mas-TRECK mice were used to deplete innate lymphoid cells and mast cells, respectively. Adoptive cell transfer, bone marrow DC culture, anti-IL-13, and Toll-like receptor (TLR) 4-deficient mice were used for further mechanistic studies. Protease allergens induced a remarkable accumulation of T H 2-favorable programmed cell death 1 ligand 2 (PD-L2) + DCs in mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCPs generated by protease allergens triggered IL-13 production from wild-type mast cells but not from TLR4-deficient mast cells, which resulted in an increase in the number of PD-L2 + DCs. Intranasal administration of FCPs induced an increase in numbers of PD-L2 + DCs in the airway, which was significantly abolished in TLR4- and mast cell-deficient mice. Injection of IL-13 restored the PD-L2 + DC population in mice lacking mast cells. Our findings unveil the "protease-FCP-TLR4-mast cell-IL-13" axis as a molecular mechanism for generation of T H 2-favorable PD-L2 + DCs in allergic asthma and suggest that targeting the PD-L2 + DC pathway might be effective in suppressing allergic T-cell responses in the airway

Memory and multitasking performance during acute allergic inflammation in seasonal allergic rhinitis.

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Trikojat, K; Buske-Kirschbaum, A; Plessow, F; Schmitt, J; Fischer, R

2017-04-01

In previous research, patients with seasonal allergic rhinitis (SAR) showed poorer school and work performance during periods of acute allergic inflammation, supporting the idea of an impact of SAR on cognitive functions. However, the specific cognitive domains particularly vulnerable to inflammatory processes are unclear. In this study, the influence of SAR on memory and multitasking performance, as two potentially vulnerable cognitive domains essential in everyday life functioning, was investigated in patients with SAR. Non-medicated patients with SAR (n = 41) and healthy non-allergic controls (n = 42) performed a dual-task paradigm and a verbal learning and memory test during and out of symptomatic allergy periods (pollen vs. non-pollen season). Disease-related factors (e.g. symptom severity, duration of symptoms, duration of disease) and allergy-related quality of life were evaluated as potential influences of cognitive performance. During the symptomatic allergy period, patients showed (1) poorer performance in word list-based learning (P = 0.028) and (2) a general slowing in processing speed (P multitasking. Yet, typical parameters indicating specific multitasking costs were not affected. A significant negative association was found between learning performance and duration of disease (r = -0.451, P = 0.004), whereas symptom severity (r = 0.326; P = 0.037) and quality of life (r = 0.379; P = 0.015) were positively associated with multitasking strategy. Our findings suggest that SAR has a differentiated and complex impact on cognitive functions, which should be considered in the management of SAR symptoms. They also call attention to the importance of selecting sensitive measures and carefully interpreting cognitive outcomes. © 2017 John Wiley & Sons Ltd.

A Population-based Clinical Study of Allergic and Non-allergic Asthma

DEFF Research Database (Denmark)

Knudsen, T.B.; Thomsen, S.F.; Nolte, H.

2009-01-01

Background. The aim of this study was to describe differences between allergic and non-allergic asthma in a large community-based sample of Danish adolescents and adults. Methods. A total of 1,186 subjects, 14 to 44 years of age, who in a screening questionnaire had reported a history of airway...... symptoms suggestive of asthma and/or allergy, or who were taking any medication for these conditions were clinically examined. All participants were interviewed about respiratory symptoms, and furthermore skin test reactivity, lung function, and airway responsiveness were measured. Results. A total of 489...

Long term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma

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Trzil, Julie E; Masseau, Isabelle; Webb, Tracy L; Chang, Chee-hoon; Dodam, John R; Cohn, Leah A; Liu, Hong; Quimby, Jessica M; Dow, Steven W; Reinero, Carol R

2014-01-01

Background Mesenchymal stem cells (MSCs) decrease airway eosinophilia, airway hyperresponsiveness (AHR), and remodeling in murine models of acutely induced asthma. We hypothesized that MSCs would diminish these hallmark features in a chronic feline asthma model. Objective To document effects of allogeneic, adipose-derived MSCs on airway inflammation, airway hyperresponsiveness (AHR), and remodeling over time and investigate mechanisms by which MSCs alter local and systemic immunologic responses in chronic experimental feline allergic asthma. Methods Cats with chronic, experimentally-induced asthma received six intravenous infusions of MSCs (0.36–2.5X10E7 MSCs/infusion) or placebo bimonthly at the time of study enrollment. Cats were evaluated at baseline and longitudinally for one year. Outcome measures included: bronchoalveolar lavage fluid cytology to assess airway eosinophilia; pulmonary mechanics and clinical scoring to assess AHR; and thoracic computed tomographic (CT) scans to assess structural changes (airway remodeling). CT scans were evaluated using a scoring system for lung attenuation (LA) and bronchial wall thickening (BWT). To assess mechanisms of MSC action, immunologic assays including allergen-specific IgE, cellular IL-10 production, and allergen-specific lymphocyte proliferation were performed. Results There were no differences between treatment groups or over time with respect to airway eosinophilia or AHR. However, significantly lower LA and BWT scores were noted in CT images of MSC-treated animals compared to placebo-treated cats at month 8 of the study (LA p=0.0311; BWT p=0.0489). No differences were noted between groups in the immunologic assays. Conclusions and Clinical Relevance When administered after development of chronic allergic feline asthma, MSCs failed to reduce airway inflammation and AHR. However, repeated administration of MSCs at the start of study did reduce computed tomographic measures of airway remodeling by month 8, though

Airway smooth muscle cells : regulators of airway inflammation

NARCIS (Netherlands)

Zuyderduyn, Suzanne

2007-01-01

Airways from asthmatic subjects are more responsive to bronchoconstrictive stimuli than airways from healthy subjects. Airway smooth muscle (ASM) cells mediate contraction of the airways by responding to the bronchoconstrictive stimuli, which was thought to be the primary role of ASM cells. In this

Airway inflammation and upper respiratory tract infection in athletes: is there a link?

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Bermon, Stéphane

2007-01-01

Upper Respiratory Tract Infection (URTI) is regarded as the most common medical condition affecting both highly trained and elite athletes, in particular those participating in endurance events. The causes of these disturbances, also occurring during training, remain unclear. Viruses such as rhinovirus, adenovirus and para-influenza virus are frequently reported as the source of URTI. However, in a few comprehensive laboratory and epidemiological studies which reported at least a 30% incidence of URTI, no identifiable pathogens were either reported or studied. A recent, longitudinal study investigated symptomatology and pathogenic etiology in sedentary controls, recreational and elite athletes. The highest incidence of URTI occurred in elite athletes. However; only 11 out of 37 illness episodes overall had pathogenic origins, and most of the unidentified upper respiratory illnesses were shorter in duration and less severe than infectious ones. This concept of inflammation without infection in athletes is quite new and leads us to consider other explanatory pathophysiological conditions. Increases in airway neutrophils, eosinophils and lymphocytes have been described under resting conditions in endurance sports, swimmers and cross-country skiers. These inflammatory patterns may be due to pollutants or chlorine-related compounds in swimmers. After intense exercise similar airways cellular profiles have been reported, with a high amount of bronchial epithelial cells. This increase in airway inflammatory cells in athletes can result from a hyperventilation-induced increase in airway osmolarity stimulating bronchial epithelial cells to release chemotactic factors. Fortunately, in most cases, these inflammatory cells express rather low level of adhesion molecules, explaining why airway inflammation may appear blunted in athletes despite numerous inflammatory cellular elements. However it can be hypothesized that a transient loss of control of this local inflammation, due

Chlorinated pool attendance, airway epithelium defects and the risks of allergic diseases in adolescents: Interrelationships revealed by circulating biomarkers

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Bernard, Alfred, E-mail: Alfred.bernard@uclouvain.be; Nickmilder, Marc; Dumont, Xavier

2015-07-15

It has been suggested that allergic diseases might be epithelial disorders driven by various environmental stressors but the epidemiological evidence supporting this concept is limited. In a cross-sectional study of 835 school adolescents (365 boys; mean age, 15.5 yr), we measured the serum concentrations of Club cell protein (CC16), surfactant-associated protein D (SP-D) and of total and aeroallergen-specific IgE. We used the serum CC16/SP-D concentration ratio as an index integrating changes in the permeability (SP-D) and secretory function (CC16) of the airway epithelium. In both sexes, early swimming in chlorinated pools emerged as the most consistent and strongest predictor of low CC16 and CC16/SP-D ratio in serum. Among girls, a low CC16/SP-D ratio was associated with increased odds (lowest vs. highest tertile) for pet sensitization (OR 2.97, 95% CI 1.19–8.22) and for hay fever in subjects sensitized to pollen (OR 4.12, 95% CI 1.28–14.4). Among boys, a low CC16/SP-D ratio was associated with increased odds for house-dust mite (HDM) sensitization (OR 2.01, 95% CI 1.11–3.73), for allergic rhinitis in subjects sensitized to HDM (OR 3.52, 95% CI 1.22–11.1) and for asthma in subjects sensitized to any aeroallergen (OR 3.38, 95% CI 1.17–11.0), HDM (OR 5.20, 95% CI 1.40–24.2) or pollen (OR 5.82, 95% CI 1.51–27.4). Odds for allergic sensitization or rhinitis also increased with increasing SP-D or decreasing CC16 in serum. Our findings support the hypothesis linking the development of allergic diseases to epithelial barrier defects due to host factors or environmental stressors such as early swimming in chlorinated pools. - Highlights: • We conducted a cross-sectional study of 835 school adolescents. • The airway epithelium integrity was evaluated by measuring serum pneumoproteins. • The risk of allergic diseases was associated with a defective airway epithelium. • Childhood swimming in chlorinated pools can cause persistent epithelial

Chlorinated pool attendance, airway epithelium defects and the risks of allergic diseases in adolescents: Interrelationships revealed by circulating biomarkers

International Nuclear Information System (INIS)

Bernard, Alfred; Nickmilder, Marc; Dumont, Xavier

2015-01-01

It has been suggested that allergic diseases might be epithelial disorders driven by various environmental stressors but the epidemiological evidence supporting this concept is limited. In a cross-sectional study of 835 school adolescents (365 boys; mean age, 15.5 yr), we measured the serum concentrations of Club cell protein (CC16), surfactant-associated protein D (SP-D) and of total and aeroallergen-specific IgE. We used the serum CC16/SP-D concentration ratio as an index integrating changes in the permeability (SP-D) and secretory function (CC16) of the airway epithelium. In both sexes, early swimming in chlorinated pools emerged as the most consistent and strongest predictor of low CC16 and CC16/SP-D ratio in serum. Among girls, a low CC16/SP-D ratio was associated with increased odds (lowest vs. highest tertile) for pet sensitization (OR 2.97, 95% CI 1.19–8.22) and for hay fever in subjects sensitized to pollen (OR 4.12, 95% CI 1.28–14.4). Among boys, a low CC16/SP-D ratio was associated with increased odds for house-dust mite (HDM) sensitization (OR 2.01, 95% CI 1.11–3.73), for allergic rhinitis in subjects sensitized to HDM (OR 3.52, 95% CI 1.22–11.1) and for asthma in subjects sensitized to any aeroallergen (OR 3.38, 95% CI 1.17–11.0), HDM (OR 5.20, 95% CI 1.40–24.2) or pollen (OR 5.82, 95% CI 1.51–27.4). Odds for allergic sensitization or rhinitis also increased with increasing SP-D or decreasing CC16 in serum. Our findings support the hypothesis linking the development of allergic diseases to epithelial barrier defects due to host factors or environmental stressors such as early swimming in chlorinated pools. - Highlights: • We conducted a cross-sectional study of 835 school adolescents. • The airway epithelium integrity was evaluated by measuring serum pneumoproteins. • The risk of allergic diseases was associated with a defective airway epithelium. • Childhood swimming in chlorinated pools can cause persistent epithelial

Mechanisms of Heightened Airway Sensitivity and Responses to Inhaled SO2 in Asthmatics.

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Reno, Anita L; Brooks, Edward G; Ameredes, Bill T

2015-01-01

Sulfur dioxide (SO2) is a problematic inhalable air pollutant in areas of widespread industrialization, not only in the United States but also in countries undergoing rapid industrialization, such as China, and it can be a potential trigger factor for asthma exacerbations. It is known that asthmatics are sensitive to the effects of SO2; however, the basis of this enhanced sensitivity remains incompletely understood. A PubMed search was performed over the course of 2014, encompassing the following terms: asthma, airway inflammation, sulfur dioxide, IL-10, mouse studies, and human studies. This search indicated that biomarkers of SO2 exposure, SO2 effects on airway epithelial cell function, and animal model data are useful in our understanding of the body's response to SO2, as are SO2-associated amplification of allergic inflammation, and potential promotion of neurogenic inflammation due to chemical irritant properties. While definitive answers are still being sought, these areas comprise important foci of consideration regarding asthmatic responses to inhaled SO2. Furthermore, IL-10 deficiency associated with asthma may be another important factor associated with an inability to resolve inflammation and mitigate oxidative stress resulting from SO2 inhalation, supporting the idea that asthmatics are predisposed to SO2 sensitivity, leading to asthma exacerbations and airway dysfunction.

Aldose reductase inhibition prevents allergic airway remodeling through PI3K/AKT/GSK3β pathway in mice.

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Umesh C S Yadav

Full Text Available Long-term and unresolved airway inflammation and airway remodeling, characteristic features of chronic asthma, if not treated could lead to permanent structural changes in the airways. Aldose reductase (AR, an aldo-sugar and lipid aldehyde metabolizing enzyme, mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. In the present study, we have examined the role of AR on airway remodeling using ovalbumin (OVA-induced chronic asthma mouse model and cultured human primary airway epithelial cells (SAECs and mouse lung fibroblasts (mLFs.Airway remodeling in chronic asthma model was established in mice sensitized and challenged twice a week with OVA for 6 weeks. AR inhibitor, fidarestat, was administered orally in drinking water after first challenge. Inflammatory cells infiltration in the lungs and goblet cell metaplasia, airway thickening, collagen deposition and airway hyper-responsiveness (AHR in response to increasing doses of methacholine were assessed. The TGFβ1-induced epithelial-mesenchymal transition (EMT in SAECs and changes in mLFs were examined to investigate AR-mediated molecular mechanism(s of airway remodeling.In the OVA-exposed mice for 6 wks inflammatory cells infiltration, levels of inflammatory cytokines and chemokines, goblet cell metaplasia, collagen deposition and AHR were significantly decreased by treatment with AR inhibitor, fidarestat. Further, inhibition of AR prevented TGFβ1-induced altered expression of E-cadherin, Vimentin, Occludin, and MMP-2 in SAECs, and alpha-smooth muscle actin and fibronectin in mLFs. Further, in SAECs, AR inhibition prevented TGFβ1- induced activation of PI3K/AKT/GSK3β pathway but not the phosphorylation of Smad2/3.Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGFβ1-induced Smad-independent and PI3K/AKT/GSK3β-dependent pathway.

Aspergillus fumigatus viability drives allergic responses to inhaled conidia.

Science.gov (United States)

Nayak, Ajay P; Croston, Tara L; Lemons, Angela R; Goldsmith, W T; Marshall, Nikki B; Kashon, Michael L; Germolec, Dori R; Beezhold, Donald H; Green, Brett J

2018-04-13

Aspergillus fumigatus induced allergic airway disease has been shown to involve conidial germination in vivo but the immunological mechanisms remain uncharacterized. A subchronic murine exposure model was used to examine the immunological mediators that are regulated in response to either culturable or non-culturable A. fumigatus conidia. Female B6C3F1/N mice were repeatedly dosed via inhalation with 1 x 105 viable or heat inactivated conidia (HIC), twice a week for 13 weeks (26 exposures). Control mice inhaled HEPA-filtered air. The influence of A. fumigatus conidial germination on the pulmonary immunopathological outcomes was evaluated by flow cytometry analysis of cellular infiltration in the airways, assessment of lung mRNA expression, and quantitative proteomics and histopathology of whole lung tissue. Repeated inhalation of viable conidia, but not HIC, resulted in allergic inflammation marked by vascular remodeling, extensive eosinophilia, and accumulation of alternatively activated macrophages (AAMs) in the murine airways. More specifically, mice that inhaled viable conidia resulted in a mixed TH1 and TH2 (IL-13) cytokine response. Recruitment of eosinophils corresponded with increased Ccl11 transcripts. Furthermore, genes associated with M2 or alternatively activated macrophage polarization (e.g. Arg1, Chil3 and Retnla) were significantly upregulated in viable A. fumigatus exposed mice. In mice inhaling HIC, CD4+ T cells expressing IFN-γ (TH1) dominated the lymphocytic infiltration. Quantitative proteomics of the lung revealed metabolic reprogramming accompanied by mitochondrial dysfunction and endoplasmic reticulum stress stimulated by oxidative stress from repetitive microbial insult. Our studies demonstrate that A. fumigatus conidial viability in vivo is critical to the immunopathological presentation of chronic fungal allergic disease. Copyright © 2018. Published by Elsevier Inc.

Influence of Asian dust particles on immune adjuvant effects and airway inflammation in asthma model mice.

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Jun Kurai

Full Text Available An Asian dust storm (ADS contains airborne particles that affect conditions such as asthma, but the mechanism of exacerbation is unclear. The objective of this study was to compare immune adjuvant effects and airway inflammation induced by airborne particles collected on ADS days and the original ADS soil (CJ-1 soil in asthma model mice.Airborne particles were collected on ADS days in western Japan. NC/Nga mice were co-sensitized by intranasal instillation with ADS airborne particles and/or Dermatophagoides farinae (Df, and with CJ-1 soil and/or Df for 5 consecutive days. Df-sensitized mice were stimulated with Df challenge intranasally at 7 days after the last Df sensitization. At 24 hours after challenge, serum allergen specific antibody, differential leukocyte count and inflammatory cytokines in bronchoalveolar lavage fluid (BALF were measured, and airway inflammation was examined histopathologically.Co-sensitization with ADS airborne particles and Df increased the neutrophil and eosinophil counts in BALF. Augmentation of airway inflammation was also observed in peribronchiolar and perivascular lung areas. Df-specific serum IgE was significantly elevated by ADS airborne particles, but not by CJ-1 soil. Levels of interleukin (IL-5, IL-13, IL-6, and macrophage inflammatory protein-2 were higher in BALF in mice treated with ADS airborne particles.These results suggest that substances attached to ADS airborne particles that are not in the original ADS soil may play important roles in immune adjuvant effects and airway inflammation.

Methyl Protodioscin from the Roots of Asparagus cochinchinensis Attenuates Airway Inflammation by Inhibiting Cytokine Production

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Ju Hee Lee

2015-01-01

Full Text Available The present study was designed to find pharmacologically active compound against airway inflammation from the roots of Asparagus cochinchinensis. The 70% ethanol extract of the roots of A. cochinchinensis (ACE was found to inhibit IL-6 production from IL-1β-treated lung epithelial cells (A549 and the major constituent, methyl protodioscin (MP, also strongly inhibited the production of IL-6, IL-8, and tumor necrosis factor- (TNF- α from A549 cells at 10–100 μM. This downregulating effect of proinflammatory cytokine production was found to be mediated, at least in part, via inhibition of c-Jun N-terminal kinase (JNK and c-Jun activation pathway. When examined on an in vivo model of airway inflammation in mice, lipopolysaccharide- (LPS- induced acute lung injury, ACE, and MP significantly inhibited cell infiltration in the bronchoalveolar lavage fluid by the oral treatment at doses of 100–400 mg/kg and 30–60 mg/kg, respectively. MP also inhibited the production of proinflammatory cytokines such as IL-6, TNF-α, and IL-1β in lung tissue. All of these findings provide scientific evidence supporting the role of A. cochinchinensis as a herbal remedy in treating airway inflammation and also suggest a therapeutic value of MP on airway inflammatory disorders.

Effect of budesonide and cetirizine hydrochloride on neurotrophic factor, airway function and chemokines CCL17 and CCL22 in patients with allergic rhinitis

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Xiang Xu

2017-11-01

Full Text Available Objective: To investigate the effect of budesonide combined with cetirizine hydrochloride on neurotrophic factor, airway function and chemokines CCL17 and CCL12 in patients with allergic rhinitis. Methods: A total of 123 patients with Allergic Rhinitis were randomly divided into three groups, A group treated with budesonide nasal spray, B group treated with cetirizine hydrochloride, C group treated with budesonide combined with cetirizine hydrochloride, then the Neurotrophic factors, airway function indexes and chemokines CCL17 and CCL12 levels in three groups were compared. Results: Before the treatments, the three groups of patients in neurotrophic factor, airway function index and chemokines CCL17, CCL22 have no differences, Compared with before the treatments, after receiving different treatments, the three groups of patients in all indicators were Showed significant differences. In the indexes of neurotrophic factor (NGF, BDNF, NT-3mRNA expression, there was no significant difference between group A and group B, and group C was lower than group A and B. In airway function indexes (FVC, FEV1 and PEF, A group was significantly higher than B group, C group was significantly higher than A group; In the chemokines CCL17 and CCL22 indicators, C group was lower than A group, A group was lower than B group, the difference was significant. Conclusions: Budesonide combined with cetirizine hydrochloride in the treatment of Allergic Rhinitis, can effectively control the patients' neurotrophic factor, pulmonary ventilation and chemokine CC17, CCL22 indicators, the effect is better than Budesonide alone or Cetirizine hydrochloride.

Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections.

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Hisert, Katherine B; Heltshe, Sonya L; Pope, Christopher; Jorth, Peter; Wu, Xia; Edwards, Rachael M; Radey, Matthew; Accurso, Frank J; Wolter, Daniel J; Cooke, Gordon; Adam, Ryan J; Carter, Suzanne; Grogan, Brenda; Launspach, Janice L; Donnelly, Seamas C; Gallagher, Charles G; Bruce, James E; Stoltz, David A; Welsh, Michael J; Hoffman, Lucas R; McKone, Edward F; Singh, Pradeep K

2017-06-15

Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments.

NEUROTROPHIN RECEPTOR BLOCKADE ATTENUATES DIESEL EXHAUST PARTICULATE MATTER (DEP) ENHANCEMENT OF ALLERGIC RESPONSES

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ABSTRACT BODY:Recent investigations have linked neurotrophins including NGF, NT-3, and BDNF to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance associated with allergic airway responses in mice. Mice administered an antibody against the low aff...

Effects of gasoline engine emissions on preexisting allergic airway responses in mice.

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Day, Kimberly C; Reed, Matthew D; McDonald, Jacob D; Seilkop, Steven K; Barrett, Edward G

2008-10-01

Gasoline-powered vehicle emissions contribute significantly to ambient air pollution. We hypothesized that exposure to gasoline engine emissions (GEE) may exacerbate preexisting allergic airway responses. Male BALB/c mice were sensitized by injection with ovalbumin (OVA) and then received a 10-min aerosolized OVA challenge. Parallel groups were sham-sensitized with saline. Mice were exposed 6 h/day to air (control, C) or GEE containing particulate matter (PM) at low (L), medium (M), or high (H) concentrations, or to the H level with PM removed by filtration (high-filtered, HF). Immediately after GEE exposure mice received another 10-min aerosol OVA challenge (pre-OVA protocol). In a second (post-OVA) protocol, mice were similarly sensitized but only challenged to OVA before air or GEE exposure. Measurements of airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL), and blood collection were performed approximately 24 h after the last exposure. In both protocols, M, H, and HF GEE exposure significantly decreased BAL neutrophils from nonsensitized mice but had no significant effect on BAL cells from OVA-sensitized mice. In the pre-OVA protocol, GEE exposure increased OVA-specific IgG(1) but had no effect on BAL interleukin (IL)-2, IL-4, IL-13, or interferon (IFN)-gamma in OVA-sensitized mice. Nonsensitized GEE-exposed mice had increased OVA-specific IgG(2a), IgE, and IL-2, but decreased total IgE. In the post-OVA protocol, GEE exposure reduced BAL IL-4, IL-5, and IFN-gamma in nonsensitized mice but had no effect on sensitized mice. These results suggest acute exposure to the gas-vapor phase of GEE suppressed inflammatory cells and cytokines from nonsensitized mice but did not substantially exacerbate allergic responses.

Protective Roles for RGS2 in a Mouse Model of House Dust Mite-Induced Airway Inflammation.

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Tresa George

Full Text Available The GTPase-accelerating protein, regulator of G-protein signalling 2 (RGS2 reduces signalling from G-protein-coupled receptors (GPCRs that signal via Gαq. In humans, RGS2 expression is up-regulated by inhaled corticosteroids (ICSs and long-acting β2-adrenoceptor agonists (LABAs such that synergy is produced in combination. This may contribute to the superior clinical efficacy of ICS/LABA therapy in asthma relative to ICS alone. In a murine model of house dust mite (HDM-induced airways inflammation, three weeks of intranasal HDM (25 μg, 3×/week reduced lung function and induced granulocytic airways inflammation. Compared to wild type animals, Rgs2-/- mice showed airways hyperresponsiveness (increased airways resistance and reduced compliance. While HDM increased pulmonary inflammation observed on hematoxylin and eosin-stained sections, there was no difference between wild type and Rgs2-/- animals. HDM-induced mucus hypersecretion was also unaffected by RGS2 deficiency. However, inflammatory cell counts in the bronchoalveolar lavage fluid of Rgs2-/- animals were significantly increased (57% compared to wild type animals and this correlated with increased granulocyte (neutrophil and eosinophil numbers. Likewise, cytokine and chemokine (IL4, IL17, IL5, LIF, IL6, CSF3, CXCLl, CXCL10 and CXCL11 release was increased by HDM exposure. Compared to wild type, Rgs2-/- animals showed a trend towards increased expression for many cytokines/chemokines, with CCL3, CCL11, CXCL9 and CXCL10 being significantly enhanced. As RGS2 expression was unaffected by HDM exposure, these data indicate that RGS2 exerts tonic bronchoprotection in HDM-induced airways inflammation. Modest anti-inflammatory and anti-remodelling roles for RGS2 are also suggested. If translatable to humans, therapies that maximize RGS2 expression may prove advantageous.

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.

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

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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.

Exposure of neonates to Respiratory Syncytial Virus is critical in determining subsequent airway response in adults

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Daly Melissa

2006-08-01

Full Text Available Abstract Background Respiratory syncytial virus (RSV is the most common cause of acute bronchiolitis in infants and the elderly. Furthermore, epidemiological data suggest that RSV infection during infancy is a potent trigger of subsequent wheeze and asthma development. However, the mechanism by which RSV contributes to asthma is complex and remains largely unknown. A recent study indicates that the age of initial RSV infection is a key factor in determining airway response to RSV rechallenge. We hypothesized that severe RSV infection during neonatal development significantly alters lung structure and the pulmonary immune micro-environment; and thus, neonatal RSV infection is crucial in the development of or predisposition to allergic inflammatory diseases such as asthma. Methods To investigate this hypothesis the present study was conducted in a neonatal mouse model of RSV-induced pulmonary inflammation and airway dysfunction. Seven-day-old mice were infected with RSV (2 × 105 TCID50/g body weight and allowed to mature to adulthood. To determine if neonatal RSV infection predisposed adult animals to enhanced pathophysiological responses to allergens, these mice were then sensitized and challenged with ovalbumin. Various endpoints including lung function, histopathology, cytokine production, and cellularity in bronchoalveolar lavage were examined. Results RSV infection in neonates alone led to inflammatory airway disease characterized by airway hyperreactivity, peribronchial and perivascular inflammation, and subepithelial fibrosis in adults. If early RSV infection was followed by allergen exposure, this pulmonary phenotype was exacerbated. The initial response to neonatal RSV infection resulted in increased TNF-α levels in bronchoalveolar lavage. Interestingly, increased levels of IL-13 and mucus hyperproduction were observed almost three months after the initial infection with RSV. Conclusion Neonatal RSV exposure results in long term

Early markers of airways inflammation and occupational asthma: rationale, study design and follow-up rates among bakery, pastry and hairdressing apprentices.

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Tossa, Paul; Bohadana, Abraham; Demange, Valérie; Wild, Pascal; Michaely, Jean-Pierre; Hannhart, Bernard; Paris, Christophe; Zmirou-Navier, Denis

2009-04-23

Occupational asthma is a common type of asthma caused by a specific agent in the workplace. The basic alteration of occupational asthma is airways inflammation. Although most patients with occupational asthma are mature adults, there is evidence that airways inflammation starts soon after inception of exposure, including during apprenticeship. Airways hyper responsiveness to methacholine is a valid surrogate marker of airways inflammation, which has proved useful in occupational epidemiology. But it is time-consuming, requires active subject's cooperation and is not readily feasible. Other non-invasive and potentially more useful tests include the forced oscillation technique, measurement of fraction exhaled nitric oxide, and eosinophils count in nasal lavage fluid. This study aims to investigate early development of airways inflammation and asthma-like symptoms in apprentice bakers, pastry-makers and hairdressers, three populations at risk of occupational asthma whose work-related exposures involve agents of different nature. The objectives are to (i) examine the performance of the non-invasive tests cited above in detecting early airways inflammation that might eventually develop into occupational asthma; and (ii) evaluate whether, and how, constitutional (e.g. atopy) and behavioural (e.g. smoking) risk factors for occupational asthma modulate the effects of allergenic and/or irritative substances involved in these occupations. This paper presents the study rationale and detailed protocol. Among 441 volunteers included at the first visit, 354 attended the fourth one. Drop outs were investigated and showed unrelated to the study outcome. Sample size and follow-up participation rates suggest that the data collected in this study will allow it to meet its objectives.

Polarized Airway Epithelial Models for Immunological Co-Culture Studies

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Papazian, Dick; Würtzen, Peter A; Hansen, Søren Werner Karlskov

2016-01-01

Epithelial cells line all cavities and surfaces throughout the body and play a substantial role in maintaining tissue homeostasis. Asthma and other atopic diseases are increasing worldwide and allergic disorders are hypothesized to be a consequence of a combination of dysregulation...... of the epithelial response towards environmental antigens and genetic susceptibility, resulting in inflammation and T cell-derived immune responses. In vivo animal models have long been used to study immune homeostasis of the airways but are limited by species restriction and lack of exposure to a natural...

Vagotomy decreases the neuronal activities of medulla oblongata and alleviates neurogenic inflammation of airways induced by repeated intra-esophageal instillation of HCl in guinea pigs.

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Chen, Zhe; Chen, Hui; Chen, Fagui; Gu, Dachuan; Sun, Lejia; Zhang, Weitao; Fan, Linfeng; Lin, Yong; Dong, Rong; Lai, Kefang

2017-12-20

Neuronal activity in the medulla oblongata and neurogenic inflammation of airways were investigated in a guinea pig model induced by repeated intra-esophageal instillation of hydrochloric acid (HCl) after vagotomy. Unilateral vagotomy was performed in the vagotomy group, while a sham-operation was performed in the sham group. Operation was not conducted in sham control group. Airway inflammation was observed with hematoxylin and eosin (HE) staining. C-fos protein was measured by immunohistochemistry (IHC) and Western blot (WB). Substance P was examined by IHC and enzyme-linked immuno sorbent assay (ELISA). Airway microvascular permeability was detected by evans blue dye (EBD) fluorescence. Inflammation of airway was observed in the trachea and bronchi after chronic HCl perfusion into the lower esophagus, and was alleviated after unilateral vagotomy. C-fos expression in the medulla oblongata was lower in the vagotomy group compared to the sham control and sham groups. Substance P-like immunoreactivity (SP-li), concentration and microvascular leakage in airway were lower in the vagotomy group than that in the other groups. Our results suggest that vagotomy improved neurogenic inflammation of airways and decreased neuronal activities, the afferent nerves and neurons in medulla oblongata may be involved in neurogenic inflammation of airways mediated by esophageal-bronchial reflex.

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

Dianthus superbus fructus suppresses airway inflammation by downregulating of inducible nitric oxide synthase in an ovalbumin-induced murine model of asthma

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2012-01-01

Background Dianthus superbus has long been used as a herbal medicine in Asia and as an anti-inflammatory agent. In this study, we evaluated the anti-inflammatory effects of Dianthus superbus fructus ethanolic extract (DSE) on Th2-type cytokines, eosinophil infiltration, and other factors in an ovalbumin (OVA)-induced murine asthma model. To study the possible mechanism of the anti-inflammatory effect of DSE, we also evaluated the expression of inducible nitric oxide synthase (iNOS) in the respiratory tract. Methods Mice were sensitized on days 0 and 14 by intraperitoneal injection of OVA. On days 21, 22 and 23 after initial sensitization, mice received an airway challenge with OVA for 1 h using an ultrasonic nebulizer. DSE was applied 1 h prior to OVA challenge. Mice were administered DSE orally at doses of 100 mg/kg or 200 mg/kg once daily from day 18 to 23. Bronchoalveolar lavage fluid (BALF) was collected 48 h after the final OVA challenge. Levels of interleukin (IL)-4, IL-13 and eotaxin in BALF were measured using enzyme-linked immunosorbent assays (ELISAs). Lung tissue sections were stained with hematoxylin and eosin for assessment of cell infiltration and mucus production with periodic acid shift staining, in conjunction with ELISA and western blot analyses for iNOS expression. Results DSE significantly reduced the levels of IL-4, IL-13, eotaxin, and immunoglobulin (Ig) E, number of inflammatory cells in BALF, and inflammatory cell infiltration and mucus production in the respiratory tract. DSE also attenuated the overexpression of iNOS protein induced by OVA challenge. Conclusion Our results suggest that DSE effectively protects against allergic airway inflammation by downregulating of iNOS expression and that DSE has potential as a therapeutic agent for allergic asthma. PMID:23110404

Anti-inflammatory effects of embelin in A549 cells and human asthmatic airway epithelial tissues.

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Lee, In-Seung; Cho, Dong-Hyuk; Kim, Ki-Suk; Kim, Kang-Hoon; Park, Jiyoung; Kim, Yumi; Jung, Ji Hoon; Kim, Kwanil; Jung, Hee-Jae; Jang, Hyeung-Jin

2018-02-01

Allergic asthma is the most common type in asthma, which is defined as a chronic inflammatory disease of the lung. In this study, we investigated whether embelin (Emb), the major component of Ardisia japonica BL. (AJB), exhibits anti-inflammatory effects on allergic asthma via inhibition of NF-κB activity using A549 cells and asthmatic airway epithelial tissues. Inflammation was induced in A549 cells, a human airway epithelial cell line, by IL-1β (10 ng/ml) treatment for 4 h. The effects of Emb on NF-κB activity and COX-2 protein expression in inflamed airway epithelial cells and human asthmatic airway epithelial tissues were analyzed via western blot. The secretion levels of NF-κB-mediated cytokines/chemokines, including IL-4, 6, 9, 13, TNF-α and eotaxin, were measured by a multiplex assay. Emb significantly blocked NF-κB activity in IL-1β-treated A549 cells and human asthmatic airway epithelial tissues. COX-2 expression was also reduced in both IL-1β-treated A549 cells and asthmatic tissues Emb application. Emb significantly reduced the secretion of IL-4, IL-6 and eotaxin in human asthmatic airway epithelial tissues by inhibiting activity of NF-κB. The results of this study suggest that Emb may be used as an anti-inflammatory agent via inhibition of NF-κB and related cytokines.

Intratracheal Administration of Mesenchymal Stem Cells Modulates Tachykinin System, Suppresses Airway Remodeling and Reduces Airway Hyperresponsiveness in an Animal Model.

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Konrad Urbanek

Full Text Available The need for new options for chronic lung diseases promotes the research on stem cells for lung repair. Bone marrow-derived mesenchymal stem cells (MSCs can modulate lung inflammation, but the data on cellular processes involved in early airway remodeling and the potential involvement of neuropeptides are scarce.To elucidate the mechanisms by which local administration of MSCs interferes with pathophysiological features of airway hyperresponsiveness in an animal model.GFP-tagged mouse MSCs were intratracheally delivered in the ovalbumin mouse model with subsequent functional tests, the analysis of cytokine levels, neuropeptide expression and histological evaluation of MSCs fate and airway pathology. Additionally, MSCs were exposed to pro-inflammatory factors in vitro.Functional improvement was observed after MSC administration. Although MSCs did not adopt lung cell phenotypes, cell therapy positively affected airway remodeling reducing the hyperplastic phase of the gain in bronchial smooth muscle mass, decreasing the proliferation of epithelium in which mucus metaplasia was also lowered. Decrease of interleukin-4, interleukin-5, interleukin-13 and increase of interleukin-10 in bronchoalveolar lavage was also observed. Exposed to pro-inflammatory cytokines, MSCs upregulated indoleamine 2,3-dioxygenase. Moreover, asthma-related in vivo upregulation of pro-inflammatory neurokinin 1 and neurokinin 2 receptors was counteracted by MSCs that also determined a partial restoration of VIP, a neuropeptide with anti-inflammatory properties.Intratracheally administered MSCs positively modulate airway remodeling, reduce inflammation and improve function, demonstrating their ability to promote tissue homeostasis in the course of experimental allergic asthma. Because of a limited tissue retention, the functional impact of MSCs may be attributed to their immunomodulatory response combined with the interference of neuropeptide system activation and tissue

Early markers of airways inflammation and occupational asthma: Rationale, study design and follow-up rates among bakery, pastry and hairdressing apprentices

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Hannhart Bernard

2009-04-01

Full Text Available Abstract Background Occupational asthma is a common type of asthma caused by a specific agent in the workplace. The basic alteration of occupational asthma is airways inflammation. Although most patients with occupational asthma are mature adults, there is evidence that airways inflammation starts soon after inception of exposure, including during apprenticeship. Airways hyper responsiveness to methacholine is a valid surrogate marker of airways inflammation, which has proved useful in occupational epidemiology. But it is time-consuming, requires active subject's cooperation and is not readily feasible. Other non-invasive and potentially more useful tests include the forced oscillation technique, measurement of fraction exhaled nitric oxide, and eosinophils count in nasal lavage fluid. Methods and design This study aims to investigate early development of airways inflammation and asthma-like symptoms in apprentice bakers, pastry-makers and hairdressers, three populations at risk of occupational asthma whose work-related exposures involve agents of different nature. The objectives are to (i examine the performance of the non-invasive tests cited above in detecting early airways inflammation that might eventually develop into occupational asthma; and (ii evaluate whether, and how, constitutional (e.g. atopy and behavioural (e.g. smoking risk factors for occupational asthma modulate the effects of allergenic and/or irritative substances involved in these occupations. This paper presents the study rationale and detailed protocol. Discussion Among 441 volunteers included at the first visit, 354 attended the fourth one. Drop outs were investigated and showed unrelated to the study outcome. Sample size and follow-up participation rates suggest that the data collected in this study will allow it to meet its objectives.

Inhibitory effect of kefiran on ovalbumin-induced lung inflammation in a murine model of asthma.

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Kwon, Ok-Kyoung; Ahn, Kyung-Seop; Lee, Mee-Young; Kim, So-Young; Park, Bo-Young; Kim, Mi-Kyoung; Lee, In-Young; Oh, Sei-Ryang; Lee, Hyeong-Kyu

2008-12-01

Kefiran is a major component of kefir which is a microbial symbiont mixture that produces jelly-like grains. This study aimed to evaluate the therapeutic availability of kefiran on the ovalbumin-induced asthma mouse model in which airway inflammation and airway hyper-responsiveness were found in the lung. BALB/c mice sensitized and challenged to ovalbumin were treated intra-gastrically with kefiran 1 hour before the ovalbumin challenge. Kefiran significantly suppressed ovalbumin-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Administration of kefiran significantly inhibited the release of both eosinophils and other inflammatory cells into bronchoalveolar lavage (BAL) fluid and lung tissue which was measured by Diff-Quik. Interleukin-4 (IL-4) and interleukin-5 (IL-5) were also reduced to normal levels after administration of kefiran in BAL fluid. Histological studies demonstrate that kefiran substantially inhibited ovalbumin-induced eosinophilia in lung tissue by H&E staining and goblet cell hyperplasia in the airway by PAS staining. Taken above data, kefiran may be useful for the treatment of inflammation of lung tissue and airway hyper-responsiveness in a murine model and may have therapeutic potential for the treatment of allergic bronchial asthma.

Bronchodilator Response in Patients with Persistent Allergic Asthma Could Not Predict Airway Hyperresponsiveness

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Petanjek Bojana B

2007-12-01

Full Text Available Anticholinergics, or specific antimuscarinic agents, by inhibition of muscarinic receptors cause bronchodilatation, which might correlate with activation of these receptors by the muscarinic agonist methacholine. The aim of this study was to determine whether a positive bronchodilator response to the anticholinergic ipratropium bromide could predict airway hyperresponsiveness in patients with persistent allergic asthma. The study comprised 40 patients with mild and moderate persistent allergic asthma. Diagnosis was established by clinical and functional follow-up (skin-prick test, spirometry, bronchodilator tests with salbutamol and ipratropium bromide, and methacholine challenge testing. The bronchodilator response was positive to both bronchodilator drugs in all patients. After salbutamol inhalation, forced expiratory volume in 1 second (FEV1 increased by 18.39 ± 6.18%, p 1 increased by 19.14 ± 6.74%, p 1 decreased by 25.75 ± 5.16%, p 20 FEV1 [provocative concentration of methacholine that results in a 20% fall in FEV1] from 0.026 to 1.914 mg/mL. Using linear regression, between methacholine challenge testing and bronchodilator response to salbutamol, a positive, weak, and stastistically significant correlation for FEV1 was found (p

Relationship between airway responsiveness to mannitol and to methacholine and markers of airway inflammation, peak flow variability and quality of life in asthma patients

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Porsbjerg, C.; Brannan, J.D.; Anderson, S.D.

2008-01-01

Background Airway hyperresponsiveness (AHR) to stimuli that cause bronchial smooth muscle (BSM) contraction indirectly through the release of endogenous mediators is thought to reflect air-way inflammation more closely compared with AHR measured by stimuli that act directly on BSM. Methods Fifty......, there was a stronger correlation between AHR to mannitol and the level of eNO [PD15 to mannitol vs. eNO (p.p.b.): r: -0.63, P

Allergic Bronchopulmonary Aspergillosis

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Juan Carlos Fernández de Córdova-Aguirre

2014-03-01

Full Text Available Allergic bronchopulmonary aspergillosis is a slowly progressive disease, caused by the fungus Aspergillus fumigatus hypersensitivity when it is found in the airway. It usually affects asthmatics and patients with cystic brosis. We report the case of a 20-year-old male patient, student, farmer and rancher with chronic respiratory disease. The diagnosis of allergic bronchopulmonary aspergillosis was made on the basis of the clinical symptoms and complementary studies.

Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients.

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Silkoff, Philip E; Laviolette, Michel; Singh, Dave; FitzGerald, J Mark; Kelsen, Steven; Backer, Vibeke; Porsbjerg, Celeste M; Girodet, Pierre-Olivier; Berger, Patrick; Kline, Joel N; Chupp, Geoffrey; Susulic, Vedrana S; Barnathan, Elliot S; Baribaud, Frédéric; Loza, Matthew J

2017-09-01

The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers. IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm 3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient

The effect of omalizumab on eosinophilic inflammation of the respiratory tract in patients with allergic asthma.

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Kupryś-Lipińska, Izabela; Molińska, Katarzyna; Kuna, Piotr

2016-01-01

Bronchial asthma is characterised by high levels of immunoglobulin E (IgE) and overproduction of pro-inflammatory cytokines, including interleukins IL-4, IL-13 and IL-5 needed for, amongst other things, the production of IgE and the differentiation, maturation, migration and survival of eosinophils. Eosinophils are one of the most important cells in allergic inflammation. Their presence in tissue is linked to the persistence of inflammatory infiltrate, tissue damage and remodelling. Although these cells are very sensitive to corticosteroids, some asthmatic patients do not respond to high doses of these drugs, even when administered systemically. Transbronchial biopsies and bronchoalveolar lavage performed in patients with steroid-resistant asthma have demonstrated higher levels of eosinophils and Th2-type cytokines (IL-4 and IL-5) compared to steroid-sensitive patients. Clinical studies have confirmed that the very effective treatment in these cases is therapy with omalizumab - an anti-IgE monoclonal antibody. The paper discusses the efficacy of omalizumab in reducing eosinophil number in peripheral blood and in the airways of asthmatic patients based on basic, clinical, observational studies and case reports. The significance of omalizumab therapy in asthma control and mechanisms that regulate the effects of omalizumab on eosinophils are evaluated.

Fas activity mediates airway inflammation during mouse adenovirus type 1 respiratory infection.

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Adkins, Laura J; Molloy, Caitlyn T; Weinberg, Jason B

2018-06-13

CD8 T cells play a key role in clearance of mouse adenovirus type 1 (MAV-1) from the lung and contribute to virus-induced airway inflammation. We tested the hypothesis that interactions between Fas ligand (FasL) and Fas mediate the antiviral and proinflammatory effects of CD8 T cells. FasL and Fas expression were increased in the lungs of C57BL/6 (B6) mice during MAV-1 respiratory infection. Viral replication and weight loss were similar in B6 and Fas-deficient (lpr) mice. Histological evidence of pulmonary inflammation was similar in B6 and lpr mice, but lung mRNA levels and airway proinflammatory cytokine concentrations were lower in MAV-1-infected lpr mice compared to infected B6 mice. Virus-induced apoptosis in lungs was not affected by Fas deficiency. Our results suggest that the proinflammatory effects of CD8 T cells during MAV-1 infection are mediated in part by Fas activation and are distinct from CD8 T cell antiviral functions. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of Low-Dose, Long-Term Roxithromycin on Airway Inflammation and Remodeling of Stable Noncystic Fibrosis Bronchiectasis

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Jifeng Liu

2014-01-01

Full Text Available Background. Noncystic fibrosis bronchiectasis (NCFB is characterized by airway expansion and recurrent acute exacerbations. Macrolide has been shown to exhibit anti-inflammatory effects in some chronic airway diseases. Objective. To assess the efficacy of roxithromycin on airway inflammation and remodeling in patients with NCFB under steady state. Methods. The study involved an open-label design in 52 eligible Chinese patients with NCFB, who were assigned to control (receiving no treatment and roxithromycin (receiving 150 mg/day for 6 months groups. At baseline and 6 months, the inflammatory markers such as interleukin- (IL-8, neutrophil elastase (NE, matrix metalloproteinase- (MMP9, hyaluronidase (HA, and type IV collagen in sputum were measured, along with the detection of dilated bronchus by throat computed tomography scan, and assessed the exacerbation. Results. Forty-three patients completed the study. The neutrophil in the sputum was decreased in roxithromycin group compared with control (P<0.05. IL-8, NE, MMP-9, HA, and type IV collagen in sputum were also decreased in roxithromycin group compared with the control group (all P<0.01. Airway thickness of dilated bronchus and exacerbation were reduced in roxithromycin group compared with the control (all P<0.05. Conclusions. Roxithromycin can reduce airway inflammation and airway thickness of dilated bronchus in patients with NCFB.

mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation.

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Sinclair, Charles; Bommakanti, Gayathri; Gardinassi, Luiz; Loebbermann, Jens; Johnson, Matthew Joseph; Hakimpour, Paul; Hagan, Thomas; Benitez, Lydia; Todor, Andrei; Machiah, Deepa; Oriss, Timothy; Ray, Anuradha; Bosinger, Steven; Ravindran, Rajesh; Li, Shuzhao; Pulendran, Bali

2017-09-08

Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that mechanistic target of rapamycin (mTOR)-dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for dendritic cell (DC) homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103 + DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b + DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic T helper cell 2 (T H 2) to neutrophilic T H 17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DCs, which produced interleukin-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Distinct patterns of inflammation in the airway lumen and bronchial mucosa of children with cystic fibrosis.

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Regamey, Nicolas; Tsartsali, Lemonia; Hilliard, Tom N; Fuchs, Oliver; Tan, Hui-Leng; Zhu, Jie; Qiu, Yu-Sheng; Alton, Eric W F W; Jeffery, Peter K; Bush, Andrew; Davies, Jane C

2012-02-01

Studies in cystic fibrosis (CF) generally focus on inflammation present in the airway lumen. Little is known about inflammation occurring in the airway wall, the site ultimately destroyed in end-stage disease. To test the hypothesis that inflammatory patterns in the lumen do not reflect those in the airway wall of children with CF. Bronchoalveolar lavage (BAL) fluid and endobronchial biopsies were obtained from 46 children with CF and 16 disease-free controls. BAL cell differential was assessed using May-Gruenwald-stained cytospins. Area profile counts of bronchial tissue immunopositive inflammatory cells were determined. BAL fluid from children with CF had a predominance of neutrophils compared with controls (median 810×10(3)/ml vs 1×10(3)/ml, p<0.0001). In contrast, subepithelial bronchial tissue from children with CF was characterised by a predominance of lymphocytes (median 961 vs 717 cells/mm(2), p=0.014), of which 82% were (CD3) T lymphocytes. In chest exacerbations, BAL fluid from children with CF had more inflammatory cells of all types compared with those with stable disease whereas, in biopsies, only the numbers of lymphocytes and macrophages, but not of neutrophils, were higher. A positive culture of Pseudomonas aeruginosa was associated with higher numbers of T lymphocytes in subepithelial bronchial tissue (median 1174 vs 714 cells/mm(2), p=0.029), but no changes were seen in BAL fluid. Cell counts in BAL fluid and biopsies were positively correlated with age but were unrelated to each other. The inflammatory response in the CF airway is compartmentalised. In contrast to the neutrophil-dominated inflammation present in the airway lumen, the bronchial mucosa is characterised by the recruitment and accumulation of lymphocytes.

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

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Barfod Kenneth K

2010-09-01

Full Text Available Abstract Background 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 lumen and histological alterations of the lungs. Hazard identifications of the biopesticides were carried out using intratracheal (i.t. instillation, followed by an inhalation study. The two commercial biopesticides used were based on the Bt. subspecies kurstaki and israelensis, respectively. Groups of BALB/c mice were i.t instilled with one bolus (3.5 × 105 or 3.4 × 106 colony forming units (CFU per mouse of either biopesticide. Control mice were instilled with sterile water. BALFs were collected and the inflammatory cells were counted and differentiated. The BALFs were also subjected to CFU counts. Results BALF cytology showed an acute inflammatory response dominated by neutrophils 24 hours after instillation of biopesticide. Four days after instillation, the neutrophil number was normalised and inflammation was dominated by lymphocytes and eosinophils, whereas 70 days after instillation, the inflammation was interstitially located with few inflammatory cells present in the lung lumen. Half of the instilled mice had remaining CFU recovered from BALF 70 days after exposure. To gain further knowledge with relevance for risk assessment, mice were exposed to aerosols of biopesticide one hour per day for 2 × 5 days. Each mouse received 1.9 × 104 CFU Bt israelensis or 2.3 × 103 CFU Bt kurstaki per exposure. Seventy days after end of the aerosol exposures, 3 out of 17 mice had interstitial lung inflammation. CFU could be recovered from 1 out of 10 mice 70 days after exposure to aerosolised Bt kurstaki. Plethysmography showed that inhalation of Bt aerosol did not induce airway irritation. Conclusions Repeated low dose aerosol

Airway inflammation in nonobstructive and obstructive chronic bronchitis with chronic haemophilus influenzae airway infection. Comparison with noninfected patients with chronic obstructive pulmonary disease

NARCIS (Netherlands)

Bresser, P.; Out, T. A.; van Alphen, L.; Jansen, H. M.; Lutter, R.

2000-01-01

Nonencapsulated Haemophilus influenzae often causes chronic infections of the lower respiratory tract in both nonobstructive and obstructive chronic bronchitis. We assessed airway inflammation in clinically stable, chronically H. influenzae-infected patients with nonobstructive (CB-HI, n = 10) and

Broncho-Vaxom attenuates allergic airway inflammation by restoring GSK3β-related T regulatory cell insufficiency.

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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.

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

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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

Th2 cytokines and asthma — The role of interleukin-5 in allergic eosinophilic disease

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Chapman Richard W

2001-03-01

Full Text Available Abstract Interleukin-5 is produced by a number of cell types, and is responsible for the maturation and release of eosinophils in the bone marrow. In humans, interleukin-5 is a very selective cytokine as a result of the restricted expression of the interleukin-5 receptor on eosinophils and basophils. Eosinophils are a prominent feature in the pulmonary inflammation that is associated with allergic airway diseases, suggesting that inhibition of interleukin-5 is a viable treatment. The present review addresses the data that relate interleukin-5 to pulmonary inflammation and function in animal models, and the use of neutralizing anti-interleukin-5 monoclonal antibodies for the treatment of asthma in humans.

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

International Nuclear Information System (INIS)

Maiellaro, Marília; Correa-Costa, Matheus; Vitoretti, Luana Beatriz; Gimenes Júnior, João Antônio; Câmara, Niels Olsen Saraiva; Tavares-de-Lima, Wothan; Farsky, Sandra Helena Poliselli; Lino-dos-Santos-Franco, Adriana

2014-01-01

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

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.

Anthropogenic Climate Change and Allergic Diseases

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Hueiwang Anna Jeng

2012-02-01

Full Text Available Climate change is expected to have an impact on various aspects of health, including mucosal areas involved in allergic inflammatory disorders that include asthma, allergic rhinitis, allergic conjunctivitis and anaphylaxis. The evidence that links climate change to the exacerbation and the development of allergic disease is increasing and appears to be linked to changes in pollen seasons (duration, onset and intensity and changes in allergen content of plants and their pollen as it relates to increased sensitization, allergenicity and exacerbations of allergic airway disease. This has significant implications for air quality and for the global food supply.

Atopic asthmatic immune phenotypes associated with airway microbiota and airway obstruction.

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Benjamin A Turturice

Full Text Available Differences in asthma severity may be related to inflammation in the airways. The lower airway microbiota has been associated with clinical features such as airway obstruction, symptom control, and response to corticosteroids.To assess the relationship between local airway inflammation, severity of disease, and the lower airway microbiota in atopic asthmatics.A cohort of young adult, atopic asthmatics with intermittent or mild/moderate persistent symptoms (n = 13 were assessed via bronchoscopy, lavage, and spirometry. These individuals were compared to age matched non-asthmatic controls (n = 6 and to themselves after six weeks of treatment with fluticasone propionate (FP. Inflammation of the airways was assessed via a cytokine and chemokine panel. Lower airway microbiota composition was determined by metagenomic shotgun sequencing.Unsupervised clustering of cytokines and chemokines prior to treatment with FP identified two asthmatic phenotypes (AP, termed AP1 and AP2, with distinct bronchoalveolar lavage inflammatory profiles. AP2 was associated with more obstruction, compared to AP1. After treatment with FP reduced MIP-1β and TNF-α and increased IL-2 was observed. A module of highly correlated cytokines that include MIP-1β and TNF-α was identified that negatively correlated with pulmonary function. Independently, IL-2 was positively correlated with pulmonary function. The airway microbiome composition correlated with asthmatic phenotypes. AP2, prior to FP treatment, was enriched with Streptococcus pneumoniae. Unique associations between IL-2 or the cytokine module and the microbiota composition of the airways were observed in asthmatics subjects prior to treatment but not after or in controls.The underlying inflammation in atopic asthma is related to the composition of microbiota and is associated with severity of airway obstruction. Treatment with inhaled corticosteroids was associated with changes in the airway inflammatory response to

Eosinophilic airway inflammation is increased in children with asthma and food allergies.

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Kulkarni, Neeta; Ragazzo, Vincenzo; Costella, Silvia; Piacentini, Giorgio; Boner, Attilio; O'Callaghan, Christopher; Fiocchi, Alessandro; Kantar, Ahmad

2012-02-01

Asthma is associated with food allergies in a significant number of children, with evidence linking allergies to asthma severity and morbidity. In this study, we tested our hypothesis that the eosinophilic lower airway inflammation is higher in asthmatic children with food allergies. The aims of the study were to compare the eosinophilic inflammatory markers in asthmatic children with and without food allergies. Children with asthma, with (n = 22) and (n = 53) without food allergies were included. All subjects were classified according to the GINA guidelines (2009) and had received at least 3 months of anti-inflammatory therapy prior to testing. Fractional exhaled nitric oxide and sputum differential counts were performed using standard techniques.   Children with asthma and food allergies had significantly higher fractional exhaled nitric oxide median (range) [(22.4 (6.1-86.9) vs. 10.3 (2.7-38.7) (p = 0.01)] and sputum eosinophil percentage [15.5 (5.0-53.0) vs. 2.0 (0-20) (p allergies. These results suggest that the children with asthma and food allergies have increased eosinophilic inflammation of the airways. © 2011 John Wiley & Sons A/S.

Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma

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Zaagsma Johan

2006-01-01

Full Text Available Abstract Background Using guinea pig tracheal preparations, we have recently shown that endogenous arginase activity attenuates inhibitory nonadrenergic noncholinergic (iNANC nerve-mediated airway smooth muscle relaxation by reducing nitric oxide (NO production – due to competition with neuronal NO-synthase (nNOS for the common substrate, L-arginine. Furthermore, in a guinea pig model of allergic asthma, airway arginase activity is markedly increased after the early asthmatic reaction (EAR, leading to deficiency of agonist-induced, epithelium-derived NO and subsequent airway hyperreactivity. In this study, we investigated whether increased arginase activity after the EAR affects iNANC nerve-derived NO production and airway smooth muscle relaxation. Methods Electrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5 – 16 Hz-induced relaxation was measured in tracheal open-ring preparations precontracted to 30% with histamine in the presence of 1 μM atropine and 3 μM indomethacin. The contribution of NO to EFS-induced relaxation was assessed by the nonselective NOS inhibitor Nω-nitro-L-arginine (L-NNA, 100 μM, while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor Nω-hydroxy-nor-L-arginine (nor-NOHA, 10 μM. Furthermore, the role of substrate availability to nNOS was measured in the presence of exogenous L-arginine (5.0 mM. Results At 6 h after ovalbumin-challenge (after the EAR, EFS-induced relaxation (ranging from 3.2 ± 1.1% at 0.5 Hz to 58.5 ± 2.2% at 16 Hz was significantly decreased compared to unchallenged controls (7.1 ± 0.8% to 75.8 ± 0.7%; P P P Conclusion The results clearly demonstrate that increased arginase activity after the allergen-induced EAR contributes to a deficiency of iNANC nerve-derived NO and decreased airway smooth muscle relaxation, presumably via increased substrate competition with nNOS.

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

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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.

Raw Cow’s Milk Prevents the Development of Airway Inflammation in a Murine House Dust Mite-Induced Asthma Model

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Suzanne Abbring

2017-08-01

Full Text Available Epidemiological studies show an inverse relation between raw cow’s milk consumption and the development of asthma. This protective effect seems to be abolished by milk processing. However, evidence for a causal relationship is lacking, and direct comparisons between raw and processed milk are hardly studied. Therefore, this study investigated the preventive capacity of raw and heated raw milk on the development of house dust mite (HDM-induced allergic asthma in mice. Six- to seven-week-old male BALB/c mice were intranasally (i.n. sensitized with 1 µg HDM or PBS on day 0, followed by an i.n. challenge with 10 µg HDM or PBS on days 7–11. In addition, mice were fed 0.5 mL raw cow’s milk, heated raw cow’s milk, or PBS three times a week throughout the study, starting 1 day before sensitization. On day 14, airway hyperresponsiveness (AHR in response to increasing doses of methacholine was measured to assess lung function. Bronchoalveolar lavage fluid (BALF and lungs were furthermore collected to study the extent of airway inflammation. Raw milk prevented both HDM-induced AHR and pulmonary eosinophilic inflammation, whereas heated raw milk did not. Both milk types suppressed the Th2-polarizing chemokine CCL17 in lung homogenates and reduced lung Th2 and Th17 cell frequency. IL-4 and IL-13 production after ex vivo restimulation of lung T cells with HDM was also reduced by both milk types. However, local IL-5 and IL-13 concentrations were only suppressed by raw milk. These findings support the asthma-protective capacity of raw cow’s milk and show the importance of reduced local type 2 cytokine levels. Heated raw milk did not show an asthma-protective effect, which indicates the involvement of heat-sensitive components. Besides causal evidence, this study provides the basis for further mechanistic studies.

Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients

DEFF Research Database (Denmark)

Silkoff, Philip E; Laviolette, Michel; Singh, Dave

2017-01-01

BACKGROUND: The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. OBJECTIVE: We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene...... expression and how this related to clinically accessible biomarkers. METHODS: IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based...... accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics....

Simvastatin Inhibits Goblet Cell Hyperplasia and Lung Arginase in a Mouse Model of Allergic Asthma: A Novel Treatment for Airway Remodeling?

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Zeki, Amir A.; Bratt, Jennifer M.; Rabowsky, Michelle; Last, Jerold A.; Kenyon, Nicholas J.

2010-01-01

Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function, and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. The statins are cholesterol-lowering drugs that inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting step of cholesterol biosynthesis in the mevalonate pathway. These drugs have been associated with improved respiratory health and ongoing clinical trials are testing their therapeutic potential in asthma. We hypothesized that simvastatin treatment of ovalbumin-exposed mice would attenuate early features of airway remodeling, by a mevalonate-dependent mechanism. BALB/c mice were initially sensitized to ovalbumin, and then exposed to 1% ovalbumin aerosol for 2 weeks after sensitization for a total of six exposures. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) were injected intraperitoneally before each ovalbumin exposure. Treatment with simvastatin attenuated goblet cell hyperplasia, arginase-1 protein expression, and total arginase enzyme activity, but did not alter airway hydroxyproline content or transforming growth factor-β1. Inhibition of goblet cell hyperplasia by simvastatin was mevalonate-dependent. No appreciable changes to airway smooth muscle cells were observed in any of the control or treatment groups. In conclusion, in an acute mouse model of allergic asthma, simvastatin inhibited early hallmarks of airway remodeling, indicators that can lead to airway thickening and fibrosis. Statins are potentially novel treatments for airway remodeling in asthma. Further studies utilizing sub-chronic or chronic allergen exposure models are needed to extend these initial findings. PMID:21078495

Bifidobacterium breve and Lactobacillus rhamnosus treatment is as effective as budesonide at reducing inflammation in a murine model for chronic asthma.

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Sagar, Seil; Morgan, Mary E; Chen, Si; Vos, Arjan P; Garssen, Johan; van Bergenhenegouwen, Jeroen; Boon, Louis; Georgiou, Niki A; Kraneveld, Aletta D; Folkerts, Gert

2014-04-16

Asthma is estimated to affect as many as 300 million people worldwide and its incidence and prevalence are rapidly increasing throughout the world, especially in children and within developing countries. Recently, there has been a growing interest in the use of potentially beneficial bacteria for allergic diseases. This study is aimed at exploring the therapeutic effects of long-term treatment with two different beneficial bacterial strains (Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1) and a glucocorticoid (budesonide), as a reference treatment, on inflammatory response in a murine model for chronic allergic asthma. To mimic the chronic disease in asthmatic patients, we used the murine ovalbumin-induced asthma model combined with prolonged allergen exposure. Airway function; pulmonary airway inflammation; airway remodelling, mRNA expression of pattern recognition receptors, Th-specific cytokines and transcription factors in lung tissue; mast cell degranulation; in vitro T cell activation; and expression of Foxp3 in blood Th cells were examined. Lactobacillus rhamnosus reduced lung resistance to a similar extent as budesonide treatment in chronically asthmatic mice. Pulmonary airway inflammation, mast cell degranulation, T cell activation and airway remodelling were suppressed by all treatments. Beneficial bacteria and budesonide differentially modulated the expression of toll-like receptors (TLRs), nod-like receptors (NLRs), cytokines and T cell transcription factors. Bifidobacterium breve induced regulatory T cell responses in the airways by increasing Il10 and Foxp3 transcription in lung tissue as well as systemic by augmenting the mean fluorescence intensity of Foxp3 in blood CD4+ T cells. These findings show that Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1 have strong anti-inflammatory properties that are comparable to budesonide and therefore may be beneficial in the treatment of chronic asthma.

Deficiency of RAMP1 attenuates antigen-induced airway hyperresponsiveness in mice.

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Manyu Li

Full Text Available Asthma is a chronic inflammatory disease affecting the lung, characterized by breathing difficulty during an attack following exposure to an environmental trigger. Calcitonin gene-related peptide (CGRP is a neuropeptide that may have a pathological role in asthma. The CGRP receptor is comprised of two components, which include the G-protein coupled receptor, calcitonin receptor-like receptor (CLR, and receptor activity-modifying protein 1 (RAMP1. RAMPs, including RAMP1, mediate ligand specificity in addition to aiding in the localization of receptors to the cell surface. Since there has been some controversy regarding the effect of CGRP on asthma, we sought to determine the effect of CGRP signaling ablation in an animal model of asthma. Using gene-targeting techniques, we generated mice deficient for RAMP1 by excising exon 3. After determining that these mice are viable and overtly normal, we sensitized the animals to ovalbumin prior to assessing airway resistance and inflammation after methacholine challenge. We found that mice lacking RAMP1 had reduced airway resistance and inflammation compared to wildtype animals. Additionally, we found that a 50% reduction of CLR, the G-protein receptor component of the CGRP receptor, also ameliorated airway resistance and inflammation in this model of allergic asthma. Interestingly, the loss of CLR from the smooth muscle cells did not alter the airway resistance, indicating that CGRP does not act directly on the smooth muscle cells to drive airway hyperresponsiveness. Together, these data indicate that signaling through RAMP1 and CLR plays a role in mediating asthma pathology. Since RAMP1 and CLR interact to form a receptor for CGRP, our data indicate that aberrant CGRP signaling, perhaps on lung endothelial and inflammatory cells, contributes to asthma pathophysiology. Finally, since RAMP-receptor interfaces are pharmacologically tractable, it may be possible to develop compounds targeting the RAMP1/CLR

Occupational upper airway disease: how work affects the nose

NARCIS (Netherlands)

Hox, V.; Steelant, B.; Fokkens, W.; Nemery, B.; Hellings, P. W.

2014-01-01

Chronic inflammation of the upper airways is common and can arbitrarily be divided into rhinitis and rhinosinusitis. Infection and allergy represent two well-characterized and most frequently diagnosed etiologies of upper airway inflammation. Persistent upper airway inflammation caused by agents

Ursodeoxycholic acid suppresses eosinophilic airway inflammation by inhibiting the function of dendritic cells through the nuclear farnesoid X receptor.

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Willart, M A M; van Nimwegen, M; Grefhorst, A; Hammad, H; Moons, L; Hoogsteden, H C; Lambrecht, B N; Kleinjan, A

2012-12-01

Ursodeoxycholic acid (UDCA) is the only known beneficial bile acid with immunomodulatory properties. Ursodeoxycholic acid prevents eosinophilic degranulation and reduces eosinophil counts in primary biliary cirrhosis. It is unknown whether UDCA would also modulate eosinophilic inflammation outside the gastrointestinal (GI) tract, such as eosinophilic airway inflammation seen in asthma. The working mechanism for its immunomodulatory effect is unknown. The immunosuppressive features of UDCA were studied in vivo, in mice, in an ovalbumin (OVA)-driven eosinophilic airway inflammation model. To study the mechanism of action of UDCA, we analyzed the effect of UDCA on eosinophils, T cells, and dendritic cell (DCs). DC function was studied in greater detail, focussing on migration and T-cell stimulatory strength in vivo and interaction with T cells in vitro as measured by time-lapse image analysis. Finally, we studied the capacity of UDCA to influence DC/T cell interaction. Ursodeoxycholic acid treatment of OVA-sensitized mice prior to OVA aerosol challenge significantly reduced eosinophilic airway inflammation compared with control animals. DCs expressed the farnesoid X receptor for UDCA. Ursodeoxycholic acid strongly promoted interleukin (IL)-12 production and enhanced the migration in DCs. The time of interaction between DCs and T cells was sharply reduced in vitro by UDCA treatment of the DCs resulting in a remarkable T-cell cytokine production. Ursodeoxycholic acid-treated DCs have less capacity than saline-treated DCs to induce eosinophilic inflammation in vivo in Balb/c mice. Ursodeoxycholic acid has the potency to suppress eosinophilic inflammation outside the GI tract. This potential comprises to alter critical function of DCs, in essence, the effect of UDCA on DCs through the modulation of the DC/T cell interaction. © 2012 John Wiley & Sons A/S.

Protective effect of Bifidobacterium infantis CGMCC313-2 on ovalbumin-induced airway asthma and β-lactoglobulin-induced intestinal food allergy mouse models

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Liu, Meng-Yun; Yang, Zhen-Yu; Dai, Wen-Kui; Huang, Jian-Qiong; Li, Yin-Hu; Zhang, Juan; Qiu, Chuang-Zhao; Wei, Chun; Zhou, Qian; Sun, Xin; Feng, Xin; Li, Dong-Fang; Wang, He-Ping; Zheng, Yue-Jie

2017-01-01

AIM To determine whether oral administration of Bifidobacterium infantis CGMCC313-2 (B. infantis CGMCC313-2) inhibits allergen-induced airway inflammation and food allergies in a mouse model. METHODS Ovalbumin (OVA)-induced allergic asthma and β-lactoglobulin-induced food allergy mouse models were used in this study. Following oral administration of B. infantis CGMCC313-2 during or after allergen sensitization, histopathologic changes in the lung and intestine were evaluated by hematoxylin and eosin (HE) staining. In the allergic asthma mouse model, we evaluated the proportion of lung-infiltrating inflammatory cells. OVA-specific IgE and IgG1 levels in serum and cytokine levels in bronchoalveolar lavage fluid (BALF) were also assessed. In the food allergy mouse model, the levels of total IgE and cytokines in serum were measured. RESULTS Oral administration of B. infantis CGMCC313-2 during or after allergen sensitization suppressed allergic inflammation in lung and intestinal tissues, while the proportion of infiltrating inflammatory cells was significantly decreased in the BALF of allergic asthma mice. Moreover, B. infantis CGMCC313-2 decreased the serum levels of total IgE in food allergy mice, and reductions in IgE and IgG1 were also observed in OVA-induced allergic asthma mice. The expression of interleukin-4 (IL-4) and IL-13 in both serum and BALF was suppressed following the administration of B. infantis CGMCC313-2, while an effect on serum IL-10 levels was not observed. CONCLUSION B. infantis CGMCC313-2 inhibits the secretion of allergen-induced IgE, IL-4 and IL-13, and attenuates allergic inflammation. PMID:28405142

Up-date on neuro-immune mechanisms involved in allergic and non-allergic rhinitis

NARCIS (Netherlands)

van Gerven, L.; Boeckxstaens, G.; Hellings, P.

2012-01-01

Non-allergic rhinitis (NAR) is a common disorder, which can be defined as chronic nasal inflammation, independent of systemic IgE-mediated mechanisms. Symptoms of NAR patients mimic those of allergic rhinitis (AR) patients. However, AR patients can easily be diagnosed with skin prick test or

S1P-induced airway smooth muscle hyperresponsiveness and lung inflammation in vivo: molecular and cellular mechanisms.

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Roviezzo, F; Sorrentino, R; Bertolino, A; De Gruttola, L; Terlizzi, M; Pinto, A; Napolitano, M; Castello, G; D'Agostino, B; Ianaro, A; Sorrentino, R; Cirino, G

2015-04-01

Sphingosine-1-phosphate (S1P) has been shown to be involved in the asthmatic disease as well in preclinical mouse experimental models of this disease. The aim of this study was to understand the mechanism(s) underlying S1P effects on the lung. BALB/c, mast cell-deficient and Nude mice were injected with S1P (s.c.) on days 0 and 7. Functional, molecular and cellular studies were performed. S1P administration to BALB/c mice increased airway smooth muscle reactivity, mucus production, PGD2 , IgE, IL-4 and IL-13 release. These features were associated to a higher recruitment of mast cells to the lung. Mast cell-deficient Kit (W) (-sh/) (W) (-sh) mice injected with S1P did not display airway smooth muscle hyper-reactivity. However, lung inflammation and IgE production were still present. Treatment in vivo with the anti-CD23 antibody B3B4, which blocks IgE production, inhibited both S1P-induced airway smooth muscle reactivity in vitro and lung inflammation. S1P administration to Nude mice did not elicit airway smooth muscle hyper-reactivity and lung inflammation. Naïve (untreated) mice subjected to the adoptive transfer of CD4+ T-cells harvested from S1P-treated mice presented all the features elicited by S1P in the lung. S1P triggers a cascade of events that sequentially involves T-cells, IgE and mast cells reproducing several asthma-like features. This model may represent a useful tool for defining the role of S1P in the mechanism of action of currently-used drugs as well as in the development of new therapeutic approaches for asthma-like diseases. © 2014 The British Pharmacological Society.

Decreased expression of indolamine 2,3-dioxygenase in childhood allergic asthma and its inverse correlation with fractional concentration of exhaled nitric oxide.

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Hu, Ying; Chen, Zhiqiang; Jin, Ling; Wang, Mei; Liao, Wei

2017-11-01

The tryptophan metabolic pathway mediated by indolamine 2,3-dioxygenase (IDO), a tryptophan-degrading enzyme, plays an important role in controlling the development of allergic inflammation. The fractional concentration of exhaled nitric oxide (FeNO) is closely associated with the allergic state and is extensively used for the clinical evaluation of airway allergic inflammation. Clinical trials have rarely assessed the expression of IDO in childhood allergic asthma and its correlation with FeNO. To evaluate the IDO level in children with childhood allergic asthma and the relation between IDO levels and FeNO. Thirty children older than 5 years who were diagnosed the first time with allergic asthma were selected from the pediatric outpatient department. Another 30 healthy children were selected as controls. The subjects were evaluated by complete medical history, pulmonary function test results, skin prick test reaction, FeNO concentration test result, eosinophil count, and a disease severity score. Peripheral venous blood and induced sputum were obtained to measure the concentrations of IDO metabolites (ie, tryptophan and kynurenine). The IDO levels in the peripheral blood and induced sputum were significantly lower in patients with childhood allergic asthma than in children in the control group. The IDO level was negatively correlated with FeNO but was not significantly correlated with age, sex, blood eosinophil count, or disease severity scale. The expression of IDO was significantly lower in childhood allergic asthma, particularly in children with high FeNO levels. There was no significant relation between IDO levels and asthma severity. Chinese Clinical Trial Register (www.chictr.org.cn) Identifier: ChiCTR-COC-15006080. Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Anti-Allergic Inflammatory Activity of Interleukin-37 Is Mediated by Novel Signaling Cascades in Human Eosinophils

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Jing Zhu

2018-06-01

Full Text Available IL-1 family regulatory cytokine IL-37b can suppress innate immunity and inflammatory activity in inflammatory diseases. In this study, IL-37b showed remarkable in vitro suppression of inflammatory tumor necrosis factor-α, IL-1β, IL-6, CCL2, and CXCL8 production in the coculture of human primary eosinophils and human bronchial epithelial BEAS-2B cells with the stimulation of bacterial toll-like receptor-2 ligand peptidoglycan, while antagonizing the activation of intracellular nuclear factor-κB, PI3K–Akt, extracellular signal-regulated kinase 1/2, and suppressing the gene transcription of allergic inflammation-related PYCARD, S100A9, and CAMP as demonstrated by flow cytometry, RNA-sequencing, and bioinformatics. Results therefore elucidated the novel anti-inflammation-related molecular mechanisms mediated by IL-37b. Using the house dust mite (HDM-induced humanized asthmatic NOD/SCID mice for preclinical study, intravenous administration of IL-37b restored the normal plasma levels of eosinophil activators CCL11 and IL-5, suppressed the elevated concentrations of Th2 and asthma-related cytokines IL-4, IL-6, and IL-13 and inflammatory IL-17, CCL5, and CCL11 in lung homogenate of asthmatic mice. Histopathological results of lung tissue illustrated that IL-37b could mitigate the enhanced mucus, eosinophil infiltration, thickened airway wall, and goblet cells. Together with similar findings using the ovalbumin- and HDM-induced allergic asthmatic mice further validated the therapeutic potential of IL-37b in allergic asthma. The above results illustrate the novel IL-37-mediated regulation of intracellular inflammation mechanism linking bacterial infection and the activation of human eosinophils and confirm the in vivo anti-inflammatory activity of IL-37b on human allergic asthma.

Assessment of sensitization to insect aeroallergens among patients with allergic rhinitis in Yazd City, Iran.

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Bemanian, Mohammad Hassan; Alizadeh Korkinejad, Narges; Shirkhoda, Shima; Nabavi, Mohammad; Pourpak, Zahra

2012-09-01

The frequency of allergic diseases such as allergic rhinitis is considerable in general population. Insect aeroallergens are important allergens which can induce airway inflammation. The aim of this study was to determine the prevalence of sensitization to insect aeroallergens in allergic rhinitis patients in Yazd as a desert city in Iran.A cross-sectional study was undertaken on 95 allergic rhinitis patients who were referred to allergy clinic of Yazd city. Skin prick tests (SPT) by standard extracts of three insect aeroallergens including Mosquito, Corn moth, Cockroach and two species of mites as common aeroallergens in allergic rhinitis (Dermatophagoid Farina, Dermatophagoid Peteronysinus) were done.SPT results showed that the most common insect aeroallergens were: mosquito (32.6%) followed by corn moth (26.3%) and cockroach (13.7%).The prevalence of SPT positive response to Dermatophagoid Peteronysinus, Dermatophagoid Farina were 8.4% and 7.4%, respectively. These results demonstrated that sensitization to insect aeroallergens was significantly more common compared to mites in patients with allergic rhinitis in Yazd city, a city surrounded by deserts. High prevalence of skin reactivity to mosquito and corn moth as insect aeroallergens in Yazd city with hot and dry climate in contrast to humid regions such as north of Iran, where mites are more frequent, indicates differences in the prevalence of aeroallergen reactivity in various areas with different climates. Our study could highlight the importance of insect aeroallergens for clinicians for better diagnosis and management of patients with allergic rhinitis.

Alteration of Inflammatory Mediators in the Upper and Lower Airways under Chronic Intermittent Hypoxia: Preliminary Animal Study

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Eun Jung Lee

2017-01-01

Full Text Available Purpose. We hypothesized that CIH may affect the upper airway immune system and aimed to verify whether CIH can induce airway inflammation in a murine obstructive sleep apnea (OSA model. Methods. C57BL6 male mice were exposed to intermittent hypoxia (CIH group; 5 ~ 21% FiO2, 120 sec cycles, 12 h/d, n=6 or room air (Sham group, n=6 for up to 4 weeks in identical chambers. Nasal and lung tissues and lavage fluid were collected and analyzed by multiplex assay. Lung lavage fluid was also utilized for FACS analysis to determine eosinophil count. Results. We determined the protein level of 24 different cytokines, chemokines, and inflammatory mediators. Among various cytokines, levels of IL-1α, IL-1β, IL-4, IL-6, and IL-13 were significantly elevated in nose or lung tissue from the CIH group. In addition, MCP-1 and periostin were elevated in nose and lung tissue and lavage fluid from the CIH group. Conclusions. CIH for 4 weeks altered the levels of inflammatory mediators in both the nose and lungs of mouse model. We suggest that the airway immune system may be deteriorated by CIH and allergic inflammation in the upper or lower airway could be worsened by sleep apnea.

Aeroallergen and food IgE sensitization and local and systemic inflammation in asthma.

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Patelis, A; Janson, C; Borres, M P; Nordvall, L; Alving, K; Malinovschi, A

2014-03-01

We recently reported an independent association between IgE sensitization to food allergens and increased airway inflammation, assessed by fraction of exhaled nitric oxide (FeNO), in a population-based study (J Allergy Clin Immunol, 130, 2012, 397). Similar studies have not been performed in populations with asthma. The aim of the present study was to investigate the allergic sensitization profile in asthmatics and examine FeNO, airway responsiveness and blood eosinophilia in relation to type and degree of IgE sensitization. FeNO, airway responsiveness, blood eosinophil count (B-Eos) and IgE sensitization to food allergens and aeroallergens were determined in 408 subjects with asthma, aged 10-34 years. Asthmatics had higher prevalence of IgE sensitization against all allergens than controls (P < 0.001). Mite, pollen, furry animal, mould and food sensitizations were each associated with increased FeNO, airway responsiveness and B-Eos in asthmatics. IgE sensitization to mould, furry animals and food allergens was independently related to FeNO (all P < 0.05) after adjustment for age, sex, height, smoking history and medication. IgE sensitization to mould (P < 0.001) and furry animals (P = 0.02) was related to airway responsiveness in a similar model. Finally, IgE sensitization to mould (P = 0.001), furry animals (P < 0.001) and food allergens (P < 0.001) was independently related to B-Eos. Independent effects of IgE sensitization to aeroallergens (furry animals and mould) and food allergens were found on both local and systemic markers of inflammation in asthma. The finding regarding food IgE sensitization is novel, and a clinical implication might be that even food sensitization must be assessed to fully understand inflammation patterns in asthma. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan, inhibits type I-IV allergic inflammation and pro-inflammatory enzymes.

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Lee, Ji Yun; Kim, Chang Jong

2010-06-01

We previously reported that arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan isolated from Forsythia koreana, exhibits anti-inflammatory, antioxidant, and analgesic effects in animal models. In addition, arctigenin inhibited eosinophil peroxidase and activated myeloperoxidase in inflamed tissues. In this study, we tested the effects of arctigenin on type I-IV allergic inflammation and pro-inflammatory enzymes in vitro and in vivo. Arctigenin significantly inhibited the heterologous passive cutaneous anaphylaxis induced by ovalbumin in mice at 15 mg/kg, p.o., and compound 48/80-induced histamine release from rat peritoneal mast cells at 10 microM. Arctigenin (15 mg/kg, p.o.) significantly inhibited reversed cutaneous anaphylaxis. Further, arctigenin (15 mg/kg, p.o.) significantly inhibited the Arthus reaction to sheep's red blood cells, decreasing the hemolysis titer, the hemagglutination titer, and the plaque-forming cell number for SRBCs. In addition, arctigenin significantly inhibited delayed type hypersensitivity at 15 mg/kg, p.o. and the formation of rosette-forming cells at 45 mg/kg, p.o. Contact dermatitis induced by picrylchloride and dinitrofluorobenzene was significantly (p arctigenin (0.3 mg/ear). Furthermore, arctigenin dose-dependently inhibited pro-inflammatory enzymes, such as cyclooxygenase-1 and 2, 5-lipoxygenase, phospholipase A2, and phosphodiesterase. Our results show that arctigenin significantly inhibited B- and T-cell mediated allergic inflammation as well as pro-inflammatory enzymes.

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

International Nuclear Information System (INIS)

Bae, Yunju; Lee, Soyoung; Kim, Sang-Hyun

2011-01-01

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

Laryngeal effects of nasal allergen provocation in singers with allergic rhinitis

NARCIS (Netherlands)

Verguts, Monique M. L.; Eggermont, Anita; Decoster, Wivine; de Jong, Felix I. C. R. S.; Hellings, Peter W.

2011-01-01

In spite of our recent insight into nasobronchial interaction mechanisms in allergic airway disease, the association between allergic rhinitis and voice complaints remains obscure. To evaluate the effects of nasal allergen provocation and seasonal grass pollen exposure on subjective and objective

Immunological role of nasal staphylococcus aureus carriage in patients with persistent allergic rhinitis

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Mohamed Yousif Atia

2008-10-01

Full Text Available Nasal carriage of staphylococcus aureus (S.aureus exerts immunomodulatory effect in patients with atopic dermatitis and it may contribute to airway inflammation and allergic response in patients with allergic rhinitis. We Aim to investigate the frequency of nasal S.aureus carriage in patients with persistent allergic rhinitis and its possible influence on their symptoms and immune markers. We chosed 20 non smoker patients with house dust mite (HDM allergy causing allergic rhinitis and 20 non smoker healthy subjects matched for age and sex. For all subjects rhinoscopy was done, skin prick test, nasal culture for S.aureus, nasal interleukin 4,nasal total IgE, serum total IgE and serum specific IgE(SSIgE for HDM. Nasal S.aureus was detected in 16/20 patients (80% and 5/20 (25% in healthy subjects with highly significant statistical difference plt0.01. Correlation of nasal staph.aureus count and different systemic and local immune markers revealed highly significant positive correlation between nasal S.aureus count and serum total IgE (r = 0.78, plt0.01 and significant positive correlation with SSIgE (HDM (r = 0.53, plt0.05, nasal total IgE (r = 0.39, plt0.05 and nasal IL-4 (r = 0.55, plt0.05. Nasal staph.aureus actively modulated the immune reaction in persistent allergic rhinitis patients by promoting local IgE production, so we recommend early detection and treatment of S.aureus carriage in patients

Impact on allergic immune response after treatment with vitamin A

DEFF Research Database (Denmark)

Matheu, Victor; Berggård, Karin; Barrios, Yvelise

2009-01-01

ABSTRACT: BACKGROUND: Vitamin A may have some influence on the immune system, but the role in allergy modulation is still unclear. OBJECTIVE: To clarify whether high levels of retinoic acid (RA) affects allergic response in vivo, we used a murine experimental model of airway allergic disease...

Comparison of Airway Responses Induced in a Mouse Model by the Gas and Particulate Fractions of Gasoline Direct Injection Engine Exhaust

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Caitlin L. Maikawa

2018-03-01

Full Text Available Diesel exhaust has been associated with asthma, but its response to other engine emissions is not clear. The increasing prevalence of vehicles with gasoline direct injection (GDI engines motivated this study, and the objective was to evaluate pulmonary responses induced by acute exposure to GDI engine exhaust in an allergic asthma murine model. Mice were sensitized with an allergen to induce airway hyperresponsiveness or treated with saline (non-allergic group. Animals were challenged for 2-h to exhaust from a laboratory GDI engine operated at conditions equivalent to a highway cruise. Exhaust was filtered to assess responses induced by the particulate and gas fractions. Short-term exposure to particulate matter from GDI engine exhaust induced upregulation of genes related to polycyclic aromatic hydrocarbon (PAH metabolism (Cyp1b1 and inflammation (TNFα in the lungs of non-allergic mice. High molecular weight PAHs dominated the particulate fraction of the exhaust, and this response was therefore likely attributable to the presence of these PAHs. The particle fraction of GDI engine exhaust further contributed to enhanced methacholine responsiveness in the central and peripheral tissues in animals with airway hyperresponsiveness. As GDI engines gain prevalence in the vehicle fleet, understanding the health impacts of their emissions becomes increasingly important.

Comparison of Airway Responses Induced in a Mouse Model by the Gas and Particulate Fractions of Gasoline Direct Injection Engine Exhaust.

Science.gov (United States)

Maikawa, Caitlin L; Zimmerman, Naomi; Ramos, Manuel; Shah, Mittal; Wallace, James S; Pollitt, Krystal J Godri

2018-03-01

Diesel exhaust has been associated with asthma, but its response to other engine emissions is not clear. The increasing prevalence of vehicles with gasoline direct injection (GDI) engines motivated this study, and the objective was to evaluate pulmonary responses induced by acute exposure to GDI engine exhaust in an allergic asthma murine model. Mice were sensitized with an allergen to induce airway hyperresponsiveness or treated with saline (non-allergic group). Animals were challenged for 2-h to exhaust from a laboratory GDI engine operated at conditions equivalent to a highway cruise. Exhaust was filtered to assess responses induced by the particulate and gas fractions. Short-term exposure to particulate matter from GDI engine exhaust induced upregulation of genes related to polycyclic aromatic hydrocarbon (PAH) metabolism ( Cyp1b1 ) and inflammation ( TNFα ) in the lungs of non-allergic mice. High molecular weight PAHs dominated the particulate fraction of the exhaust, and this response was therefore likely attributable to the presence of these PAHs. The particle fraction of GDI engine exhaust further contributed to enhanced methacholine responsiveness in the central and peripheral tissues in animals with airway hyperresponsiveness. As GDI engines gain prevalence in the vehicle fleet, understanding the health impacts of their emissions becomes increasingly important.

A 'Good' muscle in a 'Bad' environment: the importance of airway smooth muscle force adaptation to airway hyperresponsiveness.

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Bossé, Ynuk; Chapman, David G; Paré, Peter D; King, Gregory G; Salome, Cheryl M

2011-12-15

Asthma is characterized by airway inflammation, with a consequent increase in spasmogens, and exaggerated airway narrowing in response to stimuli, termed airway hyperresponsiveness (AHR). The nature of any relationship between inflammation and AHR is less clear. Recent ex vivo data has suggested a novel mechanism by which inflammation may lead to AHR, in which increased basal ASM-tone, due to the presence of spasmogens in the airways, may "strengthen" the ASM and ultimately lead to exaggerated airway narrowing. This phenomenon was termed "force adaptation" [Bossé, Y., Chin, L.Y., Paré, P.D., Seow, C.Y., 2009. Adaptation of airway smooth muscle to basal tone: relevance to airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 40, 13-18]. However, it is unknown whether the magnitude of the effect of force adaptation ex vivo could contribute to exaggerated airway narrowing in vivo. Our aim was to utilize a computational model of ASM shortening in order to quantify the potential effect of force adaptation on airway narrowing when all other mechanical factors were kept constant. The shortening in the model is dictated by a balance between physiological loads and ASM force-generating capacity at different lengths. The results suggest that the magnitude of the effect of force adaptation on ASM shortening would lead to substantially more airway narrowing during bronchial challenge at any given airway generation. We speculate that the increased basal ASM-tone in asthma, due to the presence of inflammation-derived spasmogens, produces an increase in the force-generating capacity of ASM, predisposing to AHR during subsequent challenge. Copyright © 2011 Elsevier B.V. All rights reserved.

Advances and Evolving Concepts in Allergic Asthma.

Science.gov (United States)

Tung, Hui-Ying; Li, Evan; Landers, Cameron; Nguyen, An; Kheradmand, Farrah; Knight, J Morgan; Corry, David B

2018-02-01

Allergic asthma is a heterogeneous disorder that defies a unanimously acceptable definition, but is generally recognized through its highly characteristic clinical expression of dyspnea and cough accompanied by clinical data that document reversible or exaggerated airway constriction and obstruction. The generally rising prevalence of asthma in highly industrialized societies despite significant therapeutic advances suggests that the fundamental cause(s) of asthma remain poorly understood. Detailed analyses of both the indoor (built) and outdoor environments continue to support the concept that not only inhaled particulates, especially carbon-based particulate pollution, pollens, and fungal elements, but also many noxious gases and chemicals, especially biologically derived byproducts such as proteinases, are essential to asthma pathogenesis. Phthalates, another common class of chemical pollutant found in the built environment, are emerging as potentially important mediators or attenuators of asthma. Other biological products such as endotoxin have also been confirmed to be protective in both the indoor and outdoor contexts. Proasthmatic factors are believed to activate, and in some instances initiate, pathologic inflammatory cascades through complex interactions with pattern recognition receptors (PRRs) expressed on many cell types, but especially airway epithelial cells. PRRs initiate the release of proallergic cytokines such as interleukin (IL)-33, IL-25, and others that coordinate activation of innate lymphoid cells type 2 (ILC2), T helper type 2 cells, and immunoglobulin E-secreting B cells that together promote additional inflammation and the major airway remodeling events (airway hyperresponsiveness, mucus hypersecretion) that promote airway obstruction. Proteinases, with airway fungi and viruses being potentially important sources, are emerging as critically important initiators of these inflammatory cascades in part through their effects on clotting

Studying allergic inflammation and spirometry over menstrual cycles in well-controlled asthmatic women: Changes in progesterone and estradiol affect neither FENO levels nor lung function.

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Nittner-Marszalska, Marita; Dor-Wojnarowska, Anna; Wolańczyk-Mędrala, Anna; Rosner-Tenerowicz, Anna; Zimmer, Mariusz; Dobek, Julia; Gomułka, Krzysztof; Parużyńska, Anna; Panaszek, Bernard

2018-05-01

It has been reported that female sex hormones influence on allergic inflammation and ventilation parameters in asthma but conclusions drawn by different researchers are divergent. The aim of our study was to assess the impact of progesterone (Pg) and estradiol (E) on the dynamics of allergic inflammation and spirometry test results in regularly menstruating women with stable allergic asthma. 13 women (28 days menstrual cycle), aged 18-45, taking no hormonal contraceptives, with mild and moderate asthma, without reported exacerbations at the near-ovulation and/or menstruation time, were monitored during two consecutive menstrual cycles. They had 4 visits per cycle (the first day of menstruation was assumed to be day 1 of the cycle; visits were carried out on days: 3-4, 10-11, 13-14 and 23-24). At each visit asthma symptoms, asthma control test (ACT) results, asthma treatment, fractioned nitric oxide (FENO) levels, spirometry test results, Pg and E, levels were analyzed. As a result of the study, no essential variability in FENO values and ventilation parameters' values in the course of menstruation cycle were observed. Negative correlation between FENO values and Pg concentrations was demonstrated (r = 0.27), but no correlation between FENO values and E levels was shown. No relationship between the ACT values and ventilation parameters and the levels of the sex hormones under investigation was detected. We conclude that changing levels of estradiol and progesterone (regardless of the negative correlation of progesterone and FENO values) affect neither the dynamics of allergic inflammation nor pulmonary function in women with stable allergic mild/moderate asthma. Copyright © 2018 Elsevier Inc. All rights reserved.

Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease

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Tashkin DP

2018-01-01

Full Text Available Donald P Tashkin,1 Michael E Wechsler2 1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 2Department of Medicine, National Jewish Health, Denver, CO, USA Abstract: COPD is a significant cause of morbidity and mortality. In some patients with COPD, eosinophils contribute to inflammation that promotes airway obstruction; approximately a third of stable COPD patients have evidence of eosinophilic inflammation. Although the eosinophil threshold associated with clinical relevance in patients with COPD is currently subject to debate, eosinophil counts hold potential as biomarkers to guide therapy. In particular, eosinophil counts may be useful in assessing which patients may benefit from inhaled corticosteroid therapy, particularly regarding exacerbation prevention. In addition, several therapies targeting eosinophilic inflammation are available or in development, including monoclonal antibodies targeting the IL5 ligand, the IL5 receptor, IL4, and IL13. The goal of this review was to describe the biologic characteristics of eosinophils, their role in COPD during exacerbations and stable disease, and their use as biomarkers to aid treatment decisions. We also propose an algorithm for inhaled corticosteroid use, taking into consideration eosinophil counts and pneumonia history, and emerging eosinophil-targeted therapies in COPD. Keywords: lung disease, pulmonary diseases, corticosteroids, asthma, pneumonia

Urinary Eosinophil Protein X in Childhood Asthma : Relation with Changes in Disease Control and Eosinophilic Airway Inflammation

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Nuijsink, Marianne; Hop, Wim C. J.; Sterk, Peter J.; Duiverman, Eric J.; De Jongste, Johan C.

2013-01-01

The aim of this study was to assess cross-sectional and longitudinal correlations between uEPX and other markers of asthma control and eosinophilic airway inflammation. Methods. We measured uEPX at baseline, after 1 year and after 2 years in 205 atopic asthmatic children using inhaled fluticasone.

Mediators on human airway smooth muscle.

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Armour, C; Johnson, P; Anticevich, S; Ammit, A; McKay, K; Hughes, M; Black, J

1997-01-01

1. Bronchial hyperresponsiveness in asthma may be due to several abnormalities, but must include alterations in the airway smooth muscle responsiveness and/or volume. 2. Increased responsiveness of airway smooth muscle in vitro can be induced by certain inflammatory cell products and by induction of sensitization (atopy). 3. Increased airway smooth muscle growth can also be induced by inflammatory cell products and atopic serum. 4. Mast cell numbers are increased in the airways of asthmatics and, in our studies, in airway smooth muscle that is sensitized and hyperresponsive. 5. We propose that there is a relationship between mast cells and airway smooth muscle cells which, once an allergic process has been initiated, results in the development of critical features in the lungs in asthma.

The role of diesel exhaust particles and their associated polyaromatic hydrocarbons in the induction of allergic airway disease

International Nuclear Information System (INIS)

Diaz-Sanchez, D.

1997-01-01

The increase in allergic airway disease has paralleled the increase in the use of fossil fuels. Studies were undertaken to examine whether extracts of polyaromatic hydrocarbons (PAH) from diesel exhaust particles (DEP) (PAH-DEP) acted as mucosal adjuvants to help initiate or enhance immunoglobulin E (IgE) production in response to common inhaled allergens. In vitro studies demonstrated that PAH-DEP enhanced IgE production by tonsilar B-cells in the presence of interleukin-4 (IL-4) and CD40 monoclonal antibody, and altered the nature of the IgE produced, i.e. a decrease in the CH4'-CHe5 variant, a marker for differentiation of IgE-producing B-cells, and an increase in the M2' variant. In vivo nasal provocation studies using 0.30 mg DEP in saline also showed enhanced IgE production in the human upper respiratory mucosa, accompanied by a reduced CH4'-CHe5 mRNA splice variant. The effect of DEP were also isotype-specific, with no effect on IgG, IgA, IgM, or albumin, but it produced a small increase in the IgG 4 subclass. The ability of DEP to act as an adjuvant to the ragweed allergen Amb a I was examined by nasal provocation in ragweed allergic subjects using 0.3 mg DEP, Amb a I, or both. Although allergen and DEP each enhanced ragweed-specific IgE, DEP plus allergen promoted a 16-times greater antigen-specific IgE production. Nasal challenge with DEP also influenced cytokine production. Ragweed challenge resulted in a weak response, DEP challenge caused a strong but non-specific response, while allergen plus DEP caused a significant increase in the expression of mRNA for TH 0 and TH 2 -type cytokines (IL-4, IL-5, IL-6, IL-10, IL-13) with a pronounced inhibitory effect on IFN-γ gene expression. These studies suggest that DEP can enhance B-cell differentiation, and by initiating and elevating IgE production, may play an important role in the increased incidence of allergic airway disease. (au)

The effect of long-term administered CRAC channels blocker on the functions of respiratory epithelium in guinea pig allergic asthma model.

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Sutovska, Martina; Kocmalova, Michaela; Joskova, Marta; Adamkov, Marian; Franova, Sona

2015-04-01

Previously, therapeutic potency of CRAC channels blocker was evidenced as a significant decrease in airway smooth muscle hyperreactivity, antitussive and anti-inflammatory effects. The major role of the respiratory epithelium in asthma pathogenesis was highlighted only recently and CRAC channels were proposed as the most significant route of Ca2+ entry into epithelial cells. The aim of the study was to analyse the impact of long-term administered CRAC channels blocker on airway epithelium, e.g. cytokine production and ciliary beat frequency (CBF) using an animal model of allergic asthma. Ovalbumin-induced allergic airway inflammation of guinea pigs was followed by long-term (14 days lasted) therapy by CRAC blocker (3-fluoropyridine-4-carboxylic acid, FPCA). The influence of long-term therapy on cytokines (IL-4, IL-5 and IL-13) in BALF and in plasma, immunohistochemical staining of pulmonary tissue (c-Fos positivity) and CBF in vitro were used for analysis. Decrease in cytokine levels and in c-Fos positivity confirmed an anti-inflammatory effect of long-term administered FPCA. Cytokine levels in BALF and distribution of c-Fos positivity suggested that FPCA was a more potent inhibitor of respiratory epithelium secretory functions than budesonide. FPCA and budesonide reduced CBF only insignificantly. All findings supported CRAC channels as promising target in the new strategy of antiasthmatic treatment.

Effects of omalizumab therapy on allergic rhinitis: a pilot study.

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Masieri, S; Cavaliere, C; Begvarfaj, E; Rosati, D; Minni, A

2016-12-01

The use of omalizumab, a humanized monoclonal antibody able to binding Ig-E, is currently authorized only for treatment of severe bronchial asthma. The use of omalizumab in other Ig-E related diseases is off-label, although some studies have provided promising results about it. The aim of this study was to evaluate if therapy with omalizumab in patients affected by asthma and allergic rhinitis has an impact also on allergic rhinitis-related symptoms. A longitudinal study was conducted on 11 patients affected by severe asthma and a periodic allergic rhinitis. Patients were treated with omalizumab for 24 weeks with a monthly subcutaneous administration at the dosage recommended by the current guidelines. We observed at the start and at the end of treatment: rhinitis symptoms using the Visual Analogue Scale (VAS); the state of nasal mucosa with fiberoptic nasal endoscopy; airways inflammation by measuring the Fractional Exhaled Nitric Oxide (FeNO); asthmatic symptomatology by means of the Asthma Control Test; the amount of total Ig-E in a blood sample; and the use of symptomatic drugs before and after treatment. VAS scores to measure general symptomatology and symptoms including nasal obstruction, rhinorrhea, itching and sneezing were significantly reduced. Turbinate hypertrophy was resolved in six of nine patients. Furthermore, eight patients (73%) reduced or eliminated the use of symptomatic drugs. Our data confirm the efficacy of omalizumab in the treatment of allergic rhinitis. Controlled studies will now have to be carried out to confirm these preliminary data and will specify indications for a very efficacious but still significantly expensive therapy.

Urinary eosinophil protein X in childhood asthma: relation with changes in disease control and eosinophilic airway inflammation

NARCIS (Netherlands)

Nuijsink, Marianne; Hop, Wim C. J.; Sterk, Peter J.; Duiverman, Eric J.; de Jongste, Johan C.

2013-01-01

The aim of this study was to assess cross-sectional and longitudinal correlations between uEPX and other markers of asthma control and eosinophilic airway inflammation. Methods. We measured uEPX at baseline, after 1 year and after 2 years in 205 atopic asthmatic children using inhaled fluticasone.

Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone.

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Kumagai, Kazuyoshi; Lewandowski, Ryan P; Jackson-Humbles, Daven N; Buglak, Nicholas; Li, Ning; White, Kaylin; Van Dyken, Steven J; Wagner, James G; Harkema, Jack R

2017-08-01

Exposure to elevated levels of ambient ozone in photochemical smog is associated with eosinophilic airway inflammation and nonatopic asthma in children. In the present study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced nonatopic asthma by using lymphoid cell-sufficient C57BL/6 mice, ILC-sufficient Rag2 -/- mice (devoid of T and B cells), and ILC-deficient Rag2 -/- Il2rg -/- mice (depleted of all lymphoid cells including ILCs). Mice were exposed to 0 or 0.8 parts per million ozone for 1 day or 9 consecutive weekdays (4 hr/day). A single exposure to ozone caused neutrophilic inflammation, airway epithelial injury, and reparative DNA synthesis in all strains of mice, irrespective of the presence or absence of ILCs. In contrast, 9-day exposures induced eosinophilic inflammation and mucous cell metaplasia only in the lungs of ILC-sufficient mice. Repeated ozone exposures also elicited increased messenger RNA expression of transcripts associated with type 2 immunity and airway mucus production in ILC-sufficient mice. ILC-deficient mice repeatedly exposed to ozone had no pulmonary pathology or increased gene expression related to type 2 immunity. These results suggest a new paradigm for the biologic mechanisms underlying the development of a phenotype of childhood nonatopic asthma that has been linked to ambient ozone exposures.

Effects of Salmeterol and Fluticasone Propionate Combination versus Fluticasone Propionate on Airway Function and Eosinophilic Inflammation in Mild Asthma

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Makoto Hoshino

2009-01-01

Conclusions: These findings suggest that SFC is more useful than FP in mild asthma cases. The clinical benefit of SFC provides evidence that IOS and induced sputum allows for the detection of changes in airway function and inflammation.

Airway bacteria measured by quantitative polymerase chain reaction and culture in patients with stable COPD: relationship with neutrophilic airway inflammation, exacerbation frequency, and lung function

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Bafadhel M

2015-06-01

Full Text Available Mona Bafadhel,1 Koirobi Haldar,2 Bethan Barker,2,3 Hemu Patel,4 Vijay Mistry,2,3 Michael R Barer,2–4 Ian D Pavord,1 Christopher E Brightling2,3 1Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2Department of Infection, Immunity and Inflammation, University of Leicester, 3Institute for Lung Health, National Institute for Health Research Respiratory Biomedical Research Unit, Glenfield Hospital, University of Leicester, 4Department of Clinical Microbiology, University Hospitals of Leicester NHS Trust, Leicester, UK Background: Potentially pathogenic microorganisms can be detected by quantitative real-time polymerase chain reaction (qPCR in sputum from patients with COPD, although how this technique relates to culture and clinical measures of disease is unclear. We used cross-sectional and longitudinal data to test the hypotheses that qPCR is a more sensitive measure of bacterial presence and is associated with neutrophilic airway inflammation and adverse clinical outcomes.Methods: Sputum was collected from 174 stable COPD subjects longitudinally over 12 months. Microbial sampling using culture and qPCR was performed. Spirometry and sputum measures of airway inflammation were assessed.Findings: Sputum was qPCR-positive (>106 copies/mL in 77/152 samples (Haemophilus influenzae [n=52], Moraxella catarrhalis [n=24], Streptococcus pneumoniae [n=19], and Staphylococcus aureus [n=7]. Sputum was culture-positive in 50/174 samples, with 49 out of 50 culture-positive samples having pathogen-specific qPCR bacterial loads >106 copies/mL. Samples that had qPCR copy numbers >106/mL, whether culture-positive or not, had increased sputum neutrophil counts. H. influenzae qPCR copy numbers correlated with sputum neutrophil counts (r=0.37, P<0.001, were repeatable within subjects, and were >106/mL three or more times in 19 patients, eight of whom were repeatedly sputum culture-positive. Persistence, whether

Ferulic Acid Induces Th1 Responses by Modulating the Function of Dendritic Cells and Ameliorates Th2-Mediated Allergic Airway Inflammation in Mice

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Chen-Chen Lee

2015-01-01

Full Text Available This study investigated the immunomodulatory effects of ferulic acid (FA on antigen-presenting dendritic cells (DCs in vitro and its antiallergic effects against ovalbumin- (OVA- induced Th2-mediated allergic asthma in mice. The activation of FA-treated bone marrow-derived DCs by lipopolysaccharide (LPS stimulation induced a high level of interleukin- (IL- 12 but reduced the expression levels of the proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor- (TNF- α. Compared to control-treated DCs, FA significantly enhanced the expressions of Notch ligand Delta-like 4 (Dll4, MHC class II, and CD40 molecules by these DCs. Furthermore, these FA-treated DCs enhanced T-cell proliferation and Th1 cell polarization. In animal experiments, oral administration of FA reduced the levels of OVA-specific immunoglobulin E (IgE and IgG1 and enhanced IgG2a antibody production in serum. It also ameliorated airway hyperresponsiveness and attenuated eosinophilic pulmonary infiltration in dose-dependent manners. In addition, FA treatment inhibited the production of eotaxin, Th2 cytokines (IL-4, IL-5, and IL-13, and proinflammatory cytokines but promoted the Th1 cytokine interferon- (IFN- γ production in bronchoalveolar lavage fluid (BALF and the culture supernatant of spleen cells. These findings suggest that FA exhibits an antiallergic effect via restoring Th1/Th2 imbalance by modulating DCs function in an asthmatic mouse model.

Targeting phosphoinositide 3-kinase δ for allergic asthma.

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Rowan, Wendy C; Smith, Janet L; Affleck, Karen; Amour, Augustin

2012-02-01

Chronic inflammation in the lung has long been linked to the pathogenesis of asthma. Central to this airway inflammation is a T-cell response to allergens, with Th2 cytokines driving the differentiation, survival and function of the major inflammatory cells involved in the allergic cascade. PI3Kδ (phosphoinositide 3-kinase δ) is a lipid kinase, expressed predominantly in leucocytes, where it plays a critical role in immune receptor signalling. A selective PI3Kδ inhibitor is predicted to block T-cell activation in the lung, reducing the production of pro-inflammatory Th2 cytokines. PI3Kδ is also involved in B-cell and mast cell activation. Therefore the inhibition of PI3Kδ should dampen down the inflammatory cascade involved in the asthmatic response through a wide breadth of pharmacology. Current anti-inflammatory therapies, which are based on corticosteroids, are effective in controlling inflammation in mild asthmatics, but moderate/severe asthmatic patients remain poorly controlled, experiencing recurrent exacerbations. Corticosteroids have no effect on mast cell degranulation and do not act directly on B-cells, so, overall, a PI3Kδ inhibitor has the potential to deliver improvements in onset of action, efficacy and reduced exacerbations in moderate/severe asthmatics. Additionally, PI3Kδ inhibition is expected to block effects of Th17 cells, which are increasingly implicated in steroid-insensitive asthma.

A new era of targeting the ancient gatekeepers of the immune system: toll-like agonists in the treatment of allergic rhinitis and asthma.

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Aryan, Zahra; Holgate, Stephen T; Radzioch, Danuta; Rezaei, Nima

2014-01-01

Toll-like receptors (TLR) belong to a large family of pattern recognition receptors known as the ancient 'gatekeepers' of the immune system. TLRs are located at the first line of defense against invading pathogens as well as aeroallergens, making them interesting targets to modulate the natural history of respiratory allergy. Agonists of TLRs have been widely employed in therapeutic or prophylactic preparations useful for asthma/allergic rhinitis (AR) patients. MPL® (a TLR4 agonist) and the CpG oligodeoxynucleotide of 1018 ISS, a TLR9 agonist, show strong immunogenicity effects that make them appropriate adjuvants for allergy vaccines. Targeting the TLRs can enhance the efficacy of specific allergen immunotherapy, currently the only available 'curative' treatment for respiratory allergies. In addition, intranasal administration of AZD8848 (a TLR7 agonist) and VTX-1463 (a TLR8 agonist) as stand-alone therapeutics have revealed efficacy in the relief of the symptoms of AR patients. No anaphylaxis has been so far reported with such compounds targeting TLRs, with the most common adverse effects being transient and local irritation (e.g. redness, swelling and pruritus). Many other compounds that target TLRs have been found to suppress airway inflammation, eosinophilia and airway hyper-responsiveness in various animal models of allergic inflammation. Indeed, in the future a wide variability of TLR agonists and even antagonists that exhibit anti-asthma/AR effects are likely to emerge. © 2014 S. Karger AG, Basel.

Interaction between rhinitis and asthma: state of the art.

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Frieri, Marianne

2003-01-01

Rhinitis and asthma are very prevalent allergic disorders with comorbid features, similar risk factors, and environmental triggers. Pathophysiological processes are linked via tissue histopathology, immunologic pathway, and inflammatory mediators. Allergen challenge of the upper airway can increase lower-airway responsiveness and allergen challenge of the lower airway can lead to upper-airway inflammation. Both allergic rhinitis and asthma exert a high social and economic burden in significant loss of work and school days as well as impairment for children and adults.

Exploring the context of the lung proteome within the airway mucosa following allergen challenge.

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Fehniger, Thomas E; Sato-Folatre, José-Gabriel; Malmström, Johan; Berglund, Magnus; Lindberg, Claes; Brange, Charlotte; Lindberg, Henrik; Marko-Varga, György

2004-01-01

The lung proteome is a dynamic collection of specialized proteins related to pulmonary function. Many cells of different derivations, activation states, and levels of maturity contribute to the changing environment, which produces the lung proteome. Inflammatory cells reacting to environmental challenge, for example from allergens, produce and secrete proteins which have profound effects on both resident and nonresident cells located in airways, alveoli, and the vascular tree which provides blood cells to the parenchyma alveolar bed for gas exchange. In an experimental model of allergic airway inflammation, we have compared control and allergen challenged lung compartments to determine global protein expression patterns using 2D-gel electrophoresis and subsequent spot identification by MS/MS mass spectrometry. We have then specifically isolated the epithelial mucosal layer, which lines conducting airways, from control and allergen challenged lungs, using laser capture technology and performed proteome identification on these selected cell samples. A central component of our investigations has been to contextually relate the histological features of the dynamic pulmonary environment to the changes in protein expression observed following challenge. Our results provide new information of the complexity of the submucosa/epithelium interface and the mechanisms behind the transformation of airway epithelium from normal steady states to functionally activated states.

Subchronic exposures to fungal bioaerosols promotes allergic pulmonary inflammation in naïve mice.

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Nayak, A P; Green, B J; Lemons, A R; Marshall, N B; Goldsmith, W T; Kashon, M L; Anderson, S E; Germolec, D R; Beezhold, D H

2016-06-01

Epidemiological surveys indicate that occupants of mold contaminated environments are at increased risk of respiratory symptoms. The immunological mechanisms associated with these responses require further characterization. The aim of this study was to characterize the immunotoxicological outcomes following repeated inhalation of dry Aspergillus fumigatus spores aerosolized at concentrations potentially encountered in contaminated indoor environments. Aspergillus fumigatus spores were delivered to the lungs of naïve BALB/cJ mice housed in a multi-animal nose-only chamber twice a week for a period of 13 weeks. Mice were evaluated at 24 and 48 h post-exposure for histopathological changes in lung architecture, recruitment of specific immune cells to the airways, and serum antibody responses. Germinating A. fumigatus spores were observed in lungs along with persistent fungal debris in the perivascular regions of the lungs. Repeated exposures promoted pleocellular infiltration with concomitant epithelial mucus hypersecretion, goblet cell metaplasia, subepithelial fibrosis and enhanced airway hyperreactivity. Cellular infiltration in airways was predominated by CD4(+) T cells expressing the pro-allergic cytokine IL-13. Furthermore, our studies show that antifungal T cell responses (IFN-γ(+) or IL-17A(+) ) co-expressed IL-13, revealing a novel mechanism for the dysregulated immune response to inhaled fungi. Total IgE production was augmented in animals repeatedly exposed to A. fumigatus. Repeated inhalation of fungal aerosols resulted in significant pulmonary pathology mediated by dynamic shifts in specific immune populations and their cytokines. These studies provide novel insights into the immunological mechanisms and targets that govern the health outcomes that result from repeated inhalation of fungal bioaerosols in contaminated environments. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Aspergillus-Associated Airway Disease, Inflammation, and the Innate Immune Response

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Chotirmall, Sanjay H.; Al-Alawi, Mazen; Logan, P. Mark; Greene, Catherine M.; McElvaney, Noel G.

2013-01-01

Aspergillus moulds exist ubiquitously as spores that are inhaled in large numbers daily. Whilst most are removed by anatomical barriers, disease may occur in certain circumstances. Depending on the underlying state of the human immune system, clinical consequences can ensue ranging from an excessive immune response during allergic bronchopulmonary aspergillosis to the formation of an aspergilloma in the immunocompetent state. The severest infections occur in those who are immunocompromised where invasive pulmonary aspergillosis results in high mortality rates. The diagnosis of Aspergillus-associated pulmonary disease is based on clinical, radiological, and immunological testing. An understanding of the innate and inflammatory consequences of exposure to Aspergillus species is critical in accounting for disease manifestations and preventing sequelae. The major components of the innate immune system involved in recognition and removal of the fungus include phagocytosis, antimicrobial peptide production, and recognition by pattern recognition receptors. The cytokine response is also critical facilitating cell-to-cell communication and promoting the initiation, maintenance, and resolution of the host response. In the following review, we discuss the above areas with a focus on the innate and inflammatory response to airway Aspergillus exposure and how these responses may be modulated for therapeutic benefit. PMID:23971044

Analysis of airways in computed tomography

DEFF Research Database (Denmark)

Petersen, Jens

Chronic Obstructive Pulmonary Disease (COPD) is major cause of death and disability world-wide. It affects lung function through destruction of lung tissue known as emphysema and inflammation of airways, leading to thickened airway walls and narrowed airway lumen. Computed Tomography (CT) imaging...

Human FcγRIIA induces anaphylactic and allergic reactions.

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Jönsson, Friederike; Mancardi, David A; Zhao, Wei; Kita, Yoshihiro; Iannascoli, Bruno; Khun, Huot; van Rooijen, Nico; Shimizu, Takao; Schwartz, Lawrence B; Daëron, Marc; Bruhns, Pierre

2012-03-15

IgE and IgE receptors (FcεRI) are well-known inducers of allergy. We recently found in mice that active systemic anaphylaxis depends on IgG and IgG receptors (FcγRIIIA and FcγRIV) expressed by neutrophils, rather than on IgE and FcεRI expressed by mast cells and basophils. In humans, neutrophils, mast cells, basophils, and eosinophils do not express FcγRIIIA or FcγRIV, but FcγRIIA. We therefore investigated the possible role of FcγRIIA in allergy by generating novel FcγRIIA-transgenic mice, in which various models of allergic reactions induced by IgG could be studied. In mice, FcγRIIA was sufficient to trigger active and passive anaphylaxis, and airway inflammation in vivo. Blocking FcγRIIA in vivo abolished these reactions. We identified mast cells to be responsible for FcγRIIA-dependent passive cutaneous anaphylaxis, and monocytes/macrophages and neutrophils to be responsible for FcγRIIA-dependent passive systemic anaphylaxis. Supporting these findings, human mast cells, monocytes and neutrophils produced anaphylactogenic mediators after FcγRIIA engagement. IgG and FcγRIIA may therefore contribute to allergic and anaphylactic reactions in humans.

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

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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

TREATMENT POLICY OF PEDIATRICIANS AGAINST ACUTE AND CHRONIC ALLERGIC PATHOLOGIES IN CHILDREN. DESLORATADINE

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E.A. Vishneva

2009-01-01

Full Text Available Allergic rhinitis, bronchial asthma, chronic idiopathic nettle rash, atopic dermatitis have been characterized by a stable growth in the prevalence of the allergic pathology over the last several decades. A similar pathogenesis of allergic diseases makes it possible to regard them as different manifestations of a systemic allergic inflammation. Histamine is one of the main mediators of an allergic inflammation, therefore first-line medications (drug of choice in the treatment of an allergic pathology, first of all, rhinitis and chronic nettle rash, are second-generation blockers of Н1-receptors. The proposed article discusses the issues connected with the use of antihistamines for children.Key words: allergic rhinitis, bronchial asthma, nettle rash, atopic dermatitis, treatment, antihistamines, children.

Females have stronger neurogenic response than males after non-specific nasal challenge in patients with seasonal allergic rhinitis.

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Tomljenovic, Dejan; Baudoin, Tomislav; Megla, Zeljka Bukovec; Geber, Goran; Scadding, Glenis; Kalogjera, Livije

2018-07-01

Epidemiological studies show female predominance in the prevalence of non- allergic rhinitis (NAR) and local allergic rhinitis (LAR). Experimental studies show female patients with allergic rhinitis (AR) demonstrate higher levels of sensitivity to irritants and airway hyperresponsiveness than males. Bronchial asthma shows female predominance in post-puberty patients, and gender interaction with severe asthma endotypes. Fibromyalgia, chronic fatigue syndrome, migraine and chronic cough, syndromes, which are commonly related to neurokinin substance P (SP) in the literature, also show strong female predominance. Studies have demonstrated that sex hormones, primarily oestrogens, affect mast cell activation. Mast cell proteases can amplify neurogenic inflammatory responses including the release of SP. Based on human epidemiological data and animal experimental data we hypothesized that female patients have different interaction between mast cell activation and neurogenic inflammation, i.e. substance P release, resulting in a different nasal symptom profile. To test the hypothesis we performed allergen and non-specific nasal challenges in patients with seasonal allergic rhinitis (SAR) out of season and looked for gender differences in subjective and objective responses. The interaction between subjective and objective reactivity was evaluated through the comparison of subjective symptom scores, concentrations of neurokinin substance P (SP) and cellular markers in nasal lavages after low doses of nasal allergen challenges. Female allergic subjects tended to have higher substance P (SP) concentrations both before and after non-specific challenges. The difference between post-allergen and post - hypertonic saline (HTS) challenge was highly significant in female patients (p = 0.001), while insignificant in male subjects (p = 0.14). Female patients had significantly stronger burning sensation after HTS challenge than male. These data indicate difference in the

Improved efficacy of allergen-specific immunotherapy by JAK inhibition in a murine model of allergic asthma.

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Aguilar-Pimentel, Antonio; Graessel, Anke; Alessandrini, Francesca; Fuchs, Helmut; Gailus-Durner, Valerie; Hrabě de Angelis, Martin; Russkamp, Dennis; Chaker, Adam; Ollert, Markus; Blank, Simon; Gutermuth, Jan; Schmidt-Weber, Carsten B

2017-01-01

Allergen-specific immunotherapy (AIT) is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma. Our aim was to evaluate whether AIT is more effective in suppression of local inflammation if performed under the umbrella of short-term non-specific immunomodulation using a small molecule inhibitor of JAK pathways. In C57BL/6J mice, a model of ovalbumin (OVA)-induced allergic airway inflammation and allergen-specific immunotherapy was combined with the administration of Tofacitinib (TOFA, a FDA-approved JAK inhibitor) from 48 hours prior to 48 hours after therapeutic OVA-injection. The effect of TOFA on human FOXP3+CD4+ T cells was studied in vitro. AIT combined with short-term TOFA administration was significantly more effective in suppressing total cell and eosinophil infiltration into the lung, local cytokine production including IL-1β and CXCL1 and showed a trend for the reduction of IL-4, IL-13, TNF-α and IL-6 compared to AIT alone. Furthermore, TOFA co-administration significantly reduced systemic IL-6, IL-1β and OVA-specific IgE levels and induced IgG1 to the same extent as AIT alone. Additionally, TOFA enhanced the induction of human FOXP3+CD4+ T cells. This proof of concept study shows that JAK inhibition did not inhibit tolerance induction, but improved experimental AIT at the level of local inflammation. The improved control of local inflammation might extend the use of AIT in more severe conditions such as polyallergy, asthma and high-risk patients suffering from mastocytosis or anaphylaxis.

Improved efficacy of allergen-specific immunotherapy by JAK inhibition in a murine model of allergic asthma.

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Antonio Aguilar-Pimentel

Full Text Available Allergen-specific immunotherapy (AIT is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma.Our aim was to evaluate whether AIT is more effective in suppression of local inflammation if performed under the umbrella of short-term non-specific immunomodulation using a small molecule inhibitor of JAK pathways.In C57BL/6J mice, a model of ovalbumin (OVA-induced allergic airway inflammation and allergen-specific immunotherapy was combined with the administration of Tofacitinib (TOFA, a FDA-approved JAK inhibitor from 48 hours prior to 48 hours after therapeutic OVA-injection. The effect of TOFA on human FOXP3+CD4+ T cells was studied in vitro.AIT combined with short-term TOFA administration was significantly more effective in suppressing total cell and eosinophil infiltration into the lung, local cytokine production including IL-1β and CXCL1 and showed a trend for the reduction of IL-4, IL-13, TNF-α and IL-6 compared to AIT alone. Furthermore, TOFA co-administration significantly reduced systemic IL-6, IL-1β and OVA-specific IgE levels and induced IgG1 to the same extent as AIT alone. Additionally, TOFA enhanced the induction of human FOXP3+CD4+ T cells.This proof of concept study shows that JAK inhibition did not inhibit tolerance induction, but improved experimental AIT at the level of local inflammation. The improved control of local inflammation might extend the use of AIT in more severe conditions such as polyallergy, asthma and high-risk patients suffering from mastocytosis or anaphylaxis.

Serum IgE Induced Airway Smooth Muscle Cell Remodeling Is Independent of Allergens and Is Prevented by Omalizumab

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Roth, Michael; Zhao, Feng; Zhong, Jun; Lardinois, Didier; Tamm, Michael

2015-01-01

Background Airway wall remodeling in allergic asthma is reduced after treatment with humanized anti-IgE-antibodies. We reported earlier that purified IgE, without the presence of allergens, is sufficient to induce airway wall remodeling due to airway smooth muscle cell (ASMC) activity deposing extracellular matrix. Objective We postulate that IgE contained in serum of allergic asthma patients, in the absence of allergens, stimulates ASMC remodeling activities and can be prevented by anti-IgE antibodies. Methods Isolated human ASMC were exposed to serum obtained from: (i) healthy controls, or patients with (ii) allergic asthma, (iii) non-allergic asthma, and (iv) atopic non-asthma patients. Proliferation and the deposition of collagens and fibronectin were determined after 3 and 5 days. Results Serum from patients with allergies significantly stimulated: (i) ASMC proliferation, (ii) deposition of collagen type-I (48 hours) and (iii) of fibronectin (24 hours). One hour pre-incubation with Omalizumab prevented these three effects of allergic serum, but had no significant effect on serum from healthy donors or non-allergic asthma patients. Interestingly, the addition of allergens did not further increase any of the IgE effects. Conclusion and Clinical Relevance Our data provides experimental evidence that the beneficial effect of Omalizumab on airway wall remodeling and improved lung function may be due to its direct action on IgE bound ASMC. PMID:26332463

Serum IgE Induced Airway Smooth Muscle Cell Remodeling Is Independent of Allergens and Is Prevented by Omalizumab.

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Michael Roth

Full Text Available Airway wall remodeling in allergic asthma is reduced after treatment with humanized anti-IgE-antibodies. We reported earlier that purified IgE, without the presence of allergens, is sufficient to induce airway wall remodeling due to airway smooth muscle cell (ASMC activity deposing extracellular matrix.We postulate that IgE contained in serum of allergic asthma patients, in the absence of allergens, stimulates ASMC remodeling activities and can be prevented by anti-IgE antibodies.Isolated human ASMC were exposed to serum obtained from: (i healthy controls, or patients with (ii allergic asthma, (iii non-allergic asthma, and (iv atopic non-asthma patients. Proliferation and the deposition of collagens and fibronectin were determined after 3 and 5 days.Serum from patients with allergies significantly stimulated: (i ASMC proliferation, (ii deposition of collagen type-I (48 hours and (iii of fibronectin (24 hours. One hour pre-incubation with Omalizumab prevented these three effects of allergic serum, but had no significant effect on serum from healthy donors or non-allergic asthma patients. Interestingly, the addition of allergens did not further increase any of the IgE effects.Our data provides experimental evidence that the beneficial effect of Omalizumab on airway wall remodeling and improved lung function may be due to its direct action on IgE bound ASMC.

Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation

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Luna-Gomes, Tatiana; Magalhães, Kelly G; Mesquita-Santos, Fabio P.; Bakker-Abreu, Ilka; Samico, Rafaela F.; Molinaro, Raphael; Calheiros, Andrea S.; Diaz, Bruno L.; Bozza, Patrícia T.

2011-01-01

Prostaglandin (PG)D2 is a key mediator of allergic inflammatory diseases that is mainly synthesized by mast cells, which constitutively express high levels of the terminal enzyme involved in PGD2 synthesis, the hematopoietic PGD synthase (H-PGDS). Here, we investigated whether eosinophils are also able to synthesize, and therefore, supply biologically active PGD2. PGD2 synthesis was evaluated within human blood eosinophils, in vitro-differentiated mouse eosinophils, and eosinophils infiltrating inflammatory site of mouse allergic reaction. Biological function of eosinophil-derived PGD2 was studied by employing inhibitors of synthesis and activity. Constitutive expression of H-PGDS was found within non-stimulated human circulating eosinophils. Acute stimulation of human eosinophils with A23187 (0.1 – 5 μM) evoked PGD2 synthesis, which was located at the nuclear envelope and was inhibited by pre-treatment with HQL-79 (10 μM), a specific H-PGDS inhibitor. Pre-stimulation of human eosinophils with arachidonic acid (AA; 10 μM) or human eotaxin (6 nM) also enhanced HQL-79-sensitive PGD2 synthesis, which, by acting on membrane-expressed specific receptors (DP1 and DP2), displayed an autocrine/paracrine ability to trigger leukotriene (LT)C4 synthesis and lipid body biogenesis, hallmark events of eosinophil activation. In vitro-differentiated mouse eosinophils also synthesized paracrine/autocrine active PGD2 in response to AA stimulation. In vivo, at late time point of the allergic reaction, infiltrating eosinophils found at the inflammatory site appeared as an auxiliary PGD2-synthesizing cell population. Our findings reveal that eosinophils are indeed able to synthesize and secrete PGD2, hence representing during allergic inflammation an extra cell source of PGD2, which functions as an autocrine signal for eosinophil activation. PMID:22102725

Re-defining the Unique Roles for Eosinophils in Allergic Respiratory Inflammation

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Jacobsen, Elizabeth A.; Lee, Nancy A.; Lee, James J.

2014-01-01

Summary The role of eosinophils in the progression and resolution of allergic respiratory inflammation is poorly defined despite the commonality of their presence and in some cases their use as a biomarker for disease severity and/or symptom control. However, this ambiguity belies the wealth of insights that have recently been gained through the use of eosinophil-deficient/attenuated strains of mice that have demonstrated novel immunoregulatory and remodeling/repair functions for these cells in the lung following allergen provocation. Specifically, studies of eosinophil-deficient mice suggest that eosinophils contribute to events occurring in the lungs following allergen provocation at several key moments: (i) The initiating phase of events leading to Th2-polarized pulmonary inflammation, (ii) The suppression Th1/Th17 pathways in lung draining lymph nodes, (iii) The recruitment of effector Th2 T cells to the lung, and finally (iv) Mechanisms of inflammatory resolution that re-establish pulmonary homeostasis. These suggested functions have recently been confirmed and expanded upon using allergen provocation of an inducible eosinophil-deficient strain of mice (iPHIL) that demonstrated an eosinophil-dependent mechanism(s) leading to Th2 dominated immune responses in the presence of eosinophils in contrast to neutrophilic as well as mixed Th1/Th17/Th2 variant phenotypes in the absence of eosinophils. These findings highlighted that eosinophils are not exclusively downstream mediators controlled by T cells, dendritic cells (DC), and/or innate lymphocytic cells (ILC2). Instead, eosinophils appear to be more aptly described as significant contributors in complex interrelated pathways that lead to pulmonary inflammation and subsequently promote resolution and the re-establishment of homeostatic baseline. In this review we summarize and put into the context the evolving hypotheses that are now expanding our understanding of the roles eosinophils likely have in the lung

Is recurrent respiratory infection associated with allergic respiratory disease?

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de Oliveira, Tiago Bittencourt; Klering, Everton Andrei; da Veiga, Ana Beatriz Gorini

2018-03-13

Respiratory infections cause high morbidity and mortality worldwide. This study aims to estimate the relationship between allergic respiratory diseases with the occurrence of recurrent respiratory infection (RRI) in children and adolescents. The International Study of Asthma and Allergies in Childhood questionnaire and a questionnaire that provides data on the history of respiratory infections and the use of antibiotics were used to obtain data from patients. The relationship between the presence of asthma or allergic rhinitis and the occurrence of respiratory infections in childhood was analyzed. We interviewed the caregivers of 531 children aged 0 to 15 years. The average age of participants was 7.43 years, with females accounting for 52.2%. This study found significant relationship between: presence of asthma or allergic rhinitis with RRI, with prevalence ratio (PR) of 2.47 (1.51-4.02) and 1.61 (1.34-1.93), respectively; respiratory allergies with use of antibiotics for respiratory problems, with PR of 5.32 (2.17-13.0) for asthma and of 1.64 (1.29-2.09) for allergic rhinitis; asthma and allergic rhinitis with diseases of the lower respiratory airways, with PR of 7.82 (4.63-13.21) and 1.65 (1.38-1.96), respectively. In contrast, no relationship between upper respiratory airway diseases and asthma and allergic rhinitis was observed, with PR of 0.71 (0.35-1.48) and 1.30 (0.87-1.95), respectively. RRI is associated with previous atopic diseases, and these conditions should be considered when treating children.

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

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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

[Airway oxidative stress and inflammation markers in chronic obstructive pulmonary diseases(COPD) patients are linked with exposure to traffic-related air pollution: a panel study].

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Chen, J; Zhao, Q; Liu, B B; Wang, J; Xu, H B; Zhang, Y; Song, X M; He, B; Huang, W

2016-05-01

To investigate the effects of short-term exposure to traffic-related air pollution on airway oxidative stress and inflammation in chronic obstructive pulmonary diseases (COPD) patients. A panel of forty-five diagnosed COPD patients were recruited and followed with repeated measurements of biomarkers reflecting airway oxidative stress and inflammation in exhaled breath condensate (EBC), including nitrate and nitrite, 8-isoprostane, interleukin-8 and acidity of EBC (pH), between 5(th) September in 2014 and 26(th) May in 2015. The associations between air pollution and biomarkers were analyzed with mixed-effects models, controlling for confounding covariates. The concentration of PM2.5, black carbon, NO2 and number concentration of particles with diameter less than 100 nm (PNC100), and particles in size ranges between 100 nm to 200 nm (PNC100-200) during the first follow-up were (156.5±117.7), (10.7±0.7), (165.9±66.0)μg/m(3) and 397 521±96 712, 79 421±44 090 per cubic meter, respectively; the concentration were (67.9±29.6), (3.4±1.3), (126.1±10.9) μg/m(3) and (295 682±39 430), (24 693±12 369) per cubic meter, respectively during the second follow-up. The differences were of significance, with t value being 3.10, 4.42, 2.61, 4.02, 5.12, respectively and P value being 0.005,stress. For an IQR increase in PM2.5, black carbon and PNC100-200, respective increases of 0.17 ng/ml (95% CI: 0.02-0.33), 0.12 ng/ml (95% CI: 0.01-0.24) and 0.13 ng/ml (95% CI:0.02-0.24) in interleukin-8 in EBC reflecting airway inflammation were also observed. An IQR increase in ozone was also associated with a 0.24 (95%CI: 0.05-0.42) decrease in pH of EBC reflecting increased airway inflammation. No significant association observed between air pollution and 8-isoprostane in EBC in COPD patients. Our results suggested that short-term exposure to traffic-related air pollution was responsible for exacerbation of airway oxidative stress and inflammation in COPD patients.

Supplemental and highly-elevated tocopherol doses differentially regulate allergic inflammation: reversibility of α-tocopherol and γ-tocopherol's effects

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McCary, Christine A.; Abdala-Valencia, Hiam; Berdnikovs, Sergejs; Cook-Mills, Joan M.

2011-01-01

We have reported that supplemental doses of the α- and γ-tocopherol isoforms of vitamin E decrease and increase, respectively, allergic lung inflammation. We have now assessed whether these effects of tocopherols are reversible. For these studies, mice were treated with antigen and supplemental tocopherols in a first phase of treatment followed by a 4 week clearance phase and then the mice received a second phase of antigen and tocopherol treatments. The pro-inflammatory effects of supplement...

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.

Aspergillus-Associated Airway Disease, Inflammation, and the Innate Immune Response

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Sanjay H. Chotirmall

2013-01-01

Full Text Available Aspergillus moulds exist ubiquitously as spores that are inhaled in large numbers daily. Whilst most are removed by anatomical barriers, disease may occur in certain circumstances. Depending on the underlying state of the human immune system, clinical consequences can ensue ranging from an excessive immune response during allergic bronchopulmonary aspergillosis to the formation of an aspergilloma in the immunocompetent state. The severest infections occur in those who are immunocompromised where invasive pulmonary aspergillosis results in high mortality rates. The diagnosis of Aspergillus-associated pulmonary disease is based on clinical, radiological, and immunological testing. An understanding of the innate and inflammatory consequences of exposure to Aspergillus species is critical in accounting for disease manifestations and preventing sequelae. The major components of the innate immune system involved in recognition and removal of the fungus include phagocytosis, antimicrobial peptide production, and recognition by pattern recognition receptors. The cytokine response is also critical facilitating cell-to-cell communication and promoting the initiation, maintenance, and resolution of the host response. In the following review, we discuss the above areas with a focus on the innate and inflammatory response to airway Aspergillus exposure and how these responses may be modulated for therapeutic benefit.

Overexpression of Notch ligand Delta-like-1 by dendritic cells enhances their immunoregulatory capacity and exerts antiallergic effects on Th2-mediated allergic asthma in mice.

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Lee, Chen-Chen; Lin, Chu-Lun; Leu, Sy-Jye; Lee, Yueh-Lun

2018-02-01

Dendritic cells (DCs) are professional antigen-presenting cells, and Notch ligand Delta-like-1 (DLL1) on DCs was implicated in type 1T helper (Th1) differentiation. In this study, we produced genetically engineered bone marrow-derived DCs that expressed DLL1 (DLL1-DCs) by adenoviral transduction. DLL1-DCs exerted a fully mature phenotype, and had positive effects on expression levels of interleukin (IL)-12 and costimulatory molecules. Coculture of allogeneic T cells with ovalbumin (OVA)-pulsed DLL1-DCs enhanced T cell proliferative responses and promoted Th1 cell differentiation. Furthermore, adoptive transfer of OVA-stimulated DLL1-DCs into asthmatic mice alleviated the cardinal features of allergic asthma, including immunoglobulin E (IgE) production, airway hyperresponsiveness (AHR), airway inflammation, and production of Th2-type cytokines. Notably, enhanced levels of the Th1-biased IgG 2a response and interferon (IFN)-γ production were observed in these mice. Taken together, these data indicate that DLL1-DCs promoted Th1 cell development to alter the Th1/Th2 ratio and ameliorate Th2-mediated allergic asthma in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Equine recurrent airway obstruction

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Artur Niedźwiedź

2014-10-01

Full Text Available Equine Recurrent Airway Obstruction (RAO, also known as heaves or broken wind, is one of the most common disease in middle-aged horses. Inflammation of the airway is inducted by organic dust exposure. This disease is characterized by neutrophilic inflammation, bronchospasm, excessive mucus production and pathologic changes in the bronchiolar walls. Clinical signs are resolved in 3-4 weeks after environmental changes. Horses suffering from RAO are susceptible to allergens throughout their lives, therefore they should be properly managed. In therapy the most importanthing is to eliminate dustexposure, administration of corticosteroids and use bronchodilators to improve pulmonary function.

Aspergillus in chronic lung disease: Modeling what goes on in the airways.

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Takazono, Takahiro; Sheppard, Donald C

2017-01-01

Aspergillus species cause a range of respiratory diseases in humans. While immunocompromised patients are at risk for the development of invasive infection with these opportunistic molds, patients with underlying pulmonary disease can develop chronic airway infection with Aspergillus species. These conditions span a range of inflammatory and allergic diseases including Aspergillus bronchitis, allergic bronchopulmonary aspergillosis, and severe asthma with fungal sensitization. Animal models are invaluable tools for the study of the molecular mechanism underlying the colonization of airways by Aspergillus and the host response to these non-invasive infections. In this review we summarize the state-of-the-art with respect to the available animal models of noninvasive and allergic Aspergillus airway disease; the key findings of host-pathogen interaction studies using these models; and the limitations and future directions that should guide the development and use of models for the study of these important pulmonary conditions. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Effect of anxiety and depression on pulmonary function as well as airway inflammation and remodeling in patients with bronchial asthma

Institute of Scientific and Technical Information of China (English)

Qin Yang

2017-01-01

Objective:To study the effect of anxiety and depression on pulmonary function as well as airway inflammation and remodeling in patients with bronchial asthma.Methods: A total of 118 adult patients with bronchial asthma who were treated in our hospital between September 2015 and January 2017 were divided into pure depression group (n=30), pure anxiety group (n=47), depression + anxiety group (n=19) and mental health group (n=22) according to the Self-Rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS) score. The differences in the levels of pulmonary function parameters as well as the contents of serum inflammatory factors and airway remodeling indexes were compared among the four groups. Results: FEV1, PEF and FVC levels as well as serum TIMP-1 contents of pure depression group, pure anxiety group and depression + anxiety group were lower than those of mental health group while serum IL-2, IL-4, IL-8, IL-33, VEGF, OPN, TGF-β1 and MMP-9 contents were higher than those of mental health group, and FEV1, PEF and FVC levels as well as serum TIMP-1 content of depression + anxiety group were lower than those of pure depression group and pure anxiety group while serum IL-2, IL-4, IL-8, IL-33, VEGF, OPN, TGF-β1 and MMP-9 contents were higher than those of pure depression group and pure anxiety group. Conclusion: Anxiety and depression can aggravate the pulmonary function injury, increase airway inflammation and promote airway remodeling process in patients with bronchial asthma.

Effects of drug treatment on inflammation and hyperreactivity of airways and on immune variables in cats with experimentally induced asthma.

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Reinero, Carol R; Decile, Kendra C; Byerly, Jenni R; Berghaus, Roy D; Walby, William E; Berghaus, Londa J; Hyde, Dallas M; Schelegle, Edward S; Gershwin, Laurel J

2005-07-01

To compare the effects of an orally administered corticosteroid (prednisone), an inhaled corticosteroid (flunisolide), a leukotriene-receptor antagonist (zafirlukast), an antiserotonergic drug (cyproheptadine), and a control substance on the asthmatic phenotype in cats with experimentally induced asthma. 6 cats with asthma experimentally induced by the use of Bermuda grass allergen (BGA). A randomized, crossover design was used to assess changes in the percentage of eosinophils in bronchoalveolar lavage fluid (BALF); airway hyperresponsiveness; blood lymphocyte phenotype determined by use of flow cytometry; and serum and BALF content of BGA-specific IgE, IgG, and IgA determined by use of ELISAs. Mean +/- SE eosinophil percentages in BALF when cats were administered prednisone (5.0 +/- 2.3%) and flunisolide (2.5 +/- 1.7%) were significantly lower than for the control treatment (33.7 +/- 11.1%). We did not detect significant differences in airway hyperresponsiveness or lymphocyte surface markers among treatments. Content of BGA-specific IgE in serum was significantly lower when cats were treated with prednisone (25.5 +/- 5.4%), compared with values for the control treatment (63.6 +/- 12.9%); no other significant differences were observed in content of BGA-specific immunoglobulins among treatments. Orally administered and inhaled corticosteroids decreased eosinophilic inflammation in airways of cats with experimentally induced asthma. Only oral administration of prednisone decreased the content of BGA-specific IgE in serum; no other significant local or systemic immunologic effects were detected among treatments. Inhaled corticosteroids can be considered as an alternate method for decreasing airway inflammation in cats with asthma.

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

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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

Influence of pirfenidone on airway hyperresponsiveness and inflammation in a Brown-Norway rat model of asthma.

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Mansoor, Jim K; Decile, Kendra C; Giri, Shri N; Pinkerton, Kent E; Walby, William F; Bratt, Jennifer M; Grewal, Harinder; Margolin, Solomon B; Schelegle, Edward S

2007-01-01

Pirfenidone was administered to sensitized Brown Norway rats prior to a series of ovalbumin challenges. Airway hyperresponsiveness, inflammatory cell infiltration, mucin and collagen content, and the degree of epithelium and smooth muscle staining for TGF-beta were examined in control, sensitized, and sensitized/challenged rats fed a normal diet or pirfenidone diet. Pirfenidone had no effect on airway hyperresponsiveness, but reduced distal bronchiolar cell infiltration and proximal and distal mucin content. Statistical analysis showed that the control group and sensitized/challenged pirfenidone diet group TGF-beta staining intensity scores were not significantly different from isotype controls, but that the staining intensity scores for the sensitized/challenged normal diet group was significantly different from isotype controls. These results suggest that pirfenidone treatment is effective in reducing some of the components of acute inflammation induced by allergen challenge.

Real-life study showing better control of allergic rhinitis by immunotherapy than regular pharmacotherapy

NARCIS (Netherlands)

Droessaert, V.; Timmermans, M.; Dekimpe, E.; Seys, S.; Ceuppens, J. J.; Fokkens, W. J.; Hellings, P. W.

2016-01-01

Treatment for allergic rhinitis (AR) aims at reducing the burden of allergic inflammation, either by suppression of the nasal inflammation with pharmacotherapy or by inducing tolerance via immunotherapy (IT). At present, we lack information on the comparison between the degree of symptom control in

Alterações orofaciais em doenças alérgicas de vias aéreas Orofacial alterations in allergic diseases of the airways

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Anete Branco

2007-09-01

Full Text Available OBJETIVO: Apontar as possíveis alterações orofaciais decorrentes do sintoma "obstrução nasal" em pacientes portadores de doenças alérgicas de vias aéreas superiores, por meio de revisão de literatura. FONTES DE DADOS: Levantamento bibliográfico utilizando bancos de dados eletrônicos, como Medline, Ovid, SciELO e Lilacs, com as palavras-chave "asthma", "rhinitis" e "mouth breathing", abrangendo os 30 últimos anos. Foram incluídos artigos de revisão, estudos observacionais e ensaios clínicos. SÍNTESE DOS DADOS: A obstrução nasal é encontrada freqüentemente em doenças alérgicas de vias aéreas, como rinite e asma. A respiração bucal decorrente da obstrução nasal pode interferir de maneira direta no desenvolvimento infantil, com alterações no crescimento do crânio e orofacial, na fala, na alimentação, na postura corporal, na qualidade do sono e no desempenho escolar. CONCLUSÕES: Devido à variedade de alterações orofaciais encontradas na criança respiradora bucal decorrente de obstrução nasal por doenças alérgicas de vias aéreas, é necessário realizar diagnóstico e tratamento precoces por uma equipe multidisciplinar, composta por médico, ortodontista e fonoaudiólogo, contemplando a visão de uma via respiratória única, que traz conseqüências ao crescimento e desenvolvimento do sistema motor oral.OBJECTIVE: To study possible orofacial alterations originated from nasal obstruction symptoms in patients with allergic diseases of the superior airways, through search of scientific literature about the theme. DATA SOURCES: Bibliographic survey of the last 30 years using electronic data such as Medline, Ovid, SciELO and Lilacs, and the keywords "asthma", "rhinitis" and "mouth breathing". Revision articles, observational and clinical studies were included. DATA SYNTHESIS: Nasal obstruction is often found in patients with allergic diseases of airways, such as rhinitis and asthma. The mouth breathing originated

Treatment of mice with fenbendazole attenuates allergic airways inflammation and Th2 cytokine production in a model of asthma.

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Cai, Yeping; Zhou, Jiansheng; Webb, Dianne C

2009-01-01

Mouse models have provided a significant insight into the role of T-helper (Th) 2 cytokines such as IL-5 and IL-13 in regulating eosinophilia and other key features of asthma. However, the validity of these models can be compromised by inadvertent infection of experimental mouse colonies with pathogens such as oxyurid parasites (pinworms). While the benzimidazole derivative, fenbendazole (FBZ), is commonly used to treat such outbreaks, the effects of FBZ on mouse models of Th2 disease are largely unknown. In this investigation, we show that mice fed FBZ-supplemented food during the in utero and post-weaning period developed attenuated lung eosinophilia, antigen-specific IgG1 and Th2 cytokine responses in a model of asthma. Treatment of the mediastinal lymph node cells from allergic mice with FBZ in vitro attenuated cell proliferation, IL-5 and IL-13 production and expression of the early lymphocyte activation marker, CD69 on CD4(+) T cells and CD19(+) B cells. In addition, eosinophilia and Th2 responses remained attenuated after a 4-week withholding period in allergic mice treated preweaning with FBZ. Thus, FBZ modulates the amplitude of Th2 responses both in vivo and in vitro.

Characterization and antagonism of cytokine-induced eosinophil priming

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Rosas Rosas, Ana Marcela

2006-01-01

Allergic asthma is an inflammatory disease characterized by bronchial hyper-responsiveness, airway inflammation, and reversible obstruction of the airways. In humans, cytokine activated eosinophils are thought to be important players in this process since they can release inflammatory mediators

Avaliação da inflamação das vias aéreas. Vias áreas superiores e compartimento broncopulmonar Airways inflammation evaluation. Upper and lower airways

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Luísa Geraldes

2009-05-01

Full Text Available Faz-se uma revisão sobre métodos de avaliação da inflamação nas vias aéreas que contribuam para o diagnóstico, terapêutica e prognóstico de patologias como a rinossinusite e a asma. Serão também considerados métodos susceptíveis de fornecer informação relevante sobre inflamação na DPOC. A inflamação crónica das vias aéreas condiciona fenómenos obstrutivos objectivados na função respiratória basal, na hiperreactividade brônquica e nasal e em quadros clínicos de dificuldade respiratória. A tomografia computorizada informa sobre as dimensões do lúmen, a espessura das paredes brônquicas e os índices de densidade pulmonar, alterações que decorrem da inflamação e remodelação das vias aéreas. Um processo inflamatório localizado nas vias respiratórias é susceptível de ser detectado por modificações em marcadores sistémicos de inflamação. Os métodos directos recorrem a análise imunoistoquímica de tecidos e de fluidos em condições basais ou após estimulação. Os eosinófilos aumentam em biópsias, lavados nasais e broncoalveolares na asma e na rinite e modificam-se com a terapêutica. Ocorrem alterações nas proteínas e expressão de RNAm de mediadores envolvidos na activação celular. A expectoração induzida identifica inflamação eosinofílica que se relaciona inversamente com a função ventilatória. Em cada ciclo respiratório o ar é enriquecido em compostos voláteis produzidos no decurso da respiração celular. A FENO é o biomarcador mais estudado e os seus níveis estão elevados na asma. No condensado do ar expirado identificam-se espécies reactivas de oxigénio, derivados de membrana, citocinas e quimiocinas pró-inflamatórias. Se a avaliação não invasiva da inflamação for fidedigna e reprodutível, será imprescindível na monitorização das doenças das vias aéreas.It is done a review of evaluation methods of the inflammation in upper airways and bronchi used for

Pattern of airway inflammation and remodelling in mild persistent atopic asthma and in mild persistent asthma related to gastroesophageal reflux.

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Dal Negro, R W; Guerriero, M; Micheletto, C

2012-12-01

The increase of basement membrane thickness (BMAT) represents a structural feature described as commonly characterizing airway remodelling in asthma, even if the non-atopic condition had been investigated only episodically from this point of view. Gastrooesophageal-reflux is a pathological condition which can frequently cause and/or sustain asthma in non-atopic individuals. The aim of the study was to measure BMT; some inflammatory mediators in BAL; cys-leucotrienes (LTE4) in urine; e-NO, and BHR to Methacholine (MCh) in mild atopic and in mild non-atopic, GER-related asthma. After their informed consent, 25 mild atopic (40.9 years +/- 13.1 sd, FEV1 = 95.9% pred. +/- 12.9 sd) and 39 non-atopic, GER-related asthmatics (57.3 years +/- 14.2 ds, FEVY1 = 101.3% pred. +/- 12.2 sd), nonsmoker and of a comparable asthma duration, underwent measurements of basal lung function and bronchial response to MCh (PD20 FEV1); endobronchial biopsies and BAL (in the right middle lobe), and a 24-h gastroesophageal pHmetry. Atopic GER-related asthma showed two distinct patterns of airway inflammation. The eosinophilic contribution to airway inflammation was systematically prevailing in the former group, such as: EOS = 10.7% +/- 13.4 sd vs 2.0% +/- 2.8 sd, p = 0.001; ECP = 344.9 mcg/l +/- 635.9 sd vs 59.2 mcg/l +/- 75.1 sd, p = 0.001. Data from the present study are suggesting that persistent mild atopic and mild GER-related asthma seem to represent two distinct phenotypes of asthma in terms of airway remodelling, and in particular of BMT involvement.

Comparison of airway responses in sheep of different age in precision-cut lung slices (PCLS.

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Verena A Lambermont

Full Text Available Animal models should display important characteristics of the human disease. Sheep have been considered particularly useful to study allergic airway responses to common natural antigens causing human asthma. A rationale of this study was to establish a model of ovine precision-cut lung slices (PCLS for the in vitro measurement of airway responses in newborn and adult animals. We hypothesized that differences in airway reactivity in sheep are present at different ages.Lambs were delivered spontaneously at term (147d and adult sheep lived till 18 months. Viability of PCLS was confirmed by the MTT-test. To study airway provocations cumulative concentration-response curves were performed with different allergic response mediators and biogenic amines. In addition, electric field stimulation, passive sensitization with house dust mite (HDM and mast cells staining were evaluated.PCLS from sheep were viable for at least three days. PCLS of newborn and adult sheep responded equally strong to methacholine and endothelin-1. The responses to serotonin, leukotriene D4 and U46619 differed with age. No airway contraction was evoked by histamine, except after cimetidine pretreatment. In response to EFS, airways in PCLS from adult and newborn sheep strongly contracted and these contractions were atropine sensitive. Passive sensitization with HDM evoked a weak early allergic response in PCLS from adult and newborn sheep, which notably was prolonged in airways from adult sheep. Only few mast cells were found in the lungs of non-sensitized sheep at both ages.PCLS from sheep lungs represent a useful tool to study pharmacological airway responses for at least three days. Sheep seem well suited to study mechanisms of cholinergic airway contraction. The notable differences between newborn and adult sheep demonstrate the importance of age in such studies.

Mast Cell Interactions and Crosstalk in Regulating Allergic Inflammation.

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Velez, Tania E; Bryce, Paul J; Hulse, Kathryn E

2018-04-17

This review summarizes recent findings on mast cell biology with a focus on IgE-independent roles of mast cells in regulating allergic responses. Recent studies have described novel mast cell-derived molecules, both secreted and membrane-bound, that facilitate cross-talk with a variety of immune effector cells to mediate type 2 inflammatory responses. Mast cells are complex and dynamic cells that are persistent in allergy and are capable of providing signals that lead to the initiation and persistence of allergic mechanisms.

Effects of Flavin7 on allergen induced hyperreactivity of airways

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Franova S

2009-12-01

Full Text Available Abstract Some studies have suggested that the polyphenolic compounds might reduce the occurrence of asthma symptoms. The aim of our experiments was to evaluate the effects of 21 days of the flavonoid Flavin7 administration on experimentally induced airway inflammation in ovalbumin-sensitized guinea pigs. We assessed tracheal smooth muscle reactivity by an in vitro muscle-strip method; changes in airway resistance by an in vivo plethysmographic method; histological picture of tracheal tissue; and the levels of interleukin 4 (IL-4, and interleukin 5 (IL-5 in bronchoalveolar lavage fluid (BALF. Histological investigation of tracheal tissue and the concentrations of the inflammatory cytokines IL-4 and IL-5 in BALF were used as indices of airway inflammation. Administration of Flavin7 caused a significant decrease of specific airway resistance after histamine nebulization and a decline in tracheal smooth muscle contraction amplitude in response to bronchoconstricting mediators. Flavin7 minimized the degree of inflammation estimated on the basis of eosinophil calculation and IL-4 and IL-5 concentrations. In conclusion, administration of Flavin7 showed bronchodilating and anti-inflammatory effects on allergen-induced airway inflammation.

Airway inflammation in Japanese COPD patients compared with smoking and nonsmoking controls

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Ishikawa N

2015-01-01

Full Text Available Nobuhisa Ishikawa,1 Noboru Hattori,2 Nobuoki Kohno,2 Akihiro Kobayashi,3 Tomoyuki Hayamizu,4 Malcolm Johnson5 1Department of Respiratory Medicine, Hiroshima Prefectural Hospital, Hiroshima, Japan; 2Department of Molecular and Internal Medicine, Hiroshima University, Hiroshima, Japan; 3Biomedical Data Science Department, 4Medical Affairs Respiratory Department, GlaxoSmithKline Shibuya-ku, Tokyo, Japan; 5Respiratory Global Franchise, GlaxoSmithKline, Uxbridge, UK Purpose: To assess the importance of inflammation in chronic obstructive pulmonary disease (COPD by measuring airway and systemic inflammatory biomarkers in Japanese patients with the disease and relevant control groups.Patients and methods: This was the first study of its type in Japanese COPD patients. It was a non-treatment study in which 100 participants were enrolled into one of three groups: nonsmoking controls, current or ex-smoking controls, and COPD patients. All participants underwent standard lung function assessments and provided sputum and blood samples from which the numbers of inflammatory cells and concentrations of biomarkers were measured, using standard procedures.Results: The overall trends observed in levels of inflammatory cells and biomarkers in sputum and blood in COPD were consistent with previous reports in Western studies. Increasing levels of neutrophils, interleukin 8 (IL-8, surfactant protein D (SP-D, and Krebs von den Lungen 6 (KL-6 in sputum and clara cell 16 (CC-16, high-sensitivity C-reactive protein (hs-CRP, and KL-6 in serum and plasma fibrinogen were seen in the Japanese COPD patients compared with the non-COPD control participants. In sputum, significant correlations were seen between total cell count and matrix metalloproteinase 9 (MMP-9; P<0.001, neutrophils and MMP-9 (P<0.001, macrophages and KL-6 (P<0.01, total cell count and IL-8 (P<0.05, neutrophils and IL-8 (P<0.05, and macrophages and MMP-9 (P<0.05. Significant correlations were also

Tanreqing Injection Attenuates Lipopolysaccharide-Induced Airway Inflammation through MAPK/NF-κB Signaling Pathways in Rats Model

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Liu, Wei; Jiang, Hong-li; Cai, Lin-li; Yan, Min; Dong, Shou-jin; Mao, Bing

2016-01-01

Background. Tanreqing injection (TRQ) is a commonly used herbal patent medicine for treating inflammatory airway diseases in view of its outstanding anti-inflammatory properties. In this study, we explored the signaling pathways involved in contributions of TRQ to LPS-induced airway inflammation in rats. Methods/Design. Adult male Sprague Dawley (SD) rats randomly divided into different groups received intratracheal instillation of LPS and/or intraperitoneal injection of TRQ. Bronchoalveolar Lavage Fluid (BALF) and lung samples were collected at 24 h, 48 h, and 96 h after TRQ administration. Protein and mRNA levels of tumor necrosis factor- (TNF-) α, Interleukin- (IL-) 1β, IL-6, and IL-8 in BALF and lung homogenate were observed by ELISA and real-time PCR, respectively. Lung sections were stained for p38 MAPK and NF-κB detection by immunohistochemistry. Phospho-p38 MAPK, phosphor-extracellular signal-regulated kinases ERK1/2, phospho-SAPK/JNK, phospho-NF-κB p65, phospho-IKKα/β, and phospho-IκB-α were measured by western blot analysis. Results. The results showed that TRQ significantly counteracted LPS-stimulated release of TNF-α, IL-1β, IL-6, and IL-8, attenuated cells influx in BALF, mitigated mucus hypersecretion, suppressed phosphorylation of NF-κB p65, IκB-α, ΙKKα/β, ERK1/2, JNK, and p38 MAPK, and inhibited p38 MAPK and NF-κB p65 expression in rat lungs. Conclusions. Results of the current research indicate that TRQ possesses potent exhibitory effects in LPS-induced airway inflammation by, at least partially, suppressing the MAPKs and NF-κB signaling pathways, in a general dose-dependent manner. PMID:27366191

The Effect of Serine Protease Inhibitors on Airway Inflammation in a Chronic Allergen-Induced Asthma Mouse Model

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Chih-Che Lin

2014-01-01

Full Text Available Serine protease inhibitors reportedly attenuated airway inflammation and had antioxidant in multiorgan. However, the effects of the serine protease inhibitors nafamostat mesilate (FUT, gabexate mesilate (FOY, and ulinastatin (UTI on a long-term challenged mouse model of chronic asthma are unclear. BALB/c mice (6 mice/group were intratracheally inoculated with five doses of Dermatophagoides pteronyssinus (Der p; 50 μL, 1 mg/mL at one-week intervals. Therapeutic doses of FUT (0.0625 mg/kg, FOY (20 mg/kg, or UTI (10,000 U/kg were, respectively, injected intraperitoneally into these mice. Control mice received sterile PBS. At 3 days after the last challenge, mice were sacrificed to assess airway hyperresponsiveness (AHR, remodeling, and inflammation; lung histological features; and cytokine expression profiles. Compared with untreated controls, mice treated with FUT, FOY, and UTI had decreased AHR and goblet cell hyperplasia, decreased eosinophil and neutrophil infiltration, decreased Der p-induced IL-4 levels in serum and IL-5, IL-6, IL-13, and IL-17 levels in bronchoalveolar lavage fluid, and inhibited nuclear factor (NF-κB activity in lung tissues. The serine protease inhibitors FUT, FOY, and UTI have potential therapeutic benefits for treating asthma by downregulating Th2 cytokines and Th17 cell function and inhibiting NF-κB activation in lung tissue.

Perillyl alcohol suppresses antigen-induced immune responses in the lung

International Nuclear Information System (INIS)

Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko; Dohi, Makoto

2014-01-01

Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4 + T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4 + T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects

Japanese Guideline for Allergic Conjunctival Diseases

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Etsuko Takamura

2011-01-01

Full Text Available The definition, classification, pathogenesis, test methods, clinical findings, criteria for diagnosis, and therapies of allergic conjunctival disease are summarized based on the Guidelines for Clinical Management of Allergic Conjunctival Disease (Second Edition revised in 2010. Allergic conjunctival disease is defined as “a conjunctival inflammatory disease associated with a Type I allergy accompanied by some subjective or objective symptoms.” Allergic conjunctival disease is classified into allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. Representative subjective symptoms include ocular itching, hyperemia, and lacrimation, whereas objective symptoms include conjunctival hyperemia, swelling, folliculosis, and papillae. Patients with vernal keratoconjunctivitis, which is characterized by conjunctival proliferative changes called giant papilla accompanied by varying extents of corneal lesion, such as corneal erosion and shield ulcer, complain of foreign body sensation, ocular pain, and photophobia. In the diagnosis of allergic conjunctival diseases, it is required that type I allergic diathesis is present, along with subjective and objective symptoms accompanying allergic inflammation. The diagnosis is ensured by proving a type I allergic reaction in the conjunctiva. Given that the first-line drug for the treatment of allergic conjunctival disease is an antiallergic eye drop, a steroid eye drop will be selected in accordance with the severity. In the treatment of vernal keratoconjunctivitis, an immunosuppressive eye drop will be concomitantly used with the abovementioned drugs.

Allergic Contact Dermatitis Is Associated with Significant Oxidative Stress

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S. Kaur

2014-01-01

Full Text Available Background. Research has confirmed the involvement of oxidative stress (OxS in allergic contact dermatitis whilst other inflammation-related biomarkers have been less studied. Objective. To evaluate systemic levels of selected inflammatory markers, OxS indices and adipokines as well as their associations in allergic contact dermatitis. Methods. In 40 patients, interleukin- (IL- 6, monocyte chemoattractant protein (MCP-1, and IL-10 levels were measured in sera with the Evidence Investigator Cytokine & Growth factors High-Sensitivity Array, total peroxide concentration (TPX and total antioxidant capacity (TAC by means of spectrophotometry, and the plasma concentrations of adiponectin and leptin by the quantitative sandwich enzyme immunoassay technique. Results. TNF-α level (P < 0.01 and TPX (P < 0.0001 were increased whilst IL-10 (P < 0.05 and TAC (P < 0.0001 were decreased in the patients as compared to controls. Correlation and multiple linear regression analysis identified both, TPX and TAC (inversely, as possible independent markers for evaluating allergic contact dermatitis. Adiponectin level in patients was increased (P < 0.0001, but neither adiponectin nor leptin correlated significantly with the biomarkers of inflammation or OxS. Conclusion. OxS parameters, especially TPX and OSI, reflect the degree of systemic inflammation associated with allergic contact dermatitis in the best way. The relation between OxS and adiponectin level warrants further studies.

l-2-Oxothiazolidine-4-Carboxylic Acid or α-Lipoic Acid Attenuates Airway Remodeling: Involvement of Nuclear Factor-κB (NF-κB, Nuclear Factor Erythroid 2p45-Related Factor-2 (Nrf2, and Hypoxia-Inducible Factor (HIF

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Heung Bum Lee

2012-06-01

Full Text Available Reactive oxygen species (ROS play a crucial role in the pathogenesis of acute and chronic respiratory diseases. Antioxidants have been found to ameliorate airway inflammation and hyperresponsiveness in animal models employing short-term exposure to allergen. However, little data are available on the effect of antioxidants on airway remodeling and signaling pathways in chronic asthma. In the present study, we used a long-term exposure murine model of allergic airway disease to evaluate the effects of an antioxidant, l-2-oxothiazolidine-4-carboxylic acid (OTC or α-lipoic acid (LA on airway remodeling, focusing on the ROS-related hypoxia-inducible signaling. Long-term challenge of ovalbumin (OVA increased ROS production, airway inflammation, and airway hyperresponsiveness, and developed features of airway remodeling such as excessive mucus secretion, subepithelial fibrosis, and thickening of the peribronchial smooth muscle layer. Administration of OTC or LA reduced these features of asthma, including airway remodeling, which was accompanied by suppression of transforming growth factor-β1, vascular endothelial growth factor, and T-helper 2 cytokines. In addition, OVA-induced activation of nuclear factor-κB (NF-κB, nuclear factor erythroid 2p45-related factor-2 (Nrf2, hypoxia-inducible factor (HIF-1α, and HIF-2α was reduced by OTC or LA. Our results also showed that OTC or LA down-regulated phosphoinositide 3-kinase activity and decreased phosphorylation of p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase. These findings demonstrate that OTC and LA can inhibit activation of NF-κB, Nrf2, and HIF, leading to attenuate allergen-induced airway remodeling.

Resolution of LPS-induced airway inflammation and goblet cell hyperplasia is independent of IL-18

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Lyons C Rick

2007-03-01

Full Text Available Abstract Background The resolution of inflammatory responses in the lung has not been described in detail and the role of specific cytokines influencing the resolution process is largely unknown. Methods The present study was designed to describe the resolution of inflammation from 3 h through 90 d following an acute injury by a single intratracheal instillation of F344/N rats with LPS. We documented the inflammatory cell types and cytokines found in the bronchoalveolar lavage fluid (BALF, and epithelial changes in the axial airway and investigated whether IL-18 may play a role in the resolution process by reducing its levels with anti-IL-18 antibodies. Results Three major stages of inflammation and resolution were observed in the BALF during the resolution. The first stage was characterized by PMNs that increased over 3 h to 1 d and decreased to background levels by d 6–8. The second stage of inflammation was characterized by macrophage influx reaching maximum numbers at d 6 and decreasing to background levels by d 40. A third stage of inflammation was observed for lymphocytes which were elevated over d 3–6. Interestingly, IL-18 and IL-9 levels in the BALF showed a cyclic pattern with peak levels at d 4, 8, and 16 while decreasing to background levels at d 1–2, 6, and 12. Depletion of IL-18 caused decreased PMN numbers at d 2, but no changes in inflammatory cell number or type at later time points. Conclusion These data suggest that IL-18 plays a role in enhancing the LPS-induced neutrophilic inflammation of the lung, but does not affect the resolution of inflammation.

Inflammation, oxidative stress, and higher expression levels of Nrf2 and NQO1 proteins in the airways of women chronically exposed to biomass fuel smoke.

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Mondal, Nandan Kumar; Saha, Hirak; Mukherjee, Bidisha; Tyagi, Neetu; Ray, Manas Ranjan

2018-01-24

The study was carried out to examine whether chronic exposure to smoke during daily household cooking with biomass fuel (BMF) elicits changes in airway cytology and expressions of Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2]), Keap1 (Kelch-like erythroid-cell-derived protein with CNC homology [ECH]-associated protein 1), and NQO1 (NAD(P)H:quinone oxidoreductase 1) proteins in the airways. For this, 282 BMF-using women (median age 34 year) and 236 age-matched women who cooked with liquefied petroleum gas (LPG) were enrolled. Particulate matter with diameters of LPG. Compared with LPG users, BMF users had 32% more leukocytes in circulation and their sputa were 1.4-times more cellular with significant increase in absolute number of neutrophils, lymphocytes, eosinophils, and alveolar macrophages, suggesting airway inflammation. ROS generation was 1.5-times higher in blood neutrophils and 34% higher in sputum cells of BMF users while erythrocyte SOD was 31% lower and plasma catalase was relatively unchanged, suggesting oxidative stress. In BMF users, Keap1 expression was reduced, the percentage of AEC with nuclear expression of Nrf2 was two- to three-times more, and NQO1 level in sputum cell lysate was two-times higher than that of LPG users. In conclusion, cooking with BMF was associated with Nrf2 activation and elevated NQO1 protein level in the airways. The changes may be adaptive cellular response to counteract biomass smoke-elicited oxidative stress and inflammation-related tissue injury in the airways.

Type 2 innate lymphoid cells: at the cross-roads in allergic asthma.

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van Rijt, Leonie; von Richthofen, Helen; van Ree, Ronald

2016-07-01

Allergic asthma is a chronic inflammatory disease of the lower airways that affects millions of people worldwide. Allergic asthma is a T helper 2 cell (Th2)-mediated disease, in which Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 are closely associated with the symptoms. IL-4 is needed by B cells to switch toward an IgE response, IL-5 recruits and activates eosinophils while IL-13 increases mucus production. The identification of type 2 innate lymphoid cells (ILC2), which are able to rapidly produce large amounts of IL-5 and IL-13 in response to epithelial derived cytokines, implicated a new key player besides Th2 cells. ILCs constitute a family of innate lymphocytes distinct from T and B cells. ILC2s are located in various epithelial compartments in mice and human, including the lung. The recent finding of increased numbers of ILC2s in the airways of severe asthma patients prompts further research to clarify their immunological function. Murine studies have shown that ILC2s are an early innate source of IL-5 and IL-13 after allergen exposure, which induce airway eosinophilic infiltration, mucus hyperproduction, and airway hyperresponsiveness but not allergen-specific IgE production. ILC2s contribute to the initiation as well as to the maintenance of the adaptive type 2 immune response. Here, we review the recent progress on our understanding of the role of ILC2s in the immunopathology of allergic asthma, in particular by studies using murine models which have elucidated fundamental mechanisms by which ILC2s act.

Serum progranulin as an indicator of neutrophilic airway inflammation and asthma severity.