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Sample records for acquisition airway inflammation

  1. Cholinergic regulation of airway inflammation and remodelling

    NARCIS (Netherlands)

    Kolahian, Saeed; Gosens, Reinoud

    2012-01-01

    Acetylcholine is the predominant parasympathetic neurotransmitter in the airways that regulates bronchoconstriction and mucus secretion. Recent findings suggest that acetylcholine regulates additional functions in the airways, including inflammation and remodelling during inflammatory airway disease

  2. Relationship between airway pathophysiology and airway inflammation in older asthmatics

    DEFF Research Database (Denmark)

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

    2013-01-01

    BACKGROUND AND OBJECTIVE: Asthma-related morbidity is greater in older compared with younger asthmatics. Airway closure is also greater in older asthmatics, an observation that may be explained by differences in airway inflammation. We hypothesized that in older adult patients with asthma......: Mean patient age was 67 years (confidence interval: 63-71) with a mean FEV1 of 78 % predicted (confidence interval: 70-85%). AHR correlated with sputum eosinophils (r = 0.68, P = 0.005) and eNO (r = 0.71, P ... or eNO. CONCLUSIONS: In older patients with asthma, airway inflammatory cells are linked to abnormal airway physiology. Eosinophilic airway inflammation is associated with AHR while neutrophilic inflammation may be an important determinant of airflow limitation at rest and airway closure during...

  3. Cholinergic Regulation of Airway Inflammation and Remodelling

    Directory of Open Access Journals (Sweden)

    Saeed Kolahian

    2012-01-01

    Full Text Available Acetylcholine is the predominant parasympathetic neurotransmitter in the airways that regulates bronchoconstriction and mucus secretion. Recent findings suggest that acetylcholine regulates additional functions in the airways, including inflammation and remodelling during inflammatory airway diseases. Moreover, it has become apparent that acetylcholine is synthesized by nonneuronal cells and tissues, including inflammatory cells and structural cells. In this paper, we will discuss the regulatory role of acetylcholine in inflammation and remodelling in which we will focus on the role of the airway smooth muscle cell as a target cell for acetylcholine that modulates inflammation and remodelling during respiratory diseases such as asthma and COPD.

  4. Silibinin attenuates allergic airway inflammation in mice

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-10-26

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

  5. Research on airway inflammation: present status in Mainland China

    Institute of Scientific and Technical Information of China (English)

    WANG Zeng-li

    2005-01-01

    @@ Airway inflammation involving activated eosinophils, mast cells and T lymphocytes is an established feature of asthma and has been the key target to treatment. Airway structural changes that occur in patients with asthma in response to persistent inflammation are termed airway remodeling.

  6. Association between peripheral airway function and neutrophilic inflammation in asthma

    NARCIS (Netherlands)

    Farah, Claude S.; Keulers, Laurien A. B.; Hardaker, Kate M.; Peters, Matthew J.; Berend, Norbert; Postma, Dirkje S.; Salome, Cheryl M.; King, Gregory G.

    2015-01-01

    Background and objectiveSmall airway dysfunction is associated with asthma severity and control, but its association with airway inflammation is unknown. The aim was to determine the association between sputum inflammatory cells and the site of small airway dysfunction, measured by multiple breath n

  7. Pim1 kinase protects airway epithelial cells from cigarette smoke-induced damage and airway inflammation

    NARCIS (Netherlands)

    de Vries, M.; Heijink, Hilde; Gras, R.; den Boef, L. E.; Reinders-Luinge, M.; Pouwels, S. D.; Hylkema, Machteld; van der Toorn, Marco; Brouwer, U.; van Oosterhout, A. J. M.; Nawijn, M. C.

    2014-01-01

    Exposure to cigarette smoke (CS) is the main risk factor for developing chronic obstructive pulmonary disease and can induce airway epithelial cell damage, innate immune responses, and airway inflammation. We hypothesized that cell survival factors might decrease the sensitivity of airway epithelial

  8. Airway, responsiveness and inflammation in adolescent elite swimmers

    DEFF Research Database (Denmark)

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

    2008-01-01

    . 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...

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

    DEFF Research Database (Denmark)

    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...

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

    DEFF Research Database (Denmark)

    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...

  11. New insights into the relationship between airway inflammation and asthma.

    Science.gov (United States)

    Wardlaw, A J; Brightling, C E; Green, R; Woltmann, G; Bradding, P; Pavord, I D

    2002-08-01

    Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness (AHR) and airway inflammation which is usually, but not invariably, eosinophilic. Current thoughts on the pathogenesis of asthma are focused on the idea that it is caused by an inappropriate response of the specific immune system to harmless antigens, particularly allergens such as cat dander and house dust mite, that result in Th2-mediated chronic inflammation. However, the relationship between inflammation and asthma is complex, with no good correlation between the severity of inflammation, at least as measured by the number of eosinophils, and the severity of asthma. In addition, there are a number of conditions, such as eosinophilic bronchitis and allergic rhinitis, in which there is a Th2-mediated inflammatory response, but no asthma, as measured by variable airflow obstruction or AHR. Bronchoconstriction can also occur without obvious airway inflammation, and neutrophilic inflammation can in some cases be associated with asthma. When we compared the immunopathology of eosinophilic bronchitis and asthma, the only difference we observed was that, in asthma, the airway smooth muscle (ASM) was infiltrated by mast cells, suggesting that airway obstruction and AHR are due to an ASM mast cell myositis. This observation emphasizes that the features that characterize asthma, as opposed to bronchitis, are due to abnormalities in smooth muscle responsiveness, which could be intrinsic or acquired, and that inflammation is only relevant in that it leads to these abnormalities. It also emphasizes the importance of micro-localization as an organizing principle in physiological responses to airway inflammation. Thus, if inflammation is localized to the epithelium and lamina propria, then the symptoms of bronchitis (cough and mucus hypersecretion) result, and it is only if the ASM is involved -- for reasons that remain to be established -- that asthma occurs.

  12. Eosinophilic airway inflammation in asthma is associated with an altered airway microbiome

    DEFF Research Database (Denmark)

    Sverrild, Asger; Kiilerich, Pia; Brejnrod, Asker

    2016-01-01

    BACKGROUND: Subjects with asthma have higher microbiome diversity, and an altered composition with more Proteobacteria and less Bacteroidetes compared to healthy controls. Studies comparing airway inflammation and airway microbiome are sparse, especially in subjects not on anti-inflammatory treat......BACKGROUND: Subjects with asthma have higher microbiome diversity, and an altered composition with more Proteobacteria and less Bacteroidetes compared to healthy controls. Studies comparing airway inflammation and airway microbiome are sparse, especially in subjects not on anti......-inflammatory treatment. OBJECTIVE: To describe the relationship between the airway microbiome and patterns of airway inflammation in steroid-free subjects with asthma and healthy controls. METHODS: Broncho-alveolar lavage was collected from 23 steroid-free, non-smoking subjects with asthma and 10 healthy controls....... The overall composition of the airway microbiome of asthmatics with the lowest levels of eosinophils, but not asthmatics with the highest levels of eosinophils deviated significantly from that of healthy individuals. Asthmatics with the lowest levels of eosinophils had an altered bacterial abundance profile...

  13. Endotoxin Is Not Essential for the Development of Cockroach Induced Allergic Airway Inflammation

    OpenAIRE

    2012-01-01

    Purpose Cockroach (CR) is an important inhalant allergen and can induce allergic asthma. However, the mechanism by which CR induces airway allergic inflammation and the role of endotoxin in CR extract are not clearly understood in regards to the development of airway inflammation. In this study, we evaluated whether endotoxin is essential to the development of CR induced airway allergic inflammation in mice. Materials and Methods Airway allergic inflammation was induced by intranasal administ...

  14. Mucociliary clearance, airway inflammation and nasal symptoms in urban motorcyclists

    Directory of Open Access Journals (Sweden)

    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.

  15. Animal study for airway inflammation triggered by gastroesophageal reflux

    Institute of Scientific and Technical Information of China (English)

    LAI Yun-gang; WANG Zhong-gao; JI Feng; WU Ji-min; CHEN Xiu; LI Zhen; DONG Shu-kui

    2009-01-01

    Background Gastroesophageal reflux disease with extra-esophageal symptoms, especially those with respiratory istress was attracting more and more attention. The related mechanisms were still in controversy. The purpose of the work was to explore airway inflammation triggered by gastroesophageal reflux.Methods Sixteen Sprague-Dawley rats were used as study group and 9 as control. In the study group, a plastic extender with a trumpet-shaped distal end was inserted into the lower esophagus to dilate the cardia, the pylorus was ligated. One ml of 0.1 mol/L hydrochloric acid was injected into the stomach, While a simple laparotomy was performed for control animals. All animals from two groups were sacrificed 24 hours after operation. Then tracheotomy was carried and the bronchoalveolar lavage fluid was collected in all animals. Cells in the fluid were counted and levels of intedeukin (IL)-5, -6, -8 in it were measured.Results Compared with control group, the study group presented a neutrophil pattem of airway inflammation and an elevated concentration of IL-5, -6, -8 with no significant difference regarding eosinophil count.Conclusion The gastroesophageal reflux-triggered airway inflammation is characterized by a neutrophilic airway inflammation which differed from that caused by asthma, and enhanced levels of IL-5, -6 and -8, which are similar to that caused by asthma.

  16. SUSCEPTIBILITY TO POLLUTANT-INDUCED AIRWAY INFLAMMATION IS NEUROGENICALLY MEDIATED.

    Science.gov (United States)

    Neurogenic inflammation in the airways involves the activation of sensory irritant receptors (capsaicin, VR1) by noxious stimuli and the subsequent release of neuropeptides (e.g., SP, CGRP, NKA) from these fibers. Once released, these peptides initiate and sustain symptoms of ...

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

    Science.gov (United States)

    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.

  18. Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations.

    Directory of Open Access Journals (Sweden)

    Edith T Zemanick

    Full Text Available BACKGROUND: 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. OBJECTIVE: To determine the relationships between airway microbiota, inflammation, and lung function in CF subjects treated for PEx. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

  19. Blockade of Airway Inflammation by Kaempferol via Disturbing Tyk-STAT Signaling in Airway Epithelial Cells and in Asthmatic Mice

    OpenAIRE

    Ju-Hyun Gong; Daekeun Shin; Seon-Young Han; Sin-Hye Park; Min-Kyung Kang; Jung-Lye Kim; Young-Hee Kang

    2013-01-01

    Asthma is characterized by bronchial inflammation causing increased airway hyperresponsiveness and eosinophilia. The interaction between airway epithelium and inflammatory mediators plays a key role in the asthmatic pathogenesis. The in vitro study elucidated inhibitory effects of kaempferol, a flavonoid found in apples and many berries, on inflammation in human airway epithelial BEAS-2B cells. Nontoxic kaempferol at ≤20  μ M suppressed the LPS-induced IL-8 production through the TLR4 activat...

  20. Zinc supplementation alters airway inflammation and airway hyperresponsiveness to a common allergen

    Directory of Open Access Journals (Sweden)

    Morgan Carrie I

    2011-12-01

    Full Text Available Abstract Background Zinc supplementation can modulate immunity through inhibition of NF-κB, a transcription factor that controls many immune response genes. Thus, we sought to examine the mechanism by which zinc supplementation tempers the response to a common allergen and determine its effect on allergic airway inflammation. Methods Mice were injected with zinc gluconate prior to German cockroach (GC feces (frass exposure and airway inflammation was assessed. Primary bone marrow-derived neutrophils and DMSO-differentiated HL-60 cells were used to assess the role of zinc gluconate on tumor necrosis factor (TNFα expression. NF-κB:DNA binding and IKK activity were assessed by EMSA and in vitro kinase assay. Protein levels of A20, RIP1 and TRAF6 were assessed by Western blot analysis. Establishment of allergic airway inflammation with GC frass was followed by administration of zinc gluconate. Airway hyperresponsiveness, serum IgE levels, eosinophilia and Th2 cytokine production were assessed. Results Administration of zinc gluconate prior to allergen exposure resulted in significantly decreased neutrophil infiltration and TNFα cytokine release into the airways. This correlated with decreased NF-κB activity in the whole lung. Treatment with zinc gluconate significantly decreased GC frass-mediated TNFα production from bone-marrow derived neutrophils and HL-60 cells. We confirmed zinc-mediated decreases in NF-κB:DNA binding and IKK activity in HL-60 cells. A20, a natural inhibitor of NF-κB and a zinc-fingered protein, is a potential target of zinc. Zinc treatment did not alter A20 levels in the short term, but resulted in the degradation of RIP1, an important upstream activator of IKK. TRAF6 protein levels were unaffected. To determine the application for zinc as a therapeutic for asthma, we administered zinc following the establishment of allergic airway inflammation in a murine model. Zinc supplementation decreased airway hyperresponsiveness

  1. Roles of IL-22 in Allergic Airway Inflammation

    Directory of Open Access Journals (Sweden)

    Koichi Hirose

    2013-01-01

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

  2. 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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Assessment of Airway Microbiota and Inflammation in Cystic Fibrosis Using Multiple Sampling Methods

    OpenAIRE

    Edith T Zemanick; Brandie D Wagner; Robertson, Charles E.; Stevens, Mark J.; Szefler, Stanley J; Accurso, Frank J.; Sagel, Scott D; Harris, J. Kirk

    2015-01-01

    Rationale: Oropharyngeal (OP) swabs and induced sputum (IS) are used for airway bacteria surveillance in nonexpectorating children with cystic fibrosis (CF). Molecular analyses of these airway samples detect complex microbial communities. However, the optimal noninvasive sampling approach for microbiota analyses and the clinical relevance of microbiota, particularly its relationship to airway inflammation, is not well characterized.

  5. Effects of 4 months of smoking in mice with ovalbumin-induced airway inflammation

    NARCIS (Netherlands)

    Melgert, B. N.; Timens, W.; Kerstjens, H. A.; Geerlings, M.; Luinge, M. A.; Schouten, J. P.; Postma, D. S.; Hylkema, M. N.

    2007-01-01

    Background The effects of smoking on asthma pathogenesis are complex and not well studied. We have shown recently that 3 weeks of smoking attenuates ovalbumin (OVA)-induced airway inflammation in mice and that 4-6 months of smoking induces emphysema in mice without airway inflammation. Effects of co

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Association of current smoking with airway inflammation in chronic obstructive pulmonary disease and asymptomatic smokers

    NARCIS (Netherlands)

    Willemse, BWM; ten Hacken, NHT; Rutgers, B; Postma, DS; Timens, W

    2005-01-01

    Background: Inflammation in the airways and lung parenchyma underlies fixed airway obstruction in chronic obstructive pulmonary disease. The exact role of smoking as promoting factor of inflammation in chronic obstructive pulmonary disease is not clear, partly because studies often do not distinguis

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

    DEFF Research Database (Denmark)

    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...

  9. The extract of Cordyceps sinensis inhibited airway inflammation by blocking NF-κB activity.

    Science.gov (United States)

    Chiou, Ya-Ling; Lin, Ching-Yuang

    2012-06-01

    Aiming the extract of Cordyceps sinensis significantly inhibits airway inflammation, airway hyperresponsiveness, and the infiltration of eosinophils in the airway of rats and may be related to the modulation of T helper (Th)1 and Th2 cells functions. The mechanisms of C. sinensis involved in modulation of suppression inflammation are not yet determined. In this study, the mechanism involved in the extract of C. sinensis-C.S.3-modulated suppression of inflammation was investigated in vivo and in vitro systems. The results showed that C.S.3 reduced airway inflammation in ovalbumin-induced allergic mice. Furthermore, we found C.S.3 could decrease extracellular signal-regulated kinase 1/2 signaling pathway to suppress activity of nuclear factor-κB in lung cells and cultured airway smooth muscle cells. Conclusion C.S.3 may provide clinical applications for asthma in the future.

  10. Modulation of airway inflammation and resistance in mice by a nicotinic receptor agonist.

    Science.gov (United States)

    Blanchet, M-R; Israël-Assayag, E; Cormier, Y

    2005-07-01

    Nicotinic agonists, including 1,1-dimethyl-4-phenylpiperazinium (DMPP), have anti-inflammatory properties and in some instances smooth muscle relaxing effects. Since inflammation and airway smooth muscle contraction are two major components of asthma, the present authors investigated the effects of DMPP on airway inflammation and airway resistance in a mouse model of asthma. Mice were sensitised and challenged with ovalbumin (OVA) and treated either intraperitoneally or intranasally with DMPP. The effect of DMPP was tested on airway inflammation, airway resistance and on the increase of intracellular calcium in bronchial smooth muscle cells. DMPP given either during sensitisation, OVA challenges or throughout the protocol prevented lung inflammation and decreased the serum level of OVA specific immunoglobulin E. DMPP administration reduced the number of total cells, lymphocytes and eosinophils in the bronchoalveolar lavage (BAL) fluid. Intranasal DMPP administration was as effective as dexamethasone (DEXA) in reducing total cell count and eosinophil counts in BAL fluid. DMPP, but not DEXA, reduced tissue inflammation. Intranasal DMPP, given 10 min before the test, reduced airway responsiveness to metacholine. DMPP also reduced the increase in intracellular calcium in response to bradykinin. In conclusion, these results show that 1,1-dimethyl-4-phenylpiperazinium reduces lung inflammation and prevents airway hyperresponsiveness in the mouse model of asthma.

  11. Ozone enhances the airway inflammation initiated by diesel exhaust.

    Science.gov (United States)

    Bosson, Jenny; Pourazar, Jamshid; Forsberg, Bertil; Adelroth, Ellinor; Sandström, Thomas; Blomberg, Anders

    2007-06-01

    Exposure to air pollution is associated with adverse health effects, with particulate matter (PM) and ozone (O(3)) both indicated to be of considerable importance. Diesel engine exhaust (DE) and O(3) generate substantial inflammatory effects in the airways. However, as yet it has not been determined whether a subsequent O(3) exposure would add to the diesel-induced airway inflammatory effects. Healthy subjects underwent two separate exposure series: A 1-h DE exposure at a PM-concentration of 300 microg/m(3), followed after 5h by a 2-h exposure to filtered air and 0.2 ppm O(3), respectively. Induced sputum was collected 18 h after the second exposure. A significant increase in the percentage of neutrophils (PMN) and concentration of myeloperoxidase (MPO) was seen in sputum post DE+O(3) vs. DE+air (p<0.05 and <0.05, respectively). Significant associations were observed between the responses in MPO concentration and total PMN cells (p=0.001), and also between MPO and matrix metalloproteinase-9 (MMP-9) (p<0.001). The significant increase of PMN and MPO after the DE+O(3) exposures, compared to DE+air, denotes an O(3)-induced magnification of the DE-induced inflammation. Furthermore, the correlation between responses in MPO and number of PMNs and MMP-9 illustrate that the PMNs are activated, resulting in a more potent inflammatory response. The present study indicates that O(3) exposure adds significantly to the inflammatory response that is established by diesel exhaust. This interaction between exposure to particulate pollution and O(3) in sequence should be taken into consideration when health effects of air pollution are considered.

  12. Innate Immune Responses to Engineered Nanomaterials During Allergic Airway Inflammation

    Science.gov (United States)

    Shipkowski, Kelly Anne

    The field of nanotechnology is continually advancing, and increasing amounts of consumer goods are being produced using engineered nanomaterials (ENMs). The health risks of occupational and/or consumer exposure to ENMs are not completely understood, although significant research indicates that pulmonary exposure to nanomaterials induces toxic effects in the lungs of exposed animals. Multi-walled carbon nanotubes (MWCNTs) are a specific category of ENMs and consist of sheets of graphene rolled into cylinders that are multiple layers thick in order to strengthen their rigidity. MWCNTs have a fiber-like shape, similar to that of asbestos, which allows for a high aspect ratio and makes them difficult to clear from the lung. Studies with rodent models have demonstrated that pulmonary exposure to ENMs, in particular MWCNTs, results in acute lung inflammation and the subsequent development of chronic fibrosis, suggesting a potential human health risk to individuals involved in the manufacturing of products utilizing these nanomaterials. Induction of IL-1beta secretion via activation of the inflammasome is a prime mechanism of MWCNT-induced inflammation. The inflammasome is a multi-protein scaffold found in a variety of cell types that forms in response to a variety of immune signals, including particulates. Sensitization with allergens, such as house dust mite (HDM), increases levels of the T helper 2 (Th2) cytokines IL-4 and IL-13 in mice and in humans, and there is particular cause for concern in cases of MWCNT exposure in individuals with pre-existing allergic airway disease, such as asthma. MWCNT exposure exacerbates airway inflammation and fibrosis in animal models of pre-existing allergic asthma, suggesting that individuals suffering from asthma are more susceptible to the toxic pulmonary effects of MWCNT exposure. Asthma is an exceptionally prominent human disease, and therefore the goal of this research was to better understand how pre-existing allergic airway

  13. Neutrophil elastase-mediated increase in airway temperature during inflammation

    DEFF Research Database (Denmark)

    Schmidt, Annika; Belaaouaj, Azzaq; Bissinger, Rosi

    2014-01-01

    Background How elevated temperature is generated during airway infections represents a hitherto unresolved physiological question. We hypothesized that innate immune defence mechanisms would increase luminal airway temperature during pulmonary infection. Methods We determined the temperature in t...

  14. Effects of obesity and weight loss on airway physiology and inflammation in asthma

    OpenAIRE

    2012-01-01

    Obesity is a major risk factor for asthma, but the mechanisms for the development of asthma in the setting of obesity are not known. The purpose of this article is to review the effects of obesity on airway inflammation in patients with asthma, and to discuss the effects of obesity on airway reactivity in patients with asthma.

  15. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma.

    Science.gov (United States)

    Caceres, Ana I; Brackmann, Marian; Elia, Maxwell D; Bessac, Bret F; del Camino, Donato; D'Amours, Marc; Witek, JoAnn S; Fanger, Chistopher M; Chong, Jayhong A; Hayward, Neil J; Homer, Robert J; Cohn, Lauren; Huang, Xiaozhu; Moran, Magdalene M; Jordt, Sven-Eric

    2009-06-02

    Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune, smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1 inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration and prevented the development of airway hyperreactivity. Trpa1(-/-) mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge. TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions.

  16. Stimulation of cannabinoid CB1 receptors prevents nerve-mediated airway hyperreactivity in NGF-induced inflammation in mouse airways.

    Science.gov (United States)

    Bozkurt, Turgut Emrah; Larsson, Olivia; Adner, Mikael

    2016-04-05

    Cannabinoids are known to inhibit neuronal activity and have significant immunomodulatory effects which suggest a role in inflammatory airway diseases. In the present study, we tested the hypothesis that cannabinoids have both acute and chronic modulatory effects on nerve-mediated contractions in NGF-induced airway inflammation. Contractions induced by electrical field stimulation (EFS) were examined in tracheal segments isolated from male BALB/c mice. Tissues were both used fresh or after four days of culture with NGF to induce airway inflammation, and further exposed to cannabinoid receptor agonists. In order to evaluate nerve density, tracheal segments were also examined by immunohistochemistry after in vitro treatments. The CB1 receptor agonists ACEA and ACPA inhibited the constant train EFS-induced contractions in both fresh and NGF-exposed tracheas, an effect that could be blocked by the CB1 receptor antagonist AM251. Culturing the tissues with NGF up-regulated the frequency-dependent EFS-contractions in isolated tracheas. This up-regulation could be inhibited by concomitant treatment with ACEA or ACPA. The treatment with NGF and/or ACEA did not affect the potency or the maximum response to carbachol. In histological sections, it was recognized that the enhanced effect induced by NGF was associated with an increase in nerve density, which, similarly, could be prevented by ACEA treatment. This study shows that stimulation of cannabinoid CB1 receptors modifies the increase of neuronal activity and density in NGF-induced airway inflammation and directly inhibits cholinergic contractions in the airways by a presynaptic mechanism. These findings indicate a protective role of CB1 receptors in airway inflammation.

  17. Induced Sputum for the Investigation of Airway Inflammation: Evidence for Its Clinical Application

    Directory of Open Access Journals (Sweden)

    Frederick E Hargreave

    1999-01-01

    Full Text Available Airway inflammation is considered to be the primary cause of airway diseases. Its prevention and reversal are the primary aims of treatment. Measurement of the inflammation is now possible relatively noninvasively and reliably by using induced sputum cell counts. The differential count indicates the presence and type of the inflammation (eosinophilic or neutrophilic and the total cell count the intensity. Sputum eosinophilia responds to treatment with corticosteroid, while there is increasing evidence that an isolated neutrophilia does not. Clinical judgement of airway inflammation is made difficult because of the different types of inflammation and their inconsistent correlation with the clinical features. Hence, reliable measurement of induced sputum cell counts may be useful to guide treatment in clinical practice. Consideration should now be given as to how to make it more available.

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

    Directory of Open Access Journals (Sweden)

    Claudiney de Freitas Alves

    2013-01-01

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

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

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    Umesh C S Yadav

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

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

    Science.gov (United States)

    Park, Mi Kyung; Cho, Min Kyoung; Kang, Shin Ae; Park, Hye-Kyung; Kim, Dong-Hee; Yu, Hak Sun

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Mi Kyung Park

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

  2. Effects of an acute bout of moderate-intensity exercise on postprandial lipemia and airway inflammation.

    Science.gov (United States)

    Johnson, Ariel M; Kurti, Stephanie P; Smith, Joshua R; Rosenkranz, Sara K; Harms, Craig A

    2016-03-01

    A high-fat meal (HFM) induces an increase in blood lipids (postprandial lipemia; PPL), systemic inflammation, and acute airway inflammation. While acute exercise has been shown to have anti-inflammatory and lipid-lowering effects, it is unknown whether exercise prior to an HFM will translate to reduced airway inflammation post-HFM. Our purpose was to determine the effects of an acute bout of exercise on airway inflammation post-HFM and to identify whether any protective effect of exercise on airway inflammation was associated with a reduction in PPL or systemic inflammation. In a randomized cross-over study, 12 healthy, 18- to 29-year-old men (age, 23.0 ± 3.2 years; height, 178.9 ± 5.5 cm; weight, 78.5 ± 11.7 kg) consumed an HFM (1 g fat/1 kg body weight) 12 h following exercise (EX; 60 min at 60% maximal oxygen uptake) or without exercise (CON). Fractional exhaled nitric oxide (FENO; measure of airway inflammation), triglycerides (TG), and inflammatory markers (high-sensitivity C-reactive protein, tumor-necrosis factor-alpha, and interleukin-6) were measured while fasted at 2 h and 4 h post-HFM. FENO increased over time (2 h: CON, p = 0.001; EX, p = 0.002, but not by condition (p = 0.991). TG significantly increased 2 and 4 h post-HFM (p 0.05). There were no relationships between FENO and TG or systemic inflammatory markers for any time point or condition (p > 0.05). In summary, an acute bout of moderate-intensity exercise performed 12 h prior to an HFM did not change postprandial airway inflammation or lipemia in healthy, 18- to 29-year-old men.

  3. Effects of obesity and weight loss on airway physiology and inflammation in asthma.

    Science.gov (United States)

    Sideleva, Olga; Black, Kendall; Dixon, Anne E

    2013-08-01

    Obesity is a major risk factor for asthma, but the mechanisms for the development of asthma in the setting of obesity are not known. The purpose of this article is to review the effects of obesity on airway inflammation in patients with asthma, and to discuss the effects of obesity on airway reactivity in patients with asthma. Obesity is particularly a risk factor for non-atopic asthma. Airway eosinophilic inflammation is not increased in obesity, in fact the preponderance of the evidence suggests that airway eosinophilia is decreased in obesity. There is some preliminary data suggesting that airway neutrophilia may be increased in obesity, and that this may be particularly related to dietary fats. Obesity also alters adaptive immunity, and may suppress lymphocyte function typically associated with asthmatic airway inflammation. Population based studies are somewhat inconsistent on the relationship between airway reactivity and asthma, however, recent studies in bariatric surgery show that weight loss surgery in severely obese patients decreases airway reactivity. One study suggested that this was particularly the case for those with low IgE (a marker of a low TH2 asthma phenotype), suggesting there may be some heterogeneity in asthma in obesity. There are likely to be two phenotypes of asthma in the obese: one group with early onset disease and asthma complicated by obesity, and a 2nd group with late onset disease with asthma consequent to obesity. Obesity leads to profound changes in airway function, and adaptive and innate immune responses which alter the nature of pre-existing allergic airway disease, and also cause new onset asthmatic disease.

  4. Regulation of airway inflammation and remodeling in asthmatic mice by TLR3/TRIF signal pathway.

    Science.gov (United States)

    Yang, Mei; Wang, Hao-Ying; Chen, Jian-Chang; Zhao, Jing

    2017-03-23

    This paper aims to investigate the effect of Toll-like receptors 3 (TLR3)/TIR-domain-containing adapter-inducing interferon-β (TRIF) signal pathway on the airway inflammation and remodeling in asthmatic mice. C57BL/6 and TLR3(-/-) mice were randomly divided into three groups (10 mice per group), including Control group (mice inhaled phosphate buffer saline (PBS)), Asthma group (mice inhaled ovalbumin (OVA)) and polyriboinosinic-ribocytidylic acid (poly (I: C)) group (asthmatic mice were injected intraperitoneally with TLR3 agonist poly (I: C)). Hematoxylin-eosin (HE) staining, Wright-Giemsa staining, Enzyme-linked immunosorbent assay (ELISA), Immunohistochemistry, Hydroxyproline assay, quantitative real time polymerase chain reaction (qRT-PCR) and Western blot were used to assess for the indices of airway inflammation and remodeling. In terms of WT mice, all asthma groups with or without the addition of poly (I: C) showed exaggerated inflammation and remodeling in the airways as compared to Control group, which were more seriously in poly (I: C) group than Asthma group. Furthermore, we observed the significant inhibition of airway inflammation and remodeling in the TLR3(-/-) mice in both Asthma no matter with or without addition of poly (I: C) than the WT mice. TLR3 knockout could obviously relieve the airway inflammation and remodeling in asthma through inhibiting TLR3/TRIF signaling pathway.

  5. Airway inflammation among compost workers exposed to actinomycetes spores

    Directory of Open Access Journals (Sweden)

    Kari Kulvik Heldal

    2015-05-01

    Full Text Available Objectives. To study the associations between exposure to bioaerosols and work-related symptoms, lung function and biomarkers of airway inflammation in compost workers. Materials and method. Personal full-shift exposure measurements were performed on 47 workers employed at five windrow plants (n=20 and five reactor plants (n=27. Samples were analyzed for endotoxins, bacteria, fungal and actinomycetes spores. Health examinations were performed on workers and 37 controls before and after work on the day exposure was measured. The examinations included symptoms recorded by questionnaire, lung function by spirometry and nasal dimensions by acoustic rhinometry (AR. The pneumoproteins CC16, SP-D and SP-A were measured in a blood sample drawn at the end of the day. Results. The levels of endotoxins (median 3 EU/m[sup]3[/sup] , range 0–730 EU/m[sup]3[/sup] and actinomycetes spores (median 0.2 × 10[sup]6[/sup] spores/m[sup]3[/sup] , range 0–590 × 10[sup]6[/sup] spores/m[sup]3[/sup] were significantly higher in reactor plants compared to windrow plants. However, windrow composting workers reported more symptoms than reactor composting workers, probably due to use of respiratory protection. Exposure-response relationships between actinomycetes spores exposure and respiratory effects, found as cough and nose irritation during a shift, was significantly increased (OR 4.3, 95% CI 1.1–16, OR 6.1, 95% CI 1.5–25, respectively, p<0.05 among workers exposed to 0.02–0.3 × 10[sup]6[/sup] actinomycetes spores/m 3 , and FEV1/FVC% decreased cross shift (b=–3.2, SE=1.5%, p<0.01. Effects were weaker in the highest exposed group, but these workers used respiratory protection, frequently limiting their actual exposure. No relationships were found between exposure and pneumoprotein concentrations. Conclusions. The major agent in the aerosol generated at compost plants was actinomycetes spores which was associated with work related cough symptoms and work

  6. Lipocalin2 protects against airway inflammation and hyperresponsiveness in a murine model of allergic airway disease

    DEFF Research Database (Denmark)

    Dittrich, A M; Krokowski, M; Meyer, H-A;

    2010-01-01

    Allergen-induced bronchial asthma is a chronic airway disease that involves the interplay of various genes with environmental factors triggering different inflammatory pathways.......Allergen-induced bronchial asthma is a chronic airway disease that involves the interplay of various genes with environmental factors triggering different inflammatory pathways....

  7. Is Health-Related Quality of Life Associated with Upper and Lower Airway Inflammation in Asthmatics?

    Directory of Open Access Journals (Sweden)

    Nicola Scichilone

    2013-01-01

    Full Text Available Background. Allergic diseases impair health-related quality of life (HR-QoL. However, the relationship between airway inflammation and HR-QoL in patients with asthma and rhinitis has not been fully investigated. We explored whether the inflammation of upper and lower airways is associated with HR-QoL. Methods. Twenty-two mild allergic asthmatics with concomitant rhinitis (10 males, 38 ± 17 years were recruited. The Rhinasthma was used to identify HR-QoL, and the Asthma Control Test (ACT was used to assess asthma control. Subjects underwent lung function and exhaled nitric oxide (eNO test, collection of exhaled breath condensate (EBC, and nasal wash. Results. The Rhinasthma Global Summary score (GS was 25 ± 11. No relationships were found between GS and markers of nasal allergic inflammation (% eosinophils: , ; ECP: , or bronchial inflammation (pH of the EBC: , ; bronchial NO: , ; alveolar NO: , . The mean ACT score was 18. When subjects were divided into controlled (ACT ≥ 20 and uncontrolled (ACT < 20, the alveolar NO significantly correlated with GS in uncontrolled asthmatics (, . Conclusions. Upper and lower airways inflammation appears unrelated to HR-QoL associated with respiratory symptoms. These preliminary findings suggest that, in uncontrolled asthma, peripheral airway inflammation could be responsible for impaired HR-QoL.

  8. [Effects of carbocisteine on airway inflammation and related events in SO2-exposed rats].

    Science.gov (United States)

    Ishibashi, Y; Okamura, T; Masumoto, Y; Tachiiri, T; Momo, K

    2001-01-01

    Airway inflammation leads to secretion of abnormal mucous glycoprotein and ciliary injury. To investigate the possible usefulness of carbocisteine against airway inflammation and events related to it, we conducted a study in SO2-exposed rats of the effects of carbocisteine and ambroxol, as an active control drug, on components of mucous glycoprotein (fucose, sialic acid and protein) in bronchoalveolar lavage fluid (BALF); on infiltration and activation of inflammatory cells in BALF; on tracheal and bronchial-ciliary lesions; and on cAMP levels in tracheal and alveolar tissues. Carbocisteine inhibited or improved all SO2-induced changes tested, and dosages of 125 and 250 mg/kg b.i.d. reduced fucose, sialic acid and protein contents, inflammatory cells (as markers of inflammation), free radicals, and elastase activity in BALF, and suppressed the development of ciliary lesions of the tracheal and bronchial mucosa, while ambroxol (10 mg/kg b.i.d.) showed no such effects. In addition, carbocisteine improved cAMP levels in the tracheal and alveolar tissues. These results indicate that carbocisteine is able to prevent the development of inflammation-related respiratory disease in this rat model, and that this remission of airway inflammation may be associated with carbocisteine-induced normalization of cAMP levels in tracheal and alveolar tissues as well as with its mucoregulant and anti-inflammatory effects. In conclusion, carbocisteine has a unique mucoregulant action and inhibits SO2-induced airway inflammation in a manner different from that of ambroxol.

  9. Toll-like receptor 2 regulates organic dust-induced airway inflammation.

    Science.gov (United States)

    Poole, Jill A; Wyatt, Todd A; Kielian, Tammy; Oldenburg, Peter; Gleason, Angela M; Bauer, Ashley; Golden, Gregory; West, William W; Sisson, Joseph H; Romberger, Debra J

    2011-10-01

    Organic dust exposure in agricultural environments results in significant airway inflammatory diseases. Gram-positive cell wall components are present in high concentrations in animal farming dusts, but their role in mediating dust-induced airway inflammation is not clear. This study investigated the role of Toll-like receptor (TLR) 2, a pattern recognition receptor for gram-positive cell wall products, in regulating swine facility organic dust extract (DE)-induced airway inflammation in mice. Isolated lung macrophages from TLR2 knockout mice demonstrated reduced TNF-α, IL-6, keratinocyte chemoattractant/CXCL1, but not macrophage inflammatory protein-2/CXCL2 expression, after DE stimulation ex vivo. Next, using an established mouse model of intranasal inhalation challenge, we analyzed bronchoalveolar lavage fluid and lung tissue in TLR2-deficient and wild-type (WT) mice after single and repetitive DE challenge. Neutrophil influx and select cytokines/chemokines were significantly lower in TLR2-deficient mice at 5 and 24 hours after single DE challenge. After daily exposure to DE for 2 weeks, there were significant reductions in total cellularity, neutrophil influx, and TNF-α, IL-6, CXCL1, but not CXCL2 expression, in TLR2-deficient mice as compared with WT animals. Lung pathology revealed that bronchiolar inflammation, but not alveolar inflammation, was reduced in TLR2-deficient mice after repetitive exposure. Airway hyperresponsiveness to methacholine after dust exposure was similar in both groups. Finally, airway inflammatory responses in WT mice after challenge with a TLR2 agonist, peptidoglycan, resembled DE-induced responses. Collectively, these results demonstrate that the TLR2 pathway is important in regulating swine facility organic dust-induced airway inflammation, which suggests the importance of TLR2 agonists in mediating large animal farming-induced airway inflammatory responses.

  10. Epithelial cell senescence impairs repair process and exacerbates inflammation after airway injury

    Directory of Open Access Journals (Sweden)

    Nagai Atsushi

    2011-06-01

    Full Text Available Abstract Background Genotoxic stress, such as by exposure to bromodeoxyuridine (BrdU and cigarette smoke, induces premature cell senescence. Recent evidence indicates that cellular senescence of various types of cells is accelerated in COPD patients. However, whether the senescence of airway epithelial cells contributes to the development of airway diseases is unknown. The present study was designed to test the hypothesis that premature senescence of airway epithelial cells (Clara cells impairs repair processes and exacerbates inflammation after airway injury. Methods C57/BL6J mice were injected with the Clara-cell-specific toxicant naphthalene (NA on days 0, 7, and 14, and each NA injection was followed by a daily dose of BrdU on each of the following 3 days, during which regenerating cells were allowed to incorporate BrdU into their DNA and to senesce. The p38 MAPK inhibitor SB202190 was injected 30 minutes before each BrdU dose. Mice were sacrificed at different times until day 28 and lungs of mice were obtained to investigate whether Clara cell senescence impairs airway epithelial regeneration and exacerbates airway inflammation. NCI-H441 cells were induced to senesce by exposure to BrdU or the telomerase inhibitor MST-312. Human lung tissue samples were obtained from COPD patients, asymptomatic smokers, and nonsmokers to investigate whether Clara cell senescence is accelerated in the airways of COPD patients, and if so, whether it is accompanied by p38 MAPK activation. Results BrdU did not alter the intensity of the airway epithelial injury or inflammation after a single NA exposure. However, after repeated NA exposure, BrdU induced epithelial cell (Clara cell senescence, as demonstrated by a DNA damage response, p21 overexpression, increased senescence-associated β-galactosidase activity, and growth arrest, which resulted in impaired epithelial regeneration. The epithelial senescence was accompanied by p38 MAPK-dependent airway

  11. Notch Ligand DLL4 Alleviates Allergic Airway Inflammation via Induction of a Homeostatic Regulatory Pathway

    Science.gov (United States)

    Huang, Miao-Tzu; Chen, Yi-Lien; Lien, Chia-I; Liu, Wei-Liang; Hsu, Li-Chung; Yagita, Hideo; Chiang, Bor-Luen

    2017-01-01

    Notch is a pleiotropic signaling family that has been implicated in pathogenesis of allergic airway diseases; however, the distinct function of individual Notch ligands remains elusive. We investigated whether Notch ligands, Jagged1 and DLL4, exert differential effects in OVA-induced allergic asthma. We found that whilst Jagged1 inhibition mitigated Th2-dominated airway inflammation, blockage of DLL4 aggravated the Th2-mediated asthma phenotypes. Additionally, Jagged1 signaling blockage enhanced IL-17 production and neutrophilic airway infiltration. In vitro, exogenous Jagged1 induced Th2-skewed responses, whereas augmented DLL4 signaling displayed a dual role by promoting expansion of both Tregs and Th17. In vivo, DLL4 blockage impaired Treg differentiation which plausibly resulted in exaggerated asthma phenotypes. On the contrary, administration of DLL4-expressing antigen-presenting cells promoted endogenous Treg expansion and ameliorated the allergic responses. Therefore, whilst Jagged1 induces Th2-skewed inflammation, DLL4 elicits an essential self-regulatory mechanism via Treg-mediated pathway that counterbalances Jagged1-induced Th2 responses and facilitates resolution of the airway inflammation to restore homeostasis. These findings uncover a disparate function of Jagged1 and DLL4 in allergic airway diseases, hinting feasibility of Notch ligand-specific targeting in therapy of allergic airway diseases. PMID:28262821

  12. [Effects of once-daily low-dose administration of sustained-release theophylline on airway inflammation and airway hyperresponsiveness in patients with asthma].

    Science.gov (United States)

    Terao, Ichiro

    2002-04-01

    Bronchial asthma is eosinophilic airway inflammation with enhanced airway responsiveness induced by eosinophilic granule proteins such as eosinophilic cationic protein (ECP) that are released from eosinophils. In the present study using 30 outpatients with mild to moderate asthma who had no history of treatment with steroid inhalation, we examined the effects of 4-week low-dose (200 mg/day) treatment with Uniphyl Tablets, a sustained-release theophylline formulated for once-daily dosing, on airway inflammation and airway hyperresponsiveness, as well as on respiratory function. Uniphyl Tablets significantly (p statistically significant (p V50 also showed statistically significant (p < 0.05) improvement. Mean blood theophylline concentration at the time the improvements were seen was 3.95 mg/mL. These results suggest that low-dose administration of Uniphyl Tablets has anti-airway inflammatory and anti-airway hyperresponsiveness effects in mild to moderate asthmatic patients.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Autophagy is essential for ultrafine particle-induced inflammation and mucus hyperproduction in airway epithelium.

    Science.gov (United States)

    Chen, Zhi-Hua; Wu, Yin-Fang; Wang, Ping-Li; Wu, Yan-Ping; Li, Zhou-Yang; Zhao, Yun; Zhou, Jie-Sen; Zhu, Chen; Cao, Chao; Mao, Yuan-Yuan; Xu, Feng; Wang, Bei-Bei; Cormier, Stephania A; Ying, Song-Min; Li, Wen; Shen, Hua-Hao

    2016-01-01

    Environmental ultrafine particulate matter (PM) is capable of inducing airway injury, while the detailed molecular mechanisms remain largely unclear. Here, we demonstrate pivotal roles of autophagy in regulation of inflammation and mucus hyperproduction induced by PM containing environmentally persistent free radicals in human bronchial epithelial (HBE) cells and in mouse airways. PM was endocytosed by HBE cells and simultaneously triggered autophagosomes, which then engulfed the invading particles to form amphisomes and subsequent autolysosomes. Genetic blockage of autophagy markedly reduced PM-induced expression of inflammatory cytokines, e.g. IL8 and IL6, and MUC5AC in HBE cells. Mice with impaired autophagy due to knockdown of autophagy-related gene Becn1 or Lc3b displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Interference of the autophagic flux by lysosomal inhibition resulted in accumulated autophagosomes/amphisomes, and intriguingly, this process significantly aggravated the IL8 production through NFKB1, and markedly attenuated MUC5AC expression via activator protein 1. These data indicate that autophagy is required for PM-induced airway epithelial injury, and that inhibition of autophagy exerts therapeutic benefits for PM-induced airway inflammation and mucus hyperproduction, although they are differentially orchestrated by the autophagic flux.

  15. IL-18 induces airway hyperresponsiveness and pulmonary inflammation via CD4+ T cell and IL-13.

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    Masanori Sawada

    Full Text Available IL-18 plays a key role in the pathogenesis of pulmonary inflammatory diseases including pulmonary infection, pulmonary fibrosis, lung injury and chronic obstructive pulmonary disease (COPD. However, it is unknown whether IL-18 plays any role in the pathogenesis of asthma. We hypothesized that overexpression of mature IL-18 protein in the lungs may exacerbate disease activities of asthma. We established lung-specific IL-18 transgenic mice on a Balb/c genetic background. Female mice sensitized- and challenged- with antigen (ovalbumin were used as a mouse asthma model. Pulmonary inflammation and emphysema were not observed in the lungs of naïve transgenic mice. However, airway hyperresponsiveness and airway inflammatory cells accompanied with CD4(+ T cells, CD8(+ T cells, eosinophils, neutrophils, and macrophages were significantly increased in ovalbumin-sensitized and challenged transgenic mice, as compared to wild type Balb/c mice. We also demonstrate that IL-18 induces IFN-γ, IL-13, and eotaxin in the lungs of ovalbumin-sensitized and challenged transgenic mice along with an increase in IL-13 producing CD4(+ T cells. Treatment with anti-CD4 monoclonal antibody or deletion of the IL-13 gene improves ovalbumin-induced airway hyperresponsiveness and reduces airway inflammatory cells in transgenic mice. Overexpressing the IL-18 protein in the lungs induces type 1 and type 2 cytokines and airway inflammation, and results in increasing airway hyperresponsiveness via CD4(+ T cells and IL-13 in asthma.

  16. Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation

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    Dienger Krista

    2011-09-01

    Full Text Available Abstract Background A common characteristic of allergens is that they contain proteases that can activate protease-activated receptor (PAR-2; however the mechanism by which PAR-2 regulates allergic airway inflammation is unclear. Methods Mice (wild type and PAR-2-deficient were sensitized using German cockroach (GC feces (frass, the isolated protease from GC frass, or through adoptive transfer of GC frass-treated bone marrow-derived dendritic cells (BMDC and measurements of airway inflammation (cellular infiltration, cytokine expression, and mucin production, serum IgE levels and airway hyperresponsiveness (AHR were assessed. BMDC were cultured, treated with GC frass and assessed for cytokine production. PAR-2 expression on pulmonary mDCs was determined by flow cytometry. Results Exposure to GC frass induced AHR and airway inflammation in wild type mice; however PAR-2-deficient mice had significantly attenuated responses. To directly investigate the role of the protease, we isolated the protease from GC frass and administered the endotoxin-free protease into the airways of mice in the presence of OVA. GC frass proteases were sufficient to promote the development of AHR, serum IgE, and Th2 cytokine production. PAR-2 expression on mDC was upregulated following GC frass exposure, but the presence of a functional PAR-2 did not alter antigen uptake. To determine if PAR-2 activation led to differential cytokine production, we cultured BMDC in the presence of GM-CSF and treated these cells ex vivo with GC frass. PAR-2-deficient BMDC released significantly less IL-6, IL-23 and TNFα compared to BMDC from wild type mice, suggesting PAR-2 activation was important in Th2/Th17 skewing cytokine production. To determine the role for PAR-2 on mDCs on the initiation of allergic airway inflammation, BMDCs from wild type and PAR-2-deficient mice were treated in the presence or absence of GC frass and then adoptively transferred into the airway of wild type mice

  17. Hypoxia Potentiates Allergen Induction of HIF-1α, Chemokines, Airway Inflammation, TGF-β1, and Airway Remodeling in a mouse model

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    Baek, Kwang Je; Cho, Jae Youn; Rosenthal, Peter; Alexander, Laura E. Crotty; Nizet, Victor; Broide, David H.

    2013-01-01

    Whether hypoxia contributes to airway inflammation and remodeling in asthma is unknown. In this study we used mice exposed to a hypoxic environment during allergen challenge (simulating hypoxia during an asthma exacerbation) to investigate the contribution of hypoxia to airway inflammation and remodeling. Although neither hypoxia alone, nor OVA allergen alone, induced significant neutrophil influx into the lung, the combination of OVA and hypoxia induced a synergistic 27 fold increase in peri...

  18. The effect of smoking cessation on airway inflammation in young asthma patients

    DEFF Research Database (Denmark)

    Westergaard, C G; Porsbjerg, C; Backer, V

    2014-01-01

    BACKGROUND: Smoking has been shown to have several detrimental effects on asthma, including poor symptom control, attenuated treatment response and accelerated decline in lung function. In spite of this, smoking is at least as common among asthma patients as in the rest of the population....... The aggravations of smoking on asthma may be caused by effects on airway inflammation, which has been found to be changed in asthmatic smokers. It is not known whether these smoking-induced airway inflammation changes are reversible after smoking cessation. OBJECTIVE: The aim of this study was to assess airway...... changes in asthmatic smokers before and during smoking cessation. METHODS: Forty-six smokers with asthma, all steroid-free (age range: 19-40), were recruited. All participants attempted smoking cessation over a period of 3 months. Visits were performed at weeks 0, 6 and 12 and included induced sputum, Fe...

  19. Airway inflammation in COPD after long-term withdrawal of inhaled corticosteroids

    NARCIS (Netherlands)

    Kunz, Lisette I Z; Ten Hacken, Nick H T; Lapperre, Thérèse S; Timens, Wim; Kerstjens, Huib A M; van Schadewijk, Annemarie; Vonk, Judith M; Sont, Jacob K; Snoeck-Stroband, Jiska B; Postma, Dirkje S; Sterk, Peter J; Hiemstra, Pieter S

    2017-01-01

    Long-term treatment with inhaled corticosteroids (ICS) might attenuate lung function decline and decrease airway inflammation in a subset of patients with chronic obstructive pulmonary disease (COPD), and discontinuing ICS treatment could result in further lung function decline. We hypothesised that

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

    Institute of Scientific and Technical Information of China (English)

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

    2006-01-01

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

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

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    Haahtela Tari

    2006-11-01

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

  2. 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.

  3. Wogonin Attenuates Ovalbumin Antigen-Induced Neutrophilic Airway Inflammation by Inhibiting Th17 Differentiation

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    Rie Takagi

    2014-01-01

    Full Text Available Allergic airway inflammation is generally considered to be a Th2-type immune response. Recent studies, however, have demonstrated that Th17-type immune responses also play important roles in this process, particularly in the pathogenesis of neutrophilic airway inflammation, a hallmark of severe asthma. We scrutinized several Kampo extracts that reportedly exhibit anti-inflammatory activity by using in vitro differentiation system of human and mouse naïve T cells. We found that hange-shashin-to (HST and oren-gedoku-to (OGT possess inhibitory activity for Th17 responses in vitro. Indeed, wogonin and berberine, major components common to HST and OGT, exhibit Th17-inhibitory activities in both murine and human systems in vitro. We therefore evaluated whether wogonin suppresses OVA-induced neutrophilic airway inflammation in OVA TCR-transgenic DO11.10 mice. Consequently, oral administration of wogonin significantly improved OVA-induced neutrophilic airway inflammation. Wogonin suppressed the differentiation of naïve T cells to Th17 cells, while showing no effects on activated Th17 cells.

  4. Establishment of Allergic Airway Inflammation Model in Late- phase Response of Sprague- Dawley Rats

    Institute of Scientific and Technical Information of China (English)

    朱敏敏; 傅诚章; 周钦海

    2002-01-01

    Objective To establish allergic airway inflammation model in late-phase airwayreaction of Sprague-Dawley (SD) rats. Methods Thirty-six SD rats were randomly divided intothree groups: control group (Group Ⅰ),single challenge group (Group Ⅱ),consecutive challenge group(Group Ⅲ). The rats in Group Ⅱ and Group Ⅲ were sensitized twice by injection of ovalbumin (OA) to-gether with aluminum hydroxide and Bordetella pertussis as adjuvants, followed by challenge withaerosolized OA for 20 min once in Group Ⅱ or one time on each day for one week in Group Ⅲ . Therats in Group Ⅰ received 0.9 % saline by injection and inhalation. Results Conpared uith groupⅠ , there were positive symptoms observed in the group Ⅱ and group Ⅲ; the amount of total leucocytesand eosinophil percentage in brochoalveolar lauage fluid (BALF) significantly increased (P<0.05 orP <0.01 respectively) in Group Ⅱ or Ⅲ; histopathologic changes of lung showed acute allergic inflam-mation changes in Group Ⅱ : Disrupted epithelium damaged subepithelial structure and eosinophil infiltra-tion the in the airway wall. As for the Group Ⅲ , there were allergen-induced characteristic features ofchronic allergic airways inflammation: hypertrophy and hyperplasia of bronchial smooth muscle, gobletcell hyperplasia , basement membrane thickening, eosinophil infiltration, edema. Conclusion The mod-el of allergic airway inflammation in late-phase response of SD rats was successfully established by OAsensitization (twice) and consecutive challenge.

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

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    Arizmendi Narcy G

    2011-12-01

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

  6. Different regulation of cigarette smoke induced inflammation in upper versus lower airways

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    Bracke Ken R

    2010-07-01

    Full Text Available Abstract Background Cigarette smoke (CS is known to initiate a cascade of mediator release and accumulation of immune and inflammatory cells in the lower airways. We investigated and compared the effects of CS on upper and lower airways, in a mouse model of subacute and chronic CS exposure. Methods C57BL/6 mice were whole-body exposed to mainstream CS or air, for 2, 4 and 24 weeks. Bronchoalveolar lavage fluid (BAL was obtained and tissue cryosections from nasal turbinates were stained for neutrophils and T cells. Furthermore, we evaluated GCP-2, KC, MCP-1, MIP-3α, RORc, IL-17, FoxP3, and TGF-β1 in nasal turbinates and lungs by RT-PCR. Results In both upper and lower airways, subacute CS-exposure induced the expression of GCP-2, MCP-1, MIP-3α and resulted in a neutrophilic influx. However, after chronic CS-exposure, there was a significant downregulation of inflammation in the upper airways, while on the contrary, lower airway inflammation remained present. Whereas nasal FoxP3 mRNA levels already increased after 2 weeks, lung FoxP3 mRNA increased only after 4 weeks, suggesting that mechanisms to suppress inflammation occur earlier and are more efficient in nose than in lungs. Conclusions Altogether, these data demonstrate that CS induced inflammation may be differently regulated in the upper versus lower airways in mice. Furthermore, these data may help to identify new therapeutic targets in this disease model.

  7. Azithromycin attenuates airway inflammation in a mouse model of viral bronchiolitis

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    Brody Steven L

    2010-06-01

    Full Text Available Abstract Background Viral bronchiolitis is the leading cause of hospitalization in young infants. It is associated with the development of childhood asthma and contributes to morbidity and mortality in the elderly. Currently no therapies effectively attenuate inflammation during the acute viral infection, or prevent the risk of post-viral asthma. We hypothesized that early treatment of a paramyxoviral bronchiolitis with azithromycin would attenuate acute and chronic airway inflammation. Methods Mice were inoculated with parainfluenza type 1, Sendai Virus (SeV, and treated daily with PBS or azithromycin for 7 days post-inoculation. On day 8 and 21 we assessed airway inflammation in lung tissue, and quantified immune cells and inflammatory mediators in bronchoalveolar lavage (BAL. Results Compared to treatment with PBS, azithromycin significantly attenuated post-viral weight loss. During the peak of acute inflammation (day 8, azithromycin decreased total leukocyte accumulation in the lung tissue and BAL, with the largest fold-reduction in BAL neutrophils. This decreased inflammation was independent of changes in viral load. Azithromycin significantly attenuated the concentration of BAL inflammatory mediators and enhanced resolution of chronic airway inflammation evident by decreased BAL inflammatory mediators on day 21. Conclusions In this mouse model of paramyxoviral bronchiolitis, azithromycin attenuated acute and chronic airway inflammation. These findings demonstrate anti-inflammatory effects of azithromycin that are not related to anti-viral activity. Our findings support the rationale for future prospective randomized clinical trials that will evaluate the effects of macrolides on acute viral bronchiolitis and their long-term consequences.

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

    Science.gov (United States)

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

    2016-01-01

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

  9. 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

  10. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase.

    Science.gov (United States)

    Park, Chan Sun; Bang, Bo-Ram; Kwon, Hyouk-Soo; Moon, Keun-Ai; Kim, Tae-Bum; Lee, Ki-Young; Moon, Hee-Bom; Cho, You Sook

    2012-12-15

    Recent reports have suggested that metformin has anti-inflammatory and anti-tissue remodeling properties. We investigated the potential effect of metformin on airway inflammation and remodeling in asthma. The effect of metformin treatment on airway inflammation and pivotal characteristics of airway remodeling were examined in a murine model of chronic asthma generated by repetitive challenges with ovalbumin and fungal-associated allergenic protease. To investigate the underlying mechanism of metformin, oxidative stress levels and AMP-activated protein kinase (AMPK) activation were assessed. To further elucidate the role of AMPK, we examined the effect of 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) as a specific activator of AMPK and employed AMPKα1-deficient mice as an asthma model. The role of metformin and AMPK in tissue fibrosis was evaluated using a bleomycin-induced acute lung injury model and in vitro experiments with cultured fibroblasts. Metformin suppressed eosinophilic inflammation and significantly reduced peribronchial fibrosis, smooth muscle layer thickness, and mucin secretion. Enhanced AMPK activation and decreased oxidative stress in lungs was found in metformin-treated asthmatic mice. Similar results were observed in the AICAR-treated group. In addition, the enhanced airway inflammation and fibrosis in heterozygous AMPKα1-deficient mice were induced by both allergen and bleomycin challenges. Fibronectin and collagen expression was diminished by metformin through AMPKα1 activation in cultured fibroblasts. Therefore metformin reduced both airway inflammation and remodeling at least partially through the induction of AMPK activation and decreased oxidative stress. These data provide insight into the beneficial role of metformin as a novel therapeutic drug for chronic asthma.

  11. Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury.

    Science.gov (United States)

    Gao, Wei; Yuan, Cheng; Zhang, Jingying; Li, Lingling; Yu, Like; Wiegman, Coen H; Barnes, Peter J; Adcock, Ian M; Huang, Mao; Yao, Xin

    2015-12-01

    COPD (chronic obstructive pulmonary disease) is associated with sustained inflammation, excessive injury, and accelerated lung aging. Human Klotho (KL) is an anti-aging protein that protects cells against inflammation and damage. In the present study, we quantified KL expression in the lungs of COPD patients and in an ozone-induced mouse model of COPD, and investigated the mechanisms that control KL expression and function in the airways. KL distribution and levels in human and mouse airways were measured by immunohistochemistry and Western blotting. The effect of CSE (cigarette smoke extract) on KL expression was detected in human bronchial epithelial cells. Moreover, the effect of KL on CSE-mediated inflammation and hydrogen peroxide-induced cellular injury/apoptosis was determined using siRNAs. KL expression was decreased in the lungs of smokers and further reduced in patients with COPD. Similarly, 6 weeks of exposure to ozone decreased KL levels in airway epithelial cells. CSE and TNFα (tumour necrosis factor α) decreased KL expression and release from airway epithelial cells, which was associated with enhanced pro-inflammatory cytokine expression. Moreover, KL depletion increased cell sensitivity to cigarette smoke-induced inflammation and oxidative stress-induced cell damage. These effects involved the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and Nrf2 (nuclear factor erythroid 2-related factor 2) pathways. Reduced KL expression in COPD airway epithelial cells was associated with increased oxidative stress, inflammation and apoptosis. These data provide new insights into the mechanisms associated with the accelerated lung aging in COPD development.

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

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    Romina Nassini

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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 and fibroblasts, acrolein and CS extract evoked IL-8 release, a response selectively reduced by TRPA1 antagonists. Capsaicin, agonist of the transient receptor potential vanilloid 1 (TRPV1, a channel co-expressed with TRPA1 by airway sensory nerves, and acrolein or CS (TRPA1 agonists, or the neuropeptide substance P (SP, which is released from sensory nerve terminals by capsaicin, acrolein or CS, produced neurogenic inflammation in mouse airways. However, only acrolein and CS, but not capsaicin or SP, released the keratinocyte chemoattractant (CXCL-1/KC, IL-8 analogue in bronchoalveolar lavage (BAL fluid of wild-type mice. This effect of TRPA1 agonists was attenuated by TRPA1 antagonism or in TRPA1-deficient mice, but not by pharmacological ablation of sensory nerves. CONCLUSIONS: Our results demonstrate that, although either TRPV1 or TRPA1 activation causes airway neurogenic inflammation, solely TRPA1 activation orchestrates an additional inflammatory response which is not neurogenic. This finding suggests

  13. Time course of endotoxin-induced airways' inflammation in healthy subjects.

    Science.gov (United States)

    Doyen, Virginie; Kassengera, Zaina; Dinh, Duc Huy Phong; Michel, Olivier

    2012-02-01

    Few data are available on the kinetic of the airways' inflammation induced by inhaled endotoxin in a given subject. The purpose of this study was to evaluate in healthy subjects the time-related endotoxin-induced airways' inflammation. The cells counts from the induced-sputum were evaluated before, 6 and 24 h, and 7 days after an exposure to 20 mcg inhaled endotoxin, in eight pre-selected volunteers. To avoid interference of the induced-sputum procedure on the response to endotoxin, each time-point was evaluated in randomized order at 2-weeks interval after three separate inhalations of endotoxin. A significant rise of the relative number of lymphocytes (pinflammation after 6 h, peaked at 24 h and recovered after 7 days. When repeated endotoxin inhalations are used as a model of inflammation, a wash-out period of at least 7 days should be applied between each exposure in each subject.

  14. Effect of smoking cessation on airway inflammation of rats with chronic bronchitis

    Institute of Scientific and Technical Information of China (English)

    LI Qing-yun; HUANG Shao-guang; WAN Huan-ying; WU Hua-cheng; ZHOU Tong; LI Min; DENG Wei-wu

    2007-01-01

    Background Smoking is the major cause of airway inflammation in chronic obstructive pulmonary disease (COPD),and smoking cessation is regarded as one of the important strategies for prevention and treatment of the inflammation.The inflammation of the chronic airway may be present and deteriorated even if the COPD patients stop smoking.Whether and how early smoking cessation affects the progress of inflammation is still obscure. This study was conducted to find the appropriate time for smoking cessation to terminate the airway inflammation in rats with smoke-induced chronic bronchitis.Methods A rat model of COPD was established by passively inhaling smoke mixture. Fifty-four young male Sprague-Dawley rats were randomly divided into 9 groups with different periods of smoke exposure and different time points of cessation. The inflammation markers to be detected included inflammatory cells in the bronchoalveolar lavage fluid (BALF), the myeloperoxidose (MPO) activity, the morphologic changes and the expression of ICAM-1 on the airway epithelium.Results When smoking was terminated at early stage, the inflammatory markers and related indexes were different from those of the typical chronic bronchitis group (group M7) (P<0.01). The pathologic score of group SC7 (2 weeks of smoking cessation after occurrence of typical chronic bronchitis ) was not different from that of group M7, and the level of ICAM-1 was still up-regulated (compared to group M7, P>0.05). Meanwhile, most of inflammatory cells in BALF were neutrophils compared to other groups (P<0.01).When smoking was terminated, the MPO activity was significantly lower than that of group M7 (P<0.01).Conclusions Smoking cessation at early stage can effectively inhibit the inflammatory reaction of COPD. Once chronic bronchitis occurs, little could be improved by smoking cessation.

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

    Directory of Open Access Journals (Sweden)

    Ulrike Bönisch

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

  16. Dendritic cell-nerve clusters are sites of T cell proliferation in allergic airway inflammation.

    Science.gov (United States)

    Veres, Tibor Z; Shevchenko, Marina; Krasteva, Gabriela; Spies, Emma; Prenzler, Frauke; Rochlitzer, Sabine; Tschernig, Thomas; Krug, Norbert; Kummer, Wolfgang; Braun, Armin

    2009-03-01

    Interactions between T cells and dendritic cells in the airway mucosa precede secondary immune responses to inhaled antigen. The purpose of this study was to identify the anatomical locations where dendritic cell-T cell interactions occur, resulting in T cells activation by dendritic cells. In a mouse model of allergic airway inflammation, we applied whole-mount immunohistology and confocal microscopy to visualize dendritic cells and T cells together with nerves, epithelium, and smooth muscle in three dimensions. Proliferating T cells were identified by the detection of the incorporation of the nucleotide analogue 5-ethynyl-2'-deoxyuridine into the DNA. We developed a novel quantification method that enabled the accurate determination of cell-cell contacts in a semi-automated fashion. Dendritic cell-T cell interactions occurred beneath the smooth muscle layer, but not in the epithelium. Approximately 10% of the dendritic cells were contacted by nerves, and up to 4% of T cells formed clusters with these dendritic cells. T cells that were clustered with nerve-contacting dendritic cells proliferated only in the airways of mice with allergic inflammation but not in the airways of negative controls. Taken together, these results suggest that during the secondary immune response, sensory nerves influence dendritic cell-driven T cell activation in the airway mucosa.

  17. 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.

  18. Galangin Abrogates Ovalbumin-Induced Airway Inflammation via Negative Regulation of NF-κB

    Directory of Open Access Journals (Sweden)

    Wang-Jian Zha

    2013-01-01

    Full Text Available Persistent activation of nuclear factor κB (NF-κB has been associated with the development of asthma. Galangin, the active pharmacological ingredient from Alpinia galanga, is reported to have a variety of anti-inflammatory properties in vitro via negative regulation of NF-κB. This study aimed to investigate whether galangin can abrogate ovalbumin- (OVA- induced airway inflammation by negative regulation of NF-κB. BALB/c mice sensitized and challenged with OVA developed airway hyperresponsiveness (AHR and inflammation. Galangin dose dependently inhibited OVA-induced increases in total cell counts, eosinophil counts, and interleukin-(IL- 4, IL-5, and IL-13 levels in bronchoalveolar lavage fluid, and reduced serum level of OVA-specific IgE. Galangin also attenuated AHR, reduced eosinophil infiltration and goblet cell hyperplasia, and reduced expression of inducible nitric oxide synthase and vascular cell adhesion protein-1 (VCAM-1 levels in lung tissue. Additionally, galangin blocked inhibitor of κB degradation, phosphorylation of the p65 subunit of NF-κB, and p65 nuclear translocation from lung tissues of OVA-sensitized mice. Similarly, in normal human airway smooth muscle cells, galangin blocked tumor necrosis factor-α induced p65 nuclear translocation and expression of monocyte chemoattractant protein-1, eotaxin, CXCL10, and VCAM-1. These results suggest that galangin can attenuate ovalbumin-induced airway inflammation by inhibiting the NF-κB pathway.

  19. Ambient particulate matter induces an exacerbation of airway inflammation in experimental asthma: role of interleukin-33.

    Science.gov (United States)

    Shadie, A M; Herbert, C; Kumar, R K

    2014-08-01

    High levels of ambient environmental particulate matter (PM10 i.e. interleukin (IL)-33 in airway tissues and an increased concentration of IL-33 in bronchoalveolar lavage fluid. Administration of a monoclonal neutralizing anti-mouse IL-33 antibody prior to delivery of particulates significantly suppressed the inflammatory response induced by Sydney PM10, as well as the levels of associated proinflammatory cytokines in lavage fluid. We conclude that IL-33 plays a key role in driving airway inflammation in this novel experimental model of an acute exacerbation of chronic allergic asthma induced by exposure to PM10.

  20. Do neutrophils actively participate in airway inflammation and remodeling in asthma?

    Institute of Scientific and Technical Information of China (English)

    SUN Yong-chang 孙永昌; Hong Wei Chu

    2004-01-01

    @@ Previous studies have demonstrated an increase of neutrophils in lung tissues, bronchoalveolar lavage fluid (BALF), and sputum of subjects with severe, often glucocorticoid (GC)-dependent asthma, but the mechanisms behind this are not clear.1-3 Whether neutrophils function to worsen the disease or they are simply 'bystanders' in the process of severe asthma is not certain. However, recent studies suggest a possibly active role of neutrophils in the airway inflammation and potentially in the airway remodeling of asthma.4,5

  1. Overexpression of mclca3 in airway epithelium of asthmatic murine models with airway inflammation

    Institute of Scientific and Technical Information of China (English)

    ZHANG Hui-lan; HE Li

    2010-01-01

    Asthma is a worldwide prevalent disease that is a considerable health burden in many countries.1 In recent years, the airway epithelium is increasingly recognized as a central contributor to the pathogenesis of asthma.2 One of the most highly induced genes in epithelial cells in experimental allergic airway disease is the third murine calcium-activated chloride channel homologue (mclca3, alias gob-5). Its human homology protein is hCLCA1,3,4 which has been identified as clinically relevant molecules in diseases with secretory dysfunctions including asthma and cystic fibrosis. In initial studies, mclca3 was thought to be a member of calcium-activated chloride channel (CaCCs) family,whereas some new interesting reports suggest that the two mclca3 cleavage products cannot form an anion channel on their own but may instead act as extracellular signaling molecules with as yet unknown functions and interacting partners.5

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

    Directory of Open Access Journals (Sweden)

    Haruka Aoki

    2014-01-01

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

  3. Increased concentrations of breath haloamines are not detectable in airways inflammation using SIFT-MS.

    Science.gov (United States)

    Storer, Malina K; Dummer, Jack D; Cook, Julie; McEwan, Murray; Epton, Michael J

    2011-09-01

    The haloamines, including the chloramines (H(2)NCl, HNCl(2)) and bromamine (H(2)NBr), are diffusible gases that are likely to be produced during inflammation and so may be present as markers of lung inflammation on breath. Although haloamines are quite reactive, it is possible to measure these compounds in humid samples using SIFT-MS. Until recently the quantification of haloamines in breath suffered from interference from other common breath compounds. This was overcome by heating the flow tube which removed major water cluster product ions. Despite the improvements to the method, previous attempts to measure the haloamines in breath samples from normal volunteers had found no evidence to support their presence. Since it is proposed that the haloamines may be present in higher concentrations during airways inflammation we have attempted to detect the compounds in the exhaled breath of patients with airways inflammatory conditions. On-line and off-line breath samples were analyzed; however, there was no discernable change to any of product ions when compared to ambient air or normal subjects. This suggests that despite sensitivity in the mid part per trillion range haloamines are not significantly raised in airways inflammation.

  4. Purified Aged Garlic Extract Modulates Allergic Airway Inflammation in Balb/c Mice

    Directory of Open Access Journals (Sweden)

    Zare Ahad

    2008-09-01

    Full Text Available Garlic is known as a potent spice and a medicinal herb with broad therapeutic properties ranging from antibacterial to anticancer and anticoagulant. Our previous studies have shown some immunoregulatory effects for aged garlic extract, suggesting a key role for 14-kD glycoprotein of garlic in shifting the cytokine pattern to T helper-1. In present study, we investigated the effect of 1, 2, and 3 times intraperitoneal injections of aged garlic extract on an established allergic airway inflammation in murine model (BALB/c mice. The garlic extract, isolated by biochemical method, includes proteins precipitation by ammonium sulfate. After injection of the aged garlic extract, IFN-g, anti allergen specific IgE and IgG1 were measured in lavage and serum by ELISA and histological assessment was performed on the lung tissues. The results indicated that three-time intra peritoneal injections of the aged garlic extract caused a significant decrease in the hallmark criteria of allergic airway inflammation levels which included eosinophil percentage in lavage, peribronchial lung eosinophils, IgG1 level in lavage and serum, mucous producing goblet cells grade and peribronchial and perivascular inflammation. Our findings in the present research suggested that aged garlic extract has the potential of attenuation of inflammatory features of allergic airway inflammation in murine model.

  5. Effect of Continuous Positive Airway Pressure on Airway Inflammation and Oxidative Stress in Patients with Obstructive Sleep Apnea

    Directory of Open Access Journals (Sweden)

    Promsrisuk Tichanon

    2016-01-01

    Full Text Available Background. Airway inflammation and oxidative stress may be linked in obstructive sleep apnea (OSA patients. We determined the effectiveness of continuous positive airway pressure (CPAP therapy in reducing fractional exhaled nitric oxide (FeNO and malondialdehyde (MDA levels in OSA patients. Methods. Thirteen patients with OSA and 13 normal controls were recruited. FeNO and MDA levels were measured in the controls and in OSA patients before and after three months of CPAP therapy. Results. FeNO and MDA levels were higher in the patients compared to the age and gender matched controls (FeNO: 25.9 ± 5.0 versus 17.5 ± 5.9 ppb, P<0.001; MDA: 14.6 ± 7.8 versus 2.1 ± 0.3 μmol/L, P<0.001. FeNO and MDA levels were lower post-CPAP compared to pre-CPAP (FeNO: 25.9 ± 5.0 versus 17.0 ± 2.3 ppb, P<0.001; MDA: 14.6 ± 7.8 versus 10.0 ± 6.4 μmol/L, P<0.01. Apnea-hypopnea index (15.9 ± 6.6 versus 4.1 ± 2.1/h, P<0.001 and mean arterial pressure (P<0.01 decreased following CPAP treatment. Daytime mean SpO2 (P<0.05 increased. Conclusion. Our study demonstrates that CPAP therapy yields clinical benefits by reducing upper airway inflammation and oxidative stress in OSA patients.

  6. Oxidative airway inflammation leads to systemic and vascular oxidative stress in a murine model of allergic asthma.

    Science.gov (United States)

    Al-Harbi, Naif O; Nadeem, A; Al-Harbi, Mohamed M; Imam, F; Al-Shabanah, Othman A; Ahmad, Sheikh F; Sayed-Ahmed, Mohamed M; Bahashwan, Saleh A

    2015-05-01

    Oxidant-antioxidant imbalance plays an important role in repeated cycles of airway inflammation observed in asthma. It is when reactive oxygen species (ROS) overwhelm antioxidant defenses that a severe inflammatory state becomes apparent and may impact vasculature. Several studies have shown an association between airway inflammation and cardiovascular complications; however so far none has investigated the link between airway oxidative stress and systemic/vascular oxidative stress in a murine model of asthma. Therefore, this study investigated the contribution of oxidative stress encountered in asthmatic airways in modulation of vascular/systemic oxidant-antioxidant balance. Rats were sensitized intraperitoneally with ovalbumin (OVA) in the presence of aluminum hydroxide followed by several intranasal (i.n.) challenges with OVA. Rats were then assessed for airway and vascular inflammation, oxidative stress (ROS, lipid peroxides) and antioxidants measured as total antioxidant capacity (TAC) and thiol content. Challenge with OVA led to increased airway inflammation and oxidative stress with a concomitant increase in vascular inflammation and oxidative stress. Oxidative stress in the vasculature was significantly inhibited by antioxidant treatment, N-acetyl cysteine; whereas hydrogen peroxide (H2O2) inhalation worsened it. Therefore, our study shows that oxidative airway inflammation is associated with vascular/systemic oxidative stress which might predispose these patients to increased cardiovascular risk.

  7. Allergic airway inflammation decreases lung bacterial burden following acute Klebsiella pneumoniae infection in a neutrophil- and CCL8-dependent manner.

    Science.gov (United States)

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

    2014-09-01

    The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.

  8. Pycnogenol Ameliorates Asthmatic Airway Inflammation and Inhibits the Function of Goblet Cells.

    Science.gov (United States)

    Liu, Zhaoe; Han, Bo; Chen, Xing; Wu, Qiaoling; Wang, Lijun; Li, Gang

    2016-11-01

    Pycnogenol(®) (PYC) is utilized in the treatment of various diseases ranging from chronic inflammation to circulatory diseases, but its efficacy and functional mechanism in pediatric asthma continue to remain obscure. Therefore, the purpose of this study was to investigate the effectiveness and molecular mechanism of PYC on regulation of asthmatic airway inflammation. We found that PYC with tail intravenous injection of 50 mg/kg or intragastric administration of 100 mg/kg all reduced ovalbumin (OVA)-induced airway injury. Pharmacokinetics of PYC was evaluated by high-performance liquid chromatography assay, indicating that PYC was quickly absorbed into the blood after intragastric administration, and PYC metabolism was later improved gradually with increase of time after PYC administration. PYC has a higher bioavailability of 71.96%, and it was more easily absorbed by the body. PYC inhibited the number of total inflammatory cells and levels of interleukin (IL)-4, IL-5, IL-9, and IL-13 in bronchoalveolar lavage fluid of OVA-induced mice. PYC inhibited IL-13 secretion from the Th2 cells, thereby causing a reduction in expression of the signaling molecules in JAK/STAT6 pathway in airway epithelial cells. STAT6 silence suppressed IL-13-increased acetylcholine level. STAT6 overexpression promoted expression of goblet cell metaplasia-associated molecules (FOXA3, SPDEF, and Muc5ac). PYC suppressed OVA-induced expression of FOXA3, SPDEF, and Muc5ac in lung. Our findings indicate that PYC has a higher bioavailability and it prevents emergence of OVA-induced airway injury and airway inflammation in mice by inhibiting IL-13/JAK/STAT6 pathway and blocking release of acetylcholine to reduce goblet cell metaplasia.

  9. Acquisition and adaptation of the airway microbiota in the early life of cystic fibrosis patients.

    Science.gov (United States)

    Boutin, Sébastien; Dalpke, Alexander H

    2017-12-01

    Cystic fibrosis (CF) is a genetic disease in which bacterial infections of the airways play a major role in the long-term clinical outcome. In recent years, a number of next-generation sequencing (NGS)-based studies aimed at deciphering the structure and composition of the airways' microbiota. It was shown that the nasal cavity of CF patients displays dysbiosis early in life indicating a failure in the first establishment of a healthy microbiota. In contrast, within the conducting and lower airways, the establishment occurs normally first, but is sensitive to future dysbiosis including chronic infections with classical pathogens in later life. The objective of this mini-review is to give an update on the current knowledge about the development of the microbiota in the early life of CF patients. Microbial acquisition in the human airways can be described by the island model: Microbes found in the lower airways of CF patients represent "islands" that are at first populated from the upper airways reflecting the "mainland." Colonization can be modeled following the neutral theory in which the most abundant bacteria in the mainland are also frequently found in the lower airways initially. At later times, however, the colonization process of the lower airways segregates by active selection of specific microbes. Future research should focus on those processes of microbial and host interactions to understand how microbial communities are shaped on short- and long-term scales. We point out what therapeutic consequences arise from the microbiome data obtained within ecological framework models.

  10. hMSCs suppress neutrophil-dominant airway inflammation in a murine model of asthma

    Science.gov (United States)

    Hong, Gyong Hwa; Kwon, Hyouk-Soo; Lee, Kyoung Young; Ha, Eun Hee; Moon, Keun-Ai; Kim, Seong Who; Oh, Wonil; Kim, Tae-Bum; Moon, Hee-Bom; Cho, You Sook

    2017-01-01

    Although chronic eosinophilic inflammation is a common feature in patients with asthma, some patients have neutrophil-dominant inflammation, which is known to be associated with severe asthma.Human mesenchymal stem cells (hMSCs) have shown promise in treating various refractory immunological diseases. Thus, hMSCs may represent an alternative therapeutic option for asthma patients with neutrophil-dominant inflammation, in whom current treatments are ineffective. BALB/c mice exposed to ovalbumin and polyinosinic:polycytidylic acid (Poly I:C) to induce neutrophilic airway inflammation were systemically treated with hMSCs to examine whether the hMSCs can modulate neutrophilic airway inflammation. In addition, cytokine production was evaluated in co-cultures of hMSCs with either anti-CD3/CD28-stimulated peripheral blood mononuclear cells (PBMCs) obtained from asthmatic patients or cells of the human bronchial epithelial cell line BEAS-2B to assess the response to hMSC treatment. The total number of immune cells in bronchoalveolar lavage fluid (BALF) showed a dramatic decrease in hMSC-treated asthmatic mice, and, in particular, neutrophilic infiltration was significantly attenuated. This phenomenon was accompanied by reduced CXCL15 production in the BALF. BEAS-2B cells co-cultured with hMSCs showed reduced secretion of IL-8. Moreover, decreased secretion of IL-4, IL-13 and IFN-γ was observed when human PBMCs were cultured with hMSCs, whereas IL-10 production was greatly enhanced. Our data imply that hMSCs may have a role in reducing neutrophilic airway inflammation by downregulating neutrophil chemokine production and modulating T-cell responses. PMID:28127050

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

    Directory of Open Access Journals (Sweden)

    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.

  12. ST2 Requires Th2-, but Not Th17-, Type Airway Inflammation in Epicutaneously Antigen-Sensitized Mice

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    Hideaki Morita

    2012-01-01

    Conclusions: The IL-33/ST2 pathway is crucial for Th2-cytokine-mediated eosinophilic, rather than Th17-cytokine-mediated neutrophilic, airway inflammation in mice that had been epicutaneously sensitized with antigens and then challenged with antigen.

  13. TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways

    Directory of Open Access Journals (Sweden)

    Lambrecht Bart N

    2011-09-01

    Full Text Available Abstract Inflammation of the airways, which is often associated with life-threatening infection by Gram-negative bacteria or presence of endotoxin in the bioaerosol, is still a major cause of severe airway diseases. Moreover, inhaled endotoxin may play an important role in the development and progression of airway inflammation in asthma. Pathologic changes induced by endotoxin inhalation include bronchospasm, airflow obstruction, recruitment of inflammatory cells, injury of the alveolar epithelium, and disruption of pulmonary capillary integrity leading to protein rich fluid leak in the alveolar space. Mammalian Toll-like receptors (TLRs are important signalling receptors in innate host defense. Among these receptors, TLR4 plays a critical role in the response to endotoxin. Lungs are a complex compartmentalized organ with separate barriers, namely the alveolar-capillary barrier, the microvascular endothelium, and the alveolar epithelium. An emerging theme in the field of lung immunology is that structural cells (SCs of the airways such as epithelial cells (ECs, endothelial cells, fibroblasts and other stromal cells produce activating cytokines that determine the quantity and quality of the lung immune response. This review focuses on the role of TLR4 in the innate and adaptive immune functions of the pulmonary SCs.

  14. TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways.

    Science.gov (United States)

    Perros, Frederic; Lambrecht, Bart N; Hammad, Hamida

    2011-09-24

    Inflammation of the airways, which is often associated with life-threatening infection by Gram-negative bacteria or presence of endotoxin in the bioaerosol, is still a major cause of severe airway diseases. Moreover, inhaled endotoxin may play an important role in the development and progression of airway inflammation in asthma. Pathologic changes induced by endotoxin inhalation include bronchospasm, airflow obstruction, recruitment of inflammatory cells, injury of the alveolar epithelium, and disruption of pulmonary capillary integrity leading to protein rich fluid leak in the alveolar space. Mammalian Toll-like receptors (TLRs) are important signalling receptors in innate host defense. Among these receptors, TLR4 plays a critical role in the response to endotoxin. Lungs are a complex compartmentalized organ with separate barriers, namely the alveolar-capillary barrier, the microvascular endothelium, and the alveolar epithelium. An emerging theme in the field of lung immunology is that structural cells (SCs) of the airways such as epithelial cells (ECs), endothelial cells, fibroblasts and other stromal cells produce activating cytokines that determine the quantity and quality of the lung immune response. This review focuses on the role of TLR4 in the innate and adaptive immune functions of the pulmonary SCs.

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

    Indian Academy of Sciences (India)

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

    2011-12-01

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

  16. Hypoxia Potentiates Allergen Induction of HIF-1α, Chemokines, Airway Inflammation, TGF-β1, and Airway Remodeling in a mouse model

    Science.gov (United States)

    Baek, Kwang Je; Cho, Jae Youn; Rosenthal, Peter; Alexander, Laura E. Crotty; Nizet, Victor; Broide, David H.

    2013-01-01

    Whether hypoxia contributes to airway inflammation and remodeling in asthma is unknown. In this study we used mice exposed to a hypoxic environment during allergen challenge (simulating hypoxia during an asthma exacerbation) to investigate the contribution of hypoxia to airway inflammation and remodeling. Although neither hypoxia alone, nor OVA allergen alone, induced significant neutrophil influx into the lung, the combination of OVA and hypoxia induced a synergistic 27 fold increase in peribronchial neutrophils, enhanced expression of HIF-1α and one of its target genes, the CXC-family neutrophil chemokine KC. The combination of hypoxia and OVA allergen increased eotaxin-1, peribronchial eosinophils, lung TGB-β1 expression, and indices of airway remodeling (fibrosis and smooth muscle) compared to either stimulus alone. As hypoxia is present in >90% of severe asthma exacerbations, these findings underscore the potential of hypoxia to potentiate the airway inflammatory response, remodeling, and accelerate the decline of lung function in asthma exacerbations. PMID:23499929

  17. Modulation of airway inflammation to prevent exacerbations of COPD

    Directory of Open Access Journals (Sweden)

    M. Solèr

    2005-12-01

    Full Text Available Exacerbations of chronic obstructive pulmonary disease (COPD are periods in the chronic course of this disease with symptoms of intensified inflammation, induced in part by infections but also by noninfectious irritating mechanisms. Although these exacerbations seem to be linked to accelerated long-term disease progression and impaired quality of life, there are only limited preventive measures available, apart from smoking cessation. This article compares the effectiveness of different pharmacological treatments for the prevention of COPD exacerbations, including the oral bacterial lysate OM-85. Given the differences in the mechanism of action of the treatments discussed, this opens some hope for additive or potentiating effects with combined treatments, which will have to be studied in future controlled trials.

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

    Institute of Scientific and Technical Information of China (English)

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

    2011-01-01

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

  19. Effect of tiotropium bromide combined with salmeterol fluticasone inhalation on airway function and airway inflammation in patients with moderate-severe stable COPD

    Institute of Scientific and Technical Information of China (English)

    Min Xiang

    2016-01-01

    Objective:To analyze the effect of tiotropium bromide combined with salmeterol fluticasone inhalation on airway function and airway inflammation in patients with moderate-severe stable COPD.Methods: A total of 118 patients with moderate-severe stable COPD were randomly divided into observation group and control group (n=59), control group accepted routine treatment, observation group received tiotropium bromide combined with salmeterol fluticasone inhalation treatment, and then differences in the levels of small airway function and airway wall parameters, the content of inflammatory factors and chemokines in serum and so on were compared between two groups of patients after 2 weeks of treatment.Results:After 2 weeks of treatment, small airway function parameters FEF25, FEF25-75 and FEF75 levels of observation group were significantly higher than those of control group, airway wall parameters WT, WA and T/D levels were significantly lower than those of control group, and AI level was significantly higher than that of control group; MIP-1α, PCT, NF-κB, IL-6, CRP, Eotaxin, CCL18, Lymphotactin, sFKN and MCP-1 content in serum of observation group were significantly lower than those of control group while sTNFR content was significantly higher than that of control group.Conclusions:Tiotropium bromide combined with salmeterol fluticasone inhalation therapy can optimize the overall condition in patients with moderate-severe stable COPD, which is specifically reflected on the control of the airway function and the degree of inflammation.

  20. Sesamin attenuates allergic airway inflammation through the suppression of nuclear factor-kappa B activation.

    Science.gov (United States)

    Li, Liangchang; Piao, Hongmei; Zheng, Mingyu; Jin, Zhewu; Zhao, Liguang; Yan, Guanghai

    2016-12-01

    The aim of the present study is to determine the role of sesamin, the most abundant lignan in sesame seed oil, on the regulation of allergic airway inflammation in a murine asthma model. A BALB/c mouse model with allergic asthma was used to evaluate the effects of sesamin on nuclear factor-kappa B (NF-κB) activation. An enzyme-linked immunosorbent assay was used to determine protein expression in bronchoalveolar lavage (BAL) fluids. Hematoxylin and eosin staining was performed to examine histological changes. Moreover, western blot analysis was used to detect the expression of proteins in tissues. Prior to administering sesamin, the mice developed the following pathophysiological features of asthma: An increase in the number of inflammatory cells, increased levels of interleukin (IL)-4, IL-5 and IL-13, decreased levels of interferon-γ in BAL fluids and lung tissues, increased immunoglobulin E (IgE) levels in the serum and an increased activation of NF-κB in lung tissues. Following treatment with sesamin, the mice had evidently reduced peribronchiolar inflammation and airway inflammatory cell recruitment, inhibited production of several cytokines in BAL fluids and lung tissues, and decreased IgE levels. Following inhalation of ovalbumin, the administration of sesamin also inhibited the activation of NF-κB. In addition, sesamin administration reduced the phosphorylation of p38 mitogen-activated protein kinases (MAPKs). The present study demonstrates that sesamin decreases the activation of NF-κB in order to attenuate allergic airway inflammation in a murine model of asthma, possibly via the regulation of phosphorylation of p38 MAPK. These observations provide an important molecular mechanism for the potential use of sesamin in preventing and/or treating asthma, as well as other airway inflammatory disorders.

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  2. Phloretin Attenuates Allergic Airway Inflammation and Oxidative Stress in Asthmatic Mice

    Science.gov (United States)

    Huang, Wen-Chung; Fang, Li-Wen; Liou, Chian-Jiun

    2017-01-01

    Phloretin (PT), isolated from the apple tree, was previously demonstrated to have antioxidative and anti-inflammatory effects in macrophages and anti-adiposity effects in adipocytes. Inflammatory immune cells generate high levels of reactive oxygen species (ROS) for stimulated severe airway hyperresponsiveness (AHR) and airway inflammation. In this study, we investigated whether PT could reduce oxidative stress, airway inflammation, and eosinophil infiltration in asthmatic mice, and ameliorate oxidative and inflammatory responses in tracheal epithelial cells. BALB/c mice were sensitized with ovalbumin (OVA) to induce asthma symptoms. Mice were randomly assigned to the five experimental groups: normal controls; OVA-induced asthmatic mice; and OVA-induced mice injected intraperitoneally with one of the three PT doses (5, 10, or 20 mg/kg). In addition, we treated inflammatory human tracheal epithelial cells (BEAS-2B cells) with PT to assess oxidative responses and the levels of proinflammatory cytokines and chemokines. We found that PT significantly reduced goblet cell hyperplasia and eosinophil infiltration, which decreased AHR, inflammation, and oxidative responses in the lungs of OVA-sensitized mice. PT also decreased malondialdehyde levels in the lung and reduced Th2 cytokine production in bronchoalveolar lavage fluids. Furthermore, PT reduced ROS, proinflammatory cytokines, and eotaxin production in BEAS-2B cells. PT also suppressed monocyte cell adherence to inflammatory BEAS-2B cells. These findings suggested that PT alleviated pathological changes, inflammation, and oxidative stress by inhibiting Th2 cytokine production in asthmatic mice. PT showed therapeutic potential for ameliorating asthma symptoms in the future. PMID:28243240

  3. Linker for activation of T cells contributes to airway inflammation in an asthmatic mouse model

    Institute of Scientific and Technical Information of China (English)

    GUO Xue-jun; REN Lian-ping; SUN Yi-ping; ZHOU Min; XU Wei-guo

    2010-01-01

    Background Allergic asthma is associated with airway inflammation and hyperresponsiveness caused by dysregulated production of cytokines secreted by allergen-specific helper T-type 2 (Th2) cells. The linker for activation of T cells (LAT)is a membrane-associated adaptor protein, which has been shown to take part in regulating T cell receptor (TCR)signaling and T cell homeostasis. In this study, we established an asthmatic mouse model to examine the changes in LAT levels during allergic airway disease and the effects of LAT transgenic expression on airway inflammation.Methods T ceils from mouse lung tissues were isolated from allergen challenged (ovalbumin (OVA)) and control mice,and the purity of these isolated T cells was examined by fluorescence-activated cell sorter (FACS). Semi-quantitative RT-PCR and Western blotting were used to detect the expression of the LAT gene and LAT protein, respectively. After an intranasally administered mixture of pCMV-HA-LAT plasmid and Lipofectamine 2000, 24 hours before and 72 hours after allergen challenge, the BALF cell count and the differential cytologies were studied. In addition, IL-4 and IFN-γ levels in the BALF were determined by ELISA, and pathological changes in lung tissues were observed.Results LAT protein and mRNA expression were decreased in lung T cells in a mouse model of allergen-induced airway disease. After intranasal administration of pCMV-HA-LAT, histopathological examination of the lungs showed that intervention with LAT overexpression prevented mice from developing airway inflammation, and the number of total cells,eosinophils, neutrophils, and lymphocytes in the BALF was reduced significantly compared with the OVA sensitized and challenged group. In addition, the Th2 cytokine IL-4 decreased, while the Th1 cytokine IFN-Y increased compared to the OVA sensitized and challenged group or the OVA sensitized group plus pCMV-HA treatment.Conclusion This study demonstrates that LAT might effectively diminish Th2

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

    Directory of Open Access Journals (Sweden)

    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

  5. Oroxylin A Inhibits Allergic Airway Inflammation in Ovalbumin (OVA)-Induced Asthma Murine Model.

    Science.gov (United States)

    Zhou, De-Gang; Diao, Bao-Zhong; Zhou, Wen; Feng, Jia-Long

    2016-04-01

    Oroxylin A, a natural flavonoid isolated from the medicinal herb Scutellaria baicalensis Georgi, has been reported to have anti-inflammatory property. In this study, we aimed to investigate the protective effects and mechanism of oroxylin A on allergic inflammation in OVA-induced asthma murine model. BABL/c mice were sensitized and airway-challenged with OVA to induce asthma. Oroxylin A (15, 30, and 60 mg/kg) was administered by oral gavage 1 h before the OVA treatment on day 21 to 23. The results showed that oroxylin A attenuated OVA-induced lung histopathologic changes, airway hyperresponsiveness, and the number of inflammatory cells. Oroxylin A also inhibited the levels of IL-4, IL-5, IL-13, and OVA-specific IgE in BALF. Furthermore, oroxylin A significantly inhibited OVA-induced NF-κB activation. In conclusion, these results suggested that oroxylin A inhibited airway inflammation in OVA-induced asthma murine model by inhibiting NF-κB activation. These results suggested that oroxylin A was a potential therapeutic drug for treating allergic asthma.

  6. The transcription factor PU.1 promotes alternative macrophage polarization and asthmatic airway inflammation.

    Science.gov (United States)

    Qian, Feng; Deng, Jing; Lee, Yong Gyu; Zhu, Jimmy; Karpurapu, Manjula; Chung, Sangwoon; Zheng, Jun-Nian; Xiao, Lei; Park, Gye Young; Christman, John W

    2015-12-01

    The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation. However, the role of PU.1 in alternatively activated macrophage (AAM) and asthmatic inflammation has yet been investigated. Here we report that PU.1 serves as a critical regulator of AAM polarization and promotes the pathological progress of asthmatic airway inflammation. In response to the challenge of DRA (dust mite, ragweed, and Aspergillus) allergens, conditional PU.1-deficient (PU/ER(T)(+/-)) mice displayed attenuated allergic airway inflammation, including decreased alveolar eosinophil infiltration and reduced production of IgE, which were associated with decreased mucous glands and goblet cell hyperplasia. The reduced asthmatic inflammation in PU/ER(T)(+/-) mice was restored by adoptive transfer of IL-4-induced wild-type (WT) macrophages. Moreover, after treating PU/ER(T)(+/-) mice with tamoxifen to rescue PU.1 function, the allergic asthmatic inflammation was significantly restored. In vitro studies demonstrate that treatment of PU.1-deficient macrophages with IL-4 attenuated the expression of chitinase 3-like 3 (Ym-1) and resistin-like molecule alpha 1 (Fizz-1), two specific markers of AAM polarization. In addition, PU.1 expression in macrophages was inducible in response to IL-4 challenge, which was associated with phosphorylation of signal transducer and activator of transcription 6 (STAT6). Furthermore, DRA challenge in sensitized mice almost abrogated gene expression of Ym-1 and Fizz-1 in lung tissues of PU/ER(T)(+/-) mice compared with WT mice. These data, all together, indicate that PU.1 plays a critical role in AAM polarization and asthmatic inflammation.

  7. Chronic Mild Prenatal Stress Exacerbates the Allergen-Induced Airway Inflammation in Rats

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    Paulo J. Nogueira

    1999-01-01

    Full Text Available The effects of chronic mild prenatal stress on leukocyte infiltration into the airways was investigated in rat offspring. The chronic prenatal stress consisted of transitory and variable changes in the rat's living conditions. Offspring at adult age were actively sensitized (day 0 and intratracheally challenged (day 14 with ovalbumin. Bronchoalveolar lavage was performed in the offspring at 48 h after intratracheal challenge with ovalbumin. A significant increase in total leukocyte infiltration was observed in the nonstressed offspring group and this was associated with a marked recruitment of eosinophils without a significant effect on the influx of neutrophils and mononuclear cells. In the prenatal stressed offspring, the counts of both total leukocyte and eosinophils, as well as mononuclear cells, was increased by 50% compared to the non-stressed offspring. We provide here the first experimental evidence that chronic mild unpredictable prenatal stress produces a marked increase in the allergen-induced airway inflammation in the rat offspring.

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

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    Koga Hikari

    2013-01-01

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

  9. Airway irritation, inflammation, and toxicity in mice following inhalation of metal oxide nanoparticles

    DEFF Research Database (Denmark)

    Larsen, Søren T; Jackson, Petra; Poulsen, Steen S

    2016-01-01

    in the airways following inhalation. In the present study, the acute (24 h) and persistent (13 weeks) effects in the airways after a single exposure to metal oxide nanoparticles were studied using a murine inhalation model. Mice were exposed 60 min to aerosols of either ZnO, TiO2, Al2O3 or CeO2 and the deposited...... particles except TiO2. The ranking of potency regarding induction of acute lung inflammation was Al2O3 = TiO2 CeO2 ≪ ZnO. Exposure to CeO2 gave rise to a more persistent inflammation; both neutrophilic and lymphocytic inflammation was seen 13 weeks after exposure. As the only particles, ZnO caused......Metal oxide nanoparticles are used in a broad range of industrial processes and workers may be exposed to aerosols of the particles both during production and handling. Despite the widespread use of these particles, relatively few studies have been performed to investigate the toxicological effects...

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

    Science.gov (United States)

    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.

  11. Obstructive Sleep Apnoea Modulates Airway Inflammation and Remodelling in Severe Asthma

    Science.gov (United States)

    Taillé, Camille; Rouvel-Tallec, Anny; Stoica, Maria; Danel, Claire; Dehoux, Monique; Marin-Esteban, Viviana; Pretolani, Marina; Aubier, Michel; d’Ortho, Marie-Pia

    2016-01-01

    Background Obstructive sleep apnoea (OSA) is frequently observed in severe asthma but the causal link between the 2 diseases remains hypothetical. The role of OSA-related systemic and airway neutrophilic inflammation in asthma bronchial inflammation or remodelling has been rarely investigated. The aim of this study was to compare hallmarks of inflammation in induced sputum and features of airway remodelling in bronchial biopsies from adult patients with severe asthma with and without OSA. Materials and Methods An overnight polygraphy was performed in 55 patients referred for difficult-to-treat asthma, who complained of nocturnal respiratory symptoms, poor sleep quality or fatigue. We compared sputum analysis, reticular basement membrane (RBM) thickness, smooth muscle area, vascular density and inflammatory cell infiltration in bronchial biopsies. Results In total, 27/55 patients (49%) had OSA diagnosed by overnight polygraphy. Despite a moderate increase in apnoea-hypopnoea index (AHI; 14.2±1.6 event/h [5–35]), the proportion of sputum neutrophils was higher and that of macrophages lower in OSA than non-OSA patients, with higher levels of interleukin 8 and matrix metalloproteinase 9. The RBM was significantly thinner in OSA than non-OSA patients (5.8±0.4 vs. 7.8±0.4 μm, p<0.05). RBM thickness and OSA severity assessed by the AHI were negatively correlated (rho = -0.65, p<0.05). OSA and non-OSA patients did not differ in age, sex, BMI, lung function, asthma control findings or treatment. Conclusion Mild OSA in patients with severe asthma is associated with increased proportion of neutrophils in sputum and changes in airway remodelling. PMID:26934051

  12. Obstructive Sleep Apnoea Modulates Airway Inflammation and Remodelling in Severe Asthma.

    Directory of Open Access Journals (Sweden)

    Camille Taillé

    Full Text Available Obstructive sleep apnoea (OSA is frequently observed in severe asthma but the causal link between the 2 diseases remains hypothetical. The role of OSA-related systemic and airway neutrophilic inflammation in asthma bronchial inflammation or remodelling has been rarely investigated. The aim of this study was to compare hallmarks of inflammation in induced sputum and features of airway remodelling in bronchial biopsies from adult patients with severe asthma with and without OSA.An overnight polygraphy was performed in 55 patients referred for difficult-to-treat asthma, who complained of nocturnal respiratory symptoms, poor sleep quality or fatigue. We compared sputum analysis, reticular basement membrane (RBM thickness, smooth muscle area, vascular density and inflammatory cell infiltration in bronchial biopsies.In total, 27/55 patients (49% had OSA diagnosed by overnight polygraphy. Despite a moderate increase in apnoea-hypopnoea index (AHI; 14.2 ± 1.6 event/h [5-35], the proportion of sputum neutrophils was higher and that of macrophages lower in OSA than non-OSA patients, with higher levels of interleukin 8 and matrix metalloproteinase 9. The RBM was significantly thinner in OSA than non-OSA patients (5.8 ± 0.4 vs. 7.8 ± 0.4 μm, p<0.05. RBM thickness and OSA severity assessed by the AHI were negatively correlated (rho = -0.65, p<0.05. OSA and non-OSA patients did not differ in age, sex, BMI, lung function, asthma control findings or treatment.Mild OSA in patients with severe asthma is associated with increased proportion of neutrophils in sputum and changes in airway remodelling.

  13. Effect of Moringa oleifera Lam. seed extract on ovalbumin-induced airway inflammation in guinea pigs.

    Science.gov (United States)

    Mahajan, Shailaja G; Mehta, Anita A

    2008-08-01

    To determine the therapeutic potential of herbal medicine Moringa oleifera Lam. family: Moringaceae in the control of allergic diseases, the efficacy of the ethanolic extract of the seeds of the plant (MOEE) against ovalbumin (OVA)-induced airway inflammation in guinea pigs was examined. During the experimental period, the test drugs (MOEE or dexamethasone) were administered by oral route prior to challenge with aerosolized 0.5% OVA. Bronchoconstriction tests were performed and respiratory parameters (i.e., tidal volume and respiratory rate) were measured. At the end of experiment, blood was collected from each animal to perform total and differential counts and serum was used for assay of IL-4, IL-6, and TNFalpha. Lung lavage fluid (BAL) was collected for estimation of cellular content and cytokine levels. Lung tissue histamine assays were performed using the homogenate of one lobe from each animal; a separate lobe and the trachea were subjected to histopathology to measure the degree of any airway inflammation. The results suggest that in OVA-sensitized control animals that did not receive either drug, tidal volume (V(t)) was decreased, respiration rate (f) was increased, and both the total and differential cell counts in blood and BAL fluid were increased significantly. MOEE-treatment of sensitized hosts resulted in improvement in all parameters except BAL TNFalpha and IL-4. Moreover, MOEE-treatment also showed protection against acetylcholine-induced broncho-constriction and airway inflammation which was confirmed by histological observations. The results of these studies confirm the traditional claim for the usefulness of this herb in the treatment of allergic disorders like asthma.

  14. Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD.

    Science.gov (United States)

    Staples, Karl J; Taylor, Stephen; Thomas, Steve; Leung, Stephanie; Cox, Karen; Pascal, Thierry G; Ostridge, Kristoffer; Welch, Lindsay; Tuck, Andrew C; Clarke, Stuart C; Gorringe, Andrew; Wilkinson, Tom M A

    2016-01-01

    Non-typeable Haemophilus influenzae (NTHi) is a key pathogen in COPD, being associated with airway inflammation and risk of exacerbation. Why some patients are susceptible to colonisation is not understood. We hypothesised that this susceptibility may be due to a deficiency in mucosal humoral immunity. The aim of our study (NCT01701869) was to quantify the amount and specificity of antibodies against NTHi in the lungs and the associated risk of infection and inflammation in health and COPD. Phlebotomy, sputum induction and bronchoscopy were performed on 24 mild-to-moderate COPD patients and 8 age and smoking-matched controls. BAL (Bronchoalveolar lavage) total IgG1, IgG2, IgG3, IgM and IgA concentrations were significantly increased in COPD patients compared to controls. NTHi was detected in the lungs of 7 of the COPD patients (NTHi+ve-29%) and these patients had a higher median number of previous exacerbations than NTHi-ve patients as well as evidence of increased systemic inflammation. When comparing NTHi+ve versus NTHi-ve patients we observed a decrease in the amount of both total IgG1 (p = 0.0068) and NTHi-specific IgG1 (p = 0.0433) in the BAL of NTHi+ve patients, but no differences in total IgA or IgM. We observed no evidence of decreased IgG1 in the serum of NTHi+ve patients, suggesting this phenomenon is restricted to the airway. Furthermore, the NTHi+ve patients had significantly greater levels of IL-1β (p = 0.0003), in BAL than NTHi-ve COPD patients.This study indicates that the presence of NTHi is associated with reduced levels and function of IgG1 in the airway of NTHi-colonised COPD patients. This decrease in total and NTHI-specific IgG1 was associated with greater systemic and airway inflammation and a history of more frequent exacerbations and may explain the susceptibility of some COPD patients to the impacts of NTHi.

  15. Interleukin-33 drives activation of alveolar macrophages and airway inflammation in a mouse model of acute exacerbation of chronic asthma.

    Science.gov (United States)

    Bunting, Melissa M; Shadie, Alexander M; Flesher, Rylie P; Nikiforova, Valentina; Garthwaite, Linda; Tedla, Nicodemus; Herbert, Cristan; Kumar, Rakesh K

    2013-01-01

    We investigated the role of interleukin-33 (IL-33) in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM) were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL-33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation.

  16. Interleukin-33 Drives Activation of Alveolar Macrophages and Airway Inflammation in a Mouse Model of Acute Exacerbation of Chronic Asthma

    Directory of Open Access Journals (Sweden)

    Melissa M. Bunting

    2013-01-01

    Full Text Available We investigated the role of interleukin-33 (IL-33 in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL-33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation.

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

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    Navarro-Xavier RA

    2016-05-01

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

  18. 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

  19. Antigen-specific cytotoxic T lymphocytes target airway CD103+ and CD11b+ dendritic cells to suppress allergic inflammation.

    Science.gov (United States)

    Daniels, N J; Hyde, E; Ghosh, S; Seo, K; Price, K M; Hoshino, K; Kaisho, T; Okada, T; Ronchese, F

    2016-01-01

    Allergic airway inflammation is driven by the recognition of inhaled allergen by T helper type 2 (Th2) cells in the airway and lung. Allergen-specific cytotoxic T lymphocytes (CTLs) can strongly reduce airway inflammation, however, the mechanism of their inhibitory activity is not fully defined. We used mouse models to show that allergen-specific CTLs reduced early cytokine production by Th2 cells in lung, and their subsequent accumulation and production of interleukin (IL)-4 and IL-13. In addition, treatment with specific CTLs also increased the proportion of caspase(+) dendritic cells (DCs) in mediastinal lymph node (MLN), and decreased the numbers of CD103(+) and CD11b(+) DCs in the lung. This decrease required expression of the cytotoxic mediator perforin in CTLs and of the appropriate MHC-antigen ligand on DCs, suggesting that direct CTL-DC contact was necessary. Lastly, lung imaging experiments revealed that in airway-challenged mice XCR1-GFP(+) DCs, corresponding to the CD103(+) DC subset, and XCR1-GFP(-) CD11c(+) cells, which include CD11b(+) DCs and alveolar macrophages, both clustered in the areas surrounding the small airways and were closely associated with allergen-specific CTLs. Thus, allergen-specific CTLs reduce allergic airway inflammation by depleting CD103(+) and CD11b(+) DC populations in the lung, and may constitute a mechanism through which allergic immune responses are regulated.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Determination of respiratory phase during acquisition of airway cine MR images

    Energy Technology Data Exchange (ETDEWEB)

    Kalra, Maninder; McConnell, Keith; Amin, Raouf S. [Cincinnati Children' s Hospital, Division of Pulmonary Medicine, Cincinnati, OH (United States); Donnelly, Lane F.; O' Brien, Kendall [Cincinnati Children' s Hospital, Department of Radiology, Cincinnati, OH (United States); Sandhu, Jaskaran [University of Missouri, Department of Psychiatry, Columbia, MO (United States); Johnson, James [Cincinnati Children' s Hospital, Department of Respiratory Care, Cincinnati, OH (United States)

    2006-09-15

    Subjects were imaged on a 1.5-T Signa MRI system using the head-neck vascular coil. An axial fast gradient echo cine, at the base of the second cervical vertebra, was obtained. A total of 128 images were acquired with a rapid image acquisition (one per second) over several respiratory cycles. The analog signal from the MR scanner (RF unblank) was utilized to determine the duration of the cine MR sequence. The phase of respiration was determined by analyzing the nasal air flow connected via pressure tubing to a pressure transducer outside the MR scanner room. We were thus able to determine the phase of respiration during acquisition of individual airway cine MR images. There was a wide range of airway volume measurements over the respiratory cycle with the lowest volume at end expiration and the highest at peak inspiration. (orig.)

  2. 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...... and fibroblasts, acrolein and CS extract evoked IL-8 release, a response selectively reduced by TRPA1 antagonists. Capsaicin, agonist of the transient receptor potential vanilloid 1 (TRPV1), a channel co-expressed with TRPA1 by airway sensory nerves, and acrolein or CS (TRPA1 agonists), or the neuropeptide...

  3. Neutrophilic airways inflammation in lung cancer: the role of exhaled LTB-4 and IL-8

    Directory of Open Access Journals (Sweden)

    Orlando Silvio

    2011-06-01

    Full Text Available Abstract Background Recent advances in lung cancer biology presuppose its inflammatory origin. In this regard, LTB-4 and IL-8 are recognized to play a crucial role in neutrophil recruitment into airways during lung cancer. Notwithstanding the intriguing hypothesis, the exact role of neutrophilic inflammation in tumour biology remains complex and not completely known. The aim of this study was to give our contribution in this field by investigating LTB-4 and IL-8 in the breath condensate of NSCLC patients and verifying their role in cancer development and progression. Method We enrolled 50 NSCLC patients and 35 controls. LTB-4 and IL-8 concentrations were measured in the breath condensate and the blood of all the subjects under study using EIA kits. Thirty NSCLC patients and ten controls underwent induced sputum collection and analysis. Results LTB-4 and IL-8 resulted higher in breath condensate and the blood of NSCLC patients compared to controls. Significantly higher concentrations were found as the cancer stages progressed. A positive correlation was observed between exhaled IL-8 and LTB-4 and the percentage of neutrophils in the induced sputum. Conclusion The high concentrations of exhaled LTB-4 and IL-8 showed the presence of a neutrophilic inflammation in the airways of NSCLC patients and gave a further support to the inflammatory signalling in lung cancer. These exhaled proteins could represent a suitable non-invasive marker in the diagnosis and monitoring of lung cancer.

  4. Inhibition of airway inflammation and remodeling by sitagliptin in murine chronic asthma.

    Science.gov (United States)

    Nader, Manar A

    2015-12-01

    In this study the role of sitagliptin, dipeptidyl peptidase inhibitor, DPP-4, and dexamethasone in ameliorating inflammation and remodeling of chronic asthma in a mouse model were investigated. Mice sensitized to ovalbumin were chronically challenged with aerosolized antigen for 3days a week continued for 8weeks. During this period animals were treated with sitagliptin or dexamethasone daily. Assessment of inflammatory cell, oxidative markers, total nitrate/nitrite (NOx), interleukin (IL)-13, transforming growth factor-beta1 (TGF-β1) in bronchoalveolar lavage (BAL) and/or lung tissue were done. Also histopathological and immuno-histochemical analysis for lung was carried out. Compared with vehicle alone, treatment with sitagliptin or dexamethasone significantly reduced accumulation of eosinophils and chronic inflammatory cells, subepithelial collagenization, and thickening of the airway epithelium. Also both drug reduced goblet cell hyperplasia, oxidative stress, TGF-β1, IL-13 and epithelial cytoplasmic immunoreactivity for nuclear factor κ-B (NFκ-B). These data indicate that sitagliptin like dexamethasone may play a beneficial role reducing airway inflammation and remodeling in chronic murine model of asthma.

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

    Institute of Scientific and Technical Information of China (English)

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

    2009-01-01

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

  6. Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation.

    Science.gov (United States)

    Bartlett, Nathan W; Walton, Ross P; Edwards, Michael R; Aniscenko, Juliya; Caramori, Gaetano; Zhu, Jie; Glanville, Nicholas; Choy, Katherine J; Jourdan, Patrick; Burnet, Jerome; Tuthill, Tobias J; Pedrick, Michael S; Hurle, Michael J; Plumpton, Chris; Sharp, Nigel A; Bussell, James N; Swallow, Dallas M; Schwarze, Jurgen; Guy, Bruno; Almond, Jeffrey W; Jeffery, Peter K; Lloyd, Clare M; Papi, Alberto; Killington, Richard A; Rowlands, David J; Blair, Edward D; Clarke, Neil J; Johnston, Sebastian L

    2008-02-01

    Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations.

  7. Apical Localization of Zinc Transporter ZnT4 in Human Airway Epithelial Cells and Its Loss in a Murine Model of Allergic Airway Inflammation

    Directory of Open Access Journals (Sweden)

    Chiara Murgia

    2011-10-01

    Full Text Available The apical cytoplasm of airway epithelium (AE contains abundant labile zinc (Zn ions that are involved in the protection of AE from oxidants and inhaled noxious substances. A major question is how dietary Zn traffics to this compartment. In rat airways, in vivo selenite autometallographic (Se-AMG-electron microscopy revealed labile Zn-selenium nanocrystals in structures resembling secretory vesicles in the apical cytoplasm. This observation was consistent with the starry-sky Zinquin fluorescence staining of labile Zn ions confined to the same region. The vesicular Zn transporter ZnT4 was likewise prominent in both the apical and basal parts of the epithelium both in rodent and human AE, although the apical pools were more obvious. Expression of ZnT4 mRNA was unaffected by changes in the extracellular Zn concentration. However, levels increased 3-fold during growth of cells in air liquid interface cultures and decreased sharply in the presence of retinoic acid. When comparing nasal versus bronchial human AE cells, there were significant positive correlations between levels of ZnT4 from the same subject, suggesting that nasal brushings may allow monitoring of airway Zn transporter expression. Finally, there were marked losses of both basally-located ZnT4 protein and labile Zn in the bronchial epithelium of mice with allergic airway inflammation. This study is the first to describe co-localization of zinc vesicles with the specific zinc transporter ZnT4 in airway epithelium and loss of ZnT4 protein in inflamed airways. Direct evidence that ZnT4 regulates Zn levels in the epithelium still needs to be provided. We speculate that ZnT4 is an important regulator of zinc ion accumulation in secretory apical vesicles and that the loss of labile Zn and ZnT4 in airway inflammation contributes to AE vulnerability in diseases such as asthma.

  8. Low-intensity aerobic exercise training attenuates airway inflammation and remodeling in a rat model of steroid-resistant asthma

    Institute of Scientific and Technical Information of China (English)

    Qin Qingwu; Chen Xi; Feng Juntao; Qin Ling; Hu Chengping

    2014-01-01

    Background Aerobic exercise can improve symptoms,reduce airway inflammation,and even ameliorate airway remodeling in asthmatic animals and patients.However,previous studies have focused mainly on the effect of aerobic exercise on steroid-sensitive asthma (SSA).The goals of this study were to determine the effect of low-intensity aerobic exercise training on airway hyperresponsiveness,inflammation,and remodeling in a rat model of steroid-resistant asthma (SRA) and to identify the potential mechanisms underlying these effects.Methods Endotoxin-free ovalbumin with or without lipopolysaccharide were applied to establish rat models of SRA and SSA,respectively.Airway hyperresponsiveness,inflammation,remodeling,expression of interleukin (IL)-25,IL-33,thymic stromal lymphopoietin (TSLP),high mobility group box-1 (HMGB1),and IL-17 in bronchoalveolar lavage fluid (BALF),and the role of dexamethasone (DXM) were compared between these two asthmatic rat models.The effect of low-intensity aerobic exercise training and anti-HMGB1 treatment on airway hyperresponsiveness,inflammation,and remodeling in SRA rats also was evaluated.Results SRA rats developed neutrophil-dominated airway inflammation ((29.5±4.1)% of the total cell numbers in BALF),whereas SSA rats developed eosinophil-dominated airway inflammation ((24.0±6.1)% of the total cell numbers in BALF).Compared with SSA rats,SRA rats had more severe airway hyperresponsiveness,lower levels of IL-25 ((33.6±10.3) vs.(104.8±24.9) pg/ml),IL-33 ((87.5±25.0) vs.(226.6±40.7) pg/ml),and TSLP ((1 933.2±899.5) vs.(7 224.0±992.1) pg/ml),and higher levels of HMGB1 ((21.2±4.5) vs.(5.4±1.6) ng/ml) and IL-17 ((780.5±261.7) vs.(291.4±76.4) pg/ml) in BALF (all P <0.05).However,there was no significant difference in goblet cell hyperplasia,subepithelial collagen thickness,and airway smooth muscle remodeling between the two groups.Compared with control SSA rats,airway hyperresponsiveness,inflammation,and remodeling in SRA rats

  9. Effects of woodsmoke exposure on airway inflammation in rural Guatemalan women.

    Directory of Open Access Journals (Sweden)

    Michael J Guarnieri

    Full Text Available More than two-fifths of the world's population uses solid fuels, mostly biomass, for cooking. The resulting biomass smoke exposure is a major cause of chronic obstructive pulmonary disease (COPD among women in developing countries.To assess whether lower woodsmoke exposure from use of a stove with a chimney, compared to open fires, is associated with lower markers of airway inflammation in young women.We carried out a cross-sectional analysis on a sub-cohort of participants enrolled in a randomized controlled trial in rural Guatemala, RESPIRE.We recruited 45 indigenous women at the end of the 18-month trial; 19 women who had been using the chimney stove for 18-24 months and 26 women still using open fires.We obtained spirometry and induced sputum for cell counts, gene expression of IL-8, TNF-α, MMP-9 and 12, and protein concentrations of IL-8, myeloperoxidase and fibronectin. Exhaled carbon monoxide (CO and 48-hr personal CO tubes were measured to assess smoke exposure.MMP-9 gene expression was significantly lower in women using chimney stoves. Higher exhaled CO concentrations were significantly associated with higher gene expression of IL-8, TNF-α, and MMP-9. Higher 48-hr personal CO concentrations were associated with higher gene expression of IL-8, TNF- α, MMP-9 and MMP-12; reaching statistical significance for MMP-9 and MMP-12.Compared to using an open wood fire for cooking, use of a chimney stove was associated with lower gene expression of MMP-9, a potential mediator of airway remodeling. Among all participants, indoor biomass smoke exposure was associated with higher gene expression of multiple mediators of airway inflammation and remodeling; these mechanisms may explain some of the observed association between prolonged biomass smoke exposure and COPD.

  10. AMPK agonists ameliorate sodium and fluid transport and inflammation in cystic fibrosis airway epithelial cells.

    Science.gov (United States)

    Myerburg, Michael M; King, J Darwin; Oyster, Nicholas M; Fitch, Adam C; Magill, Amy; Baty, Catherine J; Watkins, Simon C; Kolls, Jay K; Pilewski, Joseph M; Hallows, Kenneth R

    2010-06-01

    The metabolic sensor AMP-activated kinase (AMPK) inhibits both the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) Cl(-) channel and epithelial Na(+) channel (ENaC), and may inhibit secretion of proinflammatory cytokines in epithelia. Here we have tested in primary polarized CF and non-CF human bronchial epithelial (HBE) cells the effects of AMPK activators, metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-riboside (AICAR), on various parameters that contribute to CF lung disease: ENaC-dependent short-circuit currents (I(sc)), airway surface liquid (ASL) height, and proinflammatory cytokine secretion. AMPK activation after overnight treatment with either metformin (2-5 mM) or AICAR (1 mM) substantially inhibited ENaC-dependent I(sc) in both CF and non-CF airway cultures. Live-cell confocal images acquired 60 minutes after apical addition of Texas Red-dextran-containing fluid revealed significantly greater ASL heights after AICAR and metformin treatment relative to controls, suggesting that AMPK-dependent ENaC inhibition slows apical fluid reabsorption. Both metformin and AICAR decreased secretion of various proinflammatory cytokines, both with and without prior LPS stimulation. Finally, prolonged exposure to more physiologically relevant concentrations of metformin (0.03-1 mM) inhibited ENaC currents and decreased proinflammatory cytokine levels in CF HBE cells in a dose-dependent manner. These findings suggest that novel therapies to activate AMPK in the CF airway may be beneficial by blunting excessive sodium and ASL absorption and by reducing excessive airway inflammation, which are major contributors to CF lung disease.

  11. Schistosoma mansoni Tegument (Smteg) Induces IL-10 and Modulates Experimental Airway Inflammation

    Science.gov (United States)

    2016-01-01

    Background Previous studies have demonstrated that S. mansoni infection and inoculation of the parasite eggs and antigens are able to modulate airways inflammation induced by OVA in mice. This modulation was associated to an enhanced production of interleukin-10 and to an increased number of regulatory T cells. The S. mansoni schistosomulum is the first stage to come into contact with the host immune system and its tegument represents the host-parasite interface. The schistosomula tegument (Smteg) has never been studied in the context of modulation of inflammatory disorders, although immune evasion mechanisms take place in this phase of infection to guarantee the persistence of the parasite in the host. Methodology and Principal Findings The aim of this study was to evaluate the Smteg ability to modulate inflammation in an experimental airway inflammation model induced by OVA and to characterize the immune factors involved in this modulation. To achieve the objective, BALB/c mice were sensitized with ovalbumin (OVA) and then challenged with OVA aerosol after Smteg intraperitoneal inoculation. Protein extravasation and inflammatory cells were assessed in bronchoalveolar lavage and IgE levels were measured in serum. Additionally, lungs were excised for histopathological analyses, cytokine measurement and characterization of the cell populations. Inoculation with Smteg led to a reduction in the protein levels in bronchoalveolar lavage (BAL) and eosinophils in both BAL and lung tissue. In the lung tissue there was a reduction in inflammatory cells and collagen deposition as well as in IL-5, IL-13, IL-25 and CCL11 levels. Additionally, a decrease in specific anti-OVA IgE levels was observed. The reduction observed in these inflammatory parameters was associated with increased levels of IL-10 in lung tissues. Furthermore, Smteg/asthma mice showed high percentage of CD11b+F4/80+IL-10+ and CD11c+CD11b+IL-10+ cells in lungs. Conclusion Taken together, these findings

  12. Effects of nebulized ketamine on allergen-induced airway hyperresponsiveness and inflammation in actively sensitized Brown-Norway rats

    Directory of Open Access Journals (Sweden)

    Qian Yan

    2007-05-01

    Full Text Available Abstract Since airway hyperresponsiveness (AHR and allergic inflammatory changes are regarded as the primary manifestations of asthma, the main goals of asthma treatment are to decrease inflammation and maximize bronchodilation. These goals can be achieved with aerosol therapy. Intravenous administration of the anesthetic, ketamine, has been shown to trigger bronchial smooth muscle relaxation. Furthermore, increasing evidence suggests that the anti-inflammatory properties of ketamine may protect against lung injury. However, ketamine inhalation might yield the same or better results at higher airway and lower ketamine plasma concentrations for the treatment of asthma. Here, we studied the effect of ketamine inhalation on bronchial hyperresponsiveness and airway inflammation in a Brown-Norway rat model of ovalbumin(OVA-induced allergic asthma. Animals were actively sensitized by subcutaneous injection of OVA and challenged by repeated intermittent (thrice weekly exposure to aerosolized OVA for two weeks. Before challenge, the sensitizened rats received inhalation of aerosol of phosphate-buffered saline (PBS or aerosol of ketamine or injection of ketamine respectivity. Airway reactivity to acetylcholine (Ach was measured in vivo, and various inflammatory markers, including Th2 cytokines in bronchoalveolar lavage fluid (BALF, as well as induciable nitric oxide synthase (iNOS and nitric oxide (NO in lungs were examined. Our results revealed that delivery of aerosolized ketamine using an ultrasonic nebulizer markedly suppressed allergen-mediated airway hyperreactivity, airway inflammation and airway inflammatory cell infiltration into the BALF, and significantly decreased the levels of interleukin-4 (IL-4 in the BALF and expression of iNOS and the concentration of NO in the inflamed airways from OVA-treated rats. These findings collectively indicate that nebulized ketamine attenuated many of the central components of inflammatory changes and AHR in

  13. Inhibitory effect of acetamide-45 on airway inflammation and phosphodiesterase 4 in allergic rats

    Institute of Scientific and Technical Information of China (English)

    Kai WANG; Hua-hao SHEN; Jun-chun CHEN; Zhong CHEN

    2005-01-01

    Aim: To determine the effects of acetamide-45 on respiratory function, airway inflammation, and the activity of phosphodiesterase 4 (PDE4) in allergic rats.Methods: Rats were sensitized by a single intramuscular injection with ovalbumin (OVA) and were challenged with ovalbumin applied by using an aerosol repeatedly for 7 d after 2 weeks. Acetamide-45 at concentrations of 5, 10, or 30 mg/kg was then administered by intraperitoneal injection. Changes in dynamic lung compliance and lung resistance, the accumulation of inflammatory cells in bronchoalveolar lavage, PDE4 activity, and the concentration of interleukin-4 in rat lung tissue were determined. Results: Seven days of treatment with acetamide-45 prevented eosinophil accumulation in allergic rats. At doses of 5, 10, and 30 mg/kg, acetamide-45 decreased lung resistance to 0.20±0.04, 0.25±0.07, and 0.22±0.05compliance to 0.41±0.07, 0.39±0.06, and 0.42±0.09 mL/cmH2O (P<0.05 vs OVA).After being treated with different doses of acetamide-45, the PDE4 activities in the concentrations of interleukin-4 in lung tissue were 6.22± 1.13, 5.95± 1.20,and 5.68±2.20 μg/g protein (P<0.05 vs OVA). Conclusions: Acetamide-45 was found to improve respiratory function and inhibit airway inflammation in this animal model, and the PDE4 activity of lung tissue was obviously inhibited.Acetamide-45 was an effective anti-inflammatory agent in respiratory inflammation,and the mechanism of its action might depend on inhibition of PDE4.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Cockroach protease allergen induces allergic airway inflammation via epithelial cell activation

    Science.gov (United States)

    Kale, Sagar L.; Agrawal, Komal; Gaur, Shailendra Nath; Arora, Naveen

    2017-01-01

    Protease allergens are known to enhance allergic inflammation but their exact role in initiation of allergic reactions at mucosal surfaces still remains elusive. This study was aimed at deciphering the role of serine protease activity of Per a 10, a major cockroach allergen in initiation of allergic inflammation at mucosal surfaces. We demonstrate that Per a 10 increases epithelial permeability by disruption of tight junction proteins, ZO-1 and occludin, and enhances the migration of Monocyte derived dendritic cell precursors towards epithelial layer as exhibited by trans-well studies. Per a 10 exposure also leads to secretion of IL-33, TSLP and intracellular Ca2+ dependent increase in ATP levels. Further, in vivo experiments revealed that Per a 10 administration in mice elevated allergic inflammatory parameters along with high levels of IL-33, TSLP, IL-1α and uric acid in the mice lungs. We next demonstrated that Per a 10 cleaves CD23 (low affinity IgE receptor) from the surface of PBMCs and purified B cells and CD25 (IL-2 receptor) from the surface of PBMCs and purified T cells in an activity dependent manner, which might favour Th2 responses. In conclusion, protease activity of Per a 10 plays a significant role in initiation of allergic airway inflammation at the mucosal surfaces. PMID:28198394

  16. Graptopetalum paraguayense Ameliorates Airway Inflammation and Allergy in Ovalbumin- (OVA- Sensitized BALB/C Mice by Inhibiting Th2 Signal

    Directory of Open Access Journals (Sweden)

    Bao-Hong Lee

    2013-01-01

    Full Text Available Role of inflammation-induced oxidative stress in the pathogenesis and progression of chronic inflammatory airways diseases has received increasing attention in recent years. Nuclear factor erythroid 2-related factor 2 is the primary transcription factor that regulates the expression of antioxidant and detoxifying enzymes. Graptopetalum paraguayense E. Walther, a vegetable consumed in Taiwan, has been used in folk medicine for protection against liver injury through elevating antioxidation. Recently, we found that gallic acid is an active compound of Graptopetalum paraguayense E. Walther, which has been reported to inhibit T-helper 2 cytokines. Currently, we assumed that Graptopetalum paraguayense E. Walther may potentially protect against ovalbumin-induced allergy and airway inflammation. Results demonstrated that Graptopetalum paraguayense E. Walther ethanolic extracts (GPE clearly inhibited airway inflammation, mucus cell hyperplasia, and eosinophilia in OVA-challenged mice. Additionally, GPE also prevented T-cell infiltration and Th2 cytokines, including interleukin- (IL-4, IL-5, and IL-13 generations in bronchial alveolar lavage fluid. The adhesion molecules ICAM-1 and VCAM-1 were substantially reduced by GPE treatment mediated by Nrf2 activation. Moreover, GPE attenuated GATA3 expression and inhibited Th2 signals of the T cells. These findings suggested that GPE ameliorated the development of airway inflammation through immune regulation.

  17. The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in humans*

    Science.gov (United States)

    Background: The Glutathione-S-Transferase Mu 1 null genotype has been reported to be a risk factor for acute respiratory disease associated with increases in ambient air ozone. Ozone is known to cause an immediate decrease in lung function and increased airway inflammation. Howev...

  18. Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells:potential roles in airway inflammation

    Institute of Scientific and Technical Information of China (English)

    Jing Wu; Martin Post; A Keith Tanswell; Jim Hu; Rongqi Duan; Huibi Cao; Deborah Field; Catherine M Newnham; David R Koehler; Noe Zamel; Melanie A Pritchard; Paul Hertzog

    2008-01-01

    Airway inflammation is the hallmark of many respiratory disorders,such as asthma and cystic fibrosis.Changes in airway gene expression triggered by inflammation play a key role in the pathogenesis of these diseases.Genetic linkage studies suggest that ESE-2 and ESE-3,which encode epithelium-specific Ets-domain-containing transcription factors,are candidate asthma susceptibility genes.We report here that the expression of another member of the Ets family transcription factors ESE-1,as well as ESE-3,is upregulated by the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-a (TNF-a) in bronchial epithelial cell lines.Treatment of these cells with IL-1β and TNF-a resulted in a dramatic increase in mRNA expression for both ESE-1 and ESE-3.We demonstrate that the induced expression is mediated by activation of the transcription factor NF-kB.We have characterized the ESE-1 and ESE-3 promoters and have identified the NF-kB binding sequences that are required for the cytokine-induced expression.In addition,we also demonstrate that ESE-1 upregulates ESE-3 expression and downregulates its own induction by cytokines.Finally,we have shown that in Elf3 (homologous to human ESE-1) knockout mice,the expression of the inflammatory cytokine interleukin-6 (IL-6) is downregulated.Our findings suggest that ESE-1 and ESE-3 play an important role in airway inflammation.

  19. Inhibitory effects of l-theanine on airway inflammation in ovalbumin-induced allergic asthma.

    Science.gov (United States)

    Hwang, Yong Pil; Jin, Sun Woo; Choi, Jae Ho; Choi, Chul Yung; Kim, Hyung Gyun; Kim, Se Jong; Kim, Yongan; Lee, Kyung Jin; Chung, Young Chul; Jeong, Hye Gwang

    2017-01-01

    l-theanine, a water-soluble amino acid isolated from green tea (Camellia sinensis), has anti-inflammatory activity, antioxidative properties, and hepatoprotective effects. However, the anti-allergic effect of l-theanine and its underlying molecular mechanisms have not been elucidated. In this study, we investigated the protective effects of l-theanine on asthmatic responses, particularly airway inflammation and oxidative stress modulation in an ovalbumin (OVA)-induced murine model of asthma. Treatment with l-theanine dramatically attenuated the extensive trafficking of inflammatory cells into bronchoalveolar lavage fluid (BALF). Histological studies revealed that l-theanine significantly inhibited OVA-induced mucus production and inflammatory cell infiltration in the respiratory tract and blood vessels. l-theanine administration also significantly decreased the production of IgE, monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-alpha (TNF-α), and interferon-gamma in BALF. The lung weight decreased with l-theanine administration. l-theanine also markedly attenuated the OVA-induced generation of reactive oxygen species and the activation of nuclear factor kappa B (NF-κB) and matrix metalloprotease-9 in BALF. Moreover, l-theanine reduced the TNF-α-induced NF-κB activation in A549 cells. Together, these results suggest that l-theanine alleviates airway inflammation in asthma, which likely occurs via the oxidative stress-responsive NF-κB pathway, highlighting its potential as a useful therapeutic agent for asthma management.

  20. Clinical update on the use of biomarkers of airway inflammation in the management of asthma

    Directory of Open Access Journals (Sweden)

    Dorscheid DR

    2011-06-01

    Full Text Available SJ Wadsworth1,2, DD Sin1,2, DR Dorscheid1,21UBC James Hogg Research Centre, Providence Heart and Lung Institute, St Paul's Hospital, Vancouver, Canada; 2Department of Medicine, University of British Columbia, British Columbia, CanadaAbstract: Biological markers are already used in the diagnosis and treatment of cardiovascular disease and cancer. Biomarkers have great potential use in the clinic as a noninvasive means to make more accurate diagnoses, monitor disease progression, and create personalized treatment regimes. Asthma is a heterogeneous disease with several different phenotypes, generally triggered by multiple gene-environment interactions. Pulmonary function tests are most often used objectively to confirm the diagnosis. However, airflow obstruction can be variable and thus missed using spirometry. Furthermore, lung function measurements may not reflect the precise underlying pathological processes responsible for different phenotypes. Inhaled corticosteroids and ß2-agonists have been the mainstay of asthma therapy for over 30 years, but the heterogeneity of the disease means not all asthmatics respond to the same treatment. High costs and undesired side effects of drugs also drive the need for better targeted treatment of asthma. Biomarkers have the potential to indicate an individual's disease phenotype and thereby guide clinicians in their decisions regarding treatment. This review focuses on biomarkers of airway inflammation which may help us to identify, monitor, and guide treatment of asthmatics. We discuss biomarkers obtained from multiple physiological sources, including sputum, exhaled gases, exhaled breath condensate, serum, and urine. We discuss the inherent limitations and benefits of using biomarkers in a heterogeneous disease such as asthma. We also discuss how we may modify our study designs to improve the identification and potential use of potential biomarkers in asthma.Keywords: asthma, inflammation, airway

  1. Immunomodulatory effects of Escherichia coli ATCC 25922 on allergic airway inflammation in a mouse model.

    Directory of Open Access Journals (Sweden)

    Wenhui Pang

    Full Text Available BACKGROUND: Hygiene hypothesis demonstrates that the lack of microbial exposure would promote the development of allergic airway disease (AAD. Therefore, the gut microbiota, including Escherichia coli (E. coli, would probably offer a potential strategy for AAD. OBJECTIVE: To investigate whether E. coli infection is able to suppress the induction of AAD and to elucidate the underlying mechanisms. METHODS: Nonpathogenic E. coli ATCC 25922 was infected by gavage before AAD phase in three patterns: 10(8 or 10(6 CFU in neonates or 10(8 CFU in adults. Then mice were sensitized and challenged with ovalbumin (OVA to induce allergic inflammation in both the upper and lower airways. Hallmarks of AAD, in terms of eosinophil infiltration and goblet cell metaplasia in subepithelial mucosa, Th2 skewing of the immune response, and levels of T regulate cells (Tregs, were examined by histological analysis, ELISA, and flow cytometry, respectively. RESULTS: E. coli, especially neonatally infected with an optimal dose, attenuated allergic responses, including a decrease in nasal rubbing and sneezing, a reduction in eosinophil inflammation and goblet cell metaplasia in subepithelial mucosa, decreased serum levels of OVA-specific IgE, and reduced Th2 (IL-4 cytokines. In contrast, this effect came with an increase of Th1 (IFN-r and IL-2 cytokines, and an enhancement of IL-10-secreting Tregs in paratracheal lymph nodes (PTLN. CONCLUSION: E. coli suppresses allergic responses in mice, probably via a shift from Th1 to Th2 and/or induction of Tregs. Moreover, this infection is age- and dose-dependent, which may open up novel possibilities for new therapeutic interventions.

  2. Eicosanoid Mediators in the Airway Inflammation of Asthmatic Patients: What is New?

    Science.gov (United States)

    Sanak, Marek

    2016-11-01

    Lipid mediators contribute to inflammation providing both pro-inflammatory signals and terminating the inflammatory process by activation of macrophages. Among the most significant biologically lipid mediators, these are produced by free-radical or enzymatic oxygenation of arachidonic acid named "eicosanoids". There were some novel eicosanoids identified within the last decade, and many of them are measurable in clinical samples by affordable chromatography-mass spectrometry equipment or sensitive immunoassays. In this review, we present some recent advances in understanding of the signaling by eicosanoid mediators during asthmatic airway inflammation. Eicosanoid profiling in the exhaled breath condensate, induced sputum, or their metabolites measurements in urine is complementary to the cellular phenotyping of asthmatic inflammation. Special attention is paid to aspirin-exacerbated respiratory disease, a phenotype of asthma manifested by the most profound changes in the profile of eicosanoids produced. A hallmark of this type of asthma with hypersensitivity to non-steroid anti-inflammatory drugs (NSAIDs) is to increase biosynthesis of cysteinyl leukotrienes on the systemic level. It depends on transcellular biosynthesis of leukotriene C₄ by platelets that adhere to granulocytes releasing leukotriene A₄. However, other abnormalities are also reported in this type of asthma as a resistance to anti-inflammatory activity of prostaglandin E₂ or a robust eosinophil interferon-γ response resulting in cysteinyl leukotrienes production. A novel mechanism is also discussed in which an isoprostane structurally related to prostaglandin E₂ is released into exhaled breath condensate during a provoked asthmatic attack. However, it is concluded that any single eicosanoid or even their complex profile can hardly provide a thorough explanation for the mechanism of asthmatic inflammation.

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

    Directory of Open Access Journals (Sweden)

    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

  4. Airway epithelial inflammation-induced endoplasmic reticulum Ca2+ store expansion is mediated by X-box binding protein-1.

    Science.gov (United States)

    Martino, Mary E B; Olsen, John C; Fulcher, Nanette B; Wolfgang, Matthew C; O'Neal, Wanda K; Ribeiro, Carla M P

    2009-05-29

    Inflamed cystic fibrosis (CF) human bronchial epithelia (HBE), or normal HBE exposed to supernatant from mucopurulent material (SMM) from CF airways, exhibit endoplasmic reticulum (ER)/Ca(2+) store expansion and amplified Ca(2+)-mediated inflammation. HBE inflammation triggers an unfolded protein response (UPR) coupled to mRNA splicing of X-box binding protein-1 (XBP-1). Because spliced XBP-1 (XBP-1s) promotes ER expansion in other cellular models, we hypothesized that XBP-1s is responsible for the ER/Ca(2+) store expansion in inflamed HBE. XBP-1s was increased in freshly isolated infected/inflamed CF in comparison with normal HBE. The link between airway epithelial inflammation, XBP-1s, and ER/Ca(2+) store expansion was then addressed in murine airways challenged with phosphate-buffered saline or Pseudomonas aeruginosa. P. aeruginosa-challenged mice exhibited airway epithelial ER/Ca(2+) store expansion, which correlated with airway inflammation. P. aeruginosa-induced airway inflammation triggered XBP-1s in ER stress-activated indicator (ERAI) mice. To evaluate the functional role of XBP-1s in airway inflammation linked to ER/Ca(2+) store expansion, control, XBP-1s, or dominant negative XBP-1 (DN-XBP-1) stably expressing 16HBE14o(-) cell lines were used. Studies with cells transfected with an unfolded protein response element (UPRE) luciferase reporter plasmid confirmed that the UPRE was activated or inhibited by expression of XBP-1s or DN-XBP-1, respectively. Expression of XBP-1s induced ER/Ca(2+) store expansion and potentiated bradykinin-increased interleukin (IL)-8 secretion, whereas expression of DN-XBP-1 inhibited bradykinin-dependent IL-8 secretion. In addition, expression of DN-XBP-1 blunted SMM-induced ER/Ca(2+) store expansion and SMM-induced IL-8 secretion. These findings suggest that, in inflamed HBE, XBP-1s is responsible for the ER/Ca(2+) store expansion that confers amplification of Ca(2+)-dependent inflammatory responses.

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

    Science.gov (United States)

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

    2015-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Konstantinos Samitas

    2015-12-01

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

  7. Is airway inflammation in chronic obstructive pulmonary disease (COPD) a risk factor for cardiovascular events?

    Science.gov (United States)

    Calverley, Peter M A; Scott, Stephen

    2006-12-01

    Cardiovascular disease (CVD) is a very common cause of death in patients with chronic obstructive pulmonary disease (COPD). Smoking is a well-described risk factor for both COPD and CVD, but CVD in patients with COPD is likely to be due to other factors in addition to smoking. Inflammation may be an important common etiological link between COPD and CVD, being well described in both diseases. It is hypothesized that in COPD a "spill-over" of local airway inflammation into the systemic circulation could contribute to increased CVD in these patients. Inhaled corticosteroids (ICS) have well-documented anti-inflammatory effects and are commonly used for the treatment of COPD, but their effects on cardiovascular endpoints and all-cause mortality have only just started to be examined. A recent meta-analysis has suggested that ICS may reduce all-cause mortality in COPD by around 25%. A case-controlled study specifically examined the effects of ICS on myocardial infarction and suggested that ICS may decrease the incidence of MI by as much as 32%. A large multicenter prospective randomized trial (Towards a Revolution in COPD Health [TORCH]) is now ongoing and will examine the effect of fluticasone propionate in combination with salmeterol on all-cause mortality.

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

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    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.

  9. Protective effect of curcumin on acute airway inflammation of allergic asthma in mice through Notch1-GATA3 signaling pathway.

    Science.gov (United States)

    Chong, Lei; Zhang, Weixi; Nie, Ying; Yu, Gang; Liu, Liu; Lin, Li; Wen, Shunhang; Zhu, Lili; Li, Changchong

    2014-10-01

    Curcumin, a natural product derived from the plant Curcuma longa, has been found to have anti-inflammatory, antineoplastic and antifibrosis effects. It has been reported that curcumin attenuates allergic airway inflammation in mice through inhibiting NF-κB and its downstream transcription factor GATA3. It also has been proved the antineoplastic effect of curcumin through down-regulating Notch1 receptor and its downstream nuclear transcription factor NF-κB levels. In this study, we aimed to investigate the anti-inflammatory effect of curcumin on acute allergic asthma and its underlying mechanisms. 36 male BALB/c mice were randomly divided into four groups (normal, asthma, asthma+budesonide and asthma+curcumin groups). BALF (bronchoalveolar lavage fluid) and lung tissues were analyzed for airway inflammation and the expression of Notch1, Notch2, Notch3, Notch4 and the downstream transcription factor GATA3. Our findings showed that the levels of Notch1 and Notch2 receptors were up-regulated in asthma group, accompanied by the increased expression of GATA3. But the expression of Notch2 receptor was lower than Notch1 receptor. Curcumin pretreatment improved the airway inflammatory cells infiltration and reversed the increasing levels of Notch1/2 receptors and GATA3. Notch3 receptor was not expressed in all of the four groups. Notch4 receptor protein and mRNA expression level in the four groups had no significant differences. The results of the present study suggested that Notch1 and Notch2 receptor, major Notch1 receptor, played an important role in the development of allergic airway inflammation and the inhibition of Notch1-GATA3 signaling pathway by curcumin can prevent the development and deterioration of the allergic airway inflammation. This may be a possible therapeutic option of allergic asthma.

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

    Science.gov (United States)

    George, Tresa; Bell, Matthew; Chakraborty, Mainak; Siderovski, David P.; Giembycz, Mark A.

    2017-01-01

    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. PMID:28107494

  11. 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

    and fibroblasts, acrolein and CS extract evoked IL-8 release, a response selectively reduced by TRPA1 antagonists. Capsaicin, agonist of the transient receptor potential vanilloid 1 (TRPV1), a channel co-expressed with TRPA1 by airway sensory nerves, and acrolein or CS (TRPA1 agonists), or the neuropeptide...... substance P (SP), which is released from sensory nerve terminals by capsaicin, acrolein or CS), produced neurogenic inflammation in mouse airways. However, only acrolein and CS, but not capsaicin or SP, released the keratinocyte chemoattractant (CXCL-1/KC, IL-8 analogue) in bronchoalveolar lavage (BAL...

  12. Oxidative stress–induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease

    Science.gov (United States)

    Wiegman, Coen H.; Michaeloudes, Charalambos; Haji, Gulammehdi; Narang, Priyanka; Clarke, Colin J.; Russell, Kirsty E.; Bao, Wuping; Pavlidis, Stelios; Barnes, Peter J.; Kanerva, Justin; Bittner, Anton; Rao, Navin; Murphy, Michael P.; Kirkham, Paul A.; Chung, Kian Fan; Adcock, Ian M.; Brightling, Christopher E.; Davies, Donna E.; Finch, Donna K.; Fisher, Andrew J.; Gaw, Alasdair; Knox, Alan J.; Mayer, Ruth J.; Polkey, Michael; Salmon, Michael; Singh, David

    2015-01-01

    Background Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology. Objective We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. Methods Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. Results Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release. Conclusions Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell

  13. Effect of All-trans Retinoic Acid on Airway Inflammation in Asthmatic Rats and Its Mechanism

    Institute of Scientific and Technical Information of China (English)

    方红; 金红芳; 王宏伟

    2004-01-01

    Summary: The inhibitive effects of all-trans retinoic acid (ARTA) on airway inflammation in asthmatic rats and its mechanism on the basis of the regulation of nuclear factor kappaB (NF-κB) were explored. Thirty-two SD rats were randomly divided into 4 groups: control group, asthma group,dexamethasone treatment group and retinotic acid treatment group. The total and differential cell counts in the collected bronchoalveolar lavage fluid (BALF) were measured. The pathological changes in lung tissues were estimated by scoring. The expression of NF-κB inhibitor (IκBa), NF-κB,intercellular adhering molecule-1 (ICAM-1) in lung tissue was detected by immunohistochemical method. The results showed that in the two treatment groups, the total cell counts and proportion of inflammatory cells in BALF were significantly reduced, but there was no significant difference in differential cell counts in BALF between, them. The pathological changes in lung tissues in the treatment groups were significantly attenuated as compared with asthma group. Except the epithelial injury in retinotic acid treatment group was milder than in dexamethasone treatment group, the remaining lesions showed no significant difference between them. In the two treatment groups, the expression of IκBa was increased, while the expression of NF-κB and ICAM-1 decreased with the difference between the two groups being not significant. It was concluded that the similar anti-inflammatory effects and mechanism of ATRA on airway in asthmatic rats to those of dexamethasone were contributed to the increase of cytoplasmic IκBa content and suppression of NF-cB activation and expression.

  14. Protein kinase C epsilon is important in modulating organic-dust-induced airway inflammation.

    Science.gov (United States)

    Poole, Jill A; Romberger, Debra J; Bauer, Chris; Gleason, Angela M; Sisson, Joseph H; Oldenburg, Peter J; West, William W; Wyatt, Todd A

    2012-10-01

    Organic dust samples from swine confinement facilities elicit pro-inflammatory cytokine/chemokine release from bronchial epithelial cells and monocytes, dependent, in part, upon dust-induced activation of the protein kinase C (PKC) isoform, PKCε. PKCε is also rapidly activated in murine tracheal epithelial cells following in vivo organic dust challenges, yet the functional role of PKCε in modulating dust-induced airway inflammatory outcomes is not defined. Utilizing an established intranasal inhalation animal model, experiments investigated the biologic and physiologic responses following organic dust extract (ODE) treatments in wild-type (WT) and PKCε knock-out (KO) mice. We found that neutrophil influx increased more than twofold in PKCε KO mice following both a one-time challenge and 3 weeks of daily challenges with ODE as compared with WT mice. Lung pathology revealed increased bronchiolar and alveolar inflammation, lymphoid aggregates, and T cell influx in ODE-treated PKCε KO mice. Airway hyperresponsiveness to methacholine increased in PKCε KO + ODE to a greater magnitude than WT + ODE animals. There were no significant differences in cytokine/chemokine release elicited by ODE treatment between groups. However, ODE-induced nitric oxide (NO) production differed in that ODE exposure increased nitrate levels in WT mice but not in PKCε KO mice. Moreover, ODE failed to upregulate NO from ex vivo stimulated PKCε KO lung macrophages. Collectively, these studies demonstrate that PKCε-deficient mice were hypersensitive to organic dust exposure and suggest that PKCε is important in the normative lung inflammatory response to ODE. Dampening of ODE-induced NO may contribute to these enhanced inflammatory findings.

  15. Inhibitory effect of hydrogen sulfide on ozone-induced airway inflammation, oxidative stress, and bronchial hyperresponsiveness.

    Science.gov (United States)

    Zhang, Pengyu; Li, Feng; Wiegman, Coen H; Zhang, Min; Hong, Yan; Gong, Jicheng; Chang, Yan; Zhang, Junfeng Jim; Adcock, Ian; Chung, Kian Fan; Zhou, Xin

    2015-01-01

    Exposure to ozone has been associated with airway inflammation, oxidative stress, and bronchial hyperresponsiveness. The goal of this study was to examine whether these adverse effects of ozone could be prevented or reversed by hydrogen sulfide (H2S) as a reducing agent. The H2S donor sodium (NaHS) (2 mg/kg) or vehicle (PBS) was intraperitoneally injected into mice 1 hour before and after 3-hour ozone (2.5 ppm) or air exposure, and the mice were studied 24 hours later. Preventive and therapeutic treatment with NaHS reduced the ozone-induced increases in the total cells, including neutrophils and macrophages; this treatment also reduced levels of cytokines, including TNF-α, chemokine (C-X-C motif) ligand 1, IL-6, and IL-1β levels in bronchial alveolar lavage fluid; inhibited bronchial hyperresponsiveness; and attenuated ozone-induced increases in total malondialdehyde in bronchoalveolar lavage fluid and decreases in the ratio of reduced glutathione/oxidized glutathione in the lung. Ozone exposure led to decreases in the H2S production rate and in mRNA and protein levels of cystathionine-β-synthetase and cystathionine-γ-lyase in the lung. These effects were prevented and reversed by NaHS treatment. Furthermore, NaHS prevented and reversed the phosphorylation of p38 mitogen-activated protein kinase and heat shock protein 27. H2S may have preventive and therapeutic value in the treatment of airway diseases that have an oxidative stress basis.

  16. Role of neutrophilic inflammation in ozone-induced epithelial alterations in the nasal airways of rats

    Science.gov (United States)

    Cho, Hye Youn

    Ozone is a principal oxidant air pollutant in photochemical smog. Epithelial cells lining the centriacinar region of lung and the proximal aspects of nasal passage are primary target sites for ozone-induced injury in laboratory animals. Acute exposure of rats to high ambient concentrations of ozone (e.g., 0.5 ppm) results in neutrophilic inflammation, epithelial hyperplasia and mucous cell metaplasia (MCM) in the nasal transitional epithelium (NTE) lining the proximal nasal airways. The principal purpose of the present study was to investigate the role of pre-metaplastic cellular responses, especially neutrophilic inflammation, in the pathogenesis of ozone-induced MCM in rat NTE. For this purpose, three specific hypotheses-based whole-animal inhalation studies were conducted. Male F344/N rats were exposed in whole-body inhalation chambers to 0 (filtered air) or 0.5 ppm ozone for 1-3 days (8 h/day). Histochemical, immunochemical, molecular and morphometric techniques were used to investigate the ozone-induced cellular and molecular events in the NTE. Two in vitro studies were also conducted to examine the effects of ozone-inducible cytokines (i.e., tumor necrosis factor-alpha; TNF- a, and interleukin-6; IL-6) on mucin gene (rMuc-5AC) expression. Ozone induced a rapid increase of rMuc-5AC mRNA in nasal tissues within hours after the start of exposure. It preceded the appearance of MCM, and persisted with MCM. Ozone-induced neutrophilic inflammation accompanied the mucin gene upregulation, but was resolved when MCM first appeared in the NTE. Antibody-mediated depletion of circulating neutrophils attenuated ozone-induced MCM, although it did not affect the ozone-induced epithelial hyperplasia and mucin mRNA upregulation. In another study, it was found that preexisting neutrophilic rhinitis induced by endotoxin augmented the ozone-induced MCM. However, pre-existing rhinitis did not alter the severity of ozone-induced epithelial hyperplasia and mucin gene upregulation

  17. TCDD-Induced Activation of Aryl Hydrocarbon Receptor Inhibits Th17 Polarization and Regulates Non-Eosinophilic Airway Inflammation in Asthma

    OpenAIRE

    Xiao-ming Li; Juan Peng; Wen Gu; Xue-jun Guo

    2016-01-01

    The aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family, has recently been demonstrated to regulate T cell differentiation. Whether AhR activation participates in allergic airway inflammation remains unknown. In the current study, using a non-eosinophilic asthma model, we demonstrate that 2, 3, 7, 8-tetrachlorodibenzo-P-dioxin (TCDD), a potent AhR ligand, reduced the airway infiltration of neutrophils, airway hyperresponsiveness and Th17 cytokine expression. Further...

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

    Directory of Open Access Journals (Sweden)

    Smitha Kumar

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

  19. Intranasal organic dust exposure-induced airway adaptation response marked by persistent lung inflammation and pathology in mice

    OpenAIRE

    Poole, Jill A.; Wyatt, Todd A; Oldenburg, Peter J.; Elliott, Margaret K.; West, William W.; Sisson, Joseph H.; Von Essen, Susanna G.; Romberger, Debra J.

    2009-01-01

    Organic dust exposure in agricultural environments results in an inflammatory response that attenuates over time, but repetitive exposures can result in chronic respiratory disease. Animal models to study these mechanisms are limited. This study investigated the effects of single vs. repetitive dust-induced airway inflammation in mice by intranasal exposure method. Mice were exposed to swine facility dust extract (DE) or saline once and once daily for 1 and 2 wk. Dust exposure resulted in inc...

  20. Anti-HMGB1 Neutralizing Antibody Ameliorates Neutrophilic Airway Inflammation by Suppressing Dendritic Cell-Mediated Th17 Polarization

    Directory of Open Access Journals (Sweden)

    Fang Zhang

    2014-01-01

    Full Text Available We demonstrate that high mobility group box 1 protein (HMGB1 directs Th17 skewing by regulating dendritic cell (DC function. First, our in vitro studies reveal that recombinant HMGB1 (rHMGB1 activates myeloid DCs to produce IL-23 in vitro, and rHMGB1-activated DCs prime naïve lymphocytes to produce the Th17 cytokine IL-17A. Second, we demonstrate that anti-HMGB1 neutralizing antibody attenuates HMGB1 expression, neutrophilic inflammation, airway hyperresponsiveness, and Th17-related cytokine secretion in vivo by using a murine model of neutrophilic asthma induced by ovalbumin (OVA plus lipopolysaccharide (LPS. Furthermore, anti-HMGB1 neutralizing antibody decreases the number of Th17 cells in lung cells and suppresses the production of IL-23 by lung CD11C+ APCs. Finally, we show that intranasal adoptive transfer of rHMGB1-activated DCs was sufficient to restore lung neutrophilic inflammation and the Th17 response in a DC-driven model of asthma, whereas the transfer of rHMGB1 plus anti-HMGB1-treated mDCs significantly reduced these inflammation phenotypes. These data suggest, for the first time, that HMGB1 drives the DC-polarized Th17-type response in allergic lung inflammation and that blocking HMGB1 may benefit the attenuation of neutrophilic airway inflammation in asthma.

  1. Lung Function, Airway Inflammation, and Polycyclic Aromatic Hydrocarbons Exposure in Mexican Schoolchildren

    Science.gov (United States)

    Barraza-Villarreal, Albino; Escamilla-Nuñez, Maria Consuelo; Schilmann, Astrid; Hernandez-Cadena, Leticia; Li, Zheng; Romanoff, Lovisa; Sjödin, Andreas; Del Río-Navarro, Blanca Estela; Díaz-Sanchez, David; Díaz-Barriga, Fernando; Sly, Peter; Romieu, Isabelle

    2015-01-01

    Objective To determine the association of exposure to polycyclic aromatic hydrocarbons (PAHs) with lung function and pH of exhaled breath condensate (EBC) in Mexican schoolchildren. Methods A pilot study was performed in a subsample of 64 schoolchildren from Mexico City. Lung function and pH of EBC were measured and metabolites of PAHs in urine samples were determined. The association was analyzed using robust regression models. Results A 10% increase in the concentrations of 2-hydroxyfluorene was significantly negatively associated with forced expiratory volume in 1 second (−11.2 mL, 95% CI: −22.2 to −0.02), forced vital capacity (−11.6 mL, 95% CI: −22.9 to −0.2), and pH of EBC (−0.035, 95% CI: −0.066 to −0.005). Conclusion Biomarkers of PAHs exposure were inversely associated with lung function and decrease of ph of EBC as a marker of airway inflammation in Mexican schoolchildren. PMID:24500378

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

    Science.gov (United States)

    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.

  3. Airway inflammation, cough and athlete quality of life in elite female cross-country skiers: A longitudinal study.

    Science.gov (United States)

    Kennedy, M D; Davidson, W J; Wong, L E; Traves, S L; Leigh, R; Eves, N D

    2016-07-01

    The aim of this study was to investigate the effect of a season of cross-country training and racing on airway inflammation, cough symptoms, and athlete quality of life in female skiers. Eighteen elite female skiers performed sputum induction and completed the Leicester Cough Questionnaire (LCQ) and the Recovery-Stress Questionnaire (REST-Q) at three time points (T1 - May/Jun, T2 - Oct/Nov, T3 - Jan-Mar) during the year. No changes were observed between T1 and T2. However, an increase in sputum eosinophils and lymphocytes (P < 0.05) and a significant change in all three domains of the LCQ were observed between T1 and T3 (P < 0.05). A significant association was found between the total yearly hours of training and the change in the total cell count (r(2)  = 0.74; P = 0.006), and a number of other sputum cell counts between T1 and T3. No changes were observed for any domain of the REST-Q. The results of this study demonstrate that airway inflammation and cough symptoms are significantly increased in elite female cross-country skiers across a year of training and racing. The increase in airway inflammation is related to the total amount of training and is worse during the winter months when athletes are training and racing in cold, dry air.

  4. Role of neutralizing anti-murine interleukin-17A monoclonal antibody on chronic ozone-induced airway inflammation in mice.

    Science.gov (United States)

    Zhang, Min; Fei, Xia; Zhang, Guo-Qing; Zhang, Peng-Yu; Li, Feng; Bao, Wu-Ping; Zhang, Ying-Ying; Zhou, Xin

    2016-10-01

    Exposure to ozone has led to airway inflammation and airway hyperresponsiveness, which potential mechanisms relate to ozone-induced oxidative stress. IL-17 is a growing target for autoimmune and inflammatory diseases. The aim of the study was to examine the inhibitory effects of anti-murine interleukin-17A monoclonal antibody (IL-17mAb) on adverse effects of ozone which are noted above. After C57/BL6 mice were exposed to ozone (2.5ppm; 3h) for 12 times over 6 weeks, IL-17mAb, PBS was intraperitoneally injected into mice 1h after ozone or air exposure for 6 weeks and mice were studied 24h after final exposure, monitoring bronchial responsiveness, airway inflammatory cells, lung histology, levels of neutrophil-related chemokine and proinflammatory cytokines in bronchoalveolar lavage (BAL) fluid and serum, the expression of IL-17A mRNA and protein, glucocorticoid receptors (GR), and the phosphorylation of p38MAPK in lung tissues. The administration of IL-17mAb reduced the ozone-induced increases in total cells, especially neutrophils; decreased levels of cytokines, including IL-8 in BAL fluid, IL-8 and IL-17A in serum; mitigated the severity of airway hyperresponsiveness; attenuated lung inflammation scores and histologic analysis confirmed the suppression of lung inflammation, compared with the administration of a control PBS. Exposure to ozone results in increases in IL-17A production rate, mRNA and protein levels of IL-17A and the protein level of GR. These effects were halted and reversed by IL-17mAb treatment. Furthermore, IL-17mAb also reduced the phosphorylation of p38MAPK. Therefore, we conclude that IL-17mAb may be a useful therapy in ozone-related diseases, including COPD.

  5. Maternal Disononyl Phthalate Exposure Activates Allergic Airway Inflammation via Stimulatingthe Phosphoinositide 3-kinase/Akt Pathway in Rat Pups

    Institute of Scientific and Technical Information of China (English)

    CHEN Li; CHEN Jiao; XIE ChangMing; ZHAO Yan; WANG Xiu; andZHANG YunHui

    2015-01-01

    ObjectiveTo evaluate the effectof diisononyl phthalate (DINP) exposure during gestation and lacta-tion on allergic response in pups and to explore the role of phosphoinositide 3-kinase/Akt pathway on it. MethodsFemale Wistar rats were treated with DINP at different dosages (0, 5, 50,and 500 mg/kg of body weight per day). The pups were sensitized and challenged by ovalbumin (OVA). The airway response was assessed; the airway histological studies were performed by hematoxylin and eosin (HE) staining; and the relative cytokines in phosphoinositide 3-kinase (PI3K)/Akt pathway were measured by enzyme-linked immunosorbent assay (ELISA) and western blot analysis. ResultsThere was no significant difference in DINP’s effect on airway hyperresponsiveness (AHR) between male pups and female pups. In the 50 mg/(kg·d) DINP-treated group, airway response to OVA significantly increased and pups showed dramatically enhanced pulmonary resistance (RI) compared with those from controls (P<0.05). Enhanced Akt phosphorylation and NF-κB translocation, and Th2 cytokines expression were observed in pups of 50 mg/(kg·d) DINP-treated group. However, in the 5 and 500 mg/(kg·d) DINP-treated pups, no significant effects were observed. ConclusionTherewas an adjuvant effect of DINP on allergic airway inflammation in pups. Maternal DINP exposure could promote OVA-induced allergic airway response in pups in part by upregulation of PI3K/Akt pathway.

  6. Air Pollution, Airway Inflammation, and Lung Function in a Cohort Study of Mexico City Schoolchildren

    Science.gov (United States)

    Barraza-Villarreal, Albino; Sunyer, Jordi; Hernandez-Cadena, Leticia; Escamilla-Nuñez, Maria Consuelo; Sienra-Monge, Juan Jose; Ramírez-Aguilar, Matiana; Cortez-Lugo, Marlene; Holguin, Fernando; Diaz-Sánchez, David; Olin, Anna Carin; Romieu, Isabelle

    2008-01-01

    Background The biological mechanisms involved in inflammatory response to air pollution are not clearly understood. Objective In this study we assessed the association of short-term air pollutant exposure with inflammatory markers and lung function. Methods We studied a cohort of 158 asthmatic and 50 nonasthmatic school-age children, followed an average of 22 weeks. We conducted spirometric tests, measurements of fractional exhaled nitric oxide (FeNO), interleukin-8 (IL-8) in nasal lavage, and pH of exhaled breath condensate every 15 days during follow-up. Data were analyzed using linear mixed-effects models. Results An increase of 17.5 μg/m3 in the 8-hr moving average of PM2.5 levels (interquartile range) was associated with a 1.08-ppb increase in FeNO [95% confidence interval (CI), 1.01–1.16] and a 1.07-pg/mL increase in IL-8 (95% CI 0.98–1.19) in asthmatic children and a 1.16 pg/ml increase in IL-8 (95% CI, 1.00–1.36) in nonasthmatic children. The 5-day accumulated average of exposure to particulate matter < 2.5 μm in aerodynamic diamter (PM2.5) was significantly inversely associated with forced expiratory volume in 1 sec (FEV1) (p = 0.048) and forced vital capacity (FVC) (p = 0.012) in asthmatic children and with FVC (p = 0.021) in nonasthmatic children. FeNO and FEV1 were inversely associated (p = 0.005) in asthmatic children. Conclusions Exposure to PM2.5 resulted in acute airway inflammation and decrease in lung function in both asthmatic and nonasthmatic children. PMID:18560490

  7. Glyphosate-rich air samples induce IL-33, TSLP and generate IL-13 dependent airway inflammation.

    Science.gov (United States)

    Kumar, Sudhir; Khodoun, Marat; Kettleson, Eric M; McKnight, Christopher; Reponen, Tiina; Grinshpun, Sergey A; Adhikari, Atin

    2014-11-01

    Several low weight molecules have often been implicated in the induction of occupational asthma. Glyphosate, a small molecule herbicide, is widely used in the world. There is a controversy regarding a role of glyphosate in developing asthma and rhinitis among farmers, the mechanism of which is unexplored. The aim of this study was to explore the mechanisms of glyphosate induced pulmonary pathology by utilizing murine models and real environmental samples. C57BL/6, TLR4-/-, and IL-13-/- mice inhaled extracts of glyphosate-rich air samples collected on farms during spraying of herbicides or inhaled different doses of glyphosate and ovalbumin. The cellular response, humoral response, and lung function of exposed mice were evaluated. Exposure to glyphosate-rich air samples as well as glyphosate alone to the lungs increased: eosinophil and neutrophil counts, mast cell degranulation, and production of IL-33, TSLP, IL-13, and IL-5. In contrast, in vivo systemic IL-4 production was not increased. Co-administration of ovalbumin with glyphosate did not substantially change the inflammatory immune response. However, IL-13-deficiency resulted in diminished inflammatory response but did not have a significant effect on airway resistance upon methacholine challenge after 7 or 21 days of glyphosate exposure. Glyphosate-rich farm air samples as well as glyphosate alone were found to induce pulmonary IL-13-dependent inflammation and promote Th2 type cytokines, but not IL-4 for glyphosate alone. This study, for the first time, provides evidence for the mechanism of glyphosate-induced occupational lung disease.

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

    Science.gov (United States)

    Elhaik Goldman, Shirin; Moshkovits, Itay; Shemesh, Avishai; Filiba, Ayelet; Tsirulsky, Yevgeny; Vronov, Elena; Shagan, Marilou; Apte, Ron N.; Benharroch, D aniel; Karo-Atar, Danielle; Dagan, Ron; Munitz, Ariel

    2016-01-01

    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. PMID:27580126

  9. Prevention of Antigen-Induced Bronchial Hyperreactivity and Airway Inflammation in Sensitized Guinea-Pigs by Tacrolimus

    Directory of Open Access Journals (Sweden)

    J. R. Lapa e Silva

    1999-01-01

    Full Text Available We examined the effect of the immunosuppressive agent, tacrolimus (FK506, on antigen-induced bronchial hyperreactivity to acetylcholine and leukocyte infiltration into the airways of ovalbumin-challenged guinea-pigs. Subcutaneous injection of 0.5 mg/kg of FK506, 1 h before and 5 h after intra-nasal antigen challenge prevented bronchial hyperreactivity to aerosolized acetylcholine, eosinophilia in bronchoalveolar lavage (BAL fluid and bronchial tissue and the invasion of the bronchial wall by CD4+ T-lymphocytes. FK506 also suppressed ovalbumininduced increase in the number of leukocytes adhering to the pulmonary vascular endothelium and expressing α4-integrins. Inhibition by FK506 of antigen-induced bronchial hyperreactivity in sensitized guinea-pigs may thus relate to its ability to prevent the emergence of important inflammatory components of airway inflammation, such as eosinophil accumulation, as well as CD4+ T-lymphocyte infiltration into the bronchial tissue.

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

    Institute of Scientific and Technical Information of China (English)

    Jing Li; Li Luo; Xiaoyun Wang; Bin Liao; Guoping Li

    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 Andrographolide. Hyper-responsiveness was recorded. The lung tissues were assessed by histological examinations. NF-κB in lung was determined by immunofluorescence staining and Western blotting. Treatment of mice with Androqrapholide displayed lower Penh in response to asthma group mice. After treatment with Andrographolide, the extent of inflammation and cellular infltrafion in the airway were reduced. Andrographolide interrupted NF-κB to express in cell nucleus. The level of NF-κB expression was inhibited by Andrographolide. The data indicate that Andrographolide from traditional Chinese herbal medicines could inhibit extensive infiltration of inflammatory cells in lung and decrease airway hyperreactivity. Andrographolide could inhibit NF-κB expression in lung and suppress NF-κB expressed in the nucleus of airway epithelial cells. Cellular & Molecular Immunology. 2009;6(5):381-385.

  11. Distinct PKA and Epac compartmentalization in airway function and plasticity

    NARCIS (Netherlands)

    Dekkers, Bart G. J.; Racke, Kurt; Schmidt, Martina

    2013-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are obstructive lung diseases characterized by airway obstruction, airway inflammation and airway remodelling. Next to inflammatory cells and airway epithelial cells, airway mesenchymal cells, including airway smooth muscle cells and (myo)fibro

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    Initiative for Asthma guidelines were measured in addition to the health-related quality-of-life score using the Juniper asthma quality-of-life questionnaire. Findings Both ABR to mannitol as well as to methacholine was associated with elevated markers of airway inflammation: in 83% of asthma patients...... with AHR to mannitol, and in 88% of asthma patients with AHR to methacholine, the eNO level was > 20 p.p.b. Sputum% eosinophils >1% was measured in 70% of asthma patients with AHR to mannitol and in 77% of asthma patients with AHR to methacholine. In asthma patients without AHR, 15% had an eNO level >20p......, 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 patients not being treated with steroids, AHR to mannitol...

  13. Nose-only water-pipe smoking effects on airway resistance, inflammation, and oxidative stress in mice.

    Science.gov (United States)

    Nemmar, Abderrahim; Raza, Haider; Yuvaraju, Priya; Beegam, Sumaya; John, Annie; Yasin, Javed; Hameed, Rasheed S; Adeghate, Ernest; Ali, Badreldin H

    2013-11-01

    Water-pipe smoking (WPS) is a common practice in the Middle East and is now gaining popularity in Europe and the United States. However, there is a limited number of studies on the respiratory effects of WPS. More specifically, the underlying pulmonary pathophysiological mechanisms related to WPS exposure are not understood. Presently, we assessed the respiratory effects of nose-only exposure to mainstream WPS generated by commercially available honey flavored "moasel" tobacco. The duration of the session was 30 min/day and 5 days/wk for 1 mo. Control mice were exposed to air only. Here, we measured in BALB/c mice the airway resistance using forced-oscillation technique. Lung inflammation was assessed histopathologically and by biochemical analysis of bronchoalveolar lavage (BAL) fluid, and oxidative stress was evaluated biochemically by measuring lipid peroxidation, reduced glutathione and several antioxidant enzymes. Pulmonary inflammation assessment showed an increase in neutrophil and lymphocyte numbers. Likewise, airway resistance was significantly increased in the WPS group compared with controls. Tumor necrosis factor α and interleukin 6 concentrations were significantly increased in BAL fluid. Lipid peroxidation in lung tissue was significantly increased whereas the level and activity of antioxidants including reduced glutathione, glutathione S transferase, and superoxide dismutase were all significantly decreased following WPS exposure, indicating the occurrence of oxidative stress. Moreover, carboxyhemoglobin levels were significantly increased in the WPS group. We conclude that 1-mo nose-only exposure to WPS significantly increased airway resistance, inflammation, and oxidative stress. Our results provide a mechanistic explanation for the limited clinical studies that reported the detrimental respiratory effects of WPS.

  14. P2X7 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke.

    Directory of Open Access Journals (Sweden)

    Suffwan Eltom

    Full Text Available Chronic Obstructive Pulmonary Disease (COPD is a cigarette smoke (CS-driven inflammatory airway disease with an increasing global prevalence. Currently there is no effective medication to stop the relentless progression of this disease. It has recently been shown that an activator of the P2X7/inflammasome pathway, ATP, and the resultant products (IL-1β/IL-18 are increased in COPD patients. The aim of this study was to determine whether activation of the P2X7/caspase 1 pathway has a functional role in CS-induced airway inflammation. Mice were exposed to CS twice a day to induce COPD-like inflammation and the role of the P2X7 receptor was investigated. We have demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation, (increased caspase 1 activity and release of IL-1β/IL-18 in the lungs. A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were non-functional attenuated caspase 1 activation, IL-1β release and airway neutrophilia. Furthermore, we demonstrated that the role of this pathway was not restricted to early stages of disease development by showing increased caspase 1 activation in lungs from a more chronic exposure to CS and from patients with COPD. This translational data suggests the P2X7/Inflammasome pathway plays an ongoing role in disease pathogenesis. These results advocate the critical role of the P2X7/caspase 1 axis in CS-induced inflammation, highlighting this as a possible therapeutic target in combating COPD.

  15. Intratracheal therapy with autologous bone marrow-derived mononuclear cells reduces airway inflammation in horses with recurrent airway obstruction.

    Science.gov (United States)

    Barussi, Fernanda C M; Bastos, Fernanda Z; Leite, Lidiane M B; Fragoso, Felipe Y I; Senegaglia, Alexandra C; Brofman, Paulo R S; Nishiyama, Anita; Pimpão, Cláudia T; Michelotto, Pedro V

    2016-10-01

    This research evaluated the effects of bone marrow-derived mononuclear cells (BMMCs) on the inflammatory process in the equine recurrent airway obstruction (RAO). Eight horses in RAO clinical score were divided into cell therapy group (Gcel) treated with a single intratracheal dose of BMMCs, and dexamethasone group (Gdex) treated with 21days of oral dexamethasone. The horses were clinically revaluated on days 7 and 21, together with cytological evaluation of the BALF, and detection of inflammatory markers (interleukins [IL]-10, -4, and -17, and interferon γ and α). There were decreases in respiratory effort and clinical score on days 7 and 21(p<0.05) for both groups. The percentage of neutrophils decreased and macrophages increased on days 7 and 21 (p<0.005) in both groups. IL-10 levels increased in the Gcel group on day 21 compared to days 0 and 7 (p<0.05), but this was not observed in the Gdex group. The quantification of IL-4, IL-17, IFN-γ, and IFN-α did not change between evaluations in both groups. These preliminary results suggest that BMMCs may ameliorate the inflammatory response of RAO.

  16. TCDD-Induced Activation of Aryl Hydrocarbon Receptor Inhibits Th17 Polarization and Regulates Non-Eosinophilic Airway Inflammation in Asthma.

    Directory of Open Access Journals (Sweden)

    Xiao-ming Li

    Full Text Available The aryl hydrocarbon receptor (AhR, a transcription factor of the bHLH/PAS family, has recently been demonstrated to regulate T cell differentiation. Whether AhR activation participates in allergic airway inflammation remains unknown. In the current study, using a non-eosinophilic asthma model, we demonstrate that 2, 3, 7, 8-tetrachlorodibenzo-P-dioxin (TCDD, a potent AhR ligand, reduced the airway infiltration of neutrophils, airway hyperresponsiveness and Th17 cytokine expression. Furthermore, stimulation with TCDD promoted Treg differentiation and inhibited Th17 differentiation. However, the maturation of dendritic cells may not be inhibited by AhR activation. This study thus indicates a critical role of TCDD-induced AhR activation in the regulation of non-eosinophilic airway inflammation.

  17. Soluble Fibre Meal Challenge Reduces Airway Inflammation and Expression of GPR43 and GPR41 in Asthma

    Science.gov (United States)

    Halnes, Isabel; Baines, Katherine J.; Berthon, Bronwyn S.; MacDonald-Wicks, Lesley K.; Gibson, Peter G.; Wood, Lisa G.

    2017-01-01

    Short chain fatty acids (SCFAs) are produced following the fermentation of soluble fibre by gut bacteria. In animal models, both dietary fibre and SCFAs have demonstrated anti-inflammatory effects via the activation of free fatty acid receptors, such as G protein-coupled receptor 41 and 43 (GPR41 and GPR43). This pilot study examined the acute effect of a single dose of soluble fibre on airway inflammation—including changes in gene expression of free fatty acid receptors—in asthma. Adults with stable asthma consumed a soluble fibre meal (n = 17) containing 3.5 g inulin and probiotics, or a control meal (n = 12) of simple carbohydrates. Exhaled nitric oxide (eNO) was measured and induced sputum was collected at 0 and 4 h for differential cell counts, measurement of interleukin-8 (IL-8) protein concentration, and GPR41 and GPR43 gene expression. At 4 h after meal consumption, airway inflammation biomarkers, including sputum total cell count, neutrophils, macrophages, lymphocytes, sputum IL-8, and eNO significantly decreased compared to baseline in the soluble fibre group only. This corresponded with upregulated GPR41 and GPR43 sputum gene expression and improved lung function in the soluble fibre group alone. Soluble fibre has acute anti-inflammatory effects in asthmatic airways. Long-term effects of soluble fibre as an anti-inflammatory therapy in asthma warrants further investigation. PMID:28075383

  18. Soluble Fibre Meal Challenge Reduces Airway Inflammation and Expression of GPR43 and GPR41 in Asthma

    Directory of Open Access Journals (Sweden)

    Isabel Halnes

    2017-01-01

    Full Text Available Short chain fatty acids (SCFAs are produced following the fermentation of soluble fibre by gut bacteria. In animal models, both dietary fibre and SCFAs have demonstrated anti-inflammatory effects via the activation of free fatty acid receptors, such as G protein-coupled receptor 41 and 43 (GPR41 and GPR43. This pilot study examined the acute effect of a single dose of soluble fibre on airway inflammation—including changes in gene expression of free fatty acid receptors—in asthma. Adults with stable asthma consumed a soluble fibre meal (n = 17 containing 3.5 g inulin and probiotics, or a control meal (n = 12 of simple carbohydrates. Exhaled nitric oxide (eNO was measured and induced sputum was collected at 0 and 4 h for differential cell counts, measurement of interleukin-8 (IL-8 protein concentration, and GPR41 and GPR43 gene expression. At 4 h after meal consumption, airway inflammation biomarkers, including sputum total cell count, neutrophils, macrophages, lymphocytes, sputum IL-8, and eNO significantly decreased compared to baseline in the soluble fibre group only. This corresponded with upregulated GPR41 and GPR43 sputum gene expression and improved lung function in the soluble fibre group alone. Soluble fibre has acute anti-inflammatory effects in asthmatic airways. Long-term effects of soluble fibre as an anti-inflammatory therapy in asthma warrants further investigation.

  19. Dual effects of respiratory syncytial virus infections on airway inflammation by regulation of Th17/Treg responses in ovalbumin-challenged mice.

    Science.gov (United States)

    Wang, Jia; Kong, Lingwen; Luo, Qingli; Li, Bei; Wu, Jinfeng; Liu, Baojun; Wu, Xiao; Dong, Jingcheng

    2014-12-01

    We investigated the effects of respiratory syncytial virus (RSV) infections on ovalbumin (OVA)-challenged mice via regulation of Th17/Treg cell responses. BALB/c mice were challenged with OVA, followed by RSV infections twice. In OVA-challenged mice, the secretion of Th2/Th17-type cytokines, airway hyperresponsiveness and inflammation were significantly inhibited by initial RSV infection. Moreover, the in vivo findings demonstrated that initial RSV infection reversed the imbalance of Th17/Treg responses. In contrast, RSV re-infection strengthened Th2/Th17-type cytokine secretion, airway hyperresponsiveness, and inflammation, especially for lymphocyte infiltration in OVA-challenged mice. Meanwhile, RSV re-infection enhanced the imbalanced Th17/Treg responses. Upon all results reveal that RSV-induced respiratory infections may lead to dual effects pertaining to allergic airway inflammation by regulation of Th17/Treg responses.

  20. IL-25 and IL-33 Contribute to Development of Eosinophilic Airway Inflammation in Epicutaneously Antigen-Sensitized Mice.

    Directory of Open Access Journals (Sweden)

    Hideaki Morita

    Full Text Available IL-25, IL-33 and TSLP are produced predominantly by epithelial cells and are known to induce Th2-type cytokines. Th2-type cytokines are involved not only in host defense against nematodes, but also in the development of Th2-type allergic diseases. TSLP was reported to be crucial for development of allergic airway inflammation in mice after inhalation of allergens to which they had been sensitized epicutaneously (EC beforehand. However, the roles of IL-25 and IL-33 in the setting remain unclear.Mice deficient in IL-25 and IL-33 were sensitized EC with ovalbumin (OVA and then challenged intranasally with OVA. Airway inflammation, the number of inflammatory cells in bronchoalveolar lavage fluids (BALFs and airway hyperresponsiveness (AHR in the mice were determined, respectively, by histological analysis, with a hemocytometer, and by using plethysmograph chambers with a ventilator. Expression of mRNA in the skin and lungs was determined by quantitative PCR, while the BALF levels of myeloperoxidase (MPO and eosinophil peroxidase (EPO and the serum levels of IgE were determined by ELISA.Normal OVA-specific Th2- and Th17-cell responses of lymph nodes and spleens were observed in IL-25-deficient (IL-25-/- and IL-33-/- mice after EC sensitization with OVA. Nevertheless, the number of eosinophils, but not neutrophils, in the BALFs, and the levels of Th2 cytokines, but not Th17 cytokines, in the lungs were significantly decreased in the IL-25-/- and IL-33-/- mice pre-sensitized EC with OVA, followed by inhalation of OVA, whereas their levels of AHR and OVA-specific serum IgE were normal.Both IL-25 and IL-33 are critical for induction of Th2-type cytokine-mediated allergic airway eosinophilia, but not Th17-type cytokine-mediated airway neutrophilia, at the local sites of lungs in the challenge phase of mice sensitized EC with OVA. They do not affect OVA-specific T-cell induction in the sensitization phase.

  1. Murine calcium-activated chloride channel family member 3 induces asthmatic airway inflammation independently of allergen exposure

    Institute of Scientific and Technical Information of China (English)

    MEI Li; HE Li; WU Si-si; ZHANG Bo; XU Yong-jian; ZHANG Zhen-xiang; ZHAO Jian-ping

    2013-01-01

    Background Expression of murine calcium-activated chloride channel family member 3 (mCLCA3) has been reported to be increased in the airway epithelium of asthmatic mice challenged with ovalbumin (OVA).However,its role in asthmatic airway inflammation under no OVA exposure has not yet been clarified.Methods mCLCA3 plasmids were transfected into the airways of normal BALB/c mice.mCLCA3 expression and airway inflammation in mouse lung tissue were evaluated.Cell differentials and cytokines in bronchoalveolar lavage fluid (BALF) were analyzed.The expression of mCLCA3 protein and mucus protein mucin-5 subtype AC (MUC5AC) were analyzed by Western blotting.The mRNA levels of mCLCA3,MUC5AC and interleukin-13 (IL-13) were determined quantitatively.Results mCLCA3 expression was not detected in the control group while strong immunoreactivity was detected in the OVA and mCLCA3 plasmid groups,and was strictly localized to the airway epithelium.The numbers of inflammatory cells in lung tissue and BALF were increased in both mCLCA3 plasmid and OVA groups.The protein and mRNA levels of mCLCA3 and MUC5AC in the lung tissue were significantly increased in the mCLCA3 plasmid and OVA groups compared to the control group.The level of IL-13,but not IL-4,IL-5,IFN-γ,CCL2,CCL5 or CCL11,was significantly increased compared with control group in BALF in the mCLCA3 plasmid and OVA groups.The level of IL-13 in the BALF in the mCLCA3 plasmid group was much higher than that in the OVA group (P <0.05).The level of mCLCA3 mRNA in lung tissue was positively correlated with the levels of MUC5AC mRNA in lung tissue,IL-13 mRNA in lung tissue,the number of eosinophils in BALF,and the content of IL-13 protein in BALF.The level of IL-13 mRNA in lung tissue was positively correlated with the number of eosinophils in BALF and the level of MUC5AC mRNA in lung tissue.Conclusion These findings suggest that increased expression of a single-gene,mCLCA3,could simulate an asthma attack,and its mechanism may

  2. Salmeterol plus fluticasone propionate versus fluticasone propionate plus montelukast: a randomised controlled trial investigating the effects on airway inflammation in asthma

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    Woodcock Ashley

    2007-09-01

    Full Text Available Abstract Background Few studies have compared treatment strategies in patients with asthma poorly controlled on low dose inhaled corticosteroids, and little is known about the effects of different treatments on airway inflammation. In this double-blind, placebo-controlled, parallel group study, we compared the effects of salmeterol plus fluticasone propionate (FP (Seretide™; SFC and FP plus montelukast (FP/M on sputum inflammatory markers, airway responsiveness, lung function, and symptoms in adult asthmatics. Methods Sixty-six subjects were randomised to SFC or FP/M for 12 weeks. The primary outcome was changes in neutrophil, eosinophil, macrophage, lymphocyte, and epithelial cell levels in induced sputum. Additional outcomes included the change in other sputum markers of airway inflammation, airway responsiveness, symptom control, and lung function. Results Both treatments had no significant effect on induced sputum inflammatory cells, although there was a trend for a reduction in sputum eosinophils. Both treatments significantly improved airway responsiveness, whereas SFC generally led to greater improvements in symptom control and lung function than FP/M. FP/M led to significantly greater reductions in sputum cysteinyl leukotrienes than SFC (treatment ratio 1.80; 95% CI 1.09, 2.94. Conclusion Both treatments led to similar control of eosinophilic airway inflammation, although PEF and symptom control were better with SFC. Study number SAM40030 (SOLTA

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

    Science.gov (United States)

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

    2013-12-01

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

  4. 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.

  5. 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.

  6. IL-25 promotes Th2 immunity responses in airway inflammation of asthmatic mice via activation of dendritic cells.

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    Hongjia, Li; Caiqing, Zhang; Degan, Lu; Fen, Liu; Chao, Wang; Jinxiang, Wu; Liang, Dong

    2014-08-01

    Allergic asthma occurs as a consequence of inappropriate immunologic inflammation to allergens and characterized by Th2 adaptive immune response. Recent studies indicated that interleukin (IL)-25, a member of the IL-17 cytokine family, had been implicated in inducing Th2 cell-dependent inflammation in airway epithelium and IL-25-deficient mice exhibit impaired Th2 immunity responses; however, how these cytokines influence innate immune responses remains poorly understood. In this study, we used ovalbumin (OVA) sensitization and challenge to induce the murine asthmatic model and confirmed by histological analysis of lung tissues and serum levels of total and OVA-specific immunoglobulin (Ig)-E. The expression of IL-25 was detected by quantitative real-time PCR and immunohistochemistry, respectively, and the dendritic cells (DCs) activation was detected by levels of CD80 and CD86 in bronchoalveolar lavage fluid (BALF) by flow cytometry. The mice sensitized and challenged with OVA showed high expression of IL-25 in both mRNA and protein levels in lungs. We detected the expression of CD80 and CD86 in BALF was also increased. A tight correlation between IL-25 mRNA and other Th2 cells producing cytokines such as IL-4, IL-5, and IL-13 in BALF was identified. Furthermore, when the asthmatic mice were treated with inhaled corticosteroids, the inflammatory cells infiltration and the inflammatory cytokines secretion were significantly decreased. In this study, we show that IL-25 promoted the accumulation of co-stimulatory molecules of CD80 and CD86 on DCs and then induced the differentiation of prime naive CD4(+) T cells to become proinflammatory Th2 cells and promoted Th2 cytokine responses in OVA-induced airway inflammation. The ability of IL-25 to promote the activation and differentiation of DCs population was identified as a link between the IL-17 cytokine family and the innate immune response and suggested a previously unrecognized innate immune pathway that promotes Th2

  7. Tracking of Inhaled Near-Infrared Fluorescent Nanoparticles in Lungs of SKH-1 Mice with Allergic Airway Inflammation.

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    Markus, M Andrea; Napp, Joanna; Behnke, Thomas; Mitkovski, Miso; Monecke, Sebastian; Dullin, Christian; Kilfeather, Stephen; Dressel, Ralf; Resch-Genger, Ute; Alves, Frauke

    2015-12-22

    Molecular imaging of inflammatory lung diseases, such as asthma, has been limited to date. The recruitment of innate immune cells to the airways is central to the inflammation process. This study exploits these cells for imaging purposes within the lung, using inhaled polystyrene nanoparticles loaded with the near-infrared fluorescence dye Itrybe (Itrybe-NPs). By means of in vivo and ex vivo fluorescence reflectance imaging of an ovalbumin-based allergic airway inflammation (AAI) model in hairless SKH-1 mice, we show that subsequent to intranasal application of Itrybe-NPs, AAI lungs display fluorescence intensities significantly higher than those in lungs of control mice for at least 24 h. Ex vivo immunofluorescence analysis of lung tissue demonstrates the uptake of Itrybe-NPs predominantly by CD68(+)CD11c(+)ECF-L(+)MHCII(low) cells, identifying them as alveolar M2 macrophages in the peribronchial and alveolar areas. The in vivo results were validated by confocal microscopy, overlapping tile analysis, and flow cytometry, showing an amount of Itrybe-NP-containing macrophages in lungs of AAI mice significantly larger than that in controls. A small percentage of NP-containing cells were identified as dendritic cells. Flow cytometry of tracheobronchial lymph nodes showed that Itrybe-NPs were negligible in lung draining lymph nodes 24 h after inhalation. This imaging approach may advance preclinical monitoring of AAI in vivo over time and aid the investigation of the role that macrophages play during lung inflammation. Furthermore, it allows for tracking of inhaled nanoparticles and can hence be utilized for studies of the fate of potential new nanotherapeutics.

  8. 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.

  9. Flow cytometry of sputum: assessing inflammation and immune response elements in the bronchial airways**

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    Rationale: The evaluation of sputum leukocytes by flow cytometry is an opportunity to assess characteristics of cells residing in the central airways, yet it is hampered by certain inherent properties of sputum including mucus and large amounts of contaminating cells and debris. ...

  10. The many faces of airway inflammation - Asthma and chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    O'Byrne, PM; Postma, DS

    1999-01-01

    Airway diseases, predominantly asthma and chronic obstructive pulmonary disease (COPD), are among the world's most prevalent diseases. The prevalence of asthma has been incasing over the past 20 yr in most countries where this has been studied, and it affects up to 10% of the populations of most dev

  11. Airway Responsiveness: Role of Inflammation, Epithelium Damage and Smooth Muscle Tension

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    K. I. Gourgoulianis

    1999-01-01

    Full Text Available The purpose of this study was the effect of epithelium damage on mechanical responses of airway smooth muscles under different resting tension. We performed acetylcholine (ACh (10-5M-induced contraction on tracheal strips from 30 rabbits in five groups (0.5, 1, 1.5, 2 and 2.5 g before and after epithelium removal. At low resting tension (0.5-1.5g, the epithelium removal decreased the ACh-induced contractions. At 2g resting tension, the epithelium removal increased the ACh-induced contractions of airways with intact epithelium about 20%. At 2.5 g resting tension, the elevation of contraction is about 25% (p<0.01. Consequently, after epithelium loss, the resting tension determines the airway smooth muscles responsiveness. In asthma, mediators such as ACh act on already contracted inflammatory airways, which results in additional increase of contraction. In contrast, low resting tension, a condition that simulates normal tidal breathing, protects from bronchoconstriction even when the epithelium is damaged.

  12. Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice

    NARCIS (Netherlands)

    Pouwels, Simon D; van der Toorn, Marco; Hesse, Laura; Gras, Renee; Ten Hacken, Nick H T; Krysko, Dmitri V; Vandenabeele, Peter; de Vries, Maaike; van Oosterhout, Antoon J M; Heijink, Irene H; Nawijn, Martijn C

    2015-01-01

    Recent data indicate a role for airway epithelial necroptosis, a regulated form of necrosis, and the associated release of damage associated molecular patterns (DAMPs) in the development of COPD. DAMPs can activate pattern recognition receptors (PRRs), triggering innate immune responses. We hypothes

  13. An intranasal selective antisense oligonucleotide impairs lung cyclooxygenase-2 production and improves inflammation, but worsens airway function, in house dust mite sensitive mice

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    Pujols Laura

    2008-11-01

    Full Text Available Abstract Background Despite its reported pro-inflammatory activity, cyclooxygenase (COX-2 has been proposed to play a protective role in asthma. Accordingly, COX-2 might be down-regulated in the airway cells of asthmatics. This, together with results of experiments to assess the impact of COX-2 blockade in ovalbumin (OVA-sensitized mice in vivo, led us to propose a novel experimental approach using house dust mite (HDM-sensitized mice in which we mimicked altered regulation of COX-2. Methods Allergic inflammation was induced in BALBc mice by intranasal exposure to HDM for 10 consecutive days. This model reproduces spontaneous exposure to aeroallergens by asthmatic patients. In order to impair, but not fully block, COX-2 production in the airways, some of the animals received an intranasal antisense oligonucleotide. Lung COX-2 expression and activity were measured along with bronchovascular inflammation, airway reactivity, and prostaglandin production. Results We observed impaired COX-2 mRNA and protein expression in the lung tissue of selective oligonucleotide-treated sensitized mice. This was accompanied by diminished production of mPGE synthase and PGE2 in the airways. In sensitized mice, the oligonucleotide induced increased airway hyperreactivity (AHR to methacholine, but a substantially reduced bronchovascular inflammation. Finally, mRNA levels of hPGD synthase remained unchanged. Conclusion Intranasal antisense therapy against COX-2 in vivo mimicked the reported impairment of COX-2 regulation in the airway cells of asthmatic patients. This strategy revealed an unexpected novel dual effect: inflammation was improved but AHR worsened. This approach will provide insights into the differential regulation of inflammation and lung function in asthma, and will help identify pharmacological targets within the COX-2/PG system.

  14. Myeloid differentiation factor 88-dependent signaling is critical for acute organic dust-induced airway inflammation in mice.

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    Bauer, Christopher; Kielian, Tammy; Wyatt, Todd A; Romberger, Debra J; West, William W; Gleason, Angela M; Poole, Jill A

    2013-06-01

    Organic dust exposure within agricultural environments results in airway diseases. Toll-like receptor 2 (TLR2) and TLR4 only partly account for the innate response to these complex dust exposures. To determine the central pathway in mediating complex organic dust-induced airway inflammation, this study targeted the common adaptor protein, myeloid differentiation factor 88 (MyD88), and investigated the relative contributions of receptors upstream from this adaptor. Wild-type, MyD88, TLR9, TLR4, IL-1 receptor I (RI), and IL-18R knockout (KO) mice were challenged intranasally with organic dust extract (ODE) or saline, according to an established protocol. Airway hyperresponsiveness (AHR) was assessed by invasive pulmonary measurements. Bronchoalveolar lavage fluid was collected to quantitate leukocyte influx and cytokine/chemokine (TNF-α, IL-6, chemokine [C-X-C motif] ligands [CXCL1 and CXCL2]) concentrations. Lung tissue was collected for histopathology. Lung cell apoptosis was determined by a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and lymphocyte influx and intercellular adhesion molecule-1 (ICAM-1) expression were assessed by immunohistochemistry. ODE-induced AHR was significantly attenuated in MyD88 KO mice, and neutrophil influx and cytokine/chemokine production were nearly absent in MyD88 KO animals after ODE challenges. Despite a near-absent airspace inflammatory response, lung parenchymal inflammation was increased in MyD88 KO mice after repeated ODE exposures. ODE-induced epithelial-cell ICAM-1 expression was diminished in MyD88 KO mice. No difference was evident in the small degree of ODE-induced lung-cell apoptosis. Mice deficient in TLR9, TLR4, and IL-18R, but not IL-1IR, demonstrated partial protection against ODE-induced neutrophil influx and cytokine/chemokine production. Collectively, the acute organic dust-induced airway inflammatory response is highly dependent on MyD88 signaling, and is dictated, in part, by important

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

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    Karasuyama Hajime

    2011-04-01

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

  16. 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

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

    Science.gov (United States)

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

    2016-05-01

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

  18. The role of the eosinophil-selective chemokine, eotaxin, in allergic and non-allergic airways inflammation

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    Conroy Dolores M

    1997-01-01

    Full Text Available Blood eosinophilia and tissue infiltration by eosinophils are frequently observed in allergic inflammation and parasitic infections. This selective accumulation of eosinophils suggested the existence of endogenous eosinophil-selective chemoattractants. We have recently discovered a novel eosinophil-selective chemoattractant which we called eotaxin in an animal model of allergic airways disease. Eotaxin is generated in both allergic and non-allergic bronchopulmonary inflammation. The early increase in eotaxin paralled eosinophil infiltration in the lung tissue in both models. An antibody to IL-5 suppressed lung eosinophilia, correlating with an inhibition of eosinophil release from bone marrow, without affecting eotaxin generation. This suggests that endogenous IL-5 is important for eosinophil migration but does not appear to be a stimulus for eotaxin production. Constitutive levels of eotaxin observed in guinea-pig lung may be responsible for the basal lung eosinophilia observed in this species. Allergen-induced eotaxin was present mainly in the epithelium and alveolar macrophages, as detected by immunostaining. In contrast there was no upregulation of eotaxin by the epithelial cells following the injection of Sephadex beads and the alveolar macrophage and mononuclear cells surrounding the granuloma were the predominant positive staining cells. Eotaxin and related chemokines acting through the CCR3 receptor may play a major role in eosinophil recruitment in allergic inflammation and parasitic diseases and thus offer an attractive target for therapeutic intervention.

  19. 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.

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

    Science.gov (United States)

    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.

  1. Electronic cigarette liquid increases inflammation and virus infection in primary human airway epithelial cells.

    Directory of Open Access Journals (Sweden)

    Qun Wu

    Full Text Available The use of electronic cigarettes (e-cigarettes is rapidly increasing in the United States, especially among young people since e-cigarettes have been perceived as a safer alternative to conventional tobacco cigarettes. However, the scientific evidence regarding the human health effects of e-cigarettes on the lung is extremely limited. The major goal of our current study is to determine if e-cigarette use alters human young subject airway epithelial functions such as inflammatory response and innate immune defense against respiratory viral (i.e., human rhinovirus, HRV infection.We examined the effects of e-cigarette liquid (e-liquid on pro-inflammatory cytokine (e.g., IL-6 production, HRV infection and host defense molecules (e.g., short palate, lung, and nasal epithelium clone 1, SPLUNC1 in primary human airway epithelial cells from young healthy non-smokers. Additionally, we examined the role of SPLUNC1 in lung defense against HRV infection using a SPLUNC1 knockout mouse model. We found that nicotine-free e-liquid promoted IL-6 production and HRV infection. Addition of nicotine into e-liquid further amplified the effects of nicotine-free e-liquid. Moreover, SPLUNC1 deficiency in mice significantly increased lung HRV loads. E-liquid inhibited SPLUNC1 expression in primary human airway epithelial cells. These findings strongly suggest the deleterious health effects of e-cigarettes in the airways of young people. Our data will guide future studies to evaluate the impact of e-cigarettes on lung health in human populations, and help inform the public about potential health risks of e-cigarettes.

  2. Allergic airway inflammation by nasal inoculation of particulate matter (PM2.5 in NC/Nga mice.

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    Keiki Ogino

    Full Text Available To evaluate the effect of airborne particulate matter 2.5 (PM2.5 in winter on airway inflammation, water-soluble supernatant (Sup and water-insoluble precipitate (Pre in PM2.5 were inoculated in NC/Nga mice with high sensitivity to mite allergens. Sup with aluminum oxide was injected intraperitoneally for sensitization. Five days later, Sup, Pre or both Sup and Pre were inoculated via the nasal route five times for more sensitization and a challenge inoculation on the 11th day in NC/Nga mice. On the 12th day, mice were examined for airway hyperresponsiveness (AHR, BALF cell count and IL-1β concentration, mRNA expression of Th1 and Th2 cytokines, chemokines such as eotaxin 1 and eotaxin 2, inflammasomal complex molecules such as IL-1β, caspase 1 and the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3 in lung tissue as well as histopathology. The synergistic effect of Sup and Pre was observed in terms of increases in AHR, BALF cells, the mRNA expression of IL-13, eotaxin1 and IL-1β, and the IL-1β concentration in BALF. Intracellular deposits of insoluble particulates were observed in macrophages around inflammatory granulation of the mouse group treated with Sup and Pre. These results suggest that PM2.5 can induce airway hyperresponsiveness in mice with genetically high sensitivity to mite allergens by an inflammasome-associated mechanism and synergistic action of insoluble particulates and soluble components.

  3. Protective effects of the polyphenol sesamin on allergen-induced T(H2 responses and airway inflammation in mice.

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    Ching-Huei Lin

    Full Text Available Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and β-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti-oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR. Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4, IL-5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IκB-α and nuclear expression levels of NF-κB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice.

  4. Protective effects of the polyphenol sesamin on allergen-induced T(H)2 responses and airway inflammation in mice.

    Science.gov (United States)

    Lin, Ching-Huei; Shen, Mei-Lin; Zhou, Ning; Lee, Chen-Chen; Kao, Shung-Te; Wu, Dong Chuan

    2014-01-01

    Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and β-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti-oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR). Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA)-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4), IL-5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IκB-α and nuclear expression levels of NF-κB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice.

  5. 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

  6. Micropolyspora faeni causes airway inflammation but not hyperresponsiveness in sensitized ponies.

    Science.gov (United States)

    Derksen, F J; Scott, J S; Slocombe, R F; Robinson, N E

    1987-04-01

    We assessed the effect of aerosol Micropolyspora faeni challenge in two groups of ponies by measuring lung function, airway reactivity to aerosol histamine, and bronchoalveolar lavage fluid cytology. One group of ponies was sensitized by subcutaneous injection of M. faeni in complete Freund's adjuvant, and the other group served as control. In both groups of ponies, measurements were made at base line and 5 h after aerosol administration of 30 ml of saline or 30 ml of 1% wt/vol particulate M. faeni antigen in saline. Saline challenge had no effect on any of the measured variables. M. faeni challenge had no effect on pulmonary mechanics or gas exchange in the control group but significantly increased respiratory frequency and minute ventilation and decreased arterial CO2 tension in the sensitized ponies. In both groups of ponies, aerosol M. faeni challenge significantly increased total white blood cell count and neutrophil numbers in bronchoalveolar lavage fluid while large mononuclear cell numbers decreased. Airway responsiveness was unaltered by saline or M. faeni challenge in both pony groups. We conclude that aerosol M. faeni challenge induces pulmonary neutrophilia and abnormalities of ventilation but is not accompanied by airway hyperresponsiveness in sensitized ponies.

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

    Science.gov (United States)

    Uller, Lena; Mathiesen, Jesper Mosolff; Alenmyr, Lisa; Korsgren, Magnus; Ulven, Trond; Högberg, Thomas; Andersson, Gunnar; Persson, Carl GA; Kostenis, Evi

    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 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. PMID:17328802

  8. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-11-15

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

  10. 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.

  11. The Contribution of Allergen-Specific IgG to the Development of Th2-Mediated Airway Inflammation

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    Jesse W. Williams

    2012-01-01

    Full Text Available In both human asthmatics and animal models of allergy, allergen-specific IgG can contribute to Th2-mediated allergic inflammation. Mouse models have elucidated an important role for IgG and Fc-gamma receptor (FcγR signaling on antigen presenting cells (APC for the induction of airway inflammation. These studies suggest a positive feedback loop between IgG produced by the adaptive B cell response and FcγR signaling on innate immune cells. Studies of IgG and FcγRs in humans with asthma or allergic lung disease have been more controversial. Some reports have identified associations between allergen-specific IgG and severity of allergic responses, while other studies have found associations of IgG subclass IgG4 with allergic tolerance. In this paper, we review the literature to help define the nature of IgG and FcγR signaling on innate immune cells and how it contributes to the development of allergic immune responses.

  12. Effects of inhaled corticosteroids on airway inflammation in chronic obstructive pulmonary disease: a systematic review and meta-analysis

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    Jen R

    2012-09-01

    Full Text Available Rachel Jen,1 Stephen,1 Rennard,2 Don D Sin1,31Department of Medicine, Respiratory Division, University of British Columbia, Vancouver, BC, Canada; 2Internal Medicine Section of Pulmonary and Critical Care, Nebraska Medical Center, Omaha, NE, USA; 3Institute of Heart and Lung Health and the UBC James Hogg Research Center, St Paul's Hospital, Vancouver, BC, CanadaBackground: Chronic obstructive pulmonary disease (COPD is characterized by chronic inflammation in the small airways. The effect of inhaled corticosteroids (ICS on lung inflammation in COPD remains uncertain. We sought to determine the effects of ICS on inflammatory indices in bronchial biopsies and bronchoalveolar lavage fluid of patients with COPD.Methods: We searched Medline, Embase, Cinahl, and the Cochrane database for randomized, controlled clinical trials that used bronchial biopsies and bronchoalveolar lavage to evaluate the effects of ICS in stable COPD. For each chosen study, we calculated the mean differences in the concentrations of inflammatory cells before and after treatment in both intervention and control groups. These values were then converted into standardized mean differences (SMD to accommodate the differences in patient selection, clinical treatment, and biochemical procedures that were employed across the original studies. If significant heterogeneity was present (P < 0.1, then a random effects model was used to pool the original data; otherwise, a fixed effects model was used.Results: We identified eight original studies that met the inclusion criteria. Four studies used bronchial biopsies (n = 102 participants and showed that ICS were effective in reducing CD4 and CD8 cell counts (SMD, −0.52 units and −0.66 units, 95% confidence interval. The five studies used bronchoalveolar lavage fluid (n = 309, which together showed that ICS reduced neutrophil and lymphocyte counts (SMD, −0.64 units and −0.64 units, 95% confidence interval. ICS on the other hand

  13. 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.

  14. Eicosanoid Mediators in the Airway Inflammation of Asthmatic Patients: What is New?

    OpenAIRE

    Sanak, Marek

    2016-01-01

    Lipid mediators contribute to inflammation providing both pro-inflammatory signals and terminating the inflammatory process by activation of macrophages. Among the most significant biologically lipid mediators, these are produced by free-radical or enzymatic oxygenation of arachidonic acid named "eicosanoids". There were some novel eicosanoids identified within the last decade, and many of them are measurable in clinical samples by affordable chromatography-mass spectrometry equipment or sens...

  15. Acute and Subchronic Airway Inflammation after Intratracheal Instillation of Quartz and Titanium Dioxide Agglomerates in Mice

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    Martin Roursgaard

    2011-01-01

    Full Text Available This study investigated the acute and subchronic inflammatory effects of micrometer-size (micro-size and nanometer-size (nano-size particles after intratracheal (i.t. installation in mice. The role of the type of compound, polymorphism, and size of the particles was investigated. Studied compounds were the two micro-size reference quartzes, SRM1878a and DQ12, a micro- and nano-size rutile titanium dioxide (TiO2, a nano-size anatase, and an amorphous TiO2. Particles were administered by a single i.t. instillation in mice at a fixed dose of 5, 50, and 500 μg, respectively. Inflammation was evaluated from the bronchoalveolar lavage fluid (BALF content of inflammatory cells, the cytokines tumor necrosis factor alpha (TNF-α and interleukin 6 (IL-6, as well as from lung histology. Evaluations were at 24 h (acute effects and 3 months (subchronic effects after instillations. Both types of quartz induced a dose-dependent acute increase of neutrophils, IL-6, and total protein in BALF. Limited subchronic inflammation was observed. All types of TiO2 induced a dose-dependent acute increase of neutrophils in BALF. In the acute phase, micro- and nano-size rutile and nano-size amorphous TiO2 induced elevated levels of IL-6 and total protein in BALF at the highest dose. At the nano-size rutile and amorphous TiO2, subchronic lung inflammation was apparent from a dose-dependent increase in BALF macrophages. Histology showed little inflammation overall. The two types of quartz showed virtually similar inflammatory effects. Nearly similar effects were observed for two sizes of rutile TiO2. Differences were seen between the different polymorphs of nano-size TiO2, with rutile being the most inflammogenic and amorphous being the most potent in regard to acute tissue damage.

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

    Institute of Scientific and Technical Information of China (English)

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

    2013-01-01

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

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

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    Zhiyu Zhang

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

  18. 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

  19. Characterization of airway inflammation in patients with COPD using fractional exhaled nitric oxide levels: a pilot study

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    Donohue JF

    2014-07-01

    Full Text Available James F Donohue,1 Nancy Herje,2 Glenn Crater,2 Kathleen Rickard2 1Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA; 2Aerocrine, Inc., Morrisville, NC, USA Objective: To characterize fractional exhaled nitric oxide (FeNO levels that may be indicative of Th2-mediated airway inflammation in patients with chronic obstructive pulmonary disease (COPD. Methods: This single-visit, outpatient study was conducted in 200 patients aged 40 years and older with COPD. All patients underwent spirometry and FeNO testing. COPD severity was classified according to the Global initiative for chronic Obstructive Lung Disease (GOLD 2010 guidelines. Results: Patients who participated in the study had a mean age of 63.9±11.3 years and a mean smoking history of 46±29 pack years. Patients had a mean forced expiratory volume in 1 second % predicted of 53.9%±22.1%. The percentage of patients classified with COPD severity Stage I, II, III, and IV was 13%, 40%, 39%, and 8%, respectively. In addition, according to current procedural terminology codes, 32% of patients were classified as mixed COPD/asthma, 26% as COPD/emphysema, and 42% as all other codes. The mean FeNO level for all patients was 15.3±17.2 parts per billion (ppb. Overall, 89% of patients had a FeNO <25 ppb, 8% had a FeNO 25–50 ppb, and 3% had a FeNO >50 ppb. The percentages of patients with FeNO in the intermediate or high ranges of FeNO were greatest among patients with mixed COPD/asthma (intermediate, 11.5%; high, 6.6% compared with COPD/emphysema (intermediate, 8%; high, 0 and all other codes (intermediate, 6.3%; high, 1.3%. Conclusion: Increases in FeNO were identified in a subset of patients with COPD, particularly in those previously diagnosed with both COPD and asthma. Since FeNO is useful for identifying patients with airway inflammation who will have a beneficial response to treatment with an inhaled corticosteroid, these data may have important

  20. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Takai, Atsushi; Marusawa, Hiroyuki, E-mail: maru@kuhp.kyoto-u.ac.jp; Chiba, Tsutomu [Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507 (Japan)

    2011-06-22

    Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis.

  1. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID during Inflammation-Associated Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Tsutomu Chiba

    2011-06-01

    Full Text Available Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID, a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis.

  2. Ambient urban Baltimore particulate-induced airway hyperresponsiveness and inflammation in mice

    Energy Technology Data Exchange (ETDEWEB)

    Walters, D.M.; Breysse, P.N.; Wills-Karp, M. [Childrens Hospital, Cincinnati, OH (United States). Medical Centre, Division of Immunobiology

    2001-10-15

    Airborne particulate matter (PM) is hypothesized to play a role in increases in asthma prevalence, although a causal relationship has yet to be established. To investigate the effects of real-world PM exposure on airway reactivity (AHR) and bronchoalveolar lavage (BAL) cellularity, mice were exposed to a single dose (0.5 mg/ mouse) of ambient PM, coal fly ash, or diesel PM. It was found that ambient PM exposure induced increases in AHR and BAL cellularity, whereas diesel PM induced significant increases in BAL cellularity, but not AHR. On the other hand, coal fly ash exposure did not elicit significant changes in either of these parameters. Ambient PM-induced temporal changes in AHR, BAL cells, and lung cytakine levels over a 2-wk period were then examined. Ambient PM-induced AHR was sustained over 7 d. The increase in AHR was preceded by dramatic increases in BAL eosinophils, whereas a decline in AHR was associated with increases in macrophages. It is concluded that ambient PM can induce asthmalike parameters in mice, suggesting that PM exposure may be an important factor in increases in asthma prevalence.

  3. Airway epithelial NF-kappaB activation modulates asbestos-induced inflammation and mucin production in vivo.

    Science.gov (United States)

    Haegens, Astrid; Barrett, Trisha F; Gell, Joanna; Shukla, Arti; Macpherson, Maximilian; Vacek, Pamela; Poynter, Matthew E; Butnor, Kelly J; Janssen-Heininger, Yvonne M; Steele, Chad; Mossman, Brooke T

    2007-02-01

    To investigate the role of bronchiolar epithelial NF-kappaB activity in the development of inflammation and fibrogenesis in a murine model of asbestos inhalation, we used transgenic (Tg) mice expressing an IkappaBalpha mutant (IkappaBalphasr) resistant to phosphorylation-induced degradation and targeted to bronchial epithelium using the CC10 promoter. Sham and chrysotile asbestos-exposed CC10-IkappaBalphasr Tg(+) and Tg(-) mice were examined for altered epithelial cell proliferation and differentiation, cytokine profiles, lung inflammation, and fibrogenesis at 3, 9, and 40 days. KC, IL-6 and IL-1beta were increased (p < or = 0.05) in bronchoalveolar lavage fluid (BALF) from asbestos-exposed mice, but to a lesser extent (p < or = 0.05) in Tg(+) vs Tg(-) mice. Asbestos also caused increases in IL-4, MIP-1beta, and MCP-1 in BALF that were more elevated (p < or = 0.05) in Tg(+) mice at 9 days. Differential cell counts revealed eosinophils in BALF that increased (p < or = 0.05) in Tg(+) mice at 9 days, a time point corresponding with significantly increased numbers of bronchiolar epithelial cells staining positively for mucus production. At all time points, asbestos caused increased numbers of distal bronchiolar epithelial cells and peribronchiolar cells incorporating the proliferation marker, Ki-67. However, bronchiolar epithelial cell and interstitial cell labeling was diminished at 40 days (p < or = 0.05) in Tg(+) vs Tg(-) mice. Our findings demonstrate that airway epithelial NF-kappaB activity plays a role in orchestrating the inflammatory response as well as cell proliferation in response to asbestos.

  4. TLR-7 agonist attenuates airway reactivity and inflammation through Nrf2-mediated antioxidant protection in a murine model of allergic asthma.

    Science.gov (United States)

    Nadeem, Ahmed; Siddiqui, Nahid; Al-Harbi, Naif O; Al-Harbi, Mohammed M; Ahmad, Sheikh F

    2016-04-01

    Toll-like receptors (TLRs) through innate immune system recognize pathogen associated molecular patterns and play an important role in host defense against bacteria, fungi and viruses. TLR-7 is responsible for sensing single stranded nucleic acids of viruses but its activation has been shown to be protective in mouse models of asthma. The NADPH oxidase (NOX) enzymes family mainly produces reactive oxygen species (ROS) in the lung and is involved in regulation of airway inflammation in response to TLRs activation. However, NOX-4 mediated signaling in response to TLR-7 activation in a mouse model of allergic asthma has not been explored previously. Therefore, this study investigated the role TLR-7 activation and downstream oxidant-antioxidant signaling in a murine model of asthma. Mice were sensitized with ovalbumin (OVA) intraperitoneally and treated with TLR-7 agonist, resiquimod (RSQ) intranasally before each OVA challenge from days 14 to 16. Mice were then assessed for airway reactivity, inflammation, and NOX-4 and nuclear factor E2-related factor 2 (Nrf2) related signaling [inducible nitric oxide synthase (iNOS), nitrotyrosine, lipid peroxides and copper/zinc superoxide dismutase (Cu/Zn SOD)]. Treatment with RSQ reduced allergen induced airway reactivity and inflammation. This was paralleled by a decrease in ROS which was due to induction of Nrf2 and Cu/Zn SOD in RSQ treated group. Inhibition of MyD88 reversed RSQ-mediated protective effects on airway reactivity/inflammation due to reduction in Nrf2 signaling. SOD inhibition produced effects similar to MyD88 inhibition. The current study suggests that TLR-7 agonist is beneficial and may be developed into a therapeutic option in allergic asthma.

  5. Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35.

    Science.gov (United States)

    Huang, Chiung-Hui; Loo, Evelyn Xiu-Ling; Kuo, I-Chun; Soh, Gim Hooi; Goh, Denise Li-Meng; Lee, Bee Wah; Chua, Kaw Yan

    2011-07-01

    CD4(+) memory/effector T cells play a central role in orchestrating the rapid and robust immune responses upon re-encounter with specific Ags. However, the immunologic mechanism(s) underlying these responses are still not fully understood. To investigate this, we generated an allergen (major house dust mite allergen, Blo t 5)-specific murine Th2 cell line that secreted IL-4, IL-5, IL-10, and IL-13, but not IL-9 or TNF-α, upon activation by the cognate Ag. These cells also exhibited CD44(high)CD62L(-) and CD127(+) (IL-7Rα(+)) phenotypes, which are characteristics of memory/effector T cells. Experiments involving adoptive transfer of this Th2 cell line in mice, followed by three intranasal challenges with Blo t 5, induced a dexamethasone-sensitive eosinophilic airway inflammation. This was accompanied by elevation of Th2 cytokines and CC- and CXC-motif chemokines, as well as recruitment of lymphocytes and polymorphic mononuclear cells into the lungs. Moreover, Blo t 5-specific IgE was detected 4 d after the last intranasal challenge, whereas elevation of Blo t 5-specific IgG1 was found at week two. Finally, pulmonary delivery of the pVAX-IL-35 DNA construct effectively downregulated Blo t 5-specific allergic airway inflammation, and i.m. injection of pVAX-IL-35 led to long-lasting suppression of circulating Blo t 5-specific and total IgE. This model provides a robust research tool to elucidate the immunopathogenic role of memory/effector Th2 cells in allergic airway inflammation. Our results suggested that IL-35 could be a potential therapeutic target for allergic asthma through its attenuating effects on allergen-specific CD4(+) memory/effector Th2 cell-mediated airway inflammation.

  6. S-adenosylmethionine reduces airway inflammation and fibrosis in a murine model of chronic severe asthma via suppression of oxidative stress.

    Science.gov (United States)

    Yoon, Sun-Young; Hong, Gyong Hwa; Kwon, Hyouk-Soo; Park, Sunjoo; Park, So Young; Shin, Bomi; Kim, Tae-Bum; Moon, Hee-Bom; Cho, You Sook

    2016-06-03

    Increased oxidative stress has an important role in asthmatic airway inflammation and remodeling. A potent methyl donor, S-adenosylmethionine (SAMe), is known to protect against tissue injury and fibrosis through modulation of oxidative stress. The aim of this study was to evaluate the effect of SAMe on airway inflammation and remodeling in a murine model of chronic asthma. A mouse model was generated by repeated intranasal challenge with ovalbumin and Aspergillus fungal protease twice a week for 8 weeks. SAMe was orally administered every 24 h for 8 weeks. We performed bronchoalveolar lavage (BAL) fluid analysis and histopathological examination. The levels of various cytokines and 4-hydroxy-2-nonenal (HNE) were measured in the lung tissue. Cultured macrophages and fibroblasts were employed to evaluate the underlying anti-inflammatory and antifibrotic mechanisms of SAMe. The magnitude of airway inflammation and fibrosis, as well as the total BAL cell counts, were significantly suppressed in the SAMe-treated groups. A reduction in T helper type 2 pro-inflammatory cytokines and HNE levels was observed in mouse lung tissue after SAMe administration. Macrophages cultured with SAMe also showed reduced cellular oxidative stress and pro-inflammatory cytokine production. Moreover, SAMe treatment attenuated transforming growth factor-β (TGF-β)-induced fibronectin expression in cultured fibroblasts. SAMe had a suppressive effect on airway inflammation and fibrosis in a mouse model of chronic asthma, at least partially through the attenuation of oxidative stress and TGF-β-induced fibronectin expression. The results of this study suggest a potential role for SAMe as a novel therapeutic agent in chronic asthma.

  7. Bacterial infection, airway and systemic inflammation and clinical outcomes before and after treatment of AECOPD, a longitudinal and cross-sectional study.

    Science.gov (United States)

    Chang, Chun; Zhu, Hong; Shen, Ning; Chen, Yahong; He, Bei; Zhao, Jiangchao; Yao, Wanzhen

    2015-02-01

    Abstract Bacterial infection is a major cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD), which are associated with significantly increased airway and systemic inflammation. However, the relationship among bacteriology, the resolution of inflammation and clinical outcomes is largely unknown. In this study, we recruited consecutive patients hospitalized for AECOPD with purulent sputum. We measured the airway and systemic inflammation levels, the COPD assessment test (CAT) score and adverse outcomes between patients with and without potentially pathogenic microorganisms (PPM). Among sputum samples collected from the 135 episodes of AECOPD, 42 (31.1%) were PPM-positive at admission. Compared with those in the PPM-negative group, more patients in the PPM-positive group had ≥2 exacerbations in previous year and Anthonisen type I at admission and higher drop in sputum neutrophil, serum hs-CRP and CAT value from exacerbation to the subsequent baseline. No significant differences in the adverse outcomes between the two groups were observed. Among the 38 PPM-positive patients who survived and were discharged from hospital, 19 remained PPM-positive (bacterial persistence group) and 19 PPM-negative (bacterial clearance group). Both inflammation indices and CAT score decreased compared to admission in the two groups, regardless of the bacteriology at discharge. Our data suggest uncultivated bacteria and/or virus might also play important roles in causing inflammation and AECOPD.

  8. CCR3 is essential for skin eosinophilia and airway hyperresponsiveness in a murine model of allergic skin inflammation.

    Science.gov (United States)

    Ma, Weilie; Bryce, Paul J; Humbles, Alison A; Laouini, Dhafer; Yalcindag, Ali; Alenius, Harri; Friend, Daniel S; Oettgen, Hans C; Gerard, Craig; Geha, Raif S

    2002-03-01

    The CC chemokine receptor 3 (CCR3) is expressed by eosinophils, mast cells, and Th2 cells. We used CCR3(-/-) mice to assess the role of CCR3 in a murine model of allergic skin inflammation induced by repeated epicutaneous sensitization with ovalbumin (OVA), and characterized by eosinophil skin infiltration, local expression of Th2 cytokines, and airway hyperresponsiveness (AHR) to inhaled antigen. Eosinophils and the eosinophil product major basic protein were absent from the skin of sham and OVA-sensitized CCR3(-/-) mice. Mast cell numbers and expression of IL-4 mRNA were normal in skin of CCR3(-/-) mice, suggesting that CCR3 is not important for infiltration of the skin by mast cells and Th2 cells. CCR3(-/-) mice produced normal levels of OVA-specific IgE, and their splenocytes secreted normal amounts of IL-4 and IL-5 following in vitro stimulation with OVA, indicating effective generation of systemic Th2 helper responses. Recruitment of eosinophils to lung parenchyma and bronchoalveolar lavage (BAL) fluid was severely impaired in CCR3(-/-) mice, which failed to develop AHR to methacholine following antigen inhalation. These results suggest that CCR3 plays an essential role in eosinophil recruitment to the skin and the lung and in the development of AHR.

  9. Exhaled breath condensate hydrogen peroxide and pH for the assessment of lower airway inflammation in the horse.

    Science.gov (United States)

    Duz, M; Whittaker, A G; Love, S; Parkin, T D H; Hughes, K J

    2009-10-01

    Measurement of hydrogen peroxide (H(2)O(2)) concentration and pH in exhaled breath condensate (EBC) is useful for detection and monitoring of asthma in humans. In contrast, limited information on the use of these parameters for the investigation of lower airway inflammation (LAI) is available for horses. Aims of the current study were to investigate the intra- and inter-day variations of EBC H(2)O(2) concentration and pH in horses and establish any relationship(s) with LAI. Both intra- and inter-day variability of EBC H(2)O(2) concentration were large, while those of pH were small. No significant difference in the intra-day or inter-day H(2)O(2) concentrations or pH measurements were found in control or LAI horses, except for inter-day H(2)O(2) concentration in horses with LAI (p=0.019). There was no significant difference in EBC pH or H(2)O(2) concentration between control and LAI horses, however a trend for a reduced pH in horses with LAI was observed.

  10. Activated nuclear factor kappa B and airway inflammation after smoke inhalation and burn injury in sheep.

    Science.gov (United States)

    Cox, Robert A; Burke, Ann S; Jacob, Sam; Oliveras, Gloria; Murakami, Kazunori; Shimoda, Katsumi; Enkhbaatar, Perenlei; Traber, Lillian D; Herndon, David N; Traber, Daniel L; Hawkins, Hal K

    2009-01-01

    In a recent study, we have shown a rapid inflammatory cell influx across the glandular epithelium and strong proinflammatory cytokine expression at 4 hours after inhalation injury. Studies have demonstrated a significant role of nuclear factor kappa B in proinflammatory cytokine gene transcription. This study examines the acute airway inflammatory response and immunohistochemical detection of p65, a marker of nuclear factor kappa B activation, in sheep after smoke inhalation and burn injury. Pulmonary tissue from uninjured sheep and sheep at 4, 8, 12, 24, and 48 hours after inhalation and burn injury was included in the study. Following immunostaining for p65 and myeloperoxidase, the cell types and the percentage of bronchial submucosal gland cells staining for p65 and the extent of myeloperoxidase stained neutrophils in the bronchial submucosa were determined. Results indicate absence of detection of P65 before 12 hours after injury. At 12 hours after injury, strong perinuclear staining for p65 was evident in bronchial gland epithelial cells, macrophages, and endothelial cells. Bronchial submucosal gland cells showed a significant increase in the percentage of cells stained for p65 compared with uninjured animals and earlier times after injury, P macrophages, and endothelial cells. Quantitation of the neutrophil influx into the bronchial submucosa showed a significant increase compared with uninjured tissue at 24 and 48 hours after injury, P < .05. In conclusion, immunohistochemical detection of activated p65 preceded the overall inflammatory response measured in the lamina propria. However, detection of p65 did not correlate with a recent study showing rapid emigration of neutrophils at 4 hours postinjury. Together, these results suggest that p65 immunostaining may identify cells that are activated to produce proinflammatory cytokines after injury; however, the immunoexpression may not adequately reflect the temporal activation of gene transcription that may

  11. Inhibitory effect of n-butanol fraction of Moringa oleifera Lam. seeds on ovalbumin-induced airway inflammation in a guinea pig model of asthma.

    Science.gov (United States)

    Mahajan, Shailaja G; Banerjee, Aryamitra; Chauhan, Bhupendrasinh F; Padh, Harish; Nivsarkar, Manish; Mehta, Anita A

    2009-01-01

    Moringaceae, which belongs to the Moringa oleifera Lam. family, is a well-known herb used in Asian medicine as an antiallergic drug. In the present study, the efficacy of the n-butanol extract of the seeds of the plant (MONB) is examined against ovalbumin-induced airway inflammation in guinea pigs. The test drugs (MONB or dexamethasone) are administered orally prior to challenge with aerosolized 0.5% ovalbumin. During the experimental period, bronchoconstriction tests are performed, and lung function parameters are measured. The blood and bronchoalveolar lavage fluid are collected to assess cellular content, and serum is used for cytokine (tumor necrosis factor-alpha, interleukin-4, and interleukin-6) assays. Histamine assays of lung tissue are performed using lung tissue homogenate. The results suggest that in ovalbumin-sensitized model control animals, tidal volume is decreased, respiration rate is increased, and both the total and differential cell counts in blood and bronchoalveolar lavage fluid are increased significantly compared with nonsensitized controls. MONB treatment shows improvement in all parameters except bronchoalveolar lavage tumor necrosis factor-alpha and interleukin-4. Moreover, MONB treatment demonstrates protection against acetylcholine-induced bronchoconstriction and airway inflammation. These results indicate that MONB has an inhibitory effect on airway inflammation. Thus, MONB possesses an antiasthmatic property through modulation of the relationship between Th1/Th2 cytokine imbalances.

  12. Comparison of effect of granules and herbs of Bu-Shen-Yi-Qi-Tang on airway inflammation in asthmatic mice

    Institute of Scientific and Technical Information of China (English)

    Wei Ying; Lyu Yubao; Li Mihui; Luo Qingli; Sun Jing; Liu Feng; Lin Yanhua

    2014-01-01

    Background Bu-Shen-Yi-Qi-Tang (BSYQT),which is prescribed on the basis of clinical experience,is commonly used in clinics of traditional Chinese medicine (TCM) for asthma treatment.The components of BSYQT include Radix Astragali (RA),Herba Epimedii (HE) and Radix Rehmanniae (RR).The aim of this study was to compare the effect of granules and herbs of BSYQT on airway inflammation in asthmatic mice.Methods Sixty female BALB/c mice were randomly divided into the normal control (NC) group,asthmatic group (A),decoction of granules of BSYQT treatment group (GD),decoction of herbs of BSYQT treatment group (HD),and dexamethasone treatment group (DEX).The mouse asthmatic model was induced by ovalbumin (OVA) sensitization and challenge.GD and HD of BSYQT as well as DEX were prepared and administered by intragastric infusion.Airway hyperresponsiveness (AHR) to methacholine (Mch),lung histopathology analysis,inflammatory mediators in serum (IL-4,IL-5,IL-17A,IFN-γ,and eotaxin) and in lung (IL-4,IL-5,IFN-γ,and eotaxin) were selected for investigation and comparison.Results Both GD and HD treatment could decrease airway resistance (RL) and increase dynamic compliance (Cdyn) to Mch compared with the A group (P <0.05).HD treatment was more effective in RL reduction than Mch at doses of 3.125 and 6.25 mg/ml (P <0.05) and in Cdyn increase at Mch doses of 6.25 and 12.5 mg/ml (P <0.05).There were no marked differences in RL reduction and Cdyn improvement between mice in HD and DEX groups (P >0.05).Both GD and HD treatment markedly attenuated lung inflammation (P <0.05),and HD treatment demonstrated more significant therapeutic function in alleviating lung inflammation than that of GD and DEX treatment (P <0.05).Both GD and HD treatment resulted in a significant reduction in IL-4 and IL-17A levels and an increase in the IFN-γ level in serum compared with the A group (P <0.05).The effect of HD in lowering the IL-4 and IL-17A level was significantly greater than that of

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    Science.gov (United States)

    Günel, Ceren; Demirci, Buket; Eryılmaz, Aylin; Yılmaz, Mustafa; Meteoğlu, İbrahim; Ömürlü, İmran Kurt; Başal, Yeşim

    2016-01-01

    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 response

  15. Increased leptin/leptin receptor pathway affects systemic and airway inflammation in COPD former smokers

    Directory of Open Access Journals (Sweden)

    Bruno A

    2011-05-01

    Full Text Available Andreina Bruno1, Marinella Alessi2, Simona Soresi2, Anna Bonanno1, Loredana Riccobono1, Angela Marina Montalbano1, Giusy Daniela Albano1, Mark Gjomarkaj1, Mirella Profita11Institute of Biomedicine and Molecular Immunology, Italian National Research Council, Palermo, Italy; 2Dipartimento Biomedico di Biomedicina Interna e Specialistica, University Palermo, ItalyBackground: Leptin, a hormone produced mainly by adipose tissue, regulates food intake and energy expenditure. It is involved in inflammatory diseases such as chronic obstructive pulmonary disease (COPD and its deficiency is associated with increased susceptibility to the infection. The leptin receptor is expressed in the lung and in the neutrophils.Methods: We measured the levels of leptin, tumor necrosis factor alpha (TNF-a and soluble form of intercellular adhesion molecule-1 (sICAM-1 in sputum and plasma from 27 smoker and former smoker patients with stable COPD using ELISA methods. Further we analyzed leptin and its receptor expression in sputum cells from 16 COPD patients using immunocytochemistry.Results: In plasma of COPD patients, leptin was inversely correlated with TNF-a and positively correlated with the patient weight, whereas the levels of sICAM-1 were positively correlated with TNF-a. In sputum of COPD patients leptin levels were correlated with forced expiratory volume in 1 second/forced vitality capacity. Additionally, increased levels of sputum leptin and TNF-a were observed in COPD former smokers rather than smokers. Further the expression of leptin receptor in sputum neutrophils was significantly higher in COPD former smokers than in smokers, and the expression of leptin and its receptor was positively correlated in neutrophils of COPD former smokers.Conclusion: Our findings suggest a role of leptin in the local and systemic inflammation of COPD and, taking into account the involvement of neutrophils in this inflammatory disease, describe a novel aspect of the leptin

  16. FeNO as a Marker of Airways Inflammation: The Possible Implications in Childhood Asthma Management

    Directory of Open Access Journals (Sweden)

    Marcello Verini

    2010-01-01

    Full Text Available The aim of this study was to verify FeNO usefulness, as a marker of bronchial inflammation, in the assessment of therapeutic management of childhood asthma. We performed a prospective 1-year randomized clinical trial evaluating two groups of 32 children with allergic asthma: “GINA group”, in which therapy was assessed only by GINA guidelines and “FeNO group”, who followed a therapeutic program assessed also on FeNO measurements. Asthma Severity score (ASs, Asthma Exacerbation Frequency (AEf, and Asthma Therapy score (ATs were evaluated at the start of the study (T1, 6 months (T2, and 1 year after (T3. ASs and AEf significantly decreased only in the FeNO group at times T2 and T3 (p[T1-T2] = 0.0001, and p[T1-T3] = 0.01; p[T1-T2] = 0.0001; and p[T1-T3] < 0.0001, resp.. After six months of follow-up, we found a significant increase of patients under inhaled corticosteroid and/or antileukotrienes in the GINA group compared to the FeNO group (=.02. Our data show that FeNO measurements, might be a very useful additional parameter for management of asthma, which is able to avoid unnecessary inhaled corticosteroid and antileukotrienes therapies, however, mantaining a treatment sufficient to obtain a meaningful improvement of asthma.

  17. Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

    Directory of Open Access Journals (Sweden)

    Nemery Benoit

    2010-01-01

    Full Text Available Abstract Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS and environmental tobacco smoke (ETS as well as exposure to diesel exhaust particles (DEP could promote allergic sensitization or aggravate symptoms of asthma, suggesting a role for these inhaled pollutants in the pathogenesis of asthma. Mouse models are a valuable tool to study the potential effects of these pollutants in the pathogenesis of asthma, with the opportunity to investigate their impact during processes leading to sensitization, acute inflammation and chronic disease. Mice allow us to perform mechanistic studies and to evaluate the importance of specific cell types in asthma pathogenesis. In this review, the major clinical effects of tobacco smoke and diesel exhaust exposure regarding to asthma development and progression are described. Clinical data are compared with findings from murine models of asthma and inhalable pollutant exposure. Moreover, the potential mechanisms by which both pollutants could aggravate asthma are discussed.

  18. IL-1ra Secreted by ATP-Induced P2Y2 Negatively Regulates MUC5AC Overproduction via PLCβ3 during Airway Inflammation.

    Science.gov (United States)

    Jeong, Jee-Yeong; Kim, Jiwook; Kim, Bokyoum; Kim, Joowon; Shin, Yusom; Kim, Judeok; Ryu, Siejeong; Yang, Yu-Mi; Song, Kyoung Seob

    2016-01-01

    Mucus secretion is often uncontrolled in many airway inflammatory diseases of humans. Identifying the regulatory pathway(s) of mucus gene expression, mucus overproduction, and hypersecretion is important to alleviate airway inflammation in these diseases. However, the regulatory signaling pathway controlling mucus overproduction has not been fully identified yet. In this study, we report that the ATP/P2Y2 complex secretes many cytokines and chemokines to regulate airway inflammation, among which IL-1 receptor antagonist (IL-1ra) downregulates MUC5AC gene expression via the inhibition of Gαq-induced Ca(2+) signaling. IL-1ra inhibited IL-1α protein expression and secretion, and vice versa. Interestingly, ATP/P2Y2-induced IL-1ra and IL-1α secretion were both mediated by PLCβ3. A dominant-negative mutation in the PDZ-binding domain of PLCβ3 inhibited ATP/P2Y2-induced IL-1ra and IL-1α secretion. IL-1α in the presence of the ATP/P2Y2 complex activated the ERK1/2 pathway in a greater degree and for a longer duration than the ATP/P2Y2 complex itself, which was dramatically inhibited by IL-1ra. These findings suggest that secreted IL-1ra exhibits a regulatory effect on ATP/P2Y2-induced MUC5AC gene expression, through inhibition of IL-1α secretion, to maintain the mucus homeostasis in the airway. Therefore, IL-1ra could be an excellent modality for regulating inflamed airway microenvironments in respiratory diseases.

  19. Zinc sulfate inhibited inflammation of Der p2-induced airway smooth muscle cells by suppressing ERK1/2 and NF-κB phosphorylation.

    Science.gov (United States)

    Shih, Chia-Ju; Chiou, Ya-Ling

    2013-06-01

    Inflammation of airway smooth muscle cells (ASMCs) is believed to be important in causing airway hyperresponsiveness. However, zinc has been reported to be implicated in many kinds of cell inflammation. Little is known about the effect of zinc treatment on Der p2 (group II Dermatophagoides pteronyssinus)-induced inflammation from ASMCs. This study investigated effects and mechanisms of zinc in Der p2-treated ASMCs. Der p2-treated primary ASMCs were cultured with various concentrations of zinc sulfate (ZnSO₄) 6 μM, 12 μM, 24 μM, and 96 μM. The proteins and mRNAs of cytokines in ASMCs were examined by ELISA and real-time PCR. Intracellular zinc was stained with Zinquin fluorescence. The cell signaling protein expression was detected by Western blot. Der p2 was used to induce interleukin (IL)-6, IL-8, IL-1, and monocyte chemotactic protein-1 production of ASMCs. However, we found that 24 μM ZnSO₄ reduced these inflammatory mediators production of Der p2-treated primary ASMCs. Der p2-induced extracellular signal-regulated kinases (ERK) and nuclear factor-kappa B (NF-κB) phosphorylation were suppressed by supplementation of 24 μM ZnSO₄. Zinc is an anti-inflammatory agent that reduces inflammation of Der p2-treated ASMCs through the suppression of the ERK and NF-κB pathway. The results may be helpful for the development of effective treatments.

  20. ROLE OF TOLL-LIKE RECEPTOR 4 IN AIRWAY INFLAMMA-TION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASES

    Institute of Scientific and Technical Information of China (English)

    ZHOU Min; RONG Xia-jun; WAN Huan-ying; HUANG Shao-guang; LI Biao; LI Min

    2008-01-01

    Objective To confirm if pulmonary epithelial cells express Toll-like receptor 4 (TLR4) and investigate the role of TLR4 in airway inflammation of chronic obstructive pulmonary diseases (COPD). Methods The expressions of TLR4, IL-8 mRNA and NF-κB activation stimulated by differen factors [lipopolysacharides (LPS), interleukin-1β, cigarette smoking extract (CSE)] in pulmonary epithelial cells were investigated. Results LPS, CSE and IL-1β induced the production of IL-8 and activation of NF-κB. The levels of IL-8 mRNA and NF-κB protein in ElA+ cell were markedly higher than ElA-cell and A549 cell (P<0.05). The TLR4 mRNA of all the cells increased along with the increase of LPS' stimulated time. There was significant difference among different LPS' doses (12 h: P=0.039; 24 h: P=0.013). The TLR4 mRNA of ElA+ cell was higher than the other two groups (P<0.05). IL-1β induced all the cells expressing TLR4 mRNA. CSE had no effect on the expression of TLR4 mRNA. Conclusion Pulmonary epithelial cells express TLR4. LPS and IL-1β up-regulate IL-8 mediated via the activation of NF-κB induced by TLR4. But CSE up-regulates IL-8 mediated via the activation of NF-κB, which has no relation to TLR4 and may have another signal transduction pathway.

  1. Efficacy of Add-on Montelukast in Nonasthmatic Eosinophilic Bronchitis: The Additive Effect on Airway Inflammation, Cough and Life Quality

    Institute of Scientific and Technical Information of China (English)

    Wuping Bao; Ping Liu; Zhongmin Qiu; Li Yu; Jingqing Hang; Xiaohua Gao; Xin Zhou

    2015-01-01

    Background:The efficacy of montelukast (MONT),a cysteinyl leukotriene receptor antagonist,in nonasthmatic eosinophilic bronchitis (NAEB),especially its influence on cough associated life quality is still indefinite.We evaluated the efficacy of MONT combined with budesonide (BUD) as compared to BUD monotherapy in improving life quality,suppressing airway eosinophilia and cough remission in NAEB.Methods:A prospective,open-labeled,multicenter,randomized controlled trial was conducted.Patients with NAEB (aged 18-75 years) were randomized to inhaled BUD (200 μg,bid) or BUD plus oral MONT (10 μg,qn) for 4 weeks.Leicester cough questionnaire (LCQ) life quality scores,cough visual analog scale (CVAS) scores,eosinophil differential ratio (Eos),and eosinophil cationic protein (ECP) in induced sputum were monitored and compared.Results:The control and MONT groups contained 33 and 32 patients,respectively,with similar baseline characteristics.Significant with-in group improvement in CVAS,LCQ scores,Eos,and ECP was observed in both groups during treatment.After 2-week treatment,add-on treatment of MONT was significantly more effective than BUD monotherapy for CVAS decrease and LCQ scores improvement (both P < 0.05).Similar results were seen at 4-week assessment (both P < 0.05).4-week add-on therapy of MONT also resulted in a higher percentage of patients with normal sputum Eos (<2.5%) and greater decrease of ECP (both P < 0.05).Conclusions:MONT combined with BUD was demonstrated cooperative effects in improvement of life quality,suppression ofeosinophilic inflammation,and cough remission in patients with NAEB.

  2. Effects of the flavanone combination hesperetin-naringenin, and orange and grapefruit juices, on airway inflammation and remodeling in a murine asthma model.

    Science.gov (United States)

    Seyedrezazadeh, Ensiyeh; Kolahian, Saeed; Shahbazfar, Amir-Ali; Ansarin, Khalil; Pour Moghaddam, Masoud; Sakhinia, Masoud; Sakhinia, Ebrahim; Vafa, Mohammadreza

    2015-04-01

    We investigated whether flavanones, hesperetin-naringenin, orange, and grapefruit juices reduce airway inflammation and remodeling in murine chronic asthma model. To establish chronic asthma, mice received house dust mite (HDM) for 3 days in 2 weeks, followed by twice per week for 4 weeks. Concurrently, during the last 4 weeks, mice received hesperetin plus naringenin (HN), orange plus grapefruit juice (OGJ), orange juice (OJ), or grapefruit juice (GJ); whereas the asthmatic control (AC) group and non-asthmatic control (NC) group consumed water ad libitum. In histopathological examination, no goblet cells metaplasia was observed in the HN, OJ, and GJ groups; also, intra-alveolar macrophages decreased compared with those of the AC group. Hesperetin plus naringenin significantly decreased subepithelial fibrosis, smooth muscle hypertrophy in airways, and lung atelectasis compared with the AC group. Also, there was a reduction of subepithelial fibrosis in airways in OJ and GJ groups compared with AC group, but it was not noticed in OGJ group. In bronchoalveolar lavage fluid, macrophages numbers decreased in OJ and OGJ groups, whereas eosinophil numbers were increased in OJ group compared with NC group. Our finding revealed that hesperetin plus naringenin ameliorate airway structural remodeling more than orange juice and grapefruit juice in murine model of HDM-induced asthma.

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

    Directory of Open Access Journals (Sweden)

    Hofman Gerard A

    2004-11-01

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

  4. Moracin M inhibits airway inflammation by interrupting the JNK/c-Jun and NF-κB pathways in vitro and in vivo.

    Science.gov (United States)

    Lee, Ju Hee; Ko, Hae Ju; Woo, Eun-Rhan; Lee, Sang Kook; Moon, Bong Soo; Lee, Chan Woo; Mandava, Suresh; Samala, Mallesham; Lee, Jongkook; Kim, Hyun Pyo

    2016-07-15

    The therapeutic effectiveness of moracins as 2-arylbenzofuran derivatives against airway inflammation was examined. Moracin M, O, and R were isolated from the root barks of Morus alba, and they inhibited interleukin (IL)-6 production from IL-1β-treated lung epithelial cells (A549) at 101-00μM. Among them, moracin M showed the strongest inhibitory effect (IC50=8.1μM). Downregulation of IL-6 expression by moracin M was mediated by interrupting the c-Jun N-terminal kinase (JNK)/c-Jun pathway. Moracin derivatives inhibited inducible nitric oxide synthase (iNOS)-catalyzed NO production from lipopolysaccharide (LPS)-treated alveolar macrophages (MH-S) at 50-100μM. In particular, moracin M inhibited NO production by downregulating iNOS. When orally administered, moracin M (20-60mg/kg) showed comparable inhibitory action with dexamethasone (30mg/kg) against LPS-induced lung inflammation, acute lung injury, in mice with that of dexamethasone (30mg/kg). The action mechanism included interfering with the activation of nuclear transcription factor-κB in inflamed lungs. Therefore, it is concluded that moracin M inhibited airway inflammation in vitro and in vivo, and it has therapeutic potential for treating lung inflammatory disorders.

  5. Beneficial effects of cannabinoids (CB) in a murine model of allergen-induced airway inflammation: role of CB1/CB2 receptors.

    Science.gov (United States)

    Braun, Andrea; Engel, Tabea; Aguilar-Pimentel, Juan Antonio; Zimmer, Andreas; Jakob, Thilo; Behrendt, Heidrun; Mempel, Martin

    2011-04-01

    The endocannabinoid system (ECS) consists of two cannabinoid (CB) receptors, namely CB(1) and CB(2) receptor, and their endogenous (endocannabinoids) and exogenous (cannabinoids, e.g. delta-9-tetrahydrocannabinol (THC)) ligands which bind to these receptors. Based on studies suggesting a role of THC and the ECS in inflammation, the objective of this study was to examine their involvement in type I hypersensitivity using a murine model of allergic airway inflammation. THC treatment of C57BL/6 wildtype mice dramatically reduced airway inflammation as determined by significantly reduced total cell counts in bronchoalveolar lavage (BAL). These effects were greatest when mice were treated during both, the sensitization and the challenge phase. Furthermore, systemic immune responses were significantly suppressed in mice which received THC during sensitization phase. To investigate a role of CB(1/2) receptors in this setting, we used pharmacological blockade of CB(1) and/or CB(2) receptors by the selective antagonists and moreover CB(1)/CB(2) receptor double-knockout mice (CB(1)(-/-)/CB(2)(-/-)) and found neither significant changes in the cell patterns in BAL nor in immunoglobulin levels as compared to wildtype mice. Our results indicate that the activation of the ECS by applying the agonist THC is involved in the development of type I allergies. However, CB(1)/CB(2) receptor-independent signalling seems likely in the observed results.

  6. Positive correlation of airway resistance and serum asymmetric dimethylarginine level in COPD patients with systemic markers of low-grade inflammation

    Science.gov (United States)

    Tajti, Gabor; Gesztelyi, Rudolf; Pak, Krisztian; Papp, Csaba; Keki, Sandor; Szilasi, Magdolna Emma; Mikaczo, Angela; Fodor, Andrea; Szilasi, Maria; Zsuga, Judit

    2017-01-01

    The major feature of COPD is a progressive airflow limitation caused by chronic airway inflammation and consequent airway remodeling. Modified arginase and nitric oxide synthase (NOS) pathways are presumed to contribute to the inflammation and fibrosis. Asymmetric dimethylarginine (ADMA) may shunt L-arginine from the NOS pathway to the arginase one by uncoupling and competitive inhibition of NOS and by enhancing arginase activity. To attest the interplay of these pathways, the relationship between ADMA and airflow limitation, described by airway resistance (Raw), was investigated in a cohort of COPD patients. Every COPD patient willing to give consent to participate (n=74) was included. Case history, laboratory parameters, serum arginine and ADMA, pulmonary function (whole-body plethysmography), and disease-specific quality of life (St George’s Respiratory Questionnaire) were determined. Multiple linear regression was used to identify independent determinants of Raw. The final multiple model was stratified based on symptom control. The log Raw showed significant positive correlation with log ADMA in the whole sample (Pearson’s correlation coefficient: 0.25, P=0.03). This association remained significant after adjusting for confounders in the whole data set (β: 0.42; confidence interval [CI]: 0.06, 0.77; P=0.022) and in the worse-controlled stratum (β: 0.84; CI: 0.25, 1.43; P=0.007). Percent predicted value of forced expiratory flow between 25% and 75% of forced vital capacity showed that significant negative, elevated C-reactive protein exhibited significant positive relationship with Raw in the final model. Positive correlation of Raw with ADMA in COPD patients showing evidence of a systemic low-grade inflammation implies that ADMA contributes to the progression of COPD, probably by shunting L-arginine from the NOS pathway to the arginase one.

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Regulating effect of N-acetyl cysteine adjuvant therapy on airway inflammation, remodeling and so on in patients with stable COPD

    Institute of Scientific and Technical Information of China (English)

    Xiao-Feng Zhao

    2016-01-01

    Objective:To analyze the regulating effect of N-acetyl cysteine adjuvant therapy on airway inflammation, remodeling and so on in patients with stable COPD.Methods: A total of 108 cases of COPD patients who were treated in our hospital were included for study and were in stable phase after detection. According to different treatment methods, they were divided into control group 58 cases who received routine treatment and observation group 50 cases who received additional N-acetyl cysteine adjuvant therapy. Differences in levels of serum inflammation-related factors, airway remodeling indicators, Keap1-Nrf2-ARE signaling pathway, oxidation-antioxidation levels, etc were compared between two groups after treatment.Results: Serum MIP-1α, sTREM-1, IL-13, IL-8 and IP-10 values of observation group after treatment were lower than those of control group; serum TGF-β1 and Ang-Ⅱvalues of observation group after treatment were lower than those of control group, Ang-Ⅰ value was higher than that of control group and lesion bronchia T, WA and WA% values were lower than those of control group; Keap1, Nrf2 and ARE values in serum and induced sputum of observation group were higher than those of control group; serum MDA and LPO values of observation group were lower than those of control group while SOD, GSH-Px and T-AOX values were higher than those of control group.Conclusion:N-acetyl cysteine adjuvant therapy for patients with stable COPD optimizes airway inflammation, remodeling and so on, and is of positive significance in controlling long-term disease, improving outcome and so on.

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

    OpenAIRE

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

    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...

  10. IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization

    Science.gov (United States)

    Mäkelä, M. J.; Kanehiro, A.; Borish, L.; Dakhama, A.; Loader, J.; Joetham, A.; Xing, Z.; Jordana, M.; Larsen, G. L.; Gelfand, E. W.

    2000-05-01

    Cytokines play an important role in modulating inflammatory responses and, as a result, airway tone. IL-10 is a regulatory cytokine that has been suggested for treatment of asthma because of its immunosuppressive and anti-inflammatory properties. In contrast to these suggestions, we demonstrate in a model of allergic sensitization that mice deficient in IL-10 (IL-10/) develop a pulmonary inflammatory response but fail to exhibit airway hyperresponsiveness in both in vitro and in vivo assessments of lung function. Reconstitution of these deficient mice with the IL-10 gene fully restores development of airway hyperresponsiveness comparable to control mice. These results identify an important role of IL-10, downstream of the inflammatory cascade, in regulating the tone of the airways after allergic sensitization and challenge.

  11. Inflammation

    DEFF Research Database (Denmark)

    Holst-Hansen, Thomas

    Inflammation is an intricate response relying on the activation and response of both the innate immune system and the infected tissue to remove a threat. The pro-inflammatory NF-kappaB pathway has been studied extensively, among others because of its key role in regulation of inflammation. However...

  12. X-Ray based Lung Function measurement–a sensitive technique to quantify lung function in allergic airway inflammation mouse models

    Science.gov (United States)

    Dullin, C.; Markus, M. A.; Larsson, E.; Tromba, G.; Hülsmann, S.; Alves, F.

    2016-11-01

    In mice, along with the assessment of eosinophils, lung function measurements, most commonly carried out by plethysmography, are essential to monitor the course of allergic airway inflammation, to examine therapy efficacy and to correlate animal with patient data. To date, plethysmography techniques either use intubation and/or restraining of the mice and are thus invasive, or are limited in their sensitivity. We present a novel unrestrained lung function method based on low-dose planar cinematic x-ray imaging (X-Ray Lung Function, XLF) and demonstrate its performance in monitoring OVA induced experimental allergic airway inflammation in mice and an improved assessment of the efficacy of the common treatment dexamethasone. We further show that XLF is more sensitive than unrestrained whole body plethysmography (UWBP) and that conventional broncho-alveolar lavage and histology provide only limited information of the efficacy of a treatment when compared to XLF. Our results highlight the fact that a multi-parametric imaging approach as delivered by XLF is needed to address the combined cellular, anatomical and functional effects that occur during the course of asthma and in response to therapy.

  13. A novel small compound SH-2251 suppresses Th2 cell-dependent airway inflammation through selective modulation of chromatin status at the Il5 gene locus.

    Directory of Open Access Journals (Sweden)

    Junpei Suzuki

    Full Text Available IL-5 is a key cytokine that plays an important role in the development of pathological conditions in allergic inflammation. Identifying strategies to inhibit IL-5 production is important in order to establish new therapies for treating allergic inflammation. We found that SH-2251, a novel thioamide-related small compound, selectively inhibits the differentiation of IL-5-producing Th2 cells. SH-2251 inhibited the induction of active histone marks at the Il5 gene locus during Th2 cell differentiation. The recruitment of RNA polymerase II, and following expression of the Th2 cell-specific intergenic transcripts around the Il5 gene locus was also inhibited. Furthermore, Th2 cell-dependent airway inflammation in mice was suppressed by the oral administration of SH-2251. Gfi1, a transcriptional repressor, was identified as a downstream target molecule of SH-2251 using a DNA microarray analysis. The Gfi1 expression dramatically decreased in SH-2251-treated Th2 cells, and the SH-2251-mediated inhibition of IL-5-producing Th2 cell differentiation was restored by transduction of Gfi1. Therefore, our study unearthed SH-2251 as a novel therapeutic candidate for allergic inflammation that selectively inhibits active histone marks at the Il5 gene locus.

  14. A novel small compound SH-2251 suppresses Th2 cell-dependent airway inflammation through selective modulation of chromatin status at the Il5 gene locus.

    Science.gov (United States)

    Suzuki, Junpei; Kuwahara, Makoto; Tofukuji, Soichi; Imamura, Masashi; Kato, Fuminori; Nakayama, Toshinori; Ohara, Osamu; Yamashita, Masakatsu

    2013-01-01

    IL-5 is a key cytokine that plays an important role in the development of pathological conditions in allergic inflammation. Identifying strategies to inhibit IL-5 production is important in order to establish new therapies for treating allergic inflammation. We found that SH-2251, a novel thioamide-related small compound, selectively inhibits the differentiation of IL-5-producing Th2 cells. SH-2251 inhibited the induction of active histone marks at the Il5 gene locus during Th2 cell differentiation. The recruitment of RNA polymerase II, and following expression of the Th2 cell-specific intergenic transcripts around the Il5 gene locus was also inhibited. Furthermore, Th2 cell-dependent airway inflammation in mice was suppressed by the oral administration of SH-2251. Gfi1, a transcriptional repressor, was identified as a downstream target molecule of SH-2251 using a DNA microarray analysis. The Gfi1 expression dramatically decreased in SH-2251-treated Th2 cells, and the SH-2251-mediated inhibition of IL-5-producing Th2 cell differentiation was restored by transduction of Gfi1. Therefore, our study unearthed SH-2251 as a novel therapeutic candidate for allergic inflammation that selectively inhibits active histone marks at the Il5 gene locus.

  15. Detrimental effects of albuterol on airway responsiveness requires airway inflammation and is independent of β-receptor affinity in murine models of asthma

    Directory of Open Access Journals (Sweden)

    Aimi Steven

    2011-03-01

    Full Text Available Abstract Background Inhaled short acting β2-agonists (SABA, e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR and airway hyperresponsiveness (AHR in mouse models of asthma. Methods Balb/C mice were sensitized and challenged with ovalbumin (OVA and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS-albuterol or the single isomers (S- and (R-albuterol twice daily over 7 days prior to harvest. Results We found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol. Conclusions We conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S-albuterol, which lacks affinity for the β2-receptor, did not differ from (R-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.

  16. Airway Remodelling in Asthma and COPD: Findings, Similarities, and Differences Using Quantitative CT

    Directory of Open Access Journals (Sweden)

    Gaël Dournes

    2012-01-01

    Full Text Available Airway remodelling is a well-established feature in asthma and chronic obstructive lung disease (COPD, secondary to chronic airway inflammation. The structural changes found on pathological examination of remodelled airway wall have been shown to display similarities but also differences. Computed tomography (CT is today a remarkable tool to assess airway wall morphology in vivo since submillimetric acquisitions over the whole lung volume could be obtained allowing 3D evaluation. Recently, CT-derived indices extracted from CT images have been described and are thought to assess airway remodelling. This may help understand the complex mechanism underlying the remodelling process, which is still not fully understood. This paper summarizes the various methods described to quantify airway remodelling in asthma and COPD using CT, and similarities and differences between both diseases will be emphasized.

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

    DEFF Research Database (Denmark)

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

    2007-01-01

    , 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...

  18. Treating asthma means treating airway smooth muscle cells

    NARCIS (Netherlands)

    Zuyderduyn, S; Sukkar, M B; Fust, A; Dhaliwal, S; Burgess, J K

    2008-01-01

    Asthma is characterised by airway hyperresponsiveness, airway inflammation and airway remodelling. Airway smooth muscle cells are known to be the main effector cells of airway narrowing. In the present paper, studies will be discussed that have led to a novel view of the role of airway smooth muscle

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

    Directory of Open Access Journals (Sweden)

    Bunn Janice Y

    2010-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Yun Ho Choi

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

  1. A Recombinant DNA Plasmid Encoding the sIL-4R-NAP Fusion Protein Suppress Airway Inflammation in an OVA-Induced Mouse Model of Asthma.

    Science.gov (United States)

    Liu, Xin; Fu, Guo; Ji, Zhenyu; Huang, Xiabing; Ding, Cong; Jiang, Hui; Wang, Xiaolong; Du, Mingxuan; Wang, Ting; Kang, Qiaozhen

    2016-08-01

    Asthma is a chronic inflammatory airway disease. It was prevalently perceived that Th2 cells played the crucial role in asthma pathogenesis, which has been identified as the important target for anti-asthma therapy. The soluble IL-4 receptor (sIL-4R), which is the decoy receptor for Th2 cytokine IL-4, has been reported to be effective in treating asthma in phase I/II clinical trail. To develop more efficacious anti-asthma agent, we attempt to test whether the Helicobacter pylori neutrophil-activating protein (HP-NAP), a novel TLR2 agonist, would enhance the efficacy of sIL-4R in anti-asthma therapy. In our work, we constructed a pcDNA3.1-sIL-4R-NAP plasmid, named PSN, encoding fusion protein of murine sIL-4R and HP-NAP. PSN significantly inhibited airway inflammation, decreased the serum OVA-specific IgE levels and remodeled the Th1/Th2 balance. Notably, PSN is more effective on anti-asthma therapy comparing with plasmid only expressing sIL-4R.

  2. Suppression of ovalbumin-induced Th2-driven airway inflammation by β-sitosterol in a guinea pig model of asthma.

    Science.gov (United States)

    Mahajan, Shailaja G; Mehta, Anita A

    2011-01-10

    In the present study, the efficacy of β-sitosterol isolated from an n-butanol extract of the seeds of the plant Moringa oleifera (Moringaceae) was examined against ovalbumin-induced airway inflammation in guinea pigs. All animals (except group I) were sensitized subcutaneously and challenged with aerosolized 0.5% ovalbumin. The test drugs, β-sitosterol (2.5mg/kg) or dexamethasone (2.5mg/kg), were administered to the animals (p.o.) prior to challenge with ovalbumin. During the experimental period (on days 18, 21, 24 and 29), a bronchoconstriction test (0.25% acetylcholine for 30s) was performed and lung function parameters (tidal volume and respiration rate) were measured for each animal. On day 30, blood and bronchoalveolar lavaged fluid were collected to assess cellular content, and serum was collected for cytokine assays. Lung tissue was utilized for a histamine assay and for histopathology. β-sitosterol significantly increased the tidal volume (V(t)) and decreased the respiration rate (f) of sensitized and challenged guinea pigs to the level of non-sensitized control guinea pigs and lowered both the total and differential cell counts, particularly eosinophils and neutrophils, in blood and bronchoalveolar lavaged fluid. Furthermore, β-sitosterol treatment suppressed the increase in cytokine levels (TNFα, IL-4 and IL-5), with the exception of IL-6, in serum and in bronchoalveolar lavaged fluid detected in model control animals. Moreover, treatment with β-sitosterol protected against airway inflammation in lung tissue histopathology. β-sitosterol possesses anti-asthmatic actions that might be mediated by inhibiting the cellular responses and subsequent release/synthesis of Th2 cytokines. This compound may have therapeutic potential in allergic asthma.

  3. Role of Chitinase 3-Like-1 in Interleukin-18-Induced Pulmonary Type 1, Type 2, and Type 17 Inflammation; Alveolar Destruction; and Airway Fibrosis in the Murine Lung.

    Science.gov (United States)

    Kang, Min-Jong; Yoon, Chang Min; Nam, Milang; Kim, Do-Hyun; Choi, Je-Min; Lee, Chun Geun; Elias, Jack A

    2015-12-01

    Chitinase 3-like 1 (Chi3l1), which is also called YKL-40 in humans and BRP-39 in mice, is the prototypic chitinase-like protein. Recent studies have highlighted its impressive ability to regulate the nature of tissue inflammation and the magnitude of tissue injury and fibroproliferative repair. This can be appreciated in studies that highlight its induction after cigarette smoke exposure, during which it inhibits alveolar destruction and the genesis of pulmonary emphysema. IL-18 is also known to be induced and activated by cigarette smoke, and, in murine models, the IL-18 pathway has been shown to be necessary and sufficient to generate chronic obstructive pulmonary disease-like inflammation, fibrosis, and tissue destruction. However, the relationship between Chi3l1 and IL-18 has not been defined. To address this issue we characterized the expression of Chi3l1/BRP-39 in control and lung-targeted IL-18 transgenic mice. We also characterized the effects of transgenic IL-18 in mice with wild-type and null Chi3l1 loci. The former studies demonstrated that IL-18 is a potent stimulator of Chi3l1/BRP-39 and that this stimulation is mediated via IFN-γ-, IL-13-, and IL-17A-dependent mechanisms. The latter studies demonstrated that, in the absence of Chi3l1/BRP-39, IL-18 induced type 2 and type 17 inflammation and fibrotic airway remodeling were significantly ameliorated, whereas type 1 inflammation, emphysematous alveolar destruction, and the expression of cytotoxic T lymphocyte perforin, granzyme, and retinoic acid early transcript 1 expression were enhanced. These studies demonstrate that IL-18 is a potent stimulator of Chi3l1 and that Chi3l1 is an important mediator of IL-18-induced inflammatory, fibrotic, alveolar remodeling, and cytotoxic responses.

  4. CCR3 monoclonal antibody inhibits airway eosinophilic inflammation and mucus overproduction in a mouse model of asthma

    Institute of Scientific and Technical Information of China (English)

    Hua-hao SHEN; Feng XU; Gen-sheng ZHANG; Shao-bin WANG; Wei-hua XU

    2006-01-01

    Aim: To explore the effect of a rat anti-mouse CC-chemokine receptor-3 (CCR3) monoclonal antibody (CCR3 mAb) on airway eosinophilia and mucus overproduction in asthmatic mice. Methods: An asthma model was sensitized and challenged by ovalbumin (OVA) in male C57BL/6 mice. Asthmatic mice were given dual administration (intraperitoneal injection and aerosol inhalation) of CCR3 mAb or nonspecific rat IgG (ns-IgG). The number of total and differential inflammatory cells in the bronchial alveolar lavage fluid (BALF) was counted. Eosinophils number, the goblet cell percentage (GCP) and airway mucus index (AMI) were measured in the lung tissues. Interleukin (IL)-5 levels in the BALF were examined. The expression of MUC5AC and the epidermal growth factor receptor (EGFR) mRNA in the lung tissues was detected by semi-quantitative RT-PCR. The results were compared among the groups. Results: CCR3 mAb significantly suppressed the increased eosinophils in the BALF and lung tissues in OVA-challenged mice compared with ns-IgG-treated mice. IL-5 levels in the BALF in CCR3 mAb and ns-IgG administration mice exhibited no obvious changes relative to OVA-challenged asthmatic mice. CCR3 mAb reduced the increased GCP and AMI after OVA challenge and decreased the enhanced expression of MUC5AC and EGFR mRNA in lung tissues in asthmatic animals. Conclusion: CCR3 mAb can significantly inhibit airway eosinophilia and mucus overproduction in asthmatic mice. Blockage of CCR3 may represent a new strategy to asthma therapy.

  5. Warm SPA-induced hyperthermia confers protection to rats against airway inflammation evoked by capsaicin and substance P.

    Science.gov (United States)

    Fu, Yaw-Syan; Wang, Peng-Han; Liu, Shang-Pin; Huang, Wen-Hung; Huang, Hung-Tu

    2010-06-24

    Solus par aqua (SPA) is a traditional health care therapy. Warm SPA may enhance immunity and cellular defense to protect body against diseases. The present study investigated whether the warm SPA could confer protection to neurogenic inflammation in rats. The rats were immersed in water where the body core temperatures were maintained at hyperthermia (41.5 degrees C) or normothermia (37 degrees C) for a period of 15min. After SPA for 1 or 6 days, neurogenic inflammation was induced by intravenous injection of capsaicin (90microg/kg) or substance P (SP; 3microg/kg). The plasma leakage and arterial pressures in rats after neurogenic inflammation were monitored. The extent of capsaicin- or SP-induced plasma leakage and hypotension was significantly attenuated in rats on day 1 after SPA hyperthermia. However, such resistance to neurogenic inflammation was not found on day 6 after hyperthermia. Western blotting analysis showed that the expression of heat shock protein 72 (HSP 72) in the trachea on days 1 and 2 after hyperthermia was 9.61-fold and 6.66-fold, respectively, of that in normothermia. Afterwards, the hyperthermia-induced HSP 72 upregulation gradually declined in a time-dependent manner. Thus, SPA hyperthermia may protect rats against neurogenic inflammation through modulation of HSP expression.

  6. Elevated circulating PAI-1 levels are related to lung function decline, systemic inflammation, and small airway obstruction in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Wang H

    2016-09-01

    Full Text Available Hao Wang,1,2,* Ting Yang,1,2,* Diandian Li,1,2 Yanqiu Wu,1,2 Xue Zhang,1,2 Caishuang Pang,1,2 Junlong Zhang,3 Binwu Ying,3 Tao Wang,1,2 Fuqiang Wen1,2 1Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China *These authors contributed equally to this work Background: Plasminogen activator inhibitor-1 (PAI-1 and soluble urokinase-type plasminogen activator receptor (suPAR participate in inflammation and tissue remolding in various diseases, but their roles in chronic obstructive pulmonary disease (COPD are not yet clear. This study aimed to investigate if PAI-1 and suPAR were involved in systemic inflammation and small airway obstruction (SAO in COPD. Methods: Demographic and clinical characteristics, spirometry examination, and blood samples were obtained from 84 COPD patients and 51 healthy volunteers. Serum concentrations of PAI-1, suPAR, tissue inhibitor of metalloproteinase-1 (TIMP-1, Matrix metalloproteinase-9 (MMP-9, and C-reactive protein (CRP were detected with Magnetic Luminex Screening Assay. Differences between groups were statistically analyzed using one-way analysis of variance or chi-square test. Pearson’s partial correlation test (adjusted for age, sex, body mass index, cigarette status, and passive smoke exposure and multivariable linear analysis were used to explore the relationships between circulating PAI-1 and indicators of COPD. Results: First, we found that serum PAI-1 levels but not suPAR levels were significantly increased in COPD patients compared with healthy volunteers (125.56±51.74 ng/mL versus 102.98±36.62 ng/mL, P=0.007. Then, the

  7. Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice

    NARCIS (Netherlands)

    Kistemaker, Loes E.M.; van Os, Ronald P.; Dethmers-Ausema, Albertina; Bos, I. Sophie T.; Hylkema, Machteld N.; van den Berge, Maarten; Hiemstra, Pieter S; Wess, Jürgen; Meurs, Herman; Kerstjens, Huib A.M.; Gosens, Reinoud

    2015-01-01

    Anticholinergics, blocking the muscarinic M-3 receptor, are effective bronchodilators for patients with chronic obstructive pulmonary disease. Recent evidence from M-3 receptor-deficient mice (M3R-/-) indicates that M-3 receptors also regulate neutrophilic inflammation in response to cigarette smoke

  8. The environmental pollutant hexachlorobenzene causes eosinophilic and granulomatous inflammation and in vitro airways hyperreactivity in the Brown Norway rat

    Energy Technology Data Exchange (ETDEWEB)

    Michielsen, C.; Zeamari, S.; Vos, J. [Department of Pathology, Faculty of Veterinary Medicine, Utrecht University (Netherlands); Leusink-Muis, A.; Bloksma, N. [Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences and Faculty of Biology, Utrecht University, Utrecht (Netherlands)

    2002-05-01

    Based on observations that the persistent environmental pollutant hexachlorobenzene (HCB) induces inflammatory skin lesions and eosinophilic and granulomatous lung pathology as well as in vivo airways hyperresponsiveness to methacholine in the BN/SsNOlaHsd rat (Michielsen et al., Toxicol Appl Pharmacol 172:11-20, 2001), which are features of human Churg-Strauss syndrome (CSS), we have investigated whether HCB induced other features of CSS such as asthma and systemic vasculitis involving the heart and kidneys in this strain of rat. To this end, BN/SsNOlaHsd rats received control feed or feed supplemented with 450 mg/kg HCB. On days 6, 14 or 21, tracheas were isolated to assess non-specific in vitro airways hyperresponsiveness (AHR) to cumulative concentrations of arecoline and serotonin. In addition, lungs were lavaged to count and differentiate lavage cells, and skin, lungs, heart, kidneys, and lymph nodes were processed for histopathological investigation. HCB induced eosinophilic and granulomatous lung pathology in the BN/SsNOlaHsd rat, which became more severe with time and was associated with significant in vitro AHR to arecoline. Moreover, as in CSS-patients, systemic effects on spleen and lymph nodes were observed in HCB-fed BN/SsNOlaHsd rats, as well as development of skin lesions with vascular changes and eosinophilic infiltrates. In contrast, cardiac or renal involvement, frequently seen in CSS-patients, was not seen in HCB-fed rats. More importantly, there were no indications of necrotizing vasculitis, a hallmark feature of CSS, in the lungs and skin of BN/SsNOlaHsd rats. Thus, it is concluded that the persistent environmental pollutant HCB possibly induces a mild or early stage of CSS in the BN/SsNOlaHsd rat that may evolve into fully developed CSS after prolonged exposure to HCB. (orig.)

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

    Directory of Open Access Journals (Sweden)

    Shin In-Sik

    2012-10-01

    Full Text Available Abstract 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.

  10. Increase in markers of airway inflammation after ozone exposure can be observed also in stable treated asthmatics with minimal functional response to ozone

    Directory of Open Access Journals (Sweden)

    Dente Federico L

    2010-01-01

    Full Text Available Abstract Background The discrepancy between functional and inflammatory airway response to ozone has been reported in normal subjects, but few data are available for stable asthmatics regularly treated with inhaled corticosteroids. Methods Twenty-three well controlled, regularly treated, mild-to-moderate asthmatic patients underwent two sequential randomised exposures to either filtered air or ozone (0.3 ppm for 2 hours in a challenge chamber. Pulmonary function (PF was monitored, and patients with FEV1 decrease greater than 10% from pre-challenge value were considered as responders. Immediately after each exposure, exhaled breath condensate (EBC was collected to measure malondialdehyde (MDA. Six hours after each exposure, PF and EBC collection were repeated, and sputum was induced to measure inflammatory cell counts and soluble mediators (IL-8 and neutrophil elastase. The response to ozone was also evaluated according to the presence of polymorphism in oxidative stress related NQO1 and GSTM1 genes. Results After ozone exposure, sputum neutrophils significantly increased in responders (n = 8, but not in nonresponders (n = 15. Other markers of neutrophil activation in sputum supernatant and MDA in EBC significantly increased in all patients, but only in nonresponders the increase was significant. In nonresponders, sputum eosinophils also significantly increased after ozone. There was a positive correlation between ozone-induced FEV1 fall and increase in sputum neutrophils. No difference in functional or inflammatory response to ozone was observed between subjects with or without the combination of NQO1wt- GSTM1null genotypes. Conclusions Markers of neutrophilic inflammation and oxidative stress increase also in asthmatic subjects not responding to ozone. A greater functional response to ozone is associated with greater neutrophil airway recruitment in asthmatic subjects.

  11. The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD.

    Directory of Open Access Journals (Sweden)

    Kirsty E Russell

    Full Text Available Macrophage migration inhibitory factor (MIF is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD, a relatively steroid insensitive inflammatory disease is unclear, however.Sputum, bronchoalveolar lavage (BAL macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays.MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR.MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.

  12. DNA vaccine encoding Der p 2 allergen generates immunologic protection in recombinant Der p 2 allergen-induced allergic airway inflammation mice model

    Institute of Scientific and Technical Information of China (English)

    LI Guo-ping; LIU Zhi-gang; QIU Jing; RAN Pi-xin; ZHONG Nan-shan

    2005-01-01

    Background DNA immunization is a promising novel type of immunotherapy against allergy. An estimated 79.2% patients with asthma, wheezing and/or rhinitis suffer from Dermatophagoides pteronyssinus group 2 (Der p 2) allegen. The aim of the present study was to determine whether DNA vaccine encoding Der p 2 could generate immunologic protection in recombinant Der p 2 (rDer p 2) allergen-induced allergic airway inflammation mice model and to understand the role of DNA vaccination in specific-allergen immunotherapy for asthma. Methods After DNA vaccination, BALB/c mice were sensitized by intraperitoneal injection (i.p) and challenged by intranasal instillation of rDer p 2. The lung tissues were assessed using hematoxylin and eosin. Mucus-producing goblet cells were identifed using periodic acid-Schiff(PAS)/alcian blue. The total cell number and composition of bronchoalveolar lavage samples were determined. The levels of the cytokines IL-4 and IFN-γ, as well as IgE and IgG2a in the serum were determined by enzyme-linked immunosorbent assay. Allergen-specific IL-4 and IFN-γ production by spleen cells were also measured by enzyme-linked immunosorbent assay. Expression of signal transducer and activator of transcription 6 (STAT6) in splenocytes were determined by Western blot. Results DNA vaccine encoding Der p 2 allergen inhibited extensive infiltration of inflammatory cells and production of mucin induced by allergen. The influx of eosinophils into the lung interstitium was significantly reduced after administration of DNA vaccine. Significant reductions of IL-4 and increase in levels of IFN-γ in bronchoalveolar lavage fluid were observed. The allergen-specific IgE was markedly decreased in mice receiving DNA vaccination. Allergen could induce higher IFN-γ, weaker IL-4 in cultured spleen cells from mice receiving DNA vaccine. DNA vaccination inhibited STAT6 expression of spleen cells induced by allergen. Conclusion These results indicated that DNA vaccine encoding

  13. 茶多酚对哮喘大鼠气道炎症和气道重塑的干预研究%The Effects of Tea Polyphenols on Airway Inflammation and Airway Remodeling in Asthmatic Rats

    Institute of Scientific and Technical Information of China (English)

    杨青; 王尧; 李里香; 况九龙

    2012-01-01

    目的:研究茶多酚(TP)对支气管哮喘大鼠早期和晚期气道氧化应激水平及气道炎症、气道重塑的影响.方法:48只大鼠随机分对照组、哮喘组、早布地奈德(BUD)组、晚BUD组、早TP组和晚TP组,每组8只.早BUD组、早TP组在造模前2周药物干预,晚BUD组、晚TP组在造模5周后药物干预.造模12周时观察各项指标.测定支气管壁的平滑肌面积、胶原沉积面积,以及肺组织转化生长因子-β1 (TGF-β1)的表达.测定肺组织TGF-β1含量、丙二醛(MDA)含量及超氧化物歧化酶(SOD)活力.结果:早TP组、晚TP组、早BUD组干预后支气管壁平滑肌面积、胶原沉积面积和TGF-β1含量较哮喘组均有改善(P<0.05或P<0.01).晚BUD组较哮喘组无明显改善(P>0.05).哮喘组肺组织中MDA含量明显上升,SOD活性显著下降,与对照组比较差异有统计学意义(P<0.01);各药物干预后SOD活性均上升,MDA含量均下降,以早TP组最明显(P<0.01).SOD活性与MDA含量呈负相关,TGF-β1含量与MDA含量呈正相关.结论:茶多酚可能通过清除氧自由基,减少气道炎症及氧化应激,从而改善或延缓气道重塑的发生.%Objective: To observe the effects of tea polyphenols (TP) on oxidative stress level, airway inflammation and airway remodeling of early stage and late stage in asthmatic rats. Methods: Forty-eight rats were randomly divided into 6 groups, normal saline group, asthma group, early budesonide (early BUD) group, late BUD group, early TP group and late TP group. Drugs were administrated 2 weeks before sensitizing in early BUD group and early TP group, and administrated 5 weeks after sensitizing in late BUD group and late TP group. The lung tissues were harvested from rats 12 weeks after sensitizing. The smooth muscle area, collagen deposition area and the expression of transforming growth factor-β1 (TGF-βl) were assessed in bronchi and lung tissues. The contents of TGF-β1, malondialdehyde (MDA) and

  14. DNA vaccine encoding Der p2 allergen down-regulates STAT6 expression in mouse model of allergen-induced allergic airway inflammation

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background Activation of signal transducer and activator of transcription 6 (STAT6 ) plays a critical role in the late phase of Th2-dependent allergy induction. STAT6 is essential to Th2 cell differentiation, recruitment, and effector function. Our previous study confirmed that DNA vaccination inhibited STAT6 expression of spleen cells induced by allergen. In the present study, we determined whether DNA vaccine encoding Dermatophagoides pteronyssinus group 2 (Der p2 ) could down-regulate the expression and activation of STAT6 in lung tissue from asthmatic mice.Methods After DNA vaccine immunization, BALB/c mice were sensitized by intraperitoneal injection and challenged by intranasal instillation of rDer p2. The levels of the cytokines IL-4 and IL-13 in BAL fluid were measured by enzyme-linked immunosorbent assay. The lung tissue was assessed by immunohistochemical staining with anti-STAT6. The protein expression of STAT6 was determined by Western blot. The activation of STAT6 binding ability was analyzed with electrophoretic mobility shift assay.Results DNA vaccine encoding Der p2 allergen effectively decreased the levels of IL-4 and IL-13 in the asthmatic mice. Histological evidence and Western blot showed that the expression of STAT6 in the DNA treated mice was markedly attenuated. STAT6 binding to specific DNA motif in lung tissue from the gene vaccinated mice was inhibited.Conclusion DNA vaccine encoding Der p2 prevents allergic pulmonary inflammation probably by inhibiting the STAT6 signaling pathway in mice with Der p2 allergen-induced allergic airway inflammation.

  15. Anti-inflammatory effects of Tat-Annexin protein on ovalbumin-induced airway inflammation in a mouse model of asthma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sun Hwa; Kim, Dae Won; Kim, Hye Ri; Woo, Su Jung; Kim, So Mi; Jo, Hyo Sang [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Jeon, Seong Gyu [Department of Life Science, Pohang University of Science and Technology, Pohang 790-784 (Korea, Republic of); Cho, Sung-Woo [Department of Biochemistry and Molecular Biology, University of Ulsan, College of Medicine, Seoul 138-736 (Korea, Republic of); Park, Jong Hoon [Department of Biological Science, Sookmyung Women' s University, Seoul 140-742 (Korea, Republic of); Won, Moo Ho [Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701 (Korea, Republic of); Park, Jinseu [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Eum, Won Sik, E-mail: wseum@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Choi, Soo Young, E-mail: sychoi@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of)

    2012-01-20

    Highlights: Black-Right-Pointing-Pointer We construct a cell permeable Tat-ANX1 fusion protein. Black-Right-Pointing-Pointer We examined the protective effects of Tat-ANX1 protein on OVA-induced asthma in animal models. Black-Right-Pointing-Pointer Transduced Tat-ANX1 protein protects from the OVA-induced production of cytokines and eosinophils in BAL fluid. Black-Right-Pointing-Pointer Tat-ANX1 protein markedly reduced OVA-induced MAPK in lung tissues. Black-Right-Pointing-Pointer Tat-ANX1 protein could be useful as a therapeutic agent for lung disorders including asthma. -- Abstract: Chronic airway inflammation is a key feature of bronchial asthma. Annexin-1 (ANX1) is an anti-inflammatory protein that is an important modulator and plays a key role in inflammation. Although the precise action of ANX1 remains unclear, it has emerged as a potential drug target for inflammatory diseases such as asthma. To examine the protective effects of ANX1 protein on ovalbumin (OVA)-induced asthma in animal models, we used a cell-permeable Tat-ANX1 protein. Mice sensitized and challenged with OVA antigen had an increased amount of cytokines and eosinophils in their bronchoalveolar lavage (BAL) fluid. However, administration of Tat-ANX1 protein before OVA challenge significantly decreased the levels of cytokines (interleukin (IL)-4, IL-5, and IL-13) and BAL fluid in lung tissues. Furthermore, OVA significantly increased the activation of mitogen-activated protein kinase (MAPK) in lung tissues, whereas Tat-ANX1 protein markedly reduced phosphorylation of MAPKs such as extracellular signal-regulated protein kinase, p38, and stress-activated protein kinase/c-Jun N-terminal kinase. These results suggest that transduced Tat-ANX1 protein may be a potential protein therapeutic agent for the treatment of lung disorders including asthma.

  16. The effect of short-term withdrawal from continuous positive airway pressure therapy on sympathetic activity and markers of vascular inflammation in subjects with obstructive sleep apnoea.

    Science.gov (United States)

    Phillips, Craig L; Yang, Qiao; Williams, Andrew; Roth, Michael; Yee, Brendon J; Hedner, Jan A; Berend, Norbert; Grunstein, Ronald R

    2007-06-01

    Obstructive sleep apnoea (OSA) is commonly associated with cardiovascular disease and sympathetic activation. However, it is unclear whether this association is independent of obesity and to what extent treatment with nasal continuous positive airway pressure (CPAP) alleviates the vascular inflammation that underpins cardiovascular disease. We therefore evaluated whether short-term withdrawal from CPAP therapy in subjects with moderate-severe OSA would result in increased levels of sympathetic activity and circulating inflammatory cytokines independent of weight. Vascular inflammatory markers (hsCRP, hsIL-6 and hsTNF-alpha) were assessed in 20 subjects after one and seven nights of withdrawal from CPAP together with the hypoxia-responsive angiogenic marker VEGF and urinary catecholamines. Compared with baseline on CPAP, withdrawal from therapy resulted in an immediate return of OSA with an increase in RDI to 26.7 +/- 5.2 and 39.0 +/- 5.9 events per hour after one and seven nights without CPAP, respectively (both P 0.1). In conclusion, 1 week of CPAP withdrawal was associated with a return of OSA and a marked increase in sympathetic activity without a concomitant elevation of vascular inflammatory markers.

  17. Burkholderia cenocepacia K56-2 trimeric autotransporter adhesin BcaA binds TNFR1 and contributes to induce airway inflammation.

    Science.gov (United States)

    Mil-Homens, Dalila; Pinto, Sandra N; Matos, Rute G; Arraiano, Cecília; Fialho, Arsenio M

    2017-04-01

    Chronic lung disease caused by persistent bacterial infections is a major cause of morbidity and mortality in patients with cystic fibrosis (CF). CF pathogens acquire antibiotic resistance, overcome host defenses, and impose uncontrolled inflammation that ultimately may cause permanent damage of lungs' airways. Among the multiple CF-associated pathogens, Burkholderia cenocepacia and other Burkholderia cepacia complex bacteria have become prominent contributors of disease progression. Here, we demonstrate that BcaA, a trimeric autotransporter adhesin (TAA) from the epidemic strain B. cenocepacia K56-2, is a tumor necrosis factor receptor 1-interacting protein able to regulate components of the tumor necrosis factor signaling pathway and ultimately leading to a significant production of the proinflammatory cytokine IL-8. Notably, this study is the first to demonstrate that a protein belonging to the TAA family is involved in the induction of the inflammatory response during B. cenocepacia infections, contributing to the success of the pathogen. Moreover, our results reinforce the relevance of the TAA BcaA as a multifunctional protein with a major role in B. cenocepacia virulence.

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

    Directory of Open Access Journals (Sweden)

    Silvia Schnyder-Candrian

    2012-01-01

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

  19. Nitrites in induced sputum as a simple and cheap non-invasive marker of airway inflammation for asthmatic schoolchildren.

    Science.gov (United States)

    Recabarren, Arturo; Apaza, Carlos; Castro-Rodríguez, José A

    2008-08-01

    To determine if there are differences in the nitric oxide metabolites (nitrites) in sputum of patients with persistent asthma and healthy schoolchildren, we performed a case-control study in a tertiary care hospital in Arequipa, Perú. Nitrites in induced sputum samples were measured using the Griess assay in 30 persistent asthmatics (mean age of 10.1 yr) and 30 controls (mean age of 11.9 yr). The mean +/- s.d. of nitrites among asthmatics was significantly higher than the controls (16.30 +/- 8.6 vs. 10.25 +/- 4.68 nmol/ml, respectively, p = 0.001). Moreover, the nitrite level in the sputum in children with severe persistent asthma was higher than in the level found in the moderate and mild asthmatics (32.83 +/- 9.48 vs. 18.10 +/- 1.96 vs. 11.84 +/- 4.73 nmol/ml, respectively, p < 0.01 for linear trend). This study showed for the first time in children that asthmatics have significantly higher levels of nitrites in induced sputum than healthy controls and that the level of nitrite correlates with the severity of the asthma. Nitrite levels in sputum, a simple and cheap, non-invasive method, may be a good alternative to measure the severity of inflammation in asthmatic children.

  20. Exposure to multi-walled carbon nanotubes results in aggravation of airway inflammation and remodeling and in increased production of epithelium-derived innate cytokines in a mouse model of asthma.

    Science.gov (United States)

    Ronzani, Carole; Casset, Anne; Pons, Françoise

    2014-02-01

    With the development of nanotechnologies, the potential adverse effects of nanomaterials such as multi-walled carbon nanotubes (MWCNT) on the respiratory tract of asthmatics are questioned. Furthermore, investigations are necessary to understand how these effects might arise. In the present study, we hypothesized that epithelium-derived innate cytokines that are considered as important promoting factors in allergy may contribute to an aggravating effect of MWCNT on asthma. We investigated in the mouse the effect of MWCNT on systemic immune response and airway inflammation and remodeling induced by the most frequent allergen so far associated with asthma, house dust mite (HDM), and we examined the production of the innate cytokines thymic stromal lymphopoietin (TSLP), IL-25, IL-33, and GM-CSF. Mice exposed to HDM exhibited specific IgG1 in serum and inflammatory cell infiltration, and increased Th2 cytokine production, mucus hyperproduction, and collagen deposition in the airways when compared to naïve animals. Levels of total IgG1 and HDM-specific IgG1, influx of macrophages, eosinophils and neutrophils, production of collagen, TGF-β1, and mucus, as well as levels of IL-13, eotaxin, and TARC, were dose-dependently increased in mice exposed to HDM and MWCNT compared to HDM alone. These effects were associated with an increased production of TSLP, IL-25, IL-33, and GM-CSF in the airways. Our data demonstrate that MWCNT increase in a dose-dependent manner systemic immune response, as well as airway allergic inflammation and remodeling induced by HDM in the mouse. Our data suggest also a role for airway epithelium and innate cytokines in these effects.

  1. Effect of nitrated pollen on airway inflammation in asthmatic mice%硝化花粉对哮喘小鼠气道炎症的影响

    Institute of Scientific and Technical Information of China (English)

    杨玲; 韩丽; 王根发; 田烨; 周妍

    2013-01-01

    Objective To observe the allergic airway inflammation and lung pathology in mice with asthma induced by nitrated pollen. Methods Sixty mice were randomly divided into 5 groups according to different sensitization and challenge. Group A to group D were asthma model groups, and group E was normal control group. The right lung tissues of mice were obtained, the pathological changes of lung tissues were observed with HE staining, and the tracheal wall thickness (total wall area/basement membrane perimeter, WAt/Pbm) and airway smooth muscle thickness (smooth muscle area/ basement membrane perimeter, WAm/Pbm) were calculated. The cytological changes in bronchoalveolar lavage fluid ( BALF) were observed, the level of nuclear factor kappa B ( NF-KB) p65 activation and expression of 3-nitrotyrosine (3-NT) in lung tissues were determined by immunohistochemieal method, and the apoptosis of eosinophils (EOS) in lung tissues was detected by TUNEL. Results The numbers of white cells, EOS and neutrophil ( NEU) and percents of them in total cells in BALF, WAt/Pbm and WAm/Pbm, the level of NF-KB p65 activation and expression of 3-NT in each asthma model group were significantly higher than those in group E (P < 0.01), while the apoptosis rate of eosinophils in lung tissues in each group was significantly lower than that in group E (P<0.01). Compared with the other model groups, the values of those indicators in group D in which mice were immunized and challenged with nitrated pollen changed more significantly (P<0.05 or P < 0.01). Pearson correlation analysis revealed that the expression of 3-NT was significantly negatively correlated with apoptosis rate of EOS (r= -0.632, P<0.05), and was significantly positively correlated with the level of NF-KB p65 activation (r =0.667, P<0.05). Conclusion High level of oxidative stress which exists in asthmatic mice immunized and challenged with nitrated pollen may elevate the expression of 3-NT, activate NF-KB signaling pathway, delay

  2. Reduction of Eosinophils in Small Airways by Inhaled Steroids is Insufficient in Patients with Adult Asthma

    Directory of Open Access Journals (Sweden)

    Hiroshi Tanaka

    2006-01-01

    Conclusions: It was speculated that inhaled CFC-BDP and DP-FP might deposit mainly in large airways and fail to fully reach small airways, consequently allowing eosinophilic inflammation to continue in small airways.

  3. The effects of laryngeal mask airway passage simulation training on the acquisition of undergraduate clinical skills: a randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Lilford Richard J

    2011-08-01

    Full Text Available Abstract Background Effective use of the laryngeal mask airway (LMA requires learning proper insertion technique in normal patients undergoing routine surgical procedures. However, there is a move towards simulation training for learning practical clinical skills, such as LMA placement. The evidence linking different amounts of mannequin simulation training to the undergraduate clinical skill of LMA placement in real patients is limited. The purpose of this study was to compare the effectiveness in vivo of two LMA placement simulation courses of different durations. Methods Medical students (n = 126 enrolled in a randomised controlled trial. Seventy-eight of these students completed the trial. The control group (n = 38 received brief mannequin training while the intervention group (n = 40 received additional more intensive mannequin training as part of which they repeated LMA insertion until they were proficient. The anaesthetists supervising LMA placements in real patients rated the participants' performance on assessment forms. Participants completed a self-assessment questionnaire. Results Additional mannequin training was not associated with improved performance (37% of intervention participants received an overall placement rating of > 3/5 on their first patient compared to 48% of the control group, X2 = 0.81, p = 0.37. The agreement between the participants and their instructors in terms of LMA placement success rates was poor to fair. Participants reported that mannequins were poor at mimicking reality. Conclusions The results suggest that the value of extended mannequin simulation training in the case of LMA placement is limited. Educators considering simulation for the training of practical skills should reflect on the extent to which the in vitro simulation mimics the skill required and the degree of difficulty of the procedure.

  4. 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...... have become the standard with which to assess emphysema extent but airway abnormalities have so far been more challenging to quantify. Automated methods for analysis are indispensable as the visible airway tree in a CT scan can include several hundreds of individual branches. However, automation...... of scan on airway dimensions in subjects with and without COPD. The results show measured airway dimensions to be affected by differences in the level of inspiration and this dependency is again influenced by COPD. Inspiration level should therefore be accounted for when measuring airways, and airway...

  5. Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells

    NARCIS (Netherlands)

    Hoffmann, Roland F.; Zarrintan, Sina; Brandenburg, Simone M.; Kol, Arjan; de Bruin, Harold G.; Jafari, Shabnam; Dijk, Freark; Kalicharan, Dharamdajal; Kelders, Marco; Gosker, Harry R.; ten Hacken, Nick H. T.; van der Want, Johannes J.; van Oosterhout, Antoon J. M.; Heijink, Irene H.

    2013-01-01

    Background: Cigarette smoking is the major risk factor for COPD, leading to chronic airway inflammation. We hypothesized that cigarette smoke induces structural and functional changes of airway epithelial mitochondria, with important implications for lung inflammation and COPD pathogenesis. Methods:

  6. Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells

    NARCIS (Netherlands)

    Hoffmann, Roland F; Zarrintan, Sina; Brandenburg, Simone M; Kol, Arjan; de Bruin, Harold G; Jafari, Shabnam; Dijk, Freark; Kalicharan, Dharamdajal; Kelders, Marco; Gosker, Harry R; Ten Hacken, Nick Ht; van der Want, Johannes J; van Oosterhout, Antoon Jm; Heijink, Irene H

    2013-01-01

    BACKGROUND: Cigarette smoking is the major risk factor for COPD, leading to chronic airway inflammation. We hypothesized that cigarette smoke induces structural and functional changes of airway epithelial mitochondria, with important implications for lung inflammation and COPD pathogenesis. METHODS:

  7. Airway smooth muscle phenotype and function : interactions with current asthma therapies

    NARCIS (Netherlands)

    Halayko, A J; Tran, T; Ji, S Y; Yamasaki, A; Gosens, R

    2006-01-01

    Asthma incidence has climbed markedly in the past two decades despite an increased use of medications that suppress airway inflammation and repress contraction of smooth muscle that encircles the airways. Asthmatics exhibit episodes of airway inflammation that potentiates reversible airway smooth mu

  8. Airway remodeling in asthma: what really matters.

    Science.gov (United States)

    Fehrenbach, Heinz; Wagner, Christina; Wegmann, Michael

    2017-03-01

    Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and "endotyped" human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

  9. The Lung Microbiome and Airway Disease.

    Science.gov (United States)

    Lynch, Susan V

    2016-12-01

    A growing body of literature has demonstrated relationships between the composition of the airway microbiota (mixed-species communities of microbes that exist in the respiratory tract) and critical features of immune response and pulmonary function. These studies provide evidence that airway inflammatory status and capacity for repair are coassociated with specific taxonomic features of the airway microbiome. Although directionality has yet to be established, the fact that microbes are known drivers of inflammation and tissue damage suggests that in the context of chronic inflammatory airway disease, the composition and, more importantly, the function, of the pulmonary microbiome represent critical factors in defining airway disease outcomes.

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

    NARCIS (Netherlands)

    Vissers, JLM; van Esch, BCAM; Jeurink, PV; Hofman, GA; van Oosterhout, AJM

    2004-01-01

    Background: Previously, we demonstrated that OVA-loaded macrophages (OVA-M) partially suppress OVA-induced airway manifestations of asthma in BALB/c mice. In vitro studies showed that OVA-M start to produce IL-10 upon interaction with allergen-specific T cells, which might mediate their immunosuppre

  11. Airway inflammation and peripheral airway function in asthmatic patients with different control levels%不同控制水平的支气管哮喘患者气道炎症与外周气道功能状态的研究

    Institute of Scientific and Technical Information of China (English)

    潘杨; 黄克武; 叶青; 刘学松; 武宝梅; 张君; 常晓红; 逯勇; 王辰

    2009-01-01

    Objective To observe the airway inflammation and peripheral airway function in asthmatic patients with different control levels, and to investigate whether the airway inflammation profile detected by induced sputum reflects the peripheral airway dysfunction. Methods The recruited asthmatic subjects (n=66) were divided into 3 groups: asthma controlled (8 male and 13 female), asthma partly controlled (12 male and 16 female), asthma uncontrolled (6 male and 11 female). Twenty healthy subjects served as the control group (9 male and 11 female). On the 1st day, all the subjects were required to take asthma control test (ACT), and to receive measurement of lung function by osciilometry and spirometry as well as inflammatory cell profile of induced sputum and the concentration of eosinophil cationic protein (ECP). Exhaled nitric oxide (Feso) was measured on the 2nd day, and oscillometry methacholine provocation was conducted for patients whose baseline FEV_1 was ≥70% predicted. The provocation process was terminated when airway resistance was increased by twice of the basic value, or when the mcthacholine reached the highest concentration. Then airway resistance and lung function were examined after 3 minutes. Finally, airway resistance and lung function were measured again after the subjects had 5 consecutive deep inspirations (DI). Correlation analysis was conducted between ACT scores and inflammatory cells count, ECP concentrations of induced sputum and FE_(NO) among different groups. The correlations were also made between the change of peripheral airway resistance triggered by provocation or DI and ACT scores, total eosinophil, ECP level of induced sputum, FE_(NO) respectively. Results The total eosinophil count and ECP level in induced sputum and FE_(NO) in asthmatic patients increased with the decline of control level. Negative correlations between ACT scores and total eosinophil count as well as the ECP level were observed (r = -0.43, -0.56, P 0.05) with

  12. Early diagnosis of asthma in young children by using non-invasive biomarkers of airway inflammation and early lung function measurements: study protocol of a case-control study

    Directory of Open Access Journals (Sweden)

    Jöbsis Quirijn

    2009-06-01

    Full Text Available Abstract Background Asthma is the most common chronic disease in childhood, characterized by chronic airway inflammation. There are problems with the diagnosis of asthma in young children since the majority of the children with recurrent asthma-like symptoms is symptom free at 6 years, and does not have asthma. With the conventional diagnostic tools it is not possible to differentiate between preschool children with transient symptoms and children with asthma. The analysis of biomarkers of airway inflammation in exhaled breath is a non-invasive and promising technique to diagnose asthma and monitor inflammation in young children. Moreover, relatively new lung function tests (airway resistance using the interrupter technique have become available for young children. The primary objective of the ADEM study (Asthma DEtection and Monitoring study, is to develop a non-invasive instrument for an early asthma diagnosis in young children, using exhaled inflammatory markers and early lung function measurements. In addition, aetiological factors, including gene polymorphisms and gene expression profiles, in relation to the development of asthma are studied. Methods/design A prospective case-control study is started in 200 children with recurrent respiratory symptoms and 50 control subjects without respiratory symptoms. At 6 years, a definite diagnosis of asthma is made (primary outcome measure on basis of lung function assessments and current respiratory symptoms ('golden standard'. From inclusion until the definite asthma diagnosis, repeated measurements of lung function tests and inflammatory markers in exhaled breath (condensate, blood and faeces are performed. The study is registered and ethically approved. Discussion This article describes the study protocol of the ADEM study. The new diagnostic techniques applied in this study could make an early diagnosis of asthma possible. An early and reliable asthma diagnosis at 2–3 years will have

  13. 三氧化二砷对支气管哮喘免疫及气道炎症的调控%Regulation on immunity and airway inflammation of bronchial asthma by arsenic trioxide

    Institute of Scientific and Technical Information of China (English)

    李坑; 龚素波; 徐礼; 张莉; 向旭东

    2011-01-01

    Bronchial asthma (asthma) is a kind of chronic inflammation of airway, which was involved in many kinds of cells and cellular elements, such as eosinophils, T lymphocytes, neutrophil granulocytes, mastocytes, alveolar epithelial cells, and so on. Arsenic trioxide can improve the asthmatic mice's pulmonary function in experiment, and own the ability of hold the patients' asthmatic symptoms in a better state for a long time. The recent researchs indicated that the arsenic trioxide can regulate immunity and inhibit airway inflammation through many effective processes, such as inhibiting humoral immunity and proliferation of T lymphocytes at skin and lung, down-regulating expression of inflammatory factors (IL-17, IL-18, IL-23,etc), and inducing apoptosis of neutrophil granulocytes by endoplasmic reticulum stress pathway. The newest studies about the regulation on immunity and airway inflammation of asthma by arsenic trioxide were summarized, and some possible research orientation was previewed.%支气管哮喘(简称哮喘)是一种由多种细胞(嗜酸粒细胞、T细胞、中性粒细胞、肥大细胞及肺泡上皮细胞等)及细胞组分参与的气道慢性炎症性疾病.三氧化二砷在动物实验中能改善哮喘小鼠的肺功能,在临床治疗中能使患者的哮喘症状得到长期控制.新近研究表明:三氧化二砷能明显抑制小鼠的体液免疫反应,抑制小鼠的肺、皮肤等组织的T细胞增殖,能下调IL-17、IL-18和IL-23等多种炎症因子的分泌,并且通过内质网应激途径诱导中性粒细胞凋亡,从而调节免疫,抑制炎症.文章综述了三氧化二砷调控哮喘免疫及气道炎症的最新研究进展,并进行了展望.

  14. Sarcoidosis of the upper and lower airways.

    Science.gov (United States)

    Morgenthau, Adam S; Teirstein, Alvin S

    2011-12-01

    Sarcoidosis is a systemic granulomatous disease of undetermined etiology characterized by a variable clinical presentation and disease course. Although clinical granulomatous inflammation may occur within any organ system, more than 90% of sarcoidosis patients have lung disease. Sarcoidosis is considered an interstitial lung disease that is frequently characterized by restrictive physiologic dysfunction on pulmonary function tests. However, sarcoidosis also involves the airways (large and small), causing obstructive airways disease. It is one of a few interstitial lung diseases that affects the entire length of the respiratory tract - from the nose to the terminal bronchioles - and causes a broad spectrum of airways dysfunction. This article examines airway dysfunction in sarcoidosis. The anatomical structure of the airways is the organizational framework for our discussion. We discuss sarcoidosis involving the nose, sinuses, nasal passages, larynx, trachea, bronchi and small airways. Common complications of airways disease, such as, atelectasis, fibrosis, bullous leions, bronchiectasis, cavitary lesions and mycetomas, are also reviewed.

  15. Environmental and genetical factors in airway allergies

    OpenAIRE

    Katarzyna Idzik

    2012-01-01

    It is estimated that approximately 23% of the European population is clinically diagnosed with allergies. In the past three decades, an increase in the incidence of respiratory allergies was noted. At the beginning of the 20th century allergic inflammations affected only around 1% of the world population. Medical symptoms of allergic airway inflammation are variable for different patients. Airways allergy are complex phenotypes, which are determined by both genetic and...

  16. Intradermal cytosine-phosphate-guanosine treatment reduces lung inflammation but induces IFN-γ-mediated airway hyperreactivity in a murine model of natural rubber latex allergy.

    Science.gov (United States)

    Haapakoski, Rita; Karisola, Piia; Fyhrquist, Nanna; Savinko, Terhi; Wolff, Henrik; Turjanmaa, Kristiina; Palosuo, Timo; Reunala, Timo; Lauerma, Antti; Alenius, Harri

    2011-05-01

    Asthma and other allergic diseases are continuously increasing, causing considerable economic and sociologic burden to society. The hygiene hypothesis proposes that lack of microbial T helper (Th) 1-like stimulation during early childhood leads to increased Th2-driven allergic disorders later in life. Immunostimulatory cytosine-phosphate-guanosine (CpG)-oligodeoxynucleotide motifs are candidate molecules for immunotherapeutic studies, as they have been shown to shift the Th2 response toward the Th1 direction and reduce allergic symptoms. Using natural rubber latex (NRL)-induced murine model of asthma, we demonstrated that intradermal CpG administration with allergen reduced pulmonary eosinophilia, mucus production, and Th2-type cytokines, but unexpectedly induced airway hyperreactivity (AHR) to inhaled methacholine, one of the hallmarks of asthma. We found that induction in AHR was dependent on STAT4, but independent of STAT6 signaling. CpG treatment increased production of IFN-γ in the airways and shifted the ratio of CD4(+):CD8(+) T cells toward CD8(+) dominance. By blocking soluble IFN-γ with neutralizing antibody, AHR diminished and the CD4(+):CD8(+) ratio returned to CD4(+) dominance. These results indicate that increased production of IFN-γ in the lungs may lead to severe side effects, such as enhancement of bronchial hyperreactivity to inhaled allergen. This finding should be taken into consideration when planning prophylaxis treatment of asthma with intradermal CpG injections.

  17. Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma.

    Science.gov (United States)

    An, S S; Bai, T R; Bates, J H T; Black, J L; Brown, R H; Brusasco, V; Chitano, P; Deng, L; Dowell, M; Eidelman, D H; Fabry, B; Fairbank, N J; Ford, L E; Fredberg, J J; Gerthoffer, W T; Gilbert, S H; Gosens, R; Gunst, S J; Halayko, A J; Ingram, R H; Irvin, C G; James, A L; Janssen, L J; King, G G; Knight, D A; Lauzon, A M; Lakser, O J; Ludwig, M S; Lutchen, K R; Maksym, G N; Martin, J G; Mauad, T; McParland, B E; Mijailovich, S M; Mitchell, H W; Mitchell, R W; Mitzner, W; Murphy, T M; Paré, P D; Pellegrino, R; Sanderson, M J; Schellenberg, R R; Seow, C Y; Silveira, P S P; Smith, P G; Solway, J; Stephens, N L; Sterk, P J; Stewart, A G; Tang, D D; Tepper, R S; Tran, T; Wang, L

    2007-05-01

    Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not "cure" asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

  18. Routes of allergic sensitization and myeloid cell IKKβ differentially regulate antibody responses and allergic airway inflammation in male and female mice.

    Science.gov (United States)

    Bonnegarde-Bernard, Astrid; Jee, Junbae; Fial, Michael J; Steiner, Haley; DiBartola, Stephanie; Davis, Ian C; Cormet-Boyaka, Estelle; Tomé, Daniel; Boyaka, Prosper N

    2014-01-01

    Gender influences the incidence and/or the severity of several diseases and evidence suggests a higher rate of allergy and asthma among women. Most experimental models of allergy use mice sensitized via the parenteral route despite the fact that the mucosal tissues of the gastrointestinal and respiratory tracts are major sites of allergic sensitization and/or allergic responses. We analyzed allergen-specific Ab responses in mice sensitized either by gavage or intraperitoneal injection of ovalbumin together with cholera toxin as adjuvant, as well as allergic inflammation and lung functions following subsequent nasal challenge with the allergen. Female mice sensitized intraperitoneally exhibited higher levels of serum IgE than their male counterparts. After nasal allergen challenge, these female mice expressed higher Th2 responses and associated inflammation in the lung than males. On the other hand, male and female mice sensitized orally developed the same levels of allergen-specific Ab responses and similar levels of lung inflammation after allergen challenge. Interestingly, the difference in allergen-specific Ab responses between male and female mice sensitized by the intraperitoneal route was abolished in IKKβΔMye mice, which lack IKKβ in myeloid cells. In summary, the oral or systemic route of allergic sensitization and IKKβ signaling in myeloid cells regulate how the gender influences allergen-specific responses and lung allergic inflammation.

  19. Adenovirus-mediated Foxp3 expression in lung epithelial cells reduces airway inflammation in ovalbumin and cockroach-induced asthma model

    Science.gov (United States)

    Park, Soojin; Chung, Hwan-Suck; Shin, Dasom; Jung, Kyung-Hwa; Lee, Hyunil; Moon, Junghee; Bae, Hyunsu

    2016-01-01

    Foxp3 is a master regulator of CD4+CD25+ regulatory T-cell (Treg) function and is also a suppressor of SKP2 and HER2/ErbB2. There are an increasing number of reports describing the functions of Foxp3 in cell types other than Tregs. In this context, we evaluated the functions of Foxp3 in ovalbumin- and cockroach-induced asthma models. Foxp3-EGFP-expressing adenovirus or EGFP control adenovirus was administered intratracheally (i.t.), followed by challenge with ovalbumin (OVA) or cockroach extract to induce asthma. Th2 cytokine and immune cell profiles of bronchoalveolar lavage fluid (BALF), as well as serum IgE levels, were analyzed. Histological analyses were also conducted to demonstrate the effects of Foxp3 expression on airway remodeling, goblet cell hyperplasia and inflammatory responses in the lung. Adenoviral Foxp3 was expressed only in lung epithelial cells, and not in CD4+ or CD8+ cells. BALF from Foxp3 gene-delivered mice showed significantly reduced numbers of total immune cells, eosinophils, neutrophils, macrophages and lymphocytes in response to cockroach allergen or OVA. In addition, Foxp3 expression in the lung reduced the levels of Th2 cytokines and IgE in BALF and serum, respectively. Moreover, histopathological analysis also showed that Foxp3 expression substantially inhibited eosinophil infiltration into the airways, goblet cell hyperplasia and smooth muscle cell hypertrophy. Furthermore, when Tregs were depleted by diphtheria toxin in Foxp3DTR mice, the anti-asthmatic functions of Foxp3 were not altered in OVA-challenged asthma models. In this study, our results suggest that Foxp3 expression in lung epithelial cells, and not in Tregs, inhibited OVA- and cockroach extract-induced asthma. PMID:27633092

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Airway hyperresponsiveness to mannitol and methacholine and exhaled nitric oxide: a random-sample population study

    DEFF Research Database (Denmark)

    Sverrild, Asger; Porsbjerg, Celeste; Thomsen, Simon Francis;

    2010-01-01

    Studies of selected patient groups have shown that airway hyperresponsiveness (AHR) to mannitol is more specific than methacholine for the diagnosis of asthma, as well as more closely associated with markers of airway inflammation in asthma....

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Effects of azithromycin on expression of leptin and airway inflammation in rats with asthma%阿奇霉素对哮喘大鼠瘦素表达及气道炎症的影响

    Institute of Scientific and Technical Information of China (English)

    朱述阳; 嵇桂娟; 卢立国; 闫明华; 段存玲; 张文辉; 卞宏

    2013-01-01

    Objective To investigate the role of azithromycin on the expression change of leptin in airway inflammatory lung tis sues and airway smooth muscle cells(ASMC) in obese rats with asthma and its anti inflammatory effects. Methods Rats were ran domly divided into 6 groups(n = 8) :3 groups with normal weight including the control group(group A) ,asthmatic group(group B) , and azithromycin intervention group(group C) and 3 groups with obesity including the control group(group D) , asthmatic group (group E) and azithromycin intervention group(group F). The obese and asthma models were constructed. The rat ASMC was cul tured in vitro. The concentrations of leptin in serum,BALF and the supernatant of cultured ASMC were determined by ELISA,and the expression of leptin in lung tissue and ASMC was measured by Western blot. Results The total number of WBC and the num ber of neutrophils of bronchoalveolar lavage fluid(BALF) ,the protein expression of leptin in lung tissues and the leptin concentra tions in serum,BALF and supernatant in the group D,E and F all showed statistical difference compared with the corresponding groups with normal weight(P-<0. 05). Conclusion The expression of leptin in the airway inflammatory lung tissues in obese rats with asthma is increased. Azithromycin can inhibit airway inflammation and partially reduce the expression of leptin in asthmatic rats.%目的 探讨阿奇霉素对肥胖哮喘大鼠气道炎症肺组织内及气道平滑肌细胞(ASMC)内瘦素表达的变化及抗炎作用.方法 将大鼠随机分为正常对照组、正常哮喘组、正常干预组和肥胖对照组、肥胖哮喘组、肥胖干预组,建立肥胖、哮喘模型以及体外培养大鼠ASMC,采用酶联免疫吸附试验(ELISA)法测定血清、支气管肺泡灌洗液(BALF)及细胞上清液中瘦素浓度,Western blot法检测肺组织和ASMC内瘦素蛋白的表达.结果 肥胖对照组、肥胖哮喘组和肥胖干预组BALF白细胞总数及中性粒细胞数,

  4. Predictors of Airway Hyperresponsiveness in Elite Athletes

    DEFF Research Database (Denmark)

    Toennesen, Louise L; Porsbjerg, Celeste; Pedersen, Lars;

    2015-01-01

    INTRODUCTION: Elite athletes frequently suffer from asthma and airway hyperresponsiveness (AHR). We aimed to investigate predictors of airway pathophysiology in a group of unselected elite summer-sport athletes, training for the summer 2008 Olympic Games, including markers of airway inflammation......, systemic inflammation and training intensity. METHODS: 57 Danish elite summer-sport athletes with and without asthma symptoms all gave a blood sample for measurements of high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF....... In these subjects, no association was found between the levels of AHR to mannitol and methacholine (r=0.032, p=0.91). CONCLUSION: Airway hyperresponsiveness in elite athletes is related to the amount of weekly training and the level of serum TNF-α. No association was found between the level of AHR to mannitol...

  5. Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma

    Institute of Scientific and Technical Information of China (English)

    SUN Yong-chang; ZHOU Qing-tao; YAO Wan-zhen

    2005-01-01

    @@ Asthma is a chronic inflammatory airway disease characterized by the involvement of many cells (including eosinophils, mast cells, T cells, neutrophils and airway epithelial cells) and their cellular components.1 While airway eosinophilic inflammation is considered as a characteristic of asthma, our previous reports2,3 and other recent studies4,5 have demonstrated that neutrophils may play important roles in airway inflammation, or even in airway remodeling, particularly in severe asthma. The mechanisms underlying the neutrophil accumulation in asthmatic airway remain to be elucidated. Interleukin-8 (IL-8) is a potent chemotactic factor for neutrophils, and was demonstrated to be increased in asthmatic airways.6,7 More recent studies have shown that T-cell derived IL-17 can accumulate neutrophils via a IL-8 dependent pathway.8,9 Whether IL-17/IL-8 mechanism is involved in airway inflammation in severe asthma is not clear.

  6. 氧化应激反应对肥胖型哮喘小鼠气道炎症和重建影响%EFFECTS OF OXIDATIVE STRESS ON AIRWAY INFLAMMATION AND RECONSTRUCTION IN OBESE MICE WITH ASTHMA

    Institute of Scientific and Technical Information of China (English)

    陈凯; 韩伟; 唐华平; 苏毅

    2011-01-01

    目的 探讨氧化应激反应在肥胖型哮喘小鼠体内变化及其与气道炎症和重建的关系.方法 45只雌性C57/6J小鼠随机分为哮喘组(A组)、肥胖哮喘组(B组)和对照组(C组).卵清蛋白雾化吸入和高脂饮食诱导建立肥胖型哮喘模型.计数各组小鼠支气管肺泡灌洗液(BALF)中白细胞总数并分类,肺组织切片观察病理变化,并测定支气管壁总面积(WAt)、支气管平滑肌面积(WArn)、管腔基底膜周长(Pbm),ELISA法测定肺组织匀浆中白细胞介素6(IL-6)和8-异前列腺素2α(8-iso-PGF2α)水平.结果 B组小鼠BALF中白细胞总数和嗜酸性粒细胞比例、肺组织IL-6水平以及肺组织切片中WAt/Pbm和WAm/Pbm均较A组明显增高(F=2.84~32.67,P<0.05).C、A、B组小鼠血清8-iso-PGF2α水平依次升高,且与BALF中白细胞总数、肺组织IL-6水平以及WAt/Pbm存在正相关性(r=0.821、0.900、0.873,P<0.01).结论 氧化应激反应参与了肥胖型哮喘小鼠气道炎症和重建过程,抑制氧化应激可望成为肥胖型哮喘治疗的有效措施.%Objective To study oxidative stress reaction in obese mice with asthma and its association with airway inflammation and reconstruction. Methods This study consisted of 45 female C57BL/6J mice, which were randomized to three groups as group A (asthma group) > group B (obese asthma group) and group C (control group). An obese asthma model was created by egg-albumin aerosol rebreathing method and high fat diet. Total white blood cells (WBC) and classification in BALF were counted; a lung tissue section was observed pathologically; Wat, Wam, and Pbm were measured) IL-6 and 8-iso-Prostaglandin F2a (8-iso-PGF2a) in lung tissue homogenate were detected by ELISA. Results The total WBC count, ratio of eosinophils, IL-6 levels, Wat/Pbm and Wam/Pbm were markedly elevated in group B versus group A (F=2. 84-32. 67,P<0. 05). Serum 8-iso-PGF2a levels increased in order of groups C, A, and B, which were positively

  7. Effect of doxycycline on airway inflammation and remodeling in asthmatic rats%多西环素对哮喘大鼠气道炎症及气道重塑的影响

    Institute of Scientific and Technical Information of China (English)

    李静; 王亮; 杨红申; 李亚妹; 侯宏伟; 李香兰; 张聪瑶; 李玉静

    2015-01-01

    目的:探讨多西环素对哮喘大鼠气道炎症及重塑的预防作用及可能机制。方法将实验 SD 大鼠分为正常对照组、哮喘组、多西环素干预组。计数大鼠肺泡灌洗液中的细胞数并进行分类;检测血清中的白细胞介素5(IL-5)、白细胞介素13(IL-13)、肿瘤坏死因子α(TNF-α)的水平;检测肺组织中基质金属蛋白酶9(MMP-9)、肌动蛋白α(α-SMA)的表达;测定支气管基底膜周径(Pbm)、总管壁面积(WAt)、平滑肌面积(WAm)等反映气道壁厚度的指标,分析多西环素的影响。结果哮喘组与多西环素干预组的肺泡灌洗液细胞总数、嗜酸性粒细胞计数、支气管壁厚度、平滑肌厚度、血清 IL-5、IL-13及 TNF-α水平、肺组织 MMP-9、α-SMA 平均光度值均明显高于正常对照组,其中多西环素干预组均明显低于哮喘组(P <0.05)。结论多西环素可以影响炎症介质的生成及通过抑制 MMP-9的活性从而减轻哮喘的气道炎症及气道重塑。%ABSTRACT:Objective To investigate the effect of doxycycline on airway inflammation and remodeling in asthmatic rats.Methods Thirty-three male Sprague Dawley rats were randomly divided into three groups:control group,asthma group and doxycycline intervention group.Total cell number and different cell number in BALF were counted.The concentrations of serum IL-5,IL-13 were assayed by ELISA,and the concentration of serum TNF-αwas determined by radioimmunoassay.The expression of MMP-9 and α-SMA in lung tissues were observed by immunohistochemistry.Lung tissues were sliced and stained with HE.These parameters such as bronchial basement membrane perimeter (Pbm),total bronchial wall area (WAt)and smooth muscle area (WAm),which reflected the thickness of airway wall,were measured by image analysis system.Results The count of total cells and eosinophils significantly increased in asthma group and doxycycline intervention group than in control group(P <0.05),and the

  8. Inhaled corticosteroids and growth of airway function in asthmatic children

    NARCIS (Netherlands)

    Merkus, PJFM; van Pelt, W; van Houwelingen, JC; van Essen-Zandvliet, LEM; Duiverman, EJ; Kerrebijn, KF; Quanjer, PH

    2004-01-01

    Airway inflammation and remodelling play an important role in the pathophysiology of asthma. Remodelling may affect childhood lung function, and this process may be reversed by anti-inflammatory treatment. The current study assessed longitudinaily whether asthma affects growth of airway function rel

  9. Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis.

    Science.gov (United States)

    Simpson, Jodie L; Phipps, Simon; Gibson, Peter G

    2009-10-01

    Obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major global health issues. Although considered as distinct diseases, airway inflammation is a key underlying pathophysiological process in asthma, COPD and bronchiectasis. Persistent neutrophilic airway inflammation (neutrophilic bronchitis) occurs with innate immune activation and is a feature of each of these airway diseases. Little is known about the mechanisms leading to neutrophilic bronchitis and few treatments are effective in reducing neutrophil accumulation in the airways. There is a similar pattern of inflammatory mediator release and toll like receptor 2 expression in asthma, COPD and bronchiectasis. We propose the existence of an active amplification mechanism, an effector arm of the innate immune system, involving toll like receptor 2, operating in persistent neutrophilic bronchitis. Neutrophil persistence in the airways can occur through a number of mechanisms such as impaired apoptosis, efferocytosis and mucus hypersecretion, all of which are impaired in airways disease. Impairment of neutrophil clearance results in a reduced ability to respond to bacterial infection. Persistent activation of airway neutrophils may result in the persistent activation of the innate immune system resulting in further airway insult. Current therapies are limited for the treatment of neutrophilic bronchitis; possible treatments being investigated include theophylline, statins, antagonists of pro-inflammatory cytokines and macrolide antibiotics. Macrolides have shown great promise in their ability to reduce airway inflammation, and can reduce airway neutrophils, levels of CXCL8 and neutrophil proteases in the airways. Studies also show improvements in quality of life and exacerbation rates in airways diseases.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. The impact of azithromycin therapy on the airway microbiota in asthma

    OpenAIRE

    Slater, Mariel; Rivett, Damian W.; Williams, Lisa; Martin, Matthew; Harrison, Timothy W.; Sayers, Ian; Bruce, Kenneth D; Shaw, Dominick E.

    2014-01-01

    There is interest in the use of macrolide antibiotics in asthma. Macrolides have been shown to improve airway hyperresponsiveness (AHR) and measures of airway inflammation.The degree of AHR may relate to the microbiota present in the airways, with a recent study reporting that patients with asthma with a significant improvement in AHR following treatment with clarithromycin had a higher bacterial diversity prior to treatment. To our knowledge, the impact on the asthmatic airway microbiota of ...

  12. The impact of azithromycin therapy on the airway microbiota in asthma

    OpenAIRE

    Slater, Mariel; Rivett, Damian W.; Williams, Lisa; Martin, Matthew; Harrison, Timothy W.; Sayers, Ian; Bruce, Kenneth D; Shaw, Dominick E.

    2013-01-01

    There is interest in the use of macrolide antibiotics in asthma. Macrolides have been shown to improve airway hyperresponsiveness (AHR) and measures of airway inflammation.The degree of AHR may relate to the microbiota present in the airways, with a recent study reporting that patients with asthma with a significant improvement in AHR following treatment with clarithromycin had a higher bacterial diversity prior to treatment. To our knowledge, the impact on the asthmatic airway microbiota of ...

  13. Airway management in trauma

    Directory of Open Access Journals (Sweden)

    Rashid M Khan

    2011-01-01

    Full Text Available Trauma has assumed epidemic proportion. 10% of global road accident deaths occur in India. Hypoxia and airway mismanagement are known to contribute up to 34% of pre-hospital deaths in these patients. A high degree of suspicion for actual or impending airway obstruction should be assumed in all trauma patients. Objective signs of airway compromise include agitation, obtundation, cyanosis, abnormal breath sound and deviated trachea. If time permits, one should carry out a brief airway assessment prior to undertaking definitive airway management in these patients. Simple techniques for establishing and maintaining airway patency include jaw thrust maneuver and/or use of oro- and nas-opharyngeal airways. All attempts must be made to perform definitive airway management whenever airway is compromised that is not amenable to simple strategies. The selection of airway device and route- oral or -nasal, for tracheal intubation should be based on nature of patient injury, experience and skill level.

  14. The genus Prevotella in cystic fibrosis airways.

    Science.gov (United States)

    Field, Tyler R; Sibley, Christopher D; Parkins, Michael D; Rabin, Harvey R; Surette, Michael G

    2010-08-01

    Airway disease resulting from chronic bacterial colonization and consequential inflammation is the leading cause of morbidity and mortality in patients with Cystic Fibrosis (CF). Although traditionally considered to be due to only a few pathogens, recent re-examination of CF airway microbiology has revealed that polymicrobial communities that include many obligate anaerobes colonize lower airways. The purpose of this study was to examine Prevotella species in CF airways by quantitative culture and phenotypic characterization. Expectorated sputum was transferred to an anaerobic environment immediately following collection and examined by quantitative microbiology using a variety of culture media. Isolates were identified as facultative or obligate anaerobes and the later group was identified by 16S rRNA sequencing. Prevotella spp. represented the majority of isolates. Twelve different species of Prevotella were recovered from 16 patients with three species representing 65% of isolates. Multiple Prevotella species were often isolated from the same sputum sample. These isolates were biochemically characterized using Rapid ID 32A kits (BioMérieux), and for their ability to produce autoinducer-2 and beta-lactamases. Considerable phenotypic variability between isolates of the same species was observed. The quantity and composition of Prevotella species within a patients' airway microbiome varied over time. Our results suggest that the diversity and dynamics of Prevotella in CF airways may contribute to airway disease.

  15. The effect of N-acetylcysteine on the airway inflammation and remodeling of obese asthma mice%乙酰半胱氨酸对肥胖哮喘小鼠气道炎症和重建的作用

    Institute of Scientific and Technical Information of China (English)

    韩伟; 李双保; 唐华平; 陈凯; 苏毅

    2011-01-01

    Objectives To evaluate the effect of N-Acetylcysteine on the airway inflammation and remodeling of obese asthma mice with high-fat diets. Methods Forty female C57BL/6J mice were randomly divided into 4 groups, asthma group (A), obese asthma group (B), treatment group (C) and normal control group (D). Group A were sensitized and challenged by ovalbum (OVA) and normal diets. Group B were sensitized and challenged as group A but fed with high-fat diets, while group C were sensitized, challenged and fed as group B, but administrated N-Acetylcysteine 200 mg/kg. d from the third week after challenge. The cells in BALF were counted and classified after staining, IL-6 and 8-iso-PGF2α(8-iso-PGF2α) in lung tissues were detected by ELISA. WAt, WAm, Pbm, as the remodeling indices, measured in lung pathological section. All parameters were compared among 4 groups. Results In comparison with group D, the leukocytes and EOS in BALF, WAt/Pbm, WAm/Pbm in lung section were increased as well as IL-6 and 8-iso-PGF2α in lung tissue elevated in group A and group B, while the maximum changes were observed in group B (P <0. 05). After NAC treatment, the IL-6, 8-iso-PGF2α and WAt/ Pbm were decreased significantly (P <0. 05). Pearson correlation analysis showed that WAt/Pbm and IL-6 were in positive correlation with 8-iso-PGF2α (r =0. 817, 0. 737, P <0. 01). Conclusions N-Acetylcysteine can alleviate the airway inflammation and remodel reaction of asthma by a substantial inhibition of the oxidative stress reaction in lung.%目的 探讨乙酰半胱氨酸对哮喘气道炎症和重建的影响.方法 60只雌性C57/6J小鼠按随机数字表法分为哮喘组(A组),肥胖哮喘组(B组),治疗组(C组),对照组(D组),每组15只.经腹腔注射与雾化吸入卵蛋白(OVA)制作慢性哮喘模型,高脂饮食制造肥胖模型.计数支气管肺泡灌洗液(BALF)中细胞总数及分类,ELISA法测定肺组织匀浆中IL-6和8-异前列腺素F2α(8-iso-PGF2α)水平,肺组织切

  16. Alveolar inflammation in cystic fibrosis

    DEFF Research Database (Denmark)

    Ulrich, Martina; Worlitzsch, Dieter; Viglio, Simona

    2010-01-01

    BACKGROUND: In infected lungs of the cystic fibrosis (CF) patients, opportunistic pathogens and mutated cystic fibrosis transmembrane conductance regulator protein (CFTR) contribute to chronic airway inflammation that is characterized by neutrophil/macrophage infiltration, cytokine release...... accumulated in type II alveolar epithelial cells, lacking CFTR. P. aeruginosa organisms were rarely present in inflamed alveoli. CONCLUSIONS: Chronic inflammation and remodeling is present in alveolar tissues of the CF lung and needs to be addressed by anti-inflammatory therapies....

  17. Airway distensibility in Chronic Obstructive Airway Disease

    DEFF Research Database (Denmark)

    Winkler Wille, Mathilde Marie; Pedersen, Jesper Holst; Dirksen, Asger

    2013-01-01

    -20% (mild), 20%-30% (moderate) or >30% (severe). Spirometry was performed annually and participants were divided into severity groups according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Data were analysed in a mixed effects regression model with log(airway lumen diameter......Rationale – Chronic Obstructive Pulmonary Disease (COPD) is a combination of chronic bronchitis and emphysema, which both may lead to airway obstruction. Under normal circumstances, airway dimensions vary as a function of inspiration level. We aim to study the influence of COPD and emphysema...... in causing airway narrowing, the latter most likely due to loss of elastic recoil of surrounding tissue....

  18. Link between vitamin D and airway remodeling

    Directory of Open Access Journals (Sweden)

    Berraies A

    2014-04-01

    Full Text Available Anissa Berraies, Kamel Hamzaoui, Agnes HamzaouiPediatric Respiratory Diseases Department, Abderrahmen Mami Hospital, Ariana, and Research Unit 12SP15 Tunis El Manar University, Tunis, TunisiaAbstract: In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma.Keywords: vitamin D, asthma, airway remodeling, airway smooth muscle, supplementation

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

    NARCIS (Netherlands)

    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

  20. Effects of simvastatin on airway inflammation and airway mucus hypersecretion in rats with chronic obstructive pulmonary disease%辛伐他汀对慢性阻塞性肺疾病模型大鼠气道炎症和气道黏液高分泌的防治作用及其机制

    Institute of Scientific and Technical Information of China (English)

    王胜; 熊玲玲; 邓雪; 任薇; 朱春冬; 李春颖; 周群

    2015-01-01

    ,减轻气道炎症和气道黏液高分泌.%Objective To explore the preventive and therapeutic effects of simvastatin on rats with chronic obstructive pulmonary disease (COPD) and examine the mechanism of airway inflammation and airway mucus hypersecretion.Methods The rat model of COPD was established by cigarette smoking and an intratracheal injection of lipopolysaccharide (LPS).A total of 18 male Sprague-Dawley rats were randomly divided into control,COPD and simvastatin groups (n =6 each).The control and COPD groups received normal saline once daily via intragastric administration (i.g.) while the simvastatin group had simvastatin (0.5 g/L) 1 ml/100 g once daily via i.g.Pulmonary function was tested and pathological changes in bronchus and lung were observed.The bronchoalveolar lavage fluid (BALF) levels of interleukin-8 (IL-8),interleukin-17 (IL-17) and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assay (ELISA).The protein expressions of intercellular adhesion molecule 1 (ICAM-1),nuclear factor κB (NF-κB),mucin 5AC (MUC5AC) and Toll-like receptor 4 (TLR4) in rat airway were detected by immunohistochemical staining.The mRNA and protein expressions of TLR4 and MUC5AC in bronchi and lung tissue were detected by fluorescent real time quantitative polymerase chain reaction (RT-PCR) and Western blot.Results The changes of bronchi and lung tissues in COPD group were consistent with typical pathological manifestations of COPD.As compared with the COPD group,the degree of pulmonary pathological damage and the decline of pulmonary function in the simvastatin group were significantly lessened,but still remarkable as compared with the control group.The BALF levels of IL-8,IL-17 and TNF-α in the smvastatin group [(484.4 ± 11.1),(78.9 ± 2.0),(192.7 ± 2.0) ng/L] were significantly lower than those in the COPD group [(605 ±48.7),(89.9 ±6.9),(212.6 ± 10.7) ng/L],but still higher than those in the control group [(341.2 ± 21.4),(56.0 ± 2

  1. 臭氧氧化应激对小鼠急性过敏性气道炎症所致气道高反应性和黏液分泌的影响%Effects of ozone oxidative stress on the airway hyperresponsiveness and mucus production in mice with acute allergic airway inflammation

    Institute of Scientific and Technical Information of China (English)

    包爱华; 陈宇清; 张旻; 李锋; 周新

    2015-01-01

    Objective To explore the impact of ozone on the airway hyperresponsinveness (AHR),airway inflammation and mucus production in an allergic asthma mouse model.Methods Twenty-eight female BALB/c mice were randomly divided into 4 equal groups:healthy control,ozone control,asthma model,and ozone intervention.For asthma model establishing,the mice were sensitized and challenged with ovalbumin,while the controls received saline.For ozone exposure,the mice were exposed to 2.0 ppm ozone for 3 hrs,while the control treatment group exposed to filtered air for 3 hrs.Some measurements were performed 24 hrs after the exposure,including AHR,pulmonary inflammation,mucus secretion,epithelial barrier function,and the level of oxidant stress.Results Compared with the asthma model group,mice in the ozone intervention group exhibited lower LogPC100Penh (0.22 ±0.09 vs 0.50 ±0.19,t =3.06,P =0.006),higher bronchoalveolar lavage (BAL) neutrophil numbers [(0.80 ± 0.21) × 103/L vs (0.15 ± 0.06) × 103/L,t =3.63,P =0.019] and BAL concentration of lower molecular weight hyaluronan (LMW-HA) [(111 ±17) μg/Lvs (35 ±18) μg/L,t=5.12 P=0.000],TNF-α[(155 ±30) μg/Lvs (86±19) μg/L,t=2.15,P=0.044] and IL-13[(65±11) μg/Lvs (33 ±20) μg/L,t=2.95,P=0.008].Mice in the ozone intervention group showed higher lung pathological inflammation score (2.80 ± 0.10 vs 1.92 ±0.23,t =3.91,P =0.000) and upregulated expressions of TNF-α mRNA (7.0 ± 1.5 vs 3.57±1.20,t=2.65,P=0.014),CXCL-1 mRNA (7.0±1.1 vs2.5±1.0,t=4.12,P=0.000) and IL-17 mRNA (28.8 ±5.2 vs 16.4 ±4.4,t =6.33,P =0.000).Ozone exposure on the asthmatic mice also caused higher percentage of PAS positive-staining epithelial cells [(76.2 ± 8.7) % vs (55.8 ± 14.4) %,t =8.14,P =0.000] and higher epithelial surface mucus volume [(721 ± 584) nl/mm2 vs (272 ± 185) nl/mm2,t =5.78,P =0.000] as well as the MUC5ac mRNA expression (15.4 ±4.6 vs 7.0 ± 1.9,t =4.37,P =0.000).Besides,ozone exposure in the asthma model decreased epithelial

  2. Germinal Center Formation and Local Immunoglobulin E (IgE) Production in the Lung after an Airway Antigenic Challenge

    OpenAIRE

    1996-01-01

    Airway inflammation plays a central role in the pathogenesis of asthma. However, the precise contribution of all cell types in the development and maintenance of airway hyperreactivity and histopathology during allergic inflammation remains unclear. After sensitization of mice in the periphery, challenge by multiple intratracheal (i.t.) instillations of ovalbumin (OVA) results in eosinophilia, mononuclear cell infiltration, and airway epithelial changes analogous to that seen in asthma (Blyth...

  3. Suppression of allergic airway inflammation in a mouse model of asthma by exogenous mesenchymal stem cells%外源性间充质干细胞减轻支气管哮喘小鼠气道炎症的研究

    Institute of Scientific and Technical Information of China (English)

    黄芸; 欧阳海峰; 吴朔; 王文雅; 吴昌归

    2010-01-01

    目的 观察鸡卵清蛋白诱导小鼠支气管哮喘(简称哮喘)模型中外源性间充质干细胞(mesenchymal stem cells,MSC)在哮喘小鼠肺组织气道炎症中的作用.方法 45只雌性SPF级C57BL/6小鼠,体质量18~22 g.随机分为对照组(P:P:P)、哮喘组(O:P:O)和MSC治疗组(O:M:O).哮喘组与MSC治疗组第1天和第8天致敏,第15天、第16天和第17天使用OVA气道内滴入激发哮喘.MSC治疗组于哮喘造模第14天移植外源性MSC.对照组小鼠予PBS处理.三组小鼠于末次激发结束后24 h(第18天)处死,取支气管肺泡灌洗液上清,ELISA检测IL-5、IL-9及β-氨基己糖苷酶;支气管肺泡灌洗液细胞计数总细胞数、嗜酸粒细胞数;取肺组织行病理切片苏木精-伊红染色观察肺部气道炎症情况.结果 ①MSC下调了哮喘小鼠气道局部炎症;②MSC减轻了哮喘小鼠肺组织中的炎细胞浸润;③MSC减轻了哮喘小鼠气道中的肥大细胞脱颗粒现象;④MSC抑制了哮喘小鼠过度的Th2变态反应.结论 外源性MSC通过抑制Th2变态反应,减轻哮喘肺组织的气道炎症.%Objective To study the suppression of allergic airway inflammation in a mouse model of asthma by exogenous mesenchymal stem cells (MSC). Methods Forty five C57BL/6 mice were randomly divided into three groups:control group (15) ,asthmatic group (15) and MSC treated group (15). Asthma and MSC treatment groups were sensitized i. p. with OVA on day 1 and 8. Then, mice were challenged with OVA by the intratracheal route on day 15,16 and 17. On day 14,exogenous MSC (1× l06 cells in 1ml PBS) were administered through the tail vein to mice 1 day before the first airway challenge in the MSC treated group. Control mice were treated with PBS. Mice were sacrificed on day 18. BALF were obtained and centrifuged to pellets and supernatants. Pellets recovered for cellular analysis. Supernatants were stored at-80 for biochemical analyses. The total number of cells in BALF was counted and the

  4. 屋尘螨在诱导BALB/c小鼠混合型气道炎症中的作用及致病机制探讨%House dust mite induces mixed allergic airway inflammation in a murine asthma model

    Institute of Scientific and Technical Information of China (English)

    赵敏; 李智; 于永春

    2013-01-01

    目的 探讨屋尘螨(HDM)抗原在小鼠模型中诱导混合型气道炎症中的作用及其机理,为支气管哮喘的临床诊断和治疗提供理论依据.方法 BALB/c小鼠于实验第0天、7天、14天、21天、28天和35天进行PBS或HDM提取液(50μg或100 μg)滴鼻.采用头体积描记法测量小鼠的气道反应性;对支气管肺泡灌洗液(BAL)进行细胞计数和分类;酶联免疫法(ELISA)检测BAL中CXCL1、CXCL2、CCL11 (eotaxin)、IL-5、IFNγ、IL-10和IL-17的含量及血清总IgE,HDM特异性IgG1、IgG2a;采用实时荧光定量PCR检测肺组织中相关基因mRNA表达;并对肺组织PAS染色后进行病理学观察.结果 HDM抗原引起了以中性粒细胞和嗜酸性粒细胞为主的混合型气道炎症、血清HDM特异性IgG1的升高及高脚杯细胞增生(GCH)等组织学变化,其混合型气道炎症可能与CXCL1和IL-5等细胞因子的分泌增多有关,是固有免疫和适应性免疫共同活化的结果.这种炎症表型在经高浓度HDM(100 μg)致敏的小鼠中表现得更为显著.结论 HDM过敏原在小鼠模型中诱导了中性粒细胞和嗜酸性粒细胞的共同活化.%Objective To explore the potential role of house dust mite (HDM) allergen in the pathogenesis of mixed airway inflammation and provide evidence for the diagnosis and treatment of asthma.Methods BALB/c mice received an intranasal instillation of PBS or HDM extract (50 μg or 100 μg) on days 0,7,14,21,28,35.After the final challenge,airway responsiveness (AR),histological changes in the airways and immunological status were examined.Results HDM allergen elicited a mixed airway inflammation of neutrophils and eosinophils which were accompanied by an increased production of serum HDM-IgG1 and subsequent histological changes including goblet cell hyperplasia (GCH).The mixed airway inflammation was associated with the upregulation of chemokines and cytokines including CXCL1 and IL-5,representing the activation of innate

  5. Role of transforming growth factor-β in the airway inflammation and remodeling in asthma%转化生长因子-β在哮喘气道炎症与重塑中的作用

    Institute of Scientific and Technical Information of China (English)

    李明才; 何韶衡

    2004-01-01

    Transforming growth factor-β(TGF-β) was reported to be increased in asthma in some studies. Accumulation of TGF-β in airway promotes smooth muscle cell mitogenesis and hyperplasia, and in-duces fibroblast and myofibroblast and smooth muscle proliferation as well as increase in protein synthesis in connective tissue(such as collagen deposition on the reticular basement membrane). The autocrine induction of collagen expression by smooth muscle may contribute to the thickening of the reticular basement membrane, irre-versible f'throsis and remodeling seen in the airways in some asthmatics. TGF-β is considered to be a major fi-brogenic cytokine. It can increase smooth muscle mass and lead to severe bronchial obstruction in an asthma at-tack.

  6. Obesity in asthma : more neutrophilic inflammation as a possible explanation for a reduced treatment response

    NARCIS (Netherlands)

    Telenga, E. D.; Tideman, S. W.; Kerstjens, H. A. M.; ten Hacken, N. H. T.; Timens, W.; Postma, D. S.; van den Berge, M.

    2012-01-01

    Background The incidence of asthma and obesity is increasing worldwide, and reports suggest that obese patients have more severe asthma. We investigated whether obese asthma patients have more severe airway obstruction and airway hyper-responsiveness and a different type of airway inflammation than

  7. Airway Microbiota and the Implications of Dysbiosis in Asthma.

    Science.gov (United States)

    Durack, Juliana; Boushey, Homer A; Lynch, Susan V

    2016-07-01

    The mucosal surfaces of the human body are typically colonized by polymicrobial communities seeded in infancy and are continuously shaped by environmental exposures. These communities interact with the mucosal immune system to maintain homeostasis in health, but perturbations in their composition and function are associated with lower airway diseases, including asthma, a developmental and heterogeneous chronic disease with various degrees and types of airway inflammation. This review will summarize recent studies examining airway microbiota dysbioses associated with asthma and their relationship with the pathophysiology of this disease.

  8. Macrophage adaptation in airway inflammatory resolution

    Directory of Open Access Journals (Sweden)

    Manminder Kaur

    2015-09-01

    Full Text Available Bacterial and viral infections (exacerbations are particularly problematic in those with underlying respiratory disease, including post-viral infection, asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. Patients experiencing exacerbations tend to be at the more severe end of the disease spectrum and are often difficult to treat. Most of the unmet medical need remains in this patient group. Airway macrophages are one of the first cell populations to encounter airborne pathogens and, in health, exist in a state of reduced responsiveness due to interactions with the respiratory epithelium and specific factors found in the airway lumen. Granulocyte–macrophage colony-stimulating factor, interleukin-10, transforming growth factor-β, surfactant proteins and signalling via the CD200 receptor, for example, all raise the threshold above which airway macrophages can be activated. We highlight that following severe respiratory inflammation, the airspace microenvironment does not automatically re-set to baseline and may leave airway macrophages more restrained than they were at the outset. This excessive restraint is mediated in part by the clearance of apoptotic cells and components of extracellular matrix. This implies that one strategy to combat respiratory exacerbations would be to retune airway macrophage responsiveness to allow earlier bacterial recognition.

  9. Inhalation of Aspergillus fumigatus spores induces airway inflammation in mice in a similar manner as observed in Recurrent Airway Obstruction in horses Inhalación de esporas de Aspergillus fumigatus induce en ratones una inflamación de las vías aéreas similar a la observada en equinos con Obstrucción Recurrente de las Vías Aéreas

    Directory of Open Access Journals (Sweden)

    G Morán

    2011-01-01

    Full Text Available The aim of this study was to determine if mice exposed to Aspergillus (A. fumigatus spores develop airway inflammation in a similar manner to Recurrent Airway Obstruction (RAO in horses. Different groups of 2-, 5-, 6- and 8-month-old Rockefeller (RK mice were used throughout the experiment. The mice were maintained in the animal house for 16 days and kept in cages containing hay contaminated with A. fumigatus. After 16 days of mold exposure, the mice were bled and sacrificed to obtain bronchoalveolar lavage fluid (BALF or lung tissues for histological analysis. In addition, we measured the levels of A. fumigatus-specific antibodies by ELISA. The results demonstrated that inhalation of A. fumigatus spores in mice induced an inflammatory response in the lungs that was characterized by peribronchiolar and perivascular mononuclear infiltration and bronchiolar luminal exudates. Moreover, there was extensive folding of the airway epithelia, which is a sign of airway smooth muscle contraction and smooth muscle hypertrophy. In addition, we observed a high number of neutrophils and an increase in IgE, IgG1 and IgG2a antibodies in the BALF from mice that were older than 5 months and were exposed to A. fumigatus. These animals recovered from their respiratory distress when they were placed in a remission environment. We conclude that simple exposure of mice to moldy hay induces a condition that is similar to RAO in horses. Therefore, using this mouse model for the study of equine RAO offers the opportunity to approximate the immunologic response to airborne irritants and allergens as well as to evaluate pharmacological therapies.El objetivo de este estudio fue determinar si ratones expuestos a esporas de Aspergillus fumigatus desarrollan una inflamación alérgica de las vías respiratorias similar a la observada en equinos con Obstrucción Recurrente de las Vías Aéreas (ORVA. Para esto se utilizaron ratones Rockefeller (RK de 2, 5, 6 y 8 meses

  10. Effects of Flavin7 on allergen induced hyperreactivity of airways

    Directory of Open Access Journals (Sweden)

    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.

  11. Airway Surgery in Tracheostomised Patients with Wegener Granulomatosis Leading to Subglottic Stenosis.

    Science.gov (United States)

    Altun, Demet; Sivrikoz, Nükhet; Çamcı, Emre

    2015-10-01

    Wegener granulomatosis (WG) is a multisystemic disorder characterised by granulomatous inflammation of the respiratory system. The growing of proliferative tissue towards the larynx and trachea may cause airway obstruction on account of subglottic stenosis. In this situation, the surgical goal is to eliminate the airway obstruction by providing natural airway anatomy. While mild lesions do not require surgical intervention, in fixed lesions, surgical intervention is required, such as tracheostomy, laser resection and dilatation. In tracheostomised patients, granuloma formation surrounding the tracheostomy cannula may occur in the trachea. Inflammation and newly formed granulation tissue result in severe stenosis in the airways. During surgical treatment of such patients, airway management is important. In this case report, we will discuss gas exchange and airway management with jet ventilation (JV) during excision of the granulation tissue with endolaryngeal laser surgery, leading to subglottic stenosis in tracheostomised patients in WG.

  12. Environmental and genetical factors in airway allergies

    Directory of Open Access Journals (Sweden)

    Katarzyna Idzik

    2012-12-01

    Full Text Available It is estimated that approximately 23% of the European population is clinically diagnosed with allergies. In the past three decades, an increase in the incidence of respiratory allergies was noted. At the beginning of the 20th century allergic inflammations affected only around 1% of the world population. Medical symptoms of allergic airway inflammation are variable for different patients. Airways allergy are complex phenotypes, which are determined by both genetic and environmental factors. Potential environmental factors include air pollution, tobacco smoke, diet and hygienic habits. The base of phenotypes diversity is still unknown. Genetic studies of allergic disease are complex , the disease derives from the global effect of a series of genes considered individually. What is more, there are epigenetic effects and interactions among the possible causal genes and a range of environmental factors. Single nucleotide polymorphism (SNP in genes encoding chemokines and their receptors, interleukins and their receptors, eosinophil peroxidase and leukotrienes have been found as a possible factor for a development of allergic airway inflammation. It is known that SNPs are specific for different cohort.

  13. PPARγ as a Potential Target to Treat Airway Mucus Hypersecretion in Chronic Airway Inflammatory Diseases

    Directory of Open Access Journals (Sweden)

    Yongchun Shen

    2012-01-01

    Full Text Available Airway mucus hypersecretion (AMH is a key pathophysiological feature of chronic airway inflammatory diseases such as bronchial asthma, cystic fibrosis, and chronic obstructive pulmonary disease. AMH contributes to the pathogenesis of chronic airway inflammatory diseases, and it is associated with reduced lung function and high rates of hospitalization and mortality. It has been suggested that AMH should be a target in the treatment of chronic airway inflammatory diseases. Recent evidence suggests that a key regulator of airway inflammation, hyperresponsiveness, and remodeling is peroxisome proliferator-activated receptor gamma (PPARγ, a ligand-activated transcription factor that regulates adipocyte differentiation and lipid metabolism. PPARγ is expressed in structural, immune, and inflammatory cells in the lung. PPARγ is involved in mucin production, and PPARγ agonists can inhibit mucin synthesis both in vitro and in vivo. These findings suggest that PPARγ is a novel target in the treatment of AMH and that further work on this transcription factor may lead to new therapies for chronic airway inflammatory diseases.

  14. Engineering Airway Epithelium

    Directory of Open Access Journals (Sweden)

    John P. Soleas

    2012-01-01

    Full Text Available Airway epithelium is constantly presented with injurious signals, yet under healthy circumstances, the epithelium maintains its innate immune barrier and mucociliary elevator function. This suggests that airway epithelium has regenerative potential (I. R. Telford and C. F. Bridgman, 1990. In practice, however, airway regeneration is problematic because of slow turnover and dedifferentiation of epithelium thereby hindering regeneration and increasing time necessary for full maturation and function. Based on the anatomy and biology of the airway epithelium, a variety of tissue engineering tools available could be utilized to overcome the barriers currently seen in airway epithelial generation. This paper describes the structure, function, and repair mechanisms in native epithelium and highlights specific and manipulatable tissue engineering signals that could be of great use in the creation of artificial airway epithelium.

  15. Small Airway Targeted Therapy in Pediatric Asthma: Are We There Yet?

    OpenAIRE

    2013-01-01

    Asthma is characterized by inflammation of proximal and distal airways. As new formulations of extrafine aerosol particles have become available, targeting small airways for the management of asthma has been investigated. As new studies attempt to explore the correlation between small airway dysfunction and clinical outcomes in asthma, well-designed clinical trials are needed to compare targeted and standard therapy for asthma management especially in pediatric patients.

  16. Airway management in trauma

    Directory of Open Access Journals (Sweden)

    Rao B

    2004-01-01

    Full Text Available Airway Management for the victims of major trauma is the first priority in the care of the trauma victim and is a core skill in emergency medicine and critical care. Endotracheal intubation remains the gold standard for trauma airway management. Airway management in trauma patients is not just the capability to insert an oral/nasal airway or endotracheal tube beyond the vocal cords. The five components integral to modern, sophisticated airway management in trauma patients include equipment, pharmacologic adjuncts, manual techniques, physical circumstances, and patient profile. A trauma patient may require airway management in a variety of physical circumstances. Whereas, the commonly used airway management algorithms may not suffice in all these situations, the construction of a truly complete decision tree is also virtually impossible. There is consensus that it is not the intervention per se but rather the conditions, skills, and performance that might be the possible variables that affect outcome. Paramedics have only limited experience and on-the-job skills for invasive airway management. Difficult airway management is best left for the experienced physicians to handle.

  17. Inhibitory Effects of Moldavica Total Flavone on Airway Inflammation and Hyperresponsiveness in Ovalbumin-induced Asthmatic Rats%香青兰总黄酮对哮喘大鼠气道炎症及高反应性的改善作用

    Institute of Scientific and Technical Information of China (English)

    康小龙; 何承辉; 邢建国; 闫丽丽

    2013-01-01

    OBJECTIVE To investigate the effects of moldavica total flavone on airway inflammation and hyperrespon-siveness in ovalbumin-induced asthmatic rats. METHODS The cough model in rats and asthma model in cavies were made by using ammonia water and histamine-acetylcholine chloride to observe the antitussive and antiasthmatic actions. The inhibitory effect on airway inflammation and hyperresponsiveness in ovalbumin-induced asthmatic rats were observed. RESLUTS The moldavica total flavone in middle and high dose group could extend the cough latent period in rats(.P<0.05 or 0.01) and gasp latent period in cavies (P<0.01), decreased the levels of serum ovalbumin specific IgE (P<0.01) and eosinophil counts in bronchoalveolar lavage fluid (P<0.01), attenuate the contraction of tracheal smooth muscle in ovalbumin-induced asthmatic rats (P<0.05 or 0.01). CONCLUSION Moldavica total flavone has antitussive and antiasthmatic actions and may inhibit ariway inflammation and hyperresponsiveness in asthma.%目的研究香青兰总黄酮对哮喘大鼠气道炎症及高反应性的影响.方法采用氨水引咳实验和磷酸组胺-氯化乙酰胆碱引喘实验观察香青兰总黄酮的镇咳、平喘作用;同时观察香青兰总黄酮对哮喘大鼠支气管肺泡灌洗液(BALF)中白细胞分类计数和离体气管螺旋条张力的影响.结果香青兰总黄酮中、高剂量能延长小鼠咳嗽潜伏期,减少小鼠2 min内咳嗽次数(P<0.05或P<0.01),延长豚鼠引喘潜伏期(P<0.01);降低哮喘大鼠血清卵白蛋白特异性IgE水平(P<0.01),减少BALF中嗜酸性粒细胞数量(P<0.01)及减小离体气管螺旋条张力(P<0.05或P<0.01).结论 香青兰总黄酮具有一定镇咳、平喘作用;可改善哮喘气道炎症及高反应性.

  18. Indirect airway challenges

    NARCIS (Netherlands)

    Joos, GF; O'Connor, B; Anderson, SD; Chung, F; Cockcroft, DW; Dahlen, B; DiMaria, G; Foresi, A; Hargreave, FE; Holgate, ST; Inman, M; Lotvall, J; Magnussen, H; Polosa, R; Postma, DS; Riedler, J

    2003-01-01

    Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle. Di

  19. Pediatric airway nightmares.

    Science.gov (United States)

    D'Agostino, James

    2010-02-01

    Pediatric disorders that involve actual or potential airway compromise are among the most challenging cases that emergency department providers face. This article discusses the diagnosis and management of common and uncommon conditions in infants and children who may present with airway obstruction.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Retroperitoneal inflammation

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/001255.htm Retroperitoneal inflammation To use the sharing features on this page, please enable JavaScript. Retroperitoneal inflammation is swelling that occurs in the retroperitoneal space. ...

  2. Severe upper airway obstruction during sleep.

    Science.gov (United States)

    Bonekat, H William; Hardin, Kimberly A

    2003-10-01

    Few disorders may manifest with predominantly sleep-related obstructive breathing. Obstructive sleep apnea (OSA) is a common disorder, varies in severity and is associated with significant cardiovascular and neurocognitive morbidity. It is estimated that between 8 and 18 million people in the United States have at least mild OSA. Although the exact mechanism of OSA is not well-delineated, multiple factors contribute to the development of upper airway obstruction and include anatomic, mechanical, neurologic, and inflammatory changes in the pharynx. OSA may occur concomitantly with asthma. Approximately 74% of asthmatics experience nocturnal symptoms of airflow obstruction secondary to reactive airways disease. Similar cytokine, chemokine, and histologic changes are seen in both disorders. Sleep deprivation, chronic upper airway edema, and inflammation associated with OSA may further exacerbate nocturnal asthma symptoms. Allergic rhinitis may contribute to both OSA and asthma. Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA. Treatment with CPAP therapy has also been shown to improve both daytime and nighttime peak expiratory flow rates in patients with concomitant OSA and asthma. It is important for allergists to be aware of how OSA may complicate diagnosis and treatment of asthma and allergic rhinitis. A thorough sleep history and high clinical suspicion for OSA is indicated, particularly in asthma patients who are refractory to standard medication treatments.

  3. Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma%题目:抗CD69单克隆抗体对哮喘小鼠的气道炎症抑制作用研究

    Institute of Scientific and Technical Information of China (English)

    Hui-ying WANG; Yu DAI; Jiao-li WANG; Xu-yan YANG; Xin-guo JIANG

    2015-01-01

    Objective: Airway inflammation and airway hyper-responsiveness (AHR) are principle pathological mani-festations of asthma. Cluster of differentiation 69 (CD69) is a well-known co-stimulatory factor associated with the activation, proliferation as well as apoptosis of immune cels. This study aims to examine the effect of anti-CD69 monoclonal antibody (mAb) on the pathophysiology of a mouse model of asthma. Methods: A murine model of oval-bumin (OVA)-induced alergic airway inflammation was used in this study. Briefly, mice were injected with 20μg chicken OVA intraperitonealy on Days 0 and 14, folowed by aerosol provocation with 1% (0.01 g/ml) OVA on Days 24, 25, and 26. Anti-CD69 mAb or isotype IgG was injected intraperitoneally after OVA chalenge; dexamethasone (DXM) was administrated either before or after OVA chalenge. AHR, mucus production, and eosinophil infiltration in the peribronchial area were examined. The levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) in bronchoalveolar lavage fluid (BALF) were also assayed as indices of airway inflammation on Day 28 folowing OVA injection. Results: Pretreatment with DXM together with anti-CD69 mAb treatment after OVA provoca-tion completely inhibited AHR, eosinophil infiltration and mucus overproduction, and significantly reduced BALF IL-5. However, treatment with DXM alone after OVA chalenge only partially inhibited AHR, eosinophil infiltration and mucus overproduction, and did not diminish BALF IL-5. Treatment with either DXM or anti-CD69 mAb did not alter the con-centration of BALF GM-CSF. Conclusions: Anti-CD69 mAb treatment inhibits established airway inflammation as effectively as DXM pretreatment. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma and its exacerbation.%目的:气道慢性炎症和高反应性是哮喘最主要的病理生理表现,CD69是一种与免疫细胞活化、增殖及凋亡密切相

  4. Potential of Helper-Dependent Adenoviral Vectors in Modulating Airway Innate Immunity

    Institute of Scientific and Technical Information of China (English)

    Rahul Kushwah; Huibi Cao; Jim Hu

    2007-01-01

    Innate immune responses form the first line of defense against foreign insults and recently significant advances have been made in our understanding of the initiation of innate immune response along with its ability to modulate inflammation. In airway diseases such as asthma, COPD and cystic fibrosis, over reacting of the airway innate immune responses leads to cytokine imbalance and airway remodeling or damage. Helper-dependent adenoviral vectors have the potential to deliver genes to modulate airway innate immune responses and have many advantages over its predecessors. However, there still are a few limitations that need to be addressed prior to their use in clinical applications.

  5. The airway epithelium is central to the pathogenesis of asthma.

    Science.gov (United States)

    Holgate, Stephen T

    2008-03-01

    Asthma is an inflammatory disorder principally involving the conducting airways and characterised by infiltration of the airway wall with a range of inflammatory cells driven in large part by activation of Th2-type lymphocytes, mast cells and eosinophils. However a key component of asthma is the structural change that involves all of the elements of the airway wall. Here evidence is presented to suggest that the airway epithelium in asthma is fundamentally abnormal with increased susceptibility to environmental injury and impaired repair associated with activation of the epithelial-mesenchymal trophic unit (EMTU). In addition to adopting an activated phenotype, the barrier function of the epithelium is impaired through defective tight junction formation thereby facilitating penetration of potentially toxic or damaging environmental insults. Activated and repairing epithelial cells generate a range of growth factors that are involved in the early life origins of this disease as well as its progression in the form of mucous metaplasia and airway wall remodeling. By placing the epithelium at the forefront of asthma pathogenesis, different approaches to treatment can be devised focused more on protecting vulnerable airways against environmental injury rather than focusing on suppressing airway inflammation or manipulating the immune response.

  6. Characterization of inflammation in COPD : clinical and experimental approach

    NARCIS (Netherlands)

    Vernooy, J.H.J.

    2003-01-01

    Chronic inflammation is an important feature of COPD. This inflammatory response is not restricted to the local compartment - including airways, lung parenchyma, and pulmonary vasculature - but is also present in the circulation. However, the origin of the systemic inflammation present in COPD patie

  7. Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency

    DEFF Research Database (Denmark)

    Richmond, Bradley W; Brucker, Robert M; Han, Wei;

    2016-01-01

    Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced...... SIgA contributes to chronic airway inflammation and disease progression. Here we show that polymeric immunoglobulin receptor-deficient (pIgR(-/-)) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodelling and emphysema in pIgR(-/-) mice...... are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-κB activation, leukocyte infiltration and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgR(-/-) mice in germ-free conditions or treatment with the anti...

  8. Emergency airway puncture - slideshow

    Science.gov (United States)

    ... presentations/100113.htm Emergency airway puncture - series—Normal anatomy To ... larynx is a tubular structure in the neck, through which air passes to the lungs. The thryoid and cricoid cartilage form the narrowest ...

  9. Emergency airway puncture

    Science.gov (United States)

    ... inserted into the throat, just below the Adam's apple (cricoid cartilage), into the airway. In a hospital, ... Choking Browse the Encyclopedia A.D.A.M., Inc. is accredited by URAC, also known as the ...

  10. 虫草多糖对OVA过敏性哮喘鼠气道炎症和气道高反应的影响%Effects of Cordyceps Polysaccharide on the OVA-induced Airway Inflammation and Hyperresponsiveness in a Murine Asthmatic Model

    Institute of Scientific and Technical Information of China (English)

    王珊琳; 杜奋飞; 汪莉莉; 应旦红

    2011-01-01

    OBJECTIVE To observe the effects of Cordyceps polysaccharide on the antigen-induced airway eosinophilic inflammation. METHODS Thirty-two female BALB/c mice were randomly divided into four groups: control, asthma model, Cordyceps polysaccharide and Dexamethasone treatment groups. Asthma was induced by OVA administration in the asthma model, Cordyceps polysaccharide and Dexamethasone treatment groups. Cordyceps polysaccharide and Dexamethasone were administered before antigen challenge. After 12 hours of the last challenge, the mice were used to evaluate airway hyperresponsiveness(AHR). After the airway hyperresponsiveness experimentation , mice were killed and Bronchial alveolar lavage fluid (BALF) was collected to count the number of eosinophil and to measure the levels of IL-4, IL-5, IL-13. The lung tissues of inferior lobe of the left lung were obtained for the observation of lung pathological change. RESULTS ① Cordyceps polysaccharide significantly suppressed airway hyperresponsiveness in OVA-induced mice. ② Cordyceps polysaccharide attenuated the airway inflammation in the lung of OVA-induced mice. ③ In Cordyceps polysaccharide treatment groups, increase of eosinophil counts challenged by OVA was decreased in BALF of mice. ④ The increased levels of IL-4, IL-5, IL-13 challenged by OVA in BALF of mice were decreased by Cordyceps polysaccharide treatment .⑤ The increased expressions of IL-4, IL-5, IL-13 mRNA challenged by OVA in lung tissues were also decreased by cordyceps polysaccharide treatment. CONCLUSION Cordyceps polysaccharide efficiently inhibited the eosinophil inflammation in lung tissue and may be of therapeutic value as a novel treatment of asthma.%目的 观察虫草多糖是否具有抗过敏性哮喘的作用.方法 建立小鼠哮喘模型,第0,14天,分别腹腔注射OVA及其佐剂,自21 d时开始雾化吸入OVA一次,连续14d,吸入OVA前0.5 h,观察组予虫草多糖100 mg·kg-1灌胃,阳性药物腹腔注射地塞米

  11. Airway management in trauma.

    Science.gov (United States)

    Langeron, O; Birenbaum, A; Amour, J

    2009-05-01

    Maintenance of a patent and prevention of aspiration are essential for the management of the trauma patient, that requires experienced physicians in airway control techniques. Difficulties of the airway control in the trauma setting are increased by the vital failures, the risk of aspiration, the potential cervical spine injury, the combative patient, and the obvious risk of difficult tracheal intubation related to specific injury related to the trauma. Endotracheal intubation remains the gold standard in trauma patient airway management and should be performed via the oral route with a rapid sequence induction and a manual in-line stabilization maneuver, to decrease the risks previously mentioned. Different techniques to control the airway in trauma patients are presented: improvement of the laryngoscopic vision, lighted stylet tracheal intubation, retrograde technique for orotracheal intubation, the laryngeal mask and the intubating laryngeal mask airways, the combitube and cricothyroidotomy. Management of the airway in trauma patients requires regular training in these techniques and the knowledge of complementary techniques allowing tracheal intubation or oxygenation to overcome difficult intubation and to prevent major complications as hypoxemia and aspiration.

  12. Inhaled different Concentrations of Budesonide in Early Phase Interfere in Airway Inflammation and Remodeling in Asthmatic Rats%早期吸入不同浓度布地奈德对哮喘大鼠气道炎症和重构的干预

    Institute of Scientific and Technical Information of China (English)

    梁蕊; 金寿德; 邵玉霞; 张新; 刘立杰; 荣海芳

    2011-01-01

    Objective: To investigate the effect of inhaled different concentrations of budesonide in early phase on the airway inflammation and remodeling in asthmatic rats. Methods: Thirty-two rats were randomly divided into 4 groups: group A (n=8,control with saline), groupB (n=8,asthma with OVA),group C (n=8, asthma with OVA treated with low concentrations of budesonide in early phase), group D (n=8, asthma with OVA treated with high concentrations of budesonide in early phase). The bronchoalveolar lavage fluids (BALF) were classification in BALF studied in each group . The pathologic alteration of the bronchi and lung tissue was observed by HE staining. Expression of NGF and TGF-β1 were detected by immunohistochemistry, collagen deposition by Masson staining. The Morphological parameters including the number of inflammatory cell per unit airway area, bronchial basement membrane perimeter (Pbm), smooth muscle area( Wam), inner airway area( Wai), collagen area( Wcol) by computer image analysis software. Results: The total cell counts and the percentage of EOS in BALF the level of TNF-α , ET-1 increased compared with group A (P<0.01), group C and D reduced significantly compared with group B (P<0.01). The expression of NGF and TGF-β1, inflammatory cell counts around bronchus, airway smooth muscle hypertrophy ,the collagen deposition of reticular basement, airway inner wall area were significant higher than those groupA( P<0.01), the data in group C and D were significant lower than those in group B(P<0.01), there were apparent difference between group C and group D compared with group A (P<0.05,P<0.01). The difference between group C and group D.(P<0.05,P<0.01) Conclusion: Inhaled different concentrations of budesonide in early phase could apparently inhibit airway inflammation and remodeling, high concentrations of budesonide than low concentrations.%目的:研究早期吸入不同浓度布地奈德对哮喘大鼠气道炎症和气道重构的干预情况.方法:32

  13. MicroPET Evaluation of a Hydroxamate-Based MMP Inhibitor, [(18)F]FB-ML5, in a Mouse Model of Cigarette Smoke-Induced Acute Airway Inflammation.

    Science.gov (United States)

    Matusiak, Nathalie; van Waarde, Aren; Rozeveld, Dennie; van Oosterhout, Antoon J M; Heijink, Irene H; Castelli, Riccardo; Overkleeft, Herman S; Bischoff, Rainer; Dierckx, Rudi A J O; Elsinga, Philip H

    2015-10-01

    Matrix metalloproteinases (MMPs) are the main proteolytic enzymes involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). A radiolabeled MMP inhibitor, [(18)F]FB-ML5, was prepared, and its in vivo kinetics were tested in a mouse model of pulmonary inflammation. BALB/c mice were exposed for 4 days to cigarette smoke (CS) or air. On the fifth day, a dynamic microPET scan was made with [(18)F]FB-ML5. Standardized uptake values (PET-SUVmean) were 0.19 ± 0.06 in the lungs of CS-exposed mice (n = 6) compared to 0.11 ± 0.03 (n = 5) in air-exposed controls (p FB-ML5.

  14. NF-kappaB Signaling in Chronic Inflammatory Airway Disease

    Directory of Open Access Journals (Sweden)

    Michael Schuliga

    2015-06-01

    Full Text Available Asthma and chronic obstructive pulmonary disease (COPD are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments. In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression. The redox-sensitive transcription factor, nuclear factor (NF-kappaB (NF-κB, is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology. The anti-inflammatory actions of glucocorticoids (GCs, a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription. Ligand bound GC receptors (GRs bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression. However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling. Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs are potential treatments for asthma and COPD. Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression. This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD.

  15. Cromoglycate and Nedocromil: Influence on Airway Reactivity

    Science.gov (United States)

    Valletta, E. A.

    1994-01-01

    Although basic mechanisms of bronchial hyper-responsiveness (BHR) are still incompletely understood, inflammation of airways is likely to play a fundamental role in modulating BHR in patients with asthma. The involvement of several inflammatory cells (eosinophils, mast cells, lymphocytes, neutrophils, macrophages and platelets) and of bioactive mediators secreted by these cells in the pathogenesis of asthma is well documented. Sodium cromoglycate and nedocromil sodium are two pharmacological agents which have anti-allergic and anti-inflammatory properties. Their clinical effectiveness in mild to moderate asthma, and the capacity to reduce BHR under different natural and experimental conditions, make them valuable drugs for maintenance therapy in patients with asthma. PMID:18475597

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Effect of recombinant IL-12 expression vector on the regulation of airway inflammation and the immune response of pregnancy asthmatic mice%重组IL-12表达载体构建及对妊娠期哮喘小鼠气道炎症的调节与免疫应答影响

    Institute of Scientific and Technical Information of China (English)

    马佳佳; Nick Lu; 陈必良; 滑玮; 张建芳

    2013-01-01

    Objective:To construct the eukaryotic expression vector with recombinant gene of interleukin-12( IL-12) , to identify its biological activity, and after it was transfected into airway, to observe its effect on the regulation of airway inflammation and the immune response in mice of asthma during pregnancy. Methods: The cDNA fragment of mIL-12 gene, which was amplified by PCR, was inserted into pcDNA3. 1 ( + ). After the digestion by restriction enzyme and the identification of sequencing, it was transiently transfected to P815 cells by liposome. Then we observed the expression and positioning of fluorescent protein in cells. Sixty female BALB/c mice were used to construct the model of asthma during pregnancy. All mice were randomly divided into 6 different groups. Pregnancy or non-pregnancy asthma mice treated with airway perfusing of 50 μ1 recombinant plasmid pcDNA3.1 ( + ) -mIL-12 and liposome complexes were named as API group and ANP1 group respectively. Accordingly, Pregnancy or non-pregnancy asthma mice treated with empty plasmid pcDNA3. 1 ( + ) were named as AP2 group and ANP2 group. Control mice (HNP group) and health pregnancy mice (HP group) were only treated with 50 |xl PBS. 24 hours after the final challenge, the airway inflammation was evaluated by the inflammatory cell counts of bronchoalveolar lavage fluid ( BALF) and the HE staining of lung tissue. The expression of IL-12 protein We successfully constructed the specific recombinant eukaryotic expression vector pcDNA3. 1( + )-mIL-12, and its expression in P815 cells is efficient. Among the asthmatic mice during pregnancy, the inflammatory changes of lung tissue in the recombinant plasmid group were significantly lessened than that in the empty plasmid group, while the cell number of leukocytes and Eos ( eosino-phil) , Neu (neutrophils) and Lym (lymphocytes) in BALF was significantly reduced (P<0.05). Proved by the results of RT-PCR and Western blot, in mice' s lung tissue. The expression of IL-12

  18. Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency.

    Science.gov (United States)

    Richmond, Bradley W; Brucker, Robert M; Han, Wei; Du, Rui-Hong; Zhang, Yongqin; Cheng, Dong-Sheng; Gleaves, Linda; Abdolrasulnia, Rasul; Polosukhina, Dina; Clark, Peter E; Bordenstein, Seth R; Blackwell, Timothy S; Polosukhin, Vasiliy V

    2016-04-05

    Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. Here we show that polymeric immunoglobulin receptor-deficient (pIgR(-/-)) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodelling and emphysema in pIgR(-/-) mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-κB activation, leukocyte infiltration and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgR(-/-) mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodelling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodelling and emphysema.

  19. Integrated care pathways for airway diseases (AIRWAYS-ICPs)

    NARCIS (Netherlands)

    Bousquet, J.; Addis, A.; Adcock, I.; Agache, I.; Agusti, A.; Alonso, A.; Annesi-Maesano, I.; Anto, J. M.; Bachert, C.; Baena-Cagnani, C. E.; Bai, C.; Baigenzhin, A.; Barbara, C.; Barnes, P. J.; Bateman, E. D.; Beck, L.; Bedbrook, A.; Bel, E. H.; Benezet, O.; Bennoor, K. S.; Benson, M.; Bernabeu-Wittel, M.; Bewick, M.; Bindslev-Jensen, C.; Blain, H.; Blasi, F.; Bonini, M.; Bonini, S.; Boulet, L. P.; Bourdin, A.; Bourret, R.; Bousquet, P. J.; Brightling, C. E.; Briggs, A.; Brozek, J.; Buh, R.; Bush, A.; Caimmi, D.; Calderon, M.; Calverley, P.; Camargos, P. A.; Camuzat, T.; Canonica, G. W.; Carlsen, K. H.; Casale, T. B.; Cazzola, M.; Sarabia, A. M. Cepeda; Cesario, A.; Chen, Y. Z.; Chkhartishvili, E.; Chavannes, N. H.; Chiron, R.; Chuchalin, A.; Chung, K. F.; Cox, L.; Crooks, G.; Crooks, M. G.; Cruz, A. A.; Custovic, A.; Dahl, R.; Dahlen, S. E.; De Blay, F.; Dedeu, T.; Deleanu, D.; Demoly, P.; Devillier, P.; Didier, A.; Dinh-Xuan, A. T.; Djukanovic, R.; Dokic, D.; Douagui, H.; Dubakiene, R.; Eglin, S.; Elliot, F.; Emuzyte, R.; Fabbri, L.; Wagner, A. Fink; Fletcher, M.; Fokkens, W. J.; Fonseca, J.; Franco, A.; Frith, P.; Furber, A.; Gaga, M.; Garces, J.; Garcia-Aymerich, J.; Gamkrelidze, A.; Gonzales-Diaz, S.; Gouzi, F.; Guzman, M. A.; Haahtela, T.; Harrison, D.; Hayot, M.; Heaney, L. G.; Heinrich, J.; Hellings, P. W.; Hooper, J.; Humbert, M.; Hyland, M.; Iaccarino, G.; Jakovenko, D.; Jardim, J. R.; Jeandel, C.; Jenkins, C.; Johnston, S. L.; Jonquet, O.; Joos, G.; Jung, K. S.; Kalayci, O.; Karunanithi, S.; Keil, T.; Khaltaev, N.; Kolek, V.; Kowalski, M. L.; Kull, I.; Kuna, P.; Kvedariene, V.; Le, L. T.; Carlsen, K. C. Lodrup; Louis, R.; MacNee, W.; Mair, A.; Majer, I.; Manning, P.; Keenoy, E. de Manuel; Masjedi, M. R.; Meten, E.; Melo-Gomes, E.; Menzies-Gow, A.; Mercier, G.; Mercier, J.; Michel, J. P.; Miculinic, N.; Mihaltan, F.; Milenkovic, B.; Molimard, M.; Mamas, I.; Montilla-Santana, A.; Morais-Almeida, M.; Morgan, M.; N'Diaye, M.; Nafti, S.; Nekam, K.; Neou, A.; Nicod, L.; O'Hehir, R.; Ohta, K.; Paggiaro, P.; Palkonen, S.; Palmer, S.; Papadopoulos, N. G.; Papi, A.; Passalacqua, G.; Pavord, I.; Pigearias, B.; Plavec, D.; Postma, D. S.; Price, D.; Rabe, K. F.; Pontal, F. Radier; Redon, J.; Rennard, S.; Roberts, J.; Robine, J. M.; Roca, J.; Roche, N.; Rodenas, F.; Roggeri, A.; Rolland, C.; Rosado-Pinto, J.; Ryan, D.; Samolinski, B.; Sanchez-Borges, M.; Schunemann, H. J.; Sheikh, A.; Shields, M.; Siafakas, N.; Sibille, Y.; Similowski, T.; Small, I.; Sola-Morales, O.; Sooronbaev, T.; Stelmach, R.; Sterk, P. J.; Stiris, T.; Sud, P.; Tellier, V.; To, T.; Todo-Bom, A.; Triggiani, M.; Valenta, R.; Valero, A. L.; Valiulis, A.; Valovirta, E.; Van Ganse, E.; Vandenplas, O.; Vasankari, T.; Vestbo, J.; Vezzani, G.; Viegi, G.; Visier, L.; Vogelmeier, C.; Vontetsianos, T.; Wagstaff, R.; Wahn, U.; Wallaert, B.; Whalley, B.; Wickman, M.; Williams, D. M.; Wilson, N.; Yawn, B. P.; Yiallouros, P. K.; Yorgancioglu, A.; Yusuf, O. M.; Zar, H. J.; Zhong, N.; Zidarn, M.; Zuberbier, T.

    2014-01-01

    The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will ad

  20. Physiological impact of abnormal lipoxin A₄ production on cystic fibrosis airway epithelium and therapeutic potential.

    Science.gov (United States)

    Higgins, Gerard; Ringholz, Fiona; Buchanan, Paul; McNally, Paul; Urbach, Valérie

    2015-01-01

    Lipoxin A4 has been described as a major signal for the resolution of inflammation and is abnormally produced in the lungs of patients with cystic fibrosis (CF). In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF. This review highlights the unique ability of LXA4 to restore airway surface hydration, to stimulate airway epithelial repair, and to antagonise the proinflammatory program of the CF airway, circumventing some of the most difficult aspects of CF pathophysiology. The report points out novel aspects of the cellular mechanism involved in the physiological response to LXA4, including release of ATP from airway epithelial cell via pannexin channel and subsequent activation of and P2Y11 purinoreceptor. Therefore, inadequate endogenous LXA4 biosynthesis reported in CF exacerbates the ion transport abnormality and defective mucociliary clearance, in addition to impairing the resolution of inflammation, thus amplifying the vicious circle of airway dehydration, chronic infection, and inflammation.

  1. Airway reconstruction in children

    Directory of Open Access Journals (Sweden)

    Rao Sanjay

    2009-01-01

    Full Text Available Aim/Background : Airway anomalies are infrequent but potentially life threatening in children. A program to care for these difficult children was set up at our institution, and this paper summarizes our experience. Methods: A total of 34 children were enrolled in the program over a period of three years. These children were evaluated as per the standard protocols. Treatment was individualized. Results: Of these 34 children, 28 had their airways restored and are doing well. Four children continue to remain on tracheostomy and two will require long term tracheostomy. There were two deaths. All children are under surveillance as there is a risk of recurrence. Conclusions: Airway anomalies are complex problems with significant morbidity and mortality. Current therapeutic modalities allow for good results. Most children were successfully decannulated and did well.

  2. Paediatric airway management: basic aspects

    DEFF Research Database (Denmark)

    Holm-Knudsen, R J; Rasmussen, L S

    2009-01-01

    . Airway obstruction can be avoided by paying close attention to the positioning of the head of the child and by keeping the mouth of the child open during mask ventilation. The use of oral and nasopharyngeal airways, laryngeal mask airways, and cuffed endotracheal tubes is discussed with special reference...... to the circumstances in infants. A slightly different technique during laryngoscopy is suggested. The treatment of airway oedema and laryngospasm is described....

  3. 白藜芦醇对呼吸道合胞病毒感染小鼠肺部病毒滴度及其气道炎症的影响%Effect of resveratrol on pulmonary vurus titer and airway inflammation in mice infected with respiratory syncytial virus

    Institute of Scientific and Technical Information of China (English)

    臧娜; 谢晓虹; 邓昱; 李思敏; 倪科; 罗艳; 王莉佳; 刘恩梅

    2011-01-01

    Objective To study the effect of resveratrol (RES) on pulmonary virus titer and airway inflammation in mice infected with respiratory syncytial virus (RSV). Methods Twenty-four female BALB/c mice at the age of 6 -8 weeks, treated with intra-abdominal cyclophosphamide (CYP) at the dose of 100 mg/kg, were randomly divided into control group, RSV infection group, and RES treatment group (8 in each group). Five days after CYP treatment, a RES infection model was induced by intranasal drip of RES. One hour after RES infection, the mice received intraperitoneal injection of RES or inhaled it at the dose of 30mg/(kg ? D). Five days later, airway hyper-response (AHR) in lucid mice was detected. The mice were then killed to detect the pulmonary RSV titers in the lung, the number of cells in bronchoalevolar lavage fluid (BALF), inflammation in lung tissue and its score. Results The pulmonary RSV titer, the number of cells in BALF, the score of inflammation in lung tissue, and the airway AHR were significantly lower in RES treatment group than in RSV infection group (P <0. 01). However, no significant difference was observed between RES treatment group and control group. Conclusion Differenly administrated RES can relieve RSV-induced inflammation and AHR by reducing pulmonary titer and inhibiting RSV replication in vivo.%目的 研究白藜芦醇(resveratrol,RES)对呼吸道合胞病毒(respiratory syncytial virus,RSV)感染小鼠肺部病毒滴度及其所致气道炎症的影响。方法6~8周龄雌性BALB/c小鼠,环磷酰胺100 mg/kg腹腔注射后,随机分为对照组、RSV感染组、白藜芦醇腹腔注射组、白藜芦醇雾化组,每组8只。环磷酰胺处理5d后,给予RSV滴鼻建立RSV感染模型,并在RSV感染1h后给予白藜芦醇30 mg/(kg·d)腹腔注射和雾化吸入。5d后检测小鼠清醒状态下气道阻力,处死小鼠研究肺部RSV病毒滴度、肺泡灌洗液(BALF)中细胞计数、肺部病理组织炎症及评分。

  4. Effects of leptin on airway inflammation and the expression of Th1/Th2 cytokines in asthmatic rats%瘦素对支气管哮喘大鼠气道炎症及Th1/Th2细胞因子表达作用的影响

    Institute of Scientific and Technical Information of China (English)

    曹娟; 陈建辉; 朱述阳

    2009-01-01

    Objective To investigate the effects of hptin on airway inflammation and the expression of Th1/Th2 cytokines. Methods The obesity and acute asthma models were established in 40 female SD rats, which were randomly divided into a normal weight control group (group A), a normal weight asthmatic group (group B), a normal weight intervention group (group C), an obese control group (group D) and an obese asthmatic group (group E). The airway resistance and airway responsiveness were calculated by transpulmonary pressure and gas flow rate. The numbers of leukocytes, eosinophils (EOS) and neutrephils (N) in brenchoalveolar lavage fluid (BALF) were counted. The concentrations of interleukin-4 (IL-4), interferon-γ(IFN-γ) and leptin in serum and BALF were determined by ELISA. The protein and Mrna expression of leptin was measured by Western blot and RT-PCR respectively. Results The airway resistance in group C and E [(0.890±0.106)cm H2O·ml-1·s-1 (1.024±0.096)cm H2O·ml-1·s-1(1.129±0.107) cm H2O·ml-1·s-1, (0.946±0.104) cm H2O·ml-1·s-1, (1.124±0.095)cm H2O·ml-1·s-1, (1.135±0.105) cm H2O·ml-1·s-1,respectively.] was increased significantly compared to group B [(0.638±0.128) cm H2O·ml-1·s-1, (0.745±0.073) cm H2O·ml-1·s-1,(0.773±0.090) cm H2O·ml-1·s-1] (q=7.128, 8.712, 8.318, 11.300, 11.258, 11.447, all P<0.05). The numbers of leukocyte and neutrophils in group C and E [(91±9)×104/ml, (108±21)×104/ml, (12.4±4.0)×104/ml, (14.2±5.9)×104/ml, respectively.] were increased significantly compared to group B [(79±7)×104/ml, (2.4±1.1)×104/ml] (q= 2.923, 7.063, 8.629, 10.182,all P<0.05). The concentrations of IFN-γ were [(42.3±3.5) ng/L, (45.1±4.8) ng/L, (19.2±1.8) ng/L, (20.3±1.5)ng/L] in group C and E respectively, which were significantly higher than those of group B[(16.5±1.4) ng/L,(9.3±1.0) ng/L] (q= 21.607, 23.952, 16.919, 18.799, all P<0.05). The protein and Mrna expression of leptin in lung tissue in group C and E[(0.40±0.07)ng/L,(0

  5. Airway management and morbid obesity

    DEFF Research Database (Denmark)

    Kristensen, Michael S

    2010-01-01

    airway and the function of the lungs (decreased residual capacity and aggravated ventilation perfusion mismatch) worse than in lean patients. Proper planning and preparation of airway management is essential, including elevation of the patient's upper body, head and neck. Preoxygenation is mandatory...... solely on whether morbid obesity is present or not. It is important to ensure sufficient depth of anaesthesia before initiating manipulation of the airway because inadequate anaesthesia depth predisposes to aspiration if airway management becomes difficult. The intubating laryngeal mask airway is more...... pressure, noninvasive ventilation and physiotherapy....

  6. Predominant constitutive CFTR conductance in small airways

    Directory of Open Access Journals (Sweden)

    Lytle Christian

    2005-01-01

    Full Text Available Abstract Background The pathological hallmarks of chronic obstructive pulmonary disease (COPD are inflammation of the small airways (bronchiolitis and destruction of lung parenchyma (emphysema. These forms of disease arise from chronic prolonged infections, which are usually never present in the normal lung. Despite the fact that primary hygiene and defense of the airways presumably requires a well controlled fluid environment on the surface of the bronchiolar airway, very little is known of the fluid and electrolyte transport properties of airways of less than a few mm diameter. Methods We introduce a novel approach to examine some of these properties in a preparation of minimally traumatized porcine bronchioles of about 1 mm diameter by microperfusing the intact bronchiole. Results In bilateral isotonic NaCl Ringer solutions, the spontaneous transepithelial potential (TEP; lumen to bath of the bronchiole was small (mean ± sem: -3 ± 1 mV; n = 25, but when gluconate replaced luminal Cl-, the bionic Cl- diffusion potentials (-58 ± 3 mV; n = 25 were as large as -90 mV. TEP diffusion potentials from 2:1 NaCl dilution showed that epithelial Cl- permeability was at least 5 times greater than Na+ permeability. The anion selectivity sequence was similar to that of CFTR. The bionic TEP became more electronegative with stimulation by luminal forskolin (5 μM+IBMX (100 μM, ATP (100 μM, or adenosine (100 μM, but not by ionomycin. The TEP was partially inhibited by NPPB (100 μM, GlyH-101* (5–50 μM, and CFTRInh-172* (5 μM. RT-PCR gave identifying products for CFTR, α-, β-, and γ-ENaC and NKCC1. Antibodies to CFTR localized specifically to the epithelial cells lining the lumen of the small airways. Conclusion These results indicate that the small airway of the pig is characterized by a constitutively active Cl- conductance that is most likely due to CFTR.

  7. Advances in prehospital airway management.

    Science.gov (United States)

    Jacobs, Pe; Grabinsky, A

    2014-01-01

    Prehospital airway management is a key component of emergency responders and remains an important task of Emergency Medical Service (EMS) systems worldwide. The most advanced airway management techniques involving placement of oropharyngeal airways such as the Laryngeal Mask Airway or endotracheal tube. Endotracheal tube placement success is a common measure of out-of-hospital airway management quality. Regional variation in regard to training, education, and procedural exposure may be the major contributor to the findings in success and patient outcome. In studies demonstrating poor outcomes related to prehospital-attempted endotracheal intubation (ETI), both training and skill level of the provider are usually often low. Research supports a relationship between the number of intubation experiences and ETI success. National standards for certification of emergency medicine provider are in general too low to guarantee good success rate in emergency airway management by paramedics and physicians. Some paramedic training programs require more intense airway training above the national standard and some EMS systems in Europe staff their system with anesthesia providers instead. ETI remains the cornerstone of definitive prehospital airway management, However, ETI is not without risk and outcomes data remains controversial. Many systems may benefit from more input and guidance by the anesthesia department, which have higher volumes of airway management procedures and extensive training and experience not just with training of airway management but also with different airway management techniques and adjuncts.

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

    Science.gov (United States)

    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; aerodynamic diameter)* on normal airways and airways compromised with airway inflammation and excess mucus. Our project was specifically designed to (1) examine the chemical and physical characteristics of PM2.5 and other airborne 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

  9. 荷瘤小鼠髓系来源抑制性细胞对哮喘小鼠气道炎症的影响%Effects of Myeloid Derived Suppressor Cells Derived from 4T1 Tumor-Bearing Mice on Airway Inflammation of Asthmatic Mice

    Institute of Scientific and Technical Information of China (English)

    廖原; 于化鹏; 陈新; 樊慧珍; 龚雨新

    2012-01-01

    Objective To investigate the effect of myeloid derived suppressor cells (MDSCs) on airway inflammation of asthmatic mice. Methods Five male BALB/c mice aged 6 weeks were used for preparing 4T1 tumor bearing mice. Thirty female BALB/c mice aged six weeks were randomly divided into a normal control group,an athmatic model group, and a cell transplantation group. The MDSCs were separated from myeloid tissue of tumor-bearing mice using a magnetic cell sorting system and cultured in RPMI medium 1640 containing GM-CSF. The morphologic characteristics of these cells were observed under light microscope and the phenotypic figures were analyzed with flow cytometry. The mice in the model group and the cell transplantation group were sensitized by ovalbumin and then stimulated with nebulized ovalbumin. The mice in the cell transplantation group were intravenously administered MDSCs which purified by magnetic cell sorting system at 10 days after sensitization. The airway inflammation was evaluated by HE staining. The total and differential cell counts in bronchoalveolar lavage fluid ( BALF) were measured. Results The neutrophil and eosinophil infiltration in pulmonary tissue was dramatically increased in the model group,but not observed in the normal control group and was much milder in the cell transplantation group. The total cell count,the eosinophil and lymphocyte counts in BALF of the model group and the cell transplantation group were significantly higher than those of the normal control group ( P < 0. 05) , and the number of eosinophils in BALF of the cell transplantation group was decreased when compared with that of the model group (P <0. 05). Conclusion MDSCs via intravenous infusion can effectively suppress airway inflammation in a mouse asthma model.%目的 初步探讨髓系来源抑制性细胞( MDSC)对哮喘小鼠气道炎症的影响.方法 将6周龄SPF级BALB/c雄鼠5只制成4T1乳腺癌细胞成瘤小鼠,用于制备MDSC.6周龄SPF级BALB/c雌鼠30只随

  10. DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

    Science.gov (United States)

    Habibovic, Aida; Hristova, Milena; Heppner, David E.; Danyal, Karamatullah; Ather, Jennifer L.; Janssen-Heininger, Yvonne M.W.; Irvin, Charles G.; Poynter, Matthew E.; Lundblad, Lennart K.; Dixon, Anne E.; Geiszt, Miklos

    2016-01-01

    Chronic inflammation with mucous metaplasia and airway remodeling are hallmarks of allergic asthma, and these outcomes have been associated with enhanced expression and activation of EGFR signaling. Here, we demonstrate enhanced expression of EGFR ligands such as amphiregulin as well as constitutive EGFR activation in cultured nasal epithelial cells from asthmatic subjects compared with nonasthmatic controls and in lung tissues of mice during house dust mite–induced (HDM-induced) allergic inflammation. EGFR activation was associated with cysteine oxidation within EGFR and the nonreceptor tyrosine kinase Src, and both amphiregulin production and oxidative EGFR activation were diminished by pharmacologic or genetic inhibition of the epithelial NADPH oxidase dual oxidase 1 (DUOX1). DUOX1 deficiency also attenuated several EGFR-dependent features of HDM-induced allergic airway inflammation, including neutrophilic inflammation, type 2 cytokine production (IL-33, IL-13), mucous metaplasia, subepithelial fibrosis, and central airway resistance. Moreover, targeted inhibition of airway DUOX1 in mice with previously established HDM-induced allergic inflammation, by intratracheal administration of DUOX1-targeted siRNA or pharmacological NADPH oxidase inhibitors, reversed most of these outcomes. Our findings indicate an important function for DUOX1 in allergic inflammation related to persistent EGFR activation and suggest that DUOX1 targeting may represent an attractive strategy in asthma management.

  11. Inflammation and its genesis in cystic fibrosis.

    Science.gov (United States)

    Nichols, David P; Chmiel, James F

    2015-10-01

    The host inflammatory response in cystic fibrosis (CF) lung disease has long been recognized as a central pathological feature and an important therapeutic target. Indeed, many believe that bronchiectasis results largely from the oxidative and proteolytic damage comprised within an exuberant airway inflammatory response that is dominated by neutrophils. In this review, we address the longstanding argument of whether or not the inflammatory response is directly attributable to impairment of the cystic fibrosis transmembrane conductance regulator or only secondary to airway obstruction and chronic bacterial infection and challenge the importance of this distinction in the context of therapy. We also review the centrality of neutrophils in CF lung pathophysiology and highlight more recent data that suggest the importance of other cell types and signaling beyond NF-κB activation. We discuss how protease and redox imbalance are critical factors in CF airway inflammation and end by reviewing some of the more promising therapeutic approaches now under development.

  12. The adult cystic fibrosis airway microbiota is stable over time and infection type, and highly resilient to antibiotic treatment of exacerbations.

    Directory of Open Access Journals (Sweden)

    Anthony A Fodor

    Full Text Available Cystic fibrosis (CF is characterized by defective mucociliary clearance and chronic airway infection by a complex microbiota. Infection, persistent inflammation and periodic episodes of acute pulmonary exacerbation contribute to an irreversible decline in CF lung function. While the factors leading to acute exacerbations are poorly understood, antibiotic treatment can temporarily resolve pulmonary symptoms and partially restore lung function. Previous studies indicated that exacerbations may be associated with changes in microbial densities and the acquisition of new microbial species. Given the complexity of the CF microbiota, we applied massively parallel pyrosequencing to identify changes in airway microbial community structure in 23 adult CF patients during acute pulmonary exacerbation, after antibiotic treatment and during periods of stable disease. Over 350,000 sequences were generated, representing nearly 170 distinct microbial taxa. Approximately 60% of sequences obtained were from the recognized CF pathogens Pseudomonas and Burkholderia, which were detected in largely non-overlapping patient subsets. In contrast, other taxa including Prevotella, Streptococcus, Rothia and Veillonella were abundant in nearly all patient samples. Although antibiotic treatment was associated with a small decrease in species richness, there was minimal change in overall microbial community structure. Furthermore, microbial community composition was highly similar in patients during an exacerbation and when clinically stable, suggesting that exacerbations may represent intrapulmonary spread of infection rather than a change in microbial community composition. Mouthwash samples, obtained from a subset of patients, showed a nearly identical distribution of taxa as expectorated sputum, indicating that aspiration may contribute to colonization of the lower airways. Finally, we observed a strong correlation between low species richness and poor lung function

  13. The adult cystic fibrosis airway microbiota is stable over time and infection type, and highly resilient to antibiotic treatment of exacerbations.

    Science.gov (United States)

    Fodor, Anthony A; Klem, Erich R; Gilpin, Deirdre F; Elborn, J Stuart; Boucher, Richard C; Tunney, Michael M; Wolfgang, Matthew C

    2012-01-01

    Cystic fibrosis (CF) is characterized by defective mucociliary clearance and chronic airway infection by a complex microbiota. Infection, persistent inflammation and periodic episodes of acute pulmonary exacerbation contribute to an irreversible decline in CF lung function. While the factors leading to acute exacerbations are poorly understood, antibiotic treatment can temporarily resolve pulmonary symptoms and partially restore lung function. Previous studies indicated that exacerbations may be associated with changes in microbial densities and the acquisition of new microbial species. Given the complexity of the CF microbiota, we applied massively parallel pyrosequencing to identify changes in airway microbial community structure in 23 adult CF patients during acute pulmonary exacerbation, after antibiotic treatment and during periods of stable disease. Over 350,000 sequences were generated, representing nearly 170 distinct microbial taxa. Approximately 60% of sequences obtained were from the recognized CF pathogens Pseudomonas and Burkholderia, which were detected in largely non-overlapping patient subsets. In contrast, other taxa including Prevotella, Streptococcus, Rothia and Veillonella were abundant in nearly all patient samples. Although antibiotic treatment was associated with a small decrease in species richness, there was minimal change in overall microbial community structure. Furthermore, microbial community composition was highly similar in patients during an exacerbation and when clinically stable, suggesting that exacerbations may represent intrapulmonary spread of infection rather than a change in microbial community composition. Mouthwash samples, obtained from a subset of patients, showed a nearly identical distribution of taxa as expectorated sputum, indicating that aspiration may contribute to colonization of the lower airways. Finally, we observed a strong correlation between low species richness and poor lung function. Taken together, these

  14. Signaling and regulation of G protein-coupled receptors in airway smooth muscle

    Directory of Open Access Journals (Sweden)

    Penn Raymond B

    2003-03-01

    Full Text Available Abstract Signaling through G protein-coupled receptors (GPCRs mediates numerous airway smooth muscle (ASM functions including contraction, growth, and "synthetic" functions that orchestrate airway inflammation and promote remodeling of airway architecture. In this review we provide a comprehensive overview of the GPCRs that have been identified in ASM cells, and discuss the extent to which signaling via these GPCRs has been characterized and linked to distinct ASM functions. In addition, we examine the role of GPCR signaling and its regulation in asthma and asthma treatment, and suggest an integrative model whereby an imbalance of GPCR-derived signals in ASM cells contributes to the asthmatic state.

  15. Effect of Intranasal or Aerosol Challenge on Airway Inflammation in a Murine Asthma Model%滴鼻和雾化两种不同激发方式对小鼠支气管哮喘模型气道炎症的影响

    Institute of Scientific and Technical Information of China (English)

    程胜; 陈辉龙; 王正云; 王爱利; 谢敏; 曹勇; 谢俊刚; 熊维宁; 徐永健

    2014-01-01

    目的:探讨滴鼻和雾化两种不同激发方式对小鼠支气管哮喘模型气道炎症的影响,为研究和优化支气管哮喘动物模型提供实验和理论依据。方法选择鸡卵清蛋白(OVA)致敏的BALB/c小鼠,分别采用滴鼻和雾化两种不同方式进行激发,复制哮喘模型,观察支气管肺泡灌洗液(BALF)中白细胞总数和细胞分类计数,ELISA方法检测BALF上清中IL-4、IL-13含量,常规病理切片苏木精-伊红(HE)染色观察肺内炎症情况。结果滴鼻组小鼠BALF中白细胞总数最高,其次为雾化组小鼠;且滴鼻组小鼠嗜酸性粒细胞总数及中性粒细胞总数亦明显高于雾化组与正常组,差异有统计学意义(P<0.05)。滴鼻组小鼠BALF中 IL-4、IL-13水平明显高于雾化组与正常组小鼠,差异有统计学意义(P<0.05);雾化组小鼠BALF中IL-4、IL-13水平高于正常组小鼠,差异有统计学意义(P<0.05)。滴鼻组肺组织炎症反应最明显,并可见上皮细胞破坏,杯状细胞增生,支气管和血管周围有大量炎症细胞浸润,以嗜酸性粒细胞和淋巴细胞为主。雾化组炎症程度较轻,正常对照组无明显炎症改变。结论雾化吸入和经鼻滴入的激发方式都可以成功制作出支气管哮喘模型,经鼻滴入方式可以引起肺部更加明显的炎症浸润及细胞因子表达,为哮喘研究提供更好的选择。%Objective To investigate the effect of two different methods of challenge ,intranasal or aerosol exposure ,on air-way inflammation in murine asthma models ,and provide experimental and theoretical basis for the study and optimization of bronchial asthma in animal models.Methods Ovalbumin(OVA)-sensitive BALB/c mice were challenged to set up murine mod-els of atopic asthma by intranasal or aerosol exposure to OVA.The number of leukocytes and cell classifications in bronchoalve-olar lavage fluid (BALF) were measured

  16. Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

    OpenAIRE

    Rossi, Antonietta; Caiazzo, Elisabetta; Bilancia, Rossella; Riemma, Maria A.; Pagano, Ester; Cicala, Carla; Ialenti, Armando; Jordan K. Zjawiony; Izzo, Angelo A; Capasso, Raffaele; Roviezzo, Fiorentina

    2017-01-01

    Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice we...

  17. Upper airway imaging and its role in preoperative airway evaluation

    Directory of Open Access Journals (Sweden)

    Jagadish G Sutagatti

    2016-01-01

    Full Text Available Ultrasonography (USG is well-known as a fast, safe, and noninvasive technique. Its application for imaging of the airway is now gaining momentum. The upper airway has a complex anatomy, and its assessment forms a vital part of every preanesthetic evaluation. Ultrasound (US imaging can help in upper airway assessment in the preoperative period. There are various approaches to upper airway USG. The technique has its own advantages, disadvantages, and limitations. This simple yet challenging imaging technique is all set to become an important part of routine preoperative airway evaluation. This article reviews the various approaches to upper airway US imaging, interpretation of the images, limitations, and disadvantages of the technique and its varied clinical applications in the preoperative period. The scientific material presented here was hand searched from textbooks and journals, electronically from PubMed, and Google scholar using text words.

  18. A pathogenic role for the integrin CD103 in experimental allergic airways disease.

    Science.gov (United States)

    Fear, Vanessa S; Lai, Siew Ping; Zosky, Graeme R; Perks, Kara L; Gorman, Shelley; Blank, Fabian; von Garnier, Christophe; Stumbles, Philip A; Strickland, Deborah H

    2016-11-01

    The integrin CD103 is the αE chain of integrin αEβ7 that is important in the maintenance of intraepithelial lymphocytes and recruitment of T cells and dendritic cells (DC) to mucosal surfaces. The role of CD103 in intestinal immune homeostasis has been well described, however, its role in allergic airway inflammation is less well understood. In this study, we used an ovalbumin (OVA)-induced, CD103-knockout (KO) BALB/c mouse model of experimental allergic airways disease (EAAD) to investigate the role of CD103 in disease expression, CD4(+) T-cell activation and DC activation and function in airways and lymph nodes. We found reduced airways hyper-responsiveness and eosinophil recruitment to airways after aerosol challenge of CD103 KO compared to wild-type (WT) mice, although CD103 KO mice showed enhanced serum OVA-specific IgE levels. Following aerosol challenge, total numbers of effector and regulatory CD4(+) T-cell subsets were significantly increased in the airways of WT but not CD103 KO mice, as well as a lack of DC recruitment into the airways in the absence of CD103. While total airway DC numbers, and their in vivo allergen capture activity, were essentially normal in steady-state CD103 KO mice, migration of allergen-laden airway DC to draining lymph nodes was disrupted in the absence of CD103 at 24 h after aerosol challenge. These data support a role for CD103 in the pathogenesis of EAAD in BALB/c mice through local control of CD4(+) T cell and DC subset recruitment to, and migration from, the airway mucosa during induction of allergic inflammation.

  19. Integrated care pathways for airway diseases (AIRWAYS-ICPs)

    DEFF Research Database (Denmark)

    Bousquet, J; Addis, A; Adcock, I

    2014-01-01

    The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy....... AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers)....

  20. Biomarkers in Airway Diseases

    Directory of Open Access Journals (Sweden)

    Janice M Leung

    2013-01-01

    Full Text Available The inherent limitations of spirometry and clinical history have prompted clinicians and scientists to search for surrogate markers of airway diseases. Although few biomarkers have been widely accepted into the clinical armamentarium, the authors explore three sources of biomarkers that have shown promise as indicators of disease severity and treatment response. In asthma, exhaled nitric oxide measurements can predict steroid responsiveness and sputum eosinophil counts have been used to titrate anti-inflammatory therapies. In chronic obstructive pulmonary disease, inflammatory plasma biomarkers, such as fibrinogen, club cell secretory protein-16 and surfactant protein D, can denote greater severity and predict the risk of exacerbations. While the multitude of disease phenotypes in respiratory medicine make biomarker development especially challenging, these three may soon play key roles in the diagnosis and management of airway diseases.

  1. Neuropeptides control the dynamic behavior of airway mucosal dendritic cells.

    Science.gov (United States)

    Voedisch, Sabrina; Rochlitzer, Sabine; Veres, Tibor Z; Spies, Emma; Braun, Armin

    2012-01-01

    The airway mucosal epithelium is permanently exposed to airborne particles. A network of immune cells patrols at this interface to the environment. The interplay of immune cells is orchestrated by different mediators. In the current study we investigated the impact of neuronal signals on key functions of dendritic cells (DC). Using two-photon microscopic time-lapse analysis of living lung sections from CD11c-EYFP transgenic mice we studied the influence of neuropeptides on airway DC motility. Additionally, using a confocal microscopic approach, the phagocytotic capacity of CD11c(+) cells after neuropeptide stimulation was determined. Electrical field stimulation (EFS) leads to an unspecific release of neuropeptides from nerves. After EFS and treatment with the neuropeptides vasoactive intestinal peptide (VIP) or calcitonin gene-related peptide (CGRP), airway DC in living lung slices showed an altered motility. Furthermore, the EFS-mediated effect could partially be blocked by pre-treatment with the receptor antagonist CGRP(8-37). Additionally, the phagocytotic capacity of bone marrow-derived and whole lung CD11c(+) cells could be inhibited by neuropeptides CGRP, VIP, and Substance P. We then cross-linked these data with the in vivo situation by analyzing DC motility in two different OVA asthma models. Both in the acute and prolonged OVA asthma model altered neuropeptide amounts and DC motility in the airways could be measured. In summary, our data suggest that neuropeptides modulate key features motility and phagocytosis of mouse airway DC. Therefore altered neuropeptide levels in airways during allergic inflammation have impact on regulation of airway immune mechanisms and therefore might contribute to the pathophysiology of asthma.

  2. Ultrasound of the airway

    Directory of Open Access Journals (Sweden)

    Pankaj Kundra

    2011-01-01

    Full Text Available Currently, the role of ultrasound (US in anaesthesia-related airway assessment and procedural interventions is encouraging, though it is still ill defined. US can visualise anatomical structures in the supraglottic, glottic and subglottic regions. The floor of the mouth can be visualised by both transcutaneous view of the neck and also by transoral or sublinguial views. However, imaging the epiglottis can be challenging as it is suspended in air. US may detect signs suggestive of difficult intubation, but the data are limited. Other possible applications in airway management include confirmation of correct endotracheal tube placement, prediction of post-extubation stridor, evaluation of soft tissue masses in the neck prior to intubation, assessment of subglottic diameter for determination of paediatric endotracheal tube size and percutaneous dilatational tracheostomy. With development of better probes, high-resolution imaging, real-time picture and clinical experience, US has become the potential first-line noninvasive airway assessment tool in anaesthesia and intensive care practice.

  3. Anticholinergic treatment in airways diseases.

    LENUS (Irish Health Repository)

    Flynn, Robert A

    2009-10-01

    The prevalence of chronic airways diseases such as chronic obstructive pulmonary disease and asthma is increasing. They lead to symptoms such as a cough and shortness of breath, partially through bronchoconstriction. Inhaled anticholinergics are one of a number of treatments designed to treat bronchoconstriction in airways disease. Both short-acting and long-acting agents are now available and this review highlights their efficacy and adverse event profile in chronic airways diseases.

  4. Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone

    OpenAIRE

    Gallos, George; Townsend, Elizabeth; Yim, Peter; Virag, Laszlo; Zhang, Yi; Xu, Dingbang; Bacchetta, Matthew; Emala, Charles W.

    2012-01-01

    Chronic obstructive pulmonary disease and asthma are characterized by hyperreactive airway responses that predispose patients to episodes of acute airway constriction. Recent studies suggest a complex paradigm of GABAergic signaling in airways that involves GABA-mediated relaxation of airway smooth muscle. However, the cellular source of airway GABA and mechanisms regulating its release remain unknown. We questioned whether epithelium is a major source of GABA in the airway and whether the ab...

  5. Pharmacology of airway smooth muscle proliferation

    NARCIS (Netherlands)

    Gosens, Reinoud; Roscioni, Sara S.; Dekkers, Bart G. J.; Pera, Tonio; Schmidt, Martina; Schaafsma, Dedmer; Zaagsma, Johan; Meurs, Herman

    2008-01-01

    Airway smooth muscle thickening is a pathological feature that contributes significantly to airflow limitation and airway hyperresponsiveness in asthma. Ongoing research efforts aimed at identifying the mechanisms responsible for the increased airway smooth muscle mass have indicated that hyperplasi

  6. Lung inflammation and epithelial changes in a murine model of atopic asthma.

    Science.gov (United States)

    Blyth, D I; Pedrick, M S; Savage, T J; Hessel, E M; Fattah, D

    1996-05-01

    A murine model of allergen-induced airway inflammation and epithelial phenotypic change, and the time-courses of these events, are described. Mice were sensitized to ovalbumin using an adjuvant-free protocol, and challenged by multiple intratracheal instillations of ovalbumin by a non-surgical technique. Many of the characteristic features of human atopic asthma were seen in the mice. A marked eosinophilic infiltration of lung tissue and airways followed allergen challenge, and its severity increased with each challenge, as did the number of eosinophils in the blood. Lymphocytes, neutrophils, and monocytes also invaded the lungs. Airway macrophages showed signs of activation, their appearance resembling those recovered from antigen-challenged human asthmatic airways. The airway epithelium was thickened and displayed a marked goblet cell hyperplasia in terminal bronchioles and larger airways. After repeated challenges, the reticular layer beneath the basement membrane of the airway epithelium showed fibrosis, reproducing a commonly observed histologic feature of human asthma. Goblet cell hyperplasia began to appear before eosinophils or lymphocytes had migrated across the airway epithelium, and persisted for at least 11 days after the third intratracheal challenge with ovalbumin, despite the number of inflammatory cells in the lungs and airways having decreased to near-normal levels by 4 days. Plugs of mucus occluded some of the airways. These results indicate that some of the phenotypic changes in airway epithelium that follow an allergic response in the lung can be initiated before the migration of eosinophils or lymphocytes across the epithelial layer.

  7. Regulation of cyclooxygenase-2 expression by cAMP response element and mRNA stability in a human airway epithelial cell line exposed to zinc

    Science.gov (United States)

    Exposure to zinc-laden particulate matter in ambient and occupational settings has been associated with proinflammatory responses in the lung. Cyclooxygenase 2-derived eicosanoids are important modulators of airway inflammation. In this study, we characterized the transcriptional...

  8. Ca(2+)-activated K(+) channel-3.1 blocker TRAM-34 attenuates airway remodeling and eosinophilia in a murine asthma model

    NARCIS (Netherlands)

    Girodet, P.O.; Ozier, A.; Carvalho, G.; Ilina, O.; Ousova, O.; Gadeau, A.P.; Begueret, H.; Wulff, H.; Marthan, R.; Bradding, P.; Berger, P.

    2013-01-01

    Key features of asthma include bronchial hyperresponsiveness (BHR), eosinophilic airway inflammation, and bronchial remodeling, characterized by subepithelial collagen deposition, airway fibrosis, and increased bronchial smooth muscle (BSM) mass. The calcium-activated K(+) channel K(Ca)3.1 is expres

  9. Differential inflammatory response to inhaled lipopolysaccharide targeted either to the airways or the alveoli in man.

    Directory of Open Access Journals (Sweden)

    Winfried Möller

    Full Text Available Endotoxin (Lipopolysaccharide, LPS is a potent inducer of inflammation and there is various LPS contamination in the environment, being a trigger of lung diseases and exacerbation. The objective of this study was to assess the time course of inflammation and the sensitivities of the airways and alveoli to targeted LPS inhalation in order to understand the role of LPS challenge in airway disease.In healthy volunteers without any bronchial hyperresponsiveness we targeted sequentially 1, 5 and 20 µg LPS to the airways and 5 µg LPS to the alveoli using controlled aerosol bolus inhalation. Inflammatory parameters were assessed during a 72 h time period. LPS deposited in the airways induced dose dependent systemic responses with increases of blood neutrophils (peaking at 6 h, Interleukin-6 (peaking at 6 h, body temperature (peaking at 12 h, and CRP (peaking at 24 h. 5 µg LPS targeted to the alveoli caused significantly stronger effects compared to 5 µg airway LPS deposition. Local responses were studied by measuring lung function (FEV(1 and reactive oxygen production, assessed by hydrogen peroxide (H(2O(2 in fractionated exhaled breath condensate (EBC. FEV(1 showed a dose dependent decline, with lowest values at 12 h post LPS challenge. There was a significant 2-fold H(2O(2 induction in airway-EBC at 2 h post LPS inhalation. Alveolar LPS targeting resulted in the induction of very low levels of EBC-H(2O(2.Targeting LPS to the alveoli leads to stronger systemic responses compared to airway LPS targeting. Targeted LPS inhalation may provide a novel model of airway inflammation for studying the role of LPS contamination of air pollution in lung diseases, exacerbation and anti-inflammatory drugs.

  10. Airway surface liquid volume expansion induces rapid changes in amiloride-sensitive Na+ transport across upper airway epithelium-Implications concerning the resolution of pulmonary edema

    Science.gov (United States)

    Azizi, Fouad; Arredouani, Abdelilah; Mohammad, Ramzi M

    2015-01-01

    During airway inflammation, airway surface liquid volume (ASLV) expansion may result from the movement of plasma proteins and excess liquid into the airway lumen due to extravasation and elevation of subepithelial hydrostatic pressure. We previously demonstrated that elevation of submucosal hydrostatic pressure increases airway epithelium permeability resulting in ASLV expansion by 500 μL cm−2 h−1. Liquid reabsorption by healthy airway epithelium is regulated by active Na+ transport at a rate of 5 μL cm−2 h−1. Thus, during inflammation the airway epithelium may be submerged by a large volume of luminal liquid. Here, we have investigated the mechanism by which ASLV expansion alters active epithelial Na+ transport, and we have characterized the time course of the change. We used primary cultures of tracheal airway epithelium maintained under air interface (basal ASLV, depth is 7 ± 0.5 μm). To mimic airway flooding, ASLV was expanded to a depth of 5 mm. On switching from basal to expanded ASLV conditions, short-circuit current (Isc, a measure of total transepithelial active ion transport) declined by 90% with a half-time (t1/2) of 1 h. 24 h after the switch, there was no significant change in ATP concentration nor in the number of functional sodium pumps as revealed by [3H]-ouabain binding. However, amiloride-sensitive uptake of 22Na+ was reduced by 70% upon ASLV expansion. This process is reversible since after returning cells back to air interface, Isc recovered with a t1/2 of 5–10 h. These results may have important clinical implications concerning the development of Na+ channels activators and resolution of pulmonary edema. PMID:26333829

  11. Predictors of neutrophilic airway inflammation in young smokers with asthma

    DEFF Research Database (Denmark)

    Westergaard, Christian Grabow; Munck, Christian; Helby, Jens

    2014-01-01

    . The investigation also included analysis for effect of pack years, current tobacco consumption, body mass index, lung function, FeNO; methacholine and mannitol responsiveness, atopy, gender, asthma history and presence of bacteria. The most common potentially pathogenic bacteria found were Streptococcus spp...... smokers, neutrophilia may be induced when a certain threshold of tobacco consumption is reached....... asthmatic smokers not on steroid treatment, including analysis of tobacco history and bacterial colonization. Methods: In a cross-sectional study, 52 steroid-free, current smokers with asthma were examined with induced sputum, fractional exhaled nitric oxide (FeNO), lung function, ACQ6 score, mannitol...

  12. Effects of streptozotocin diabetes on antigen-induced airway inflammation

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Asthma and diabetes mellitus are common diseases and the concurrence is correspondingly expected to occur commonly. Several studies,1,2 however, indicate that the incidence of asthma in diabetic patients is less than that in the residual population. In the same individual, clinical asthma appears to be less severe when diabetes is superimposed.3 In addition, the onset of the diabetic state is accompanied by diminution of symptoms of previously existing bronchial asthma.

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

    Directory of Open Access Journals (Sweden)

    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

  14. Effects of cysteinyl leukotrienes and leukotriene receptor antagonists on markers of inflammation

    DEFF Research Database (Denmark)

    Sampson, Anthony P; Pizzichini, Emilio; Bisgaard, Hans

    2003-01-01

    The understanding that asthma pathophysiology includes an inflammatory component has spurred the more aggressive use of anti-inflammatory therapies and created a need for effective tools to measure inflammation. Biomarkers of airway inflammation proposed are obtained by methods that are direct bu...

  15. Tight junctions in pulmonary epithelia during lung inflammation

    OpenAIRE

    Wittekindt, Oliver H.

    2016-01-01

    Inflammatory lung diseases like asthma bronchiale, chronic obstructive pulmonary disease and allergic airway inflammation are widespread public diseases that constitute an enormous burden to the health systems. Mainly classified as inflammatory diseases, the treatment focuses on strategies interfering with local inflammatory responses by the immune system. Inflammatory lung diseases predispose patients to severe lung failures like alveolar oedema, respiratory distress syndrome and acute lung ...

  16. FasL基因和屋尘螨过敏原基因共表达质粒DNA疫苗对屋尘螨致敏/激发小鼠气道炎症的作用%Effects of DNA vaccine encoding both FasL and house dust mite allergen Der p2 on the airway inflammations in mice sensitized/challenged with house dust mite

    Institute of Scientific and Technical Information of China (English)

    王彦; 林科雄; 王长征; 吴奎; 毕玉田

    2011-01-01

    目的:观察FasL基因和屋尘螨过敏原Der p2基因共表达质粒的DNA疫苗(DNA-FasL-Der p2)对屋尘螨致敏/激发小鼠气道炎症的作用.方法:DNA-FasL-Der p2肌注接种屋尘螨致敏/激发C57BL/6小鼠,再次激发后处死小鼠.观察肺组织病理变化,检测支气管肺泡灌洗液(BALF)细胞总数和分类计数,以及IL-5、IFN-γ水平.并与仅编码Der p2基因的DNA疫苗(DNA-Der p2)比较.结果:接种DNA-FasL-Der p2和DNA-Der p2均能显著减轻屋尘螨致敏/激发小鼠气道炎症.减少BALF中细胞总数和嗜酸粒细胞比例.降低BALF中IL-5水平,以DNA-FasL-Der p2更显著.结论:DNA-FasL-Derp2可有效抑制屋尘螨致敏/激发小鼠气道炎症,而且比DNA-Der p2更有效.%Objective To investigate the effects of DNA vaccine encoding both FasL and house dust mite (HDM) allergen Der p2 (DNA-FasL-Der p2) on the airway inflammation in mice challenged with HDM.Methods HDM sensitized and challenged C57BL/6 mice were immunized with DNA-FasL-Der p2 or DNA-Der p2 (without FasL)DNA vaccine,then they were re-challenged with HDM.Two days after the last challenge, bronchoalveolar lavage fluid (BALF) was collected and lung histology was examined.The levels of IL-5 and IFN-γ in BALF supematants were analyzed by ELISA, total cell count and differential cell count in BALF sediment were determined.Results Both DNA-FasL-Der p2 and DNA-Der p2 relieved airway inflammation and decreased the level of IL-5, total cell count and the percentage of eosinophils in BALF.The improvement of DNA-FasL-Der p2 was more significant than that of DNA-Der p2.Conclusion DNA-FasL-Der p2 could reduce airway allergic inflammation in HDM-challenged mice.And DNA-FasL-Der p2 was more effective than that of DNA-Der p2.

  17. The role of the extracellular matrix and specific growth factors in the regulation of inflammation and remodelling in asthma

    NARCIS (Netherlands)

    Burgess, Janette K

    2009-01-01

    Asthma is a disease characterised by persistent inflammation and structural changes in the airways, referred to as airway remodelling. The mechanisms underlying these processes may be interdependent or they may be separate processes that are driven by common factors. The levels of a variety of growt

  18. 肥胖型哮喘小鼠体内氧化应激反应变化及其与气道炎症和重构的关系%Oxidative Stress in Airway Inflammation and Remodeling of Obese Mice with Asthma

    Institute of Scientific and Technical Information of China (English)

    韩伟; 陈凯; 唐华平; 苏毅

    2011-01-01

    Objective To evaluate the effects of oxidative stress in the airway inflammation and remodeling of high-fat diet induced obese mice with asthma. Methods Sixty female C57/6J mice were randomly divided into four groups,k, an asthma group,an obese group,an obese asthma group,and a control group. The mice in the asthma group were sensitized and challenged with ovalbumin ( OVA) and fed with normal diets. The mice in the obese group were fed with high-fat diets. The mice in the obese asthma group were sensitized and challenged as the asthma group,and fed as the obese group. The mice in the control group were sensitized and challenged with normal saline and fed with normal diets. After 12 weeks, bronehoalveolar lavage fluid (BALF) were collected for total and differential cell count. IL-6 and 8-iso-prostaglandin F2a (8-iso-PGF2a) in lung tissue homognate were detected by ELISA. The pathological changes were observed under light microscope by HE staining. Meanwhile the remodeling indices including total bronchial wall area ( Wat) , smooth muscle area ( Wam) ,and bronchial basement membrane perimeter ( Pbm) were measured. Results In comparison with the obese group and the asthma group,the leukocytes and eosinophils in BALF, Wat/ Pbm, and IL-6 in lung tissue increased significantly in the obese asthma group (P < 0. 05). 8-iso-PGF2a in lung tissue increased in sequence of the control group, the obese group,the asthma group, and the obese asthma group significantly. Pearson correlation analysis showed that leukocyte in BALF, Wat/ Pbm,and IL-6 were in positive correlation with 8-iso-PGF2a (r = 0. 828,0. 863,0. 891 .respectively, F<0.01). Conclusion Oxidative stress is involved in the airway inflammation and remodeling of obese asthma mice with high-fat diets.%目的 探讨肥胖型哮喘小鼠体内氧化应激反应变化及其与气道炎症和重构的关系。方法 60只雌性C57/6J小鼠随机分为哮喘组、肥胖组、肥胖哮喘组和对照组。哮喘组在普通

  19. 香烟烟雾对支气管哮喘患者气道炎性反应及肺功能的影响%Influence of the cigarette smoke in the airway inflammation and pulmonary function of the asthmatic patients

    Institute of Scientific and Technical Information of China (English)

    张彩苹; 杜永成; 许建英

    2011-01-01

    Objective To explore the influence of the cigarette smoke in the airway inflammation and pulmonary function of the asthmatic patients. Methods Twenty-five cases of asthmatic patients with cigarette smoke exposure, 22 cases of asthmatic patients without cigarette smoke exposure and 20 cases of normal control persons were involved in this study. The proportion of various inflammatory cells in the induced sputum, the levels of serum interleukin (IL)-8 and IL-4 and lung function (FEV1% expected value,FEV1/FVC% ) were detected. Results The infiltrating of neutrophils was primarily found in sputum of the asthmatic patients with cigarette smoke exposure, but the infiltrating of eosinophils was mainly in sputum of the asthmatic patients without cigarette smoke exposure. The levels of serum IL-8 and IL-4 of peripheral blood of asthmatic patients with cigarette smoke exposure [(277.02 ±71.37), (171.69 ±31.01) ng/L] were significantly higher than those in asthmatic patients without cigarette smoke exposure [(158.88 ± 21.95 ),( 111.42 ± 21.69 ) ng/L] and normal control persons [( 116.78 ± 71.37 ), (73.94 ± 15.72 ) ng/L] (P < 0.01 ).The FEV1% expected value and FEV1/FVC% of the asthmatic patients with cigarette smoke exposure [(51.12 ± 13.30) %, ( 49.16 ± 11.09 )%] was lower than those of asthmatic patients without cigarette smokeexposure [(81.81 ± 5.82)%, (79.00 ± 3.86)%] and normal control persona [(95.50 ± 10.11 )%, (83.18 ±6.04)%] (P < 0.01 ). The level of serum IL-8 was positively correlated to the neutrophils percentage in the induced sputum (r =0.742,P< 0.01 ) ,while negatively correlated to the FEV1% expected value(r =-0.739,P < 0.01 ). Conclusion Cigarette smoke may influence the airway inflammation of the asthmatic patients and accelerate the deterioration of their lung function by promoting the producing of IL-8.%目的 探讨香烟烟雾对支气管哮喘(简称哮喘)患者气道炎性反应

  20. Mechanisms of Cigarette Smoke Effects on Human Airway Smooth Muscle.

    Directory of Open Access Journals (Sweden)

    Mark E Wylam

    Full Text Available Cigarette smoke contributes to or exacerbates airway diseases such as asthma and COPD, where airway hyperresponsiveness and airway smooth muscle (ASM proliferation are key features. While factors such as inflammation contribute to asthma in part by enhancing agonist-induced intracellular Ca(2+ ([Ca(2+]i responses of ASM, the mechanisms by which cigarette smoke affect ASM are still under investigation. In the present study, we tested the hypothesis that cigarette smoke enhances the expression and function of Ca(2+ regulatory proteins leading to increased store operated Ca(2+ entry (SOCE and cell proliferation. Using isolated human ASM (hASM cells, incubated in the presence and absence cigarette smoke extract (CSE we determined ([Ca(2+]i responses and expression of relevant proteins as well as ASM proliferation, reactive oxidant species (ROS and cytokine generation. CSE enhanced [Ca(2+]i responses to agonist and SOCE: effects mediated by increased expression of TRPC3, CD38, STIM1, and/or Orai1, evident by attenuation of CSE effects when siRNAs against these proteins were used, particularly Orai1. CSE also increased hASM ROS generation and cytokine secretion. In addition, we found in the airways of patients with long-term smoking history, TRPC3 and CD38 expression were significantly increased compared to life-long never-smokers, supporting the role of these proteins in smoking effects. Finally, CSE enhanced hASM proliferation, an effect confirmed by upregulation of PCNA and Cyclin E. These results support a critical role for Ca(2+ regulatory proteins and enhanced SOCE to alter airway structure and function in smoking-related airway disease.

  1. Aeroallergen challenge promotes dendritic cell proliferation in the airways.

    Science.gov (United States)

    Veres, Tibor Z; Voedisch, Sabrina; Spies, Emma; Valtonen, Joona; Prenzler, Frauke; Braun, Armin

    2013-02-01

    Aeroallergen provocation induces the rapid accumulation of CD11c(+)MHC class II (MHC II)(+) dendritic cells (DCs) in the lungs, which is driven by an increased recruitment of blood-derived DC precursors. Recent data show, however, that well-differentiated DCs proliferate in situ in various tissues. This may also contribute to their allergen-induced expansion; therefore, we studied DC proliferation in the airways of mice in the steady state and after local aeroallergen provocation. Confocal whole-mount microscopy was used to visualize proliferating DCs in different microanatomical compartments of the lung. We demonstrate that in the steady state, CD11c(+)MHC II(+) DCs proliferate in both the epithelial and subepithelial layers of the airway mucosa as well as in the lung parenchyma. A 1-h pulse of the nucleotide 5-ethynyl-2'-deoxyuridine was sufficient to label 5% of DCs in both layers of the airway mucosa. On the level of whole-lung tissue, 3-5% of both CD11b(+) and CD11b(-) DC populations and 0.3% of CD11c(+)MHC II(low) lung macrophages incorporated 5-ethynyl-2'-deoxyuridine. Aeroallergen provocation caused a 3-fold increase in the frequency of locally proliferating DCs in the airway mucosa. This increase in mucosal DC proliferation was later followed by an elevation in the number of DCs. The recruitment of monocyte-derived inflammatory DCs contributed to the increasing number of DCs in the lung parenchyma, but not in the airway mucosa. We conclude that local proliferation significantly contributes to airway DC homeostasis in the steady state and that it is the major mechanism underlying the expansion of the mucosal epithelial/subepithelial DC network in allergic inflammation.

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

    Directory of Open Access Journals (Sweden)

    Zhuang-Gui Chen

    Full Text Available Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. However, the initiating factor that links airway inflammation to remodeling is unknown. Thymic stromal lymphopoietin (TSLP, an epithelium-derived cytokine, can strongly activate lung dendritic cells (DCs through the TSLP-TSLPR and OX40L-OX40 signaling pathways to promote Th2 differentiation. To determine whether TSLP is the underlying trigger of airway remodeling in chronic allergen-induced asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM extracts for up to 5 consecutive weeks. We showed that repeated respiratory exposure to HDM caused significant airway eosinophilic inflammation, peribronchial collagen deposition, goblet cell hyperplasia, and airway hyperreactivity (AHR to methacholine. These effects were accompanied with a salient Th2 response that was characterized by the upregulation of Th2-typed cytokines, such as IL-4 and IL-13, as well as the transcription factor GATA-3. Moreover, the levels of TSLP and transforming growth factor beta 1 (TGF-β1 were also increased in the airway. We further demonstrated, using the chronic HDM-induced asthma model, that the inhibition of Th2 responses via neutralization of TSLP with an anti-TSLP mAb reversed airway inflammation, prevented structural alterations, and decreased AHR to methacholine and TGF-β1 level. These results suggest that TSLP plays a pivotal role in the initiation and persistence of airway inflammation and remodeling in the context of chronic allergic asthma.

  3. Pain related inflammation analysis using infrared images

    Science.gov (United States)

    Bhowmik, Mrinal Kanti; Bardhan, Shawli; Das, Kakali; Bhattacharjee, Debotosh; Nath, Satyabrata

    2016-05-01

    Medical Infrared Thermography (MIT) offers a potential non-invasive, non-contact and radiation free imaging modality for assessment of abnormal inflammation having pain in the human body. The assessment of inflammation mainly depends on the emission of heat from the skin surface. Arthritis is a disease of joint damage that generates inflammation in one or more anatomical joints of the body. Osteoarthritis (OA) is the most frequent appearing form of arthritis, and rheumatoid arthritis (RA) is the most threatening form of them. In this study, the inflammatory analysis has been performed on the infrared images of patients suffering from RA and OA. For the analysis, a dataset of 30 bilateral knee thermograms has been captured from the patient of RA and OA by following a thermogram acquisition standard. The thermograms are pre-processed, and areas of interest are extracted for further processing. The investigation of the spread of inflammation is performed along with the statistical analysis of the pre-processed thermograms. The objectives of the study include: i) Generation of a novel thermogram acquisition standard for inflammatory pain disease ii) Analysis of the spread of the inflammation related to RA and OA using K-means clustering. iii) First and second order statistical analysis of pre-processed thermograms. The conclusion reflects that, in most of the cases, RA oriented inflammation affects bilateral knees whereas inflammation related to OA present in the unilateral knee. Also due to the spread of inflammation in OA, contralateral asymmetries are detected through the statistical analysis.

  4. Airway dysbiosis: Haemophilus influenzae and Tropheryma in poorly controlled asthma.

    Science.gov (United States)

    Simpson, Jodie L; Daly, Joshua; Baines, Katherine J; Yang, Ian A; Upham, John W; Reynolds, Paul N; Hodge, Sandra; James, Alan L; Hugenholtz, Philip; Willner, Dana; Gibson, Peter G

    2016-03-01

    Asthma is a chronic inflammatory disorder of the airways where bacteria may act as protagonists of chronic inflammation. Little is known about the relation of airway inflammation to the presence of specific bacterial taxa. We sought to describe the sputum microbiome in adults with poorly controlled asthma.DNA was extracted from induced sputum and microbial communities were profiled using 16S rRNA pyrosequencing. Bacterial species were characterised, and the relationship between microbial populations, asthma inflammatory subtypes and other covariates was explored. Real-time PCR was used to identify Tropheryma whipplei and Haemophilus influenzae in sputum.Adults with neutrophilic asthma had reduced bacterial diversity and species richness. Tropheryma was identified and confirmed with real-time PCR in 12 (40%) participants. Haemophilus occurred most often in a group of younger atopic males with an increased proportion of neutrophils. PCR confirmed the presence of H. influenzae in 35 (76%) participants with poorly controlled asthma.There are phenotype-specific alterations to the airway microbiome in asthma. Reduced bacterial diversity combined with a high prevalence of H. influenzae was observed in neutrophilic asthma, whereas eosinophilic asthma had abundant T. whipplei.

  5. RAGE: a new frontier in chronic airways disease.

    Science.gov (United States)

    Sukkar, Maria B; Ullah, Md Ashik; Gan, Wan Jun; Wark, Peter A B; Chung, Kian Fan; Hughes, J Margaret; Armour, Carol L; Phipps, Simon

    2012-11-01

    Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.

  6. T cell subsets in human airways prior to and following endobronchial administration of endotoxin

    DEFF Research Database (Denmark)

    Ronit, Andreas; Plovsing, Ronni R; Gaardbo, Julie C

    2015-01-01

    BACKGROUND AND OBJECTIVES: Bronchial instillation of lipopolysaccharide (LPS) provides a reversible model of lung inflammation that may resemble early stages of acute respiratory distress syndrome (ARDS). We investigated the distributions of T-cell subsets in the human airways and sought to deter...

  7. Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice

    DEFF Research Database (Denmark)

    Yao, Xianglan; Dai, Cuilian; Fredriksson, Karin

    2012-01-01

    with reductions in lung mRNA levels of Th2 and Th17 cytokines, as well as chemokines (CCL7, CCL11, CCL24). huApoE4 mice had an intermediate phenotype, with attenuated AHR and IgE production, compared with muApoE mice, whereas airway inflammation and mucous cell metaplasia were not reduced. In contrast, HDM...

  8. IL-17A modulates oxidant stress-induced airway hyperresponsiveness but not emphysema.

    Science.gov (United States)

    Pinart, Mariona; Zhang, Min; Li, Feng; Hussain, Farhana; Zhu, Jie; Wiegman, Coen; Ryffel, Bernard; Chung, Kian Fan

    2013-01-01

    IL-17A induces the release of pro-inflammatory cytokines and of reactive oxygen species which could lead to neutrophilic inflammation. We determined the role of IL-17 receptor (IL-17R) signalling in oxidant-induced lung emphysema and airway hyperresponsiveness. IL-17R(-/-) and wild-type C57/BL6 mice were exposed to ozone (3 ppm; 3 hours) for 12 times over 6 weeks. Bronchial responsiveness to acetylcholine was measured, and lungs were retrieved. Mean linear intercept (Lm) and isometric contractile responses of intrapulmonary airways to acetylcholine were determined. In wild-type mice but not in IL-17R(-/-), chronic ozone exposure caused airway hyperresponsiveness. The increase in Lm after chronic ozone exposure of wild-type mice was also observed in IL-17R(-/-) mice. The increased maximal contractile response to acetylcholine seen in airways of wild-type mice exposed to ozone was abolished in IL-17R(-/-) mice. p38-mitogen-activated protein kinase (MAPK) and dexamethasone-dependent increase in contractile response was reduced in airways from IL-17R(-/-) ozone-exposed mice. Lung inflammation scores were not altered in IL-17R(-/-) mice exposed to ozone compared to wild-type mice. The increased release of IL-17 and IL-1β, and the activation of p38 MAPK in the lungs of ozone-exposed mice was reduced in IL-17R(-/-) mice. IL-17R signalling underlies the increase in airway hyperresponsiveness seen after ozone exposure, mediated by the increased contractility of airway smooth muscle. The emphysema and lung inflammation induced by ozone is not dependent on IL-17.

  9. IL-17A modulates oxidant stress-induced airway hyperresponsiveness but not emphysema.

    Directory of Open Access Journals (Sweden)

    Mariona Pinart

    Full Text Available IL-17A induces the release of pro-inflammatory cytokines and of reactive oxygen species which could lead to neutrophilic inflammation. We determined the role of IL-17 receptor (IL-17R signalling in oxidant-induced lung emphysema and airway hyperresponsiveness. IL-17R(-/- and wild-type C57/BL6 mice were exposed to ozone (3 ppm; 3 hours for 12 times over 6 weeks. Bronchial responsiveness to acetylcholine was measured, and lungs were retrieved. Mean linear intercept (Lm and isometric contractile responses of intrapulmonary airways to acetylcholine were determined. In wild-type mice but not in IL-17R(-/-, chronic ozone exposure caused airway hyperresponsiveness. The increase in Lm after chronic ozone exposure of wild-type mice was also observed in IL-17R(-/- mice. The increased maximal contractile response to acetylcholine seen in airways of wild-type mice exposed to ozone was abolished in IL-17R(-/- mice. p38-mitogen-activated protein kinase (MAPK and dexamethasone-dependent increase in contractile response was reduced in airways from IL-17R(-/- ozone-exposed mice. Lung inflammation scores were not altered in IL-17R(-/- mice exposed to ozone compared to wild-type mice. The increased release of IL-17 and IL-1β, and the activation of p38 MAPK in the lungs of ozone-exposed mice was reduced in IL-17R(-/- mice. IL-17R signalling underlies the increase in airway hyperresponsiveness seen after ozone exposure, mediated by the increased contractility of airway smooth muscle. The emphysema and lung inflammation induced by ozone is not dependent on IL-17.

  10. Vessel-guided Airway Tree Segmentation

    DEFF Research Database (Denmark)

    Lo, P.; Sporring, J.; Ashraf, H.;

    2010-01-01

    This paper presents a method for airway tree segmentation that uses a combination of a trained airway appearance model, vessel and airway orientation information, and region growing. We propose a voxel classification approach for the appearance model, which uses a classifier that is trained...... to differentiate between airway and non-airway voxels. This is in contrast to previous works that use either intensity alone or hand crafted models of airway appearance. We show that the appearance model can be trained with a set of easily acquired, incomplete, airway tree segmentations. A vessel orientation...

  11. Airway complications after lung transplantation.

    Science.gov (United States)

    Machuzak, Michael; Santacruz, Jose F; Gildea, Thomas; Murthy, Sudish C

    2015-01-01

    Airway complications after lung transplantation present a formidable challenge to the lung transplant team, ranging from mere unusual images to fatal events. The exact incidence of complications is wide-ranging depending on the type of event, and there is still evolution of a universal characterization of the airway findings. Management is also wide-ranging. Simple observation or simple balloon bronchoplasty is sufficient in many cases, but vigilance following more severe necrosis is required for late development of both anastomotic and nonanastomotic airway strictures. Furthermore, the impact of coexisting infection, rejection, and medical disease associated with high-level immunosuppression further complicates care.

  12. Airway vascular reactivity and vascularisation in human chronic airway disease

    NARCIS (Netherlands)

    Bailey, Simon R; Boustany, Sarah; Burgess, Janette K; Hirst, Stuart J; Sharma, Hari S; Simcock, David E; Suravaram, Padmini R; Weckmann, Markus

    2009-01-01

    Altered bronchial vascular reactivity and remodelling including angiogenesis are documented features of asthma and other chronic inflammatory airway diseases. Expansion of the bronchial vasculature under these conditions involves both functional (vasodilation, hyperperfusion, increased microvascular

  13. A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha.

    Science.gov (United States)

    Lee, Kyung Sun; Kim, So Ri; Park, Hee Sun; Park, Seoung Ju; Min, Kyung Hoon; Lee, Ka Young; Choe, Yeong Hun; Hong, Sang Hyun; Han, Hyo Jin; Lee, Young Rae; Kim, Jong Suk; Atlas, Daphne; Lee, Yong Chul

    2007-12-31

    Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-kappaB and hypoxia-inducible factor-1alpha (HIF-1alpha) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-kappaB and HIF-1alpha as well as reducing ROS generation in allergic airway disease.

  14. Airway Epithelium Stimulates Smooth Muscle Proliferation

    OpenAIRE

    Malavia, Nikita K.; Raub, Christopher B.; Mahon, Sari B.; Brenner, Matthew; Reynold A Panettieri; George, Steven C.

    2009-01-01

    Communication between the airway epithelium and stroma is evident during embryogenesis, and both epithelial shedding and increased smooth muscle proliferation are features of airway remodeling. Hence, we hypothesized that after injury the airway epithelium could modulate airway smooth muscle proliferation. Fully differentiated primary normal human bronchial epithelial (NHBE) cells at an air–liquid interface were co-cultured with serum-deprived normal primary human airway smooth muscle cells (...

  15. Beyond corticosteroids: future prospects in the management of inflammation in COPD

    Directory of Open Access Journals (Sweden)

    N. Roche

    2011-09-01

    Full Text Available Inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD. Exposure to cigarette smoke induces the recruitment of inflammatory cells in the airways and stimulates innate and adaptive immune mechanisms. Airway inflammation is involved in increased bronchial wall thickness, increased bronchial smooth muscle tone, mucus hypersecretion and loss of parenchymal elastic structures. Oxidative stress impairs tissue integrity, accelerates lung ageing and reduces the efficacy of corticosteroids by decreasing levels of histone deacetylase-2. Protease–antiprotease imbalance impairs tissues and is involved in inflammatory processes. Inflammation is also present in the pulmonary artery wall and at the systemic level in COPD patients, and may be involved in COPD-associated comorbidities. Proximal airways inflammation contributes to symptoms of chronic bronchitis while distal and parenchymal inflammation relates to airflow obstruction, emphysema and hyperinflation. Basal levels of airways and systemic inflammation are increased in frequent exacerbators. Inhaled corticosteroids are much less effective in COPD than in asthma, which relates to the intrinsically poor reversibility of COPD-related airflow obstruction and to molecular mechanisms of resistance relating to oxidative stress. Ongoing research aims at developing new drugs targeting more intimately COPD-specific mechanisms of inflammation, hypersecretion and tissue destruction and repair. Among new anti-inflammatory agents, phosphodiesterase-4 inhibitors have been the first to emerge.

  16. Airway management and morbid obesity

    DEFF Research Database (Denmark)

    Kristensen, Michael S

    2010-01-01

    Morbidly obese patients present with excess fatty tissue externally on the breast, neck, thoracic wall and abdomen and internally in the mouth, pharynx and abdomen. This excess tissue tends to make access (intubation, tracheostomy) to and patency (during sedation or mask ventilation) of the upper...... in morbidly obese patients and should be followed by actions to counteract atelectasis formation. The decision as to weather to use a rapid sequence induction, an awake intubation or a standard induction with hypnotics should depend on the thorough airway examination and comorbidity and should not be based...... solely on whether morbid obesity is present or not. It is important to ensure sufficient depth of anaesthesia before initiating manipulation of the airway because inadequate anaesthesia depth predisposes to aspiration if airway management becomes difficult. The intubating laryngeal mask airway is more...

  17. 益气涤痰化瘀方对哮喘小鼠气道炎症及Th1/Th2平衡的影响%Effects of YiQi DiTan HuaYu Formula on Th1/Th2 Balance and Airway Inflammation of Mice with Asthma

    Institute of Scientific and Technical Information of China (English)

    赵文娟; 袁嘉丽; 陈静; 邢海晶; 韩妮萍

    2015-01-01

    目的:探讨益气涤痰化瘀方对哮喘小鼠气道炎症及Th1/Th2平衡的调节作用。方法:将SPF级BALB/c雌性小鼠50只随机分为正常对照组、哮喘模型组,益气涤痰化瘀方低、中、高剂量组。采用卵清白蛋白(OVA)腹腔注射及雾化激发法构建哮喘模型,益气涤痰化瘀方干预治疗。观察各组小鼠行为学改变;制作肺组织病理切片行镜下观察;收集肺泡灌洗液(BALF)进行白细胞总数及分类计数;取小鼠血清以ELISA法检测IFN-γ、IL-4的变化。结果:1)与哮喘模型组比较,药物干预组哮喘症状有所减轻,肺组织炎性细胞浸润减轻;2)益气涤痰化瘀方中剂量组小鼠BALF中白细胞总数和嗜酸性粒细胞(EOS)、中性粒细胞(NEU)、淋巴细胞(LYM)分类计数较哮喘模型组减少(P<0.05);3)与哮喘模型组比较,益气涤痰化瘀方高、中剂量组小鼠血清IFN-γ浓度升高(P<0.05),IL-4浓度降低(P<0.05)。结论:益气涤痰化瘀方可对免疫细胞Th2优势所致的免疫失衡状态进行调节,恢复Th1/Th2平衡;益气涤痰化瘀方可能通过调节机体平衡而减轻哮喘急性气道炎性病变,从而起到防治哮喘的作用。%Objective:To observe the adjustment of YiQi DiTan HuaYu formula to Th1/Th2 balance and air-way inflammation of mice with asthma. Methods:Fifty SPF BALB/c female mice were randomized into normal con-trol group, asthma model group, high, moderate and low dosages groups of YiQi DiTan HuaYu formula. The mice models were established through peritoneal injection of ovalbumin (OVA) and atomization-excited method, and they were intervened by YiQi DiTan HuaYu formula. To observe behavioral changes of the mice in different groups;to prepare pathological section of the lung and observe the section under the microscope; to count total white blood cells and classifications after collecting broncho-alveolar lavage fluid (BALF);to draw the serum from the mice and to

  18. Smoking-induced CXCL14 expression in the human airway epithelium links chronic obstructive pulmonary disease to lung cancer.

    Science.gov (United States)

    Shaykhiev, Renat; Sackrowitz, Rachel; Fukui, Tomoya; Zuo, Wu-Lin; Chao, Ion Wa; Strulovici-Barel, Yael; Downey, Robert J; Crystal, Ronald G

    2013-09-01

    CXCL14, a recently described epithelial cytokine, plays putative multiple roles in inflammation and carcinogenesis. In the context that chronic obstructive pulmonary disease (COPD) and lung cancer are both smoking-related disorders associated with airway epithelial disorder and inflammation, we hypothesized that the airway epithelium responds to cigarette smoking with altered CXCL14 gene expression, contributing to the disease-relevant phenotype. Using genome-wide microarrays with subsequent immunohistochemical analysis, the data demonstrate that the expression of CXCL14 is up-regulated in the airway epithelium of healthy smokers and further increased in COPD smokers, especially within hyperplastic/metaplastic lesions, in association with multiple genes relevant to epithelial structural integrity and cancer. In vitro experiments revealed that the expression of CXCL14 is induced in the differentiated airway epithelium by cigarette smoke extract, and that epidermal growth factor mediates CXCL14 up-regulation in the airway epithelium through its effects on the basal stem/progenitor cell population. Analyses of two independent lung cancer cohorts revealed a dramatic up-regulation of CXCL14 expression in adenocarcinoma and squamous-cell carcinoma. High expression of the COPD-associated CXCL14-correlating cluster of genes was linked in lung adenocarcinoma with poor survival. These data suggest that the smoking-induced expression of CXCL14 in the airway epithelium represents a novel potential molecular link between smoking-associated airway epithelial injury, COPD, and lung cancer.

  19. Muc5b is required for airway defence.

    Science.gov (United States)

    Roy, Michelle G; Livraghi-Butrico, Alessandra; Fletcher, Ashley A; McElwee, Melissa M; Evans, Scott E; Boerner, Ryan M; Alexander, Samantha N; Bellinghausen, Lindsey K; Song, Alfred S; Petrova, Youlia M; Tuvim, Michael J; Adachi, Roberto; Romo, Irlanda; Bordt, Andrea S; Bowden, M Gabriela; Sisson, Joseph H; Woodruff, Prescott G; Thornton, David J; Rousseau, Karine; De la Garza, Maria M; Moghaddam, Seyed J; Karmouty-Quintana, Harry; Blackburn, Michael R; Drouin, Scott M; Davis, C William; Terrell, Kristy A; Grubb, Barbara R; O'Neal, Wanda K; Flores, Sonia C; Cota-Gomez, Adela; Lozupone, Catherine A; Donnelly, Jody M; Watson, Alan M; Hennessy, Corinne E; Keith, Rebecca C; Yang, Ivana V; Barthel, Lea; Henson, Peter M; Janssen, William J; Schwartz, David A; Boucher, Richard C; Dickey, Burton F; Evans, Christopher M

    2014-01-16

    Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.

  20. A new removable airway stent

    Directory of Open Access Journals (Sweden)

    Tore Amundsen

    2016-09-01

    Full Text Available Background: Malignant airway obstruction is a feared complication and will most probably occur more frequently in the future because of increasing cancer incidence and increased life expectancy in cancer patients. Minimal invasive treatment using airway stents represents a meaningful and life-saving palliation. We present a new removable airway stent for improved individualised treatment. Methods: To our knowledge, the new airway stent is the world's first knitted and uncovered self-expanding metal stent, which can unravel and be completely removed. In an in vivo model using two anaesthetised and spontaneously breathing pigs, we deployed and subsequently removed the stents by unravelling the device. The procedures were executed by flexible bronchoscopy in an acute and a chronic setting – a ‘proof-of-principle’ study. Results: The new stent was easily and accurately deployed in the central airways, and it remained fixed in its original position. It was easy to unravel and completely remove from the airways without clinically significant complications. During the presence of the stent in the chronic study, granulation tissue was induced. This tissue disappeared spontaneously with the removal. Conclusions: The new removable stent functioned according to its purpose and unravelled easily, and it was completely removed without significant technical or medical complications. Induced granulation tissue disappeared spontaneously. Further studies on animals and humans are needed to define its optimal indications and future use.

  1. Vessel-guided airway tree segmentation

    DEFF Research Database (Denmark)

    Lo, Pechin Chien Pau; Sporring, Jon; Ashraf, Haseem

    2010-01-01

    This paper presents a method for airway tree segmentation that uses a combination of a trained airway appearance model, vessel and airway orientation information, and region growing. We propose a voxel classification approach for the appearance model, which uses a classifier that is trained...... to differentiate between airway and non-airway voxels. This is in contrast to previous works that use either intensity alone or hand crafted models of airway appearance. We show that the appearance model can be trained with a set of easily acquired, incomplete, airway tree segmentations. A vessel orientation...... similarity measure is introduced, which indicates how similar the orientation of an airway candidate is to the orientation of the neighboring vessel. We use this vessel orientation similarity measure to overcome regions in the airway tree that have a low response from the appearance model. The proposed...

  2. Small airway impairment in moderate to severe asthmatics without significant proximal airway obstruction.

    Science.gov (United States)

    Perez, Thierry; Chanez, Pascal; Dusser, Daniel; Devillier, Philippe

    2013-11-01

    Asthma is a disease characterized by inflammation which affects both proximal and distal airways. We evaluated the prevalence of small airway obstruction (SAO) in a group of clinically stable asthmatics with both normal forced expiratory volume in the first second (FEV1) and normal FEV1/forced vital capacity (FVC) and treated with an association of inhaled corticosteroids (ICSs) and long acting β2-agonists (LABAs). Clinical evaluation included the measurement of dyspnea, asthma control test and drug compliance. The prevalence of SAO was estimated by spirometry and plethysmography and defined by the presence of one or more of the following criteria: functional residual capacity (FRC) > 120% predicted (pred), residual volume (RV) > pred + 1.64 residual standard deviation (RSD), RV/total lung capacity (TLC) > pred + 1.64 RSD, forced expiratory flow (FEF)25-75% slow vital capacity (SVC) - FVC > 10%. Among the 441 patients who were included, 222 had normal FEV1 and FEV1/FVC. At least one criteria of SAO was found in 115 (52%) mainly lung hyperinflation (39% based on high FRC, RV or RV/TLC) and more rarely distal airflow limitation (15% based on FEF25-75% or FEF50%) or expiratory trapping (10% based on increased SVC - FVC). In the patients with only SAO (no PAO), there was no relationship between SAO, asthma history and the scores of dyspnea, asthma control or drug compliance. These results suggest that in asthmatics with normal FEV1 and FEV1/FVC, treated with ICSs and LABAs, SAO is found in more than half of the patients indicating that the routinely used lung function tests can underestimate dysfunctions occurring in the small airways.

  3. Airway epithelial NF-κB activation promotes Mycoplasma pneumoniae clearance in mice.

    Directory of Open Access Journals (Sweden)

    Di Jiang

    Full Text Available Respiratory infections including atypical bacteria Mycoplasma pneumoniae (Mp contribute to the pathobiology of asthma and chronic obstructive pulmonary disease (COPD. Mp infection mainly targets airway epithelium and activates various signaling pathways such as nuclear factor κB (NF-κB. We have shown that short palate, lung, and nasal epithelium clone 1 (SPLUNC1 serves as a novel host defense protein and is up-regulated upon Mp infection through NF-κB activation in cultured human and mouse primary airway epithelial cells. However, the in vivo role of airway epithelial NF-κB activation in host defense against Mp infection has not been investigated. In the current study, we investigated the effects of in vivo airway epithelial NF-κB activation on lung Mp clearance and its association with airway epithelial SPLUNC1 expression.Non-antimicrobial tetracycline analog 9-t-butyl doxycycline (9-TB was initially optimized in mouse primary tracheal epithelial cell culture, and then utilized to induce in vivo airway epithelial specific NF-κB activation in conditional NF-κB transgenic mice (CC10-(CAIKKβ with or without Mp infection. Lung Mp load and inflammation were evaluated, and airway epithelial SPLUNC1 protein was examined by immunohistochemistry. We found that 9-TB treatment in NF-κB transgene positive (Tg+, but not transgene negative (Tg- mice significantly reduced lung Mp load. Moreover, 9-TB increased airway epithelial SPLUNC1 protein expression in NF-κB Tg+ mice.By using the non-antimicrobial 9-TB, our study demonstrates that in vivo airway epithelial NF-κB activation promotes lung bacterial clearance, which is accompanied by increased epithelial SPLUNC1 expression.

  4. Inflammation and Heart Disease

    Science.gov (United States)

    ... Disease Venous Thromboembolism Aortic Aneurysm More Inflammation and Heart Disease Updated:Oct 12,2016 Understand the risks of ... inflammation causes cardiovascular disease, inflammation is common for heart disease and stroke patients and is thought to be ...

  5. Upper airway resistance syndrome.

    Science.gov (United States)

    Montserrat, J M; Badia, J R

    1999-03-01

    This article reviews the clinical picture, diagnosis and management of the upper airway resistance syndrome (UARS). Presently, there is not enough data on key points like the frequency of UARS and the morbidity associated with this condition. Furthermore, the existence of LIARS as an independent sleep disorder and its relation with snoring and obstructive events is in debate. The diagnosis of UARS is still a controversial issue. The technical limitations of the classic approach to monitor airflow with thermistors and inductance plethysmography, as well as the lack of a precise definition of hypopnea, may have led to a misinterpretation of UARS as an independent diagnosis from the sleep apnea/hypopnea syndrome. The diagnosis of this syndrome can be missed using a conventional polysomnographic setting unless appropriate techniques are applied. The use of an esophageal balloon to monitor inspiratory effort is currently the gold standard. However, other sensitive methods such as the use of a pneumotachograph and, more recently, nasal cannula/pressure transducer systems or on-line monitoring of respiratory impedance with the forced oscillation technique may provide other interesting possibilities. Recognition and characterization of this subgroup of patients within sleep breathing disorders is important because they are symptomatic and may benefit from treatment. Management options to treat UARS comprise all those currently available for sleep apnea/hypopnea syndrome (SAHS). However, the subset of patients classically identified as LIARS that exhibit skeletal craneo-facial abnormalities might possibly obtain further benefit from maxillofacial surgery.

  6. Haemophilus influenzae infection drives IL-17-mediated neutrophilic allergic airways disease.

    Directory of Open Access Journals (Sweden)

    Ama-Tawiah Essilfie

    2011-10-01

    Full Text Available A subset of patients with stable asthma has prominent neutrophilic and reduced eosinophilic inflammation, which is associated with attenuated airways hyper-responsiveness (AHR. Haemophilus influenzae has been isolated from the airways of neutrophilic asthmatics; however, the nature of the association between infection and the development of neutrophilic asthma is not understood. Our aim was to investigate the effects of H. influenzae respiratory infection on the development of hallmark features of asthma in a mouse model of allergic airways disease (AAD. BALB/c mice were intraperitoneally sensitized to ovalbumin (OVA and intranasally challenged with OVA 12-15 days later to induce AAD. Mice were infected with non-typeable H. influenzae during or 10 days after sensitization, and the effects of infection on the development of key features of AAD were assessed on day 16. T-helper 17 cells were enumerated by fluorescent-activated cell sorting and depleted with anti-IL-17 neutralizing antibody. We show that infection in AAD significantly reduced eosinophilic inflammation, OVA-induced IL-5, IL-13 and IFN-γ responses and AHR; however, infection increased airway neutrophil influx in response to OVA challenge. Augmented neutrophilic inflammation correlated with increased IL-17 responses and IL-17 expressing macrophages and neutrophils (early, innate and T lymphocytes (late, adaptive in the lung. Significantly, depletion of IL-17 completely abrogated infection-induced neutrophilic inflammation during AAD. In conclusion, H. influenzae infection synergizes with AAD to induce Th17 immune responses that drive the development of neutrophilic and suppress eosinophilic inflammation during AAD. This results in a phenotype that is similar to neutrophilic asthma. Infection-induced neutrophilic inflammation in AAD is mediated by IL-17 responses.

  7. Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes.

    Science.gov (United States)

    Szul, Tomasz; Bratcher, Preston E; Fraser, Kyle B; Kong, Michele; Tirouvanziam, Rabindra; Ingersoll, Sarah; Sztul, Elizabeth; Rangarajan, Sunil; Blalock, J Edwin; Xu, Xin; Gaggar, Amit

    2016-03-01

    Proteases are important regulators of pulmonary remodeling and airway inflammation. Recently, we have characterized the enzyme prolyl endopeptidase (PE), a serine peptidase, as a critical protease in the generation of the neutrophil chemoattractant tripeptide Pro-Gly-Pro (PGP) from collagen. However, PE has been characterized as a cytosolic enzyme, and the mechanism mediating PE release extracellularly remains unknown. We examined the role of exosomes derived from airway epithelia as a mechanism for PE release and the potential extracellular signals that regulate the release of these exosomes. We demonstrate a specific regulatory pathway of exosome release from airway epithelia and identify PE as novel exosome cargo. LPS stimulation of airway epithelial cells induces release of PE-containing exosomes, which is significantly attenuated by small interfering RNA depletion of Toll-like receptor 4 (TLR4). These differences were recapitulated upon intratracheal LPS administration in mice competent versus deficient for TLR4 signaling. Finally, sputum samples from subjects with cystic fibrosis colonized with Pseudomonas aeruginosa demonstrate elevated exosome content and increased PE levels. This TLR4-based mechanism highlights the first report of nonstochastic release of exosomes in the lung and couples TLR4 activation with matrikine generation. The increased quantity of these proteolytic exosomes in the airways of subjects with chronic lung disease highlights a new mechanism of injury and inflammation in the pathogenesis of pulmonary disorders.

  8. The compatible solute ectoine reduces the exacerbating effect of environmental model particles on the immune response of the airways.

    Science.gov (United States)

    Unfried, Klaus; Kroker, Matthias; Autengruber, Andrea; Gotić, Marijan; Sydlik, Ulrich

    2014-01-01

    Exposure of humans to particulate air pollution has been correlated with the incidence and aggravation of allergic airway diseases. In predisposed individuals, inhalation of environmental particles can lead to an exacerbation of immune responses. Previous studies demonstrated a beneficial effect of the compatible solute ectoine on lung inflammation in rats exposed to carbon nanoparticles (CNP) as a model of environmental particle exposure. In the current study we investigated the effect of such a treatment on airway inflammation in a mouse allergy model. Ectoine in nonsensitized animals significantly reduced the neutrophilic lung inflammation after CNP exposure. This effect was accompanied by a reduction of inflammatory factors in the bronchoalveolar lavage. Reduced IL-6 levels in the serum also indicate the effects of ectoine on systemic inflammation. In sensitized animals, an aggravation of the immune response was observed when animals were exposed to CNP prior to antigen provocation. The coadministration of ectoine together with the particles significantly reduced this exacerbation. The data indicate the role of neutrophilic lung inflammation in the exacerbation of allergic airway responses. Moreover, the data suggest to use ectoine as a preventive treatment to avoid the exacerbation of allergic airway responses induced by environmental air pollution.

  9. The Compatible Solute Ectoine Reduces the Exacerbating Effect of Environmental Model Particles on the Immune Response of the Airways

    Directory of Open Access Journals (Sweden)

    Klaus Unfried

    2014-01-01

    Full Text Available Exposure of humans to particulate air pollution has been correlated with the incidence and aggravation of allergic airway diseases. In predisposed individuals, inhalation of environmental particles can lead to an exacerbation of immune responses. Previous studies demonstrated a beneficial effect of the compatible solute ectoine on lung inflammation in rats exposed to carbon nanoparticles (CNP as a model of environmental particle exposure. In the current study we investigated the effect of such a treatment on airway inflammation in a mouse allergy model. Ectoine in nonsensitized animals significantly reduced the neutrophilic lung inflammation after CNP exposure. This effect was accompanied by a reduction of inflammatory factors in the bronchoalveolar lavage. Reduced IL-6 levels in the serum also indicate the effects of ectoine on systemic inflammation. In sensitized animals, an aggravation of the immune response was observed when animals were exposed to CNP prior to antigen provocation. The coadministration of ectoine together with the particles significantly reduced this exacerbation. The data indicate the role of neutrophilic lung inflammation in the exacerbation of allergic airway responses. Moreover, the data suggest to use ectoine as a preventive treatment to avoid the exacerbation of allergic airway responses induced by environmental air pollution.

  10. Nebulized lidocaine blunts airway hyper-responsiveness in experimental feline asthma.

    Science.gov (United States)

    Nafe, Laura A; Guntur, Vamsi P; Dodam, John R; Lee-Fowler, Tekla M; Cohn, Leah A; Reinero, Carol R

    2013-08-01

    Nebulized lidocaine may be a corticosteroid-sparing drug in human asthmatics, reducing airway resistance and peripheral blood eosinophilia. We hypothesized that inhaled lidocaine would be safe in healthy and experimentally asthmatic cats, diminishing airflow limitation and eosinophilic airway inflammation in the latter population. Healthy (n = 5) and experimentally asthmatic (n = 9) research cats were administered 2 weeks of nebulized lidocaine (2 mg/kg q8h) or placebo (saline) followed by a 2-week washout and crossover to the alternate treatment. Cats were anesthetized to measure the response to inhaled methacholine (MCh) after each treatment. Placebo and doubling doses of methacholine (0.0625-32.0000 mg/ml) were delivered and results were expressed as the concentration of MCh increasing baseline airway resistance by 200% (EC200Raw). Bronchoalveolar lavage was performed after each treatment and eosinophil numbers quantified. Bronchoalveolar lavage fluid (BALF) % eosinophils and EC200Raw within groups after each treatment were compared using a paired t-test (P eosinophils in asthmatic cats treated with lidocaine (36±10%) or placebo (33 ± 6%). However, lidocaine increased the EC200Raw compared with placebo 10 ± 2 versus 5 ± 1 mg/ml; P = 0.043). Chronic nebulized lidocaine was well-tolerated in all cats, and lidocaine did not induce airway inflammation or airway hyper-responsiveness in healthy cats. Lidocaine decreased airway response to MCh in asthmatic cats without reducing airway eosinophilia, making it unsuitable for monotherapy. However, lidocaine may serve as a novel adjunctive therapy in feline asthmatics with beneficial effects on airflow obstruction.

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

    Directory of Open Access Journals (Sweden)

    Kenneth R Eyring

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

  12. CT analysis of peripheral airway and lung lesions of patients with asthma and COPD

    Energy Technology Data Exchange (ETDEWEB)

    Itoh, Takayuki; Tanaka, Hiroshi; Sahara, Shin; Ohnishi, Tetsuro; Abe, Shosaku [Sapporo Medical Univ. (Japan). School of Medicine; Koba, Hiroyuki [Teinekeijinkai Hospital, Sapporo (Japan); Ueno, Kan [Hitachi Medico Technology Corp., Tokyo (Japan)

    2002-12-01

    We compared peripheral airway and lung parenchyma images among patients with asthma, chronic obstructive pulmonary disease (COPD) and healthy controls using high-resolution CT images taken by a multidetector-row CT scanner (Aquillion, Toshiba, Japan). CT images were saved as digital image and communication (DICOM) files and %low attenuation area (LAA) (<-960 Hounsfield Unit) was calculated with the imaging software. %LAA was significantly increased in patients with COPD (p<0.0001) and smokers with stable asthma (p<0.01) as compared with healthy controls. In stable asthma, mucous plugging in the airway sometime appeared, while during asthma exacerbation small nodules and mosaic pattern of peripheral lung field appeared. Since smoker's patients with asthma have hyper-secretion of sputum due to smoking, mucous plugging and airway inflammation may easily occur and consequently air trapping may increase. In the future, image diagnosis of peripheral airway should develop for early detection of airway diseases as a non-invasive examination. On the other hand, micro focus X-ray computed tomography system (Hitachi Medico Technology Co., Japan) can display CT images closely similar to the pictures of microscopic findings and it will be a useful tool to analyze radiologic-pathologic correlations of peripheral airways and lung parenchyma. (author)

  13. 1,25-二羟维生素D3处理的树突细胞在变应性气道炎症中的免疫调节作用%Immunoregulatory role of 1,25-dihydroxyvltamin D3-treated dendritic cells in allergic airway inflammation

    Institute of Scientific and Technical Information of China (English)

    夏俊波膊; 王长征; 马建新; 安晓静

    2009-01-01

    airway inflammation.Methods Mouse bone maiTow-derived DCs were treated by 1,25(OH)2D3 for72 h.The expression levels ofdifferent Notch ligands:Jaggedl,Jtmoged2,Deltal,Delta3,and Delta4 in these DCs were detected by RT-PCR and westem blotting.Mouse spleen CIM+T cells were cultured with 1,25(OH)2D3-treated DCs or 1,25(OH)2D3-treated DCs Mocked by polyclone antibody of Jaggedl or Jagged2(control group)for48 h.The pementage of CIM4CD25+Foxp3+T cells in CD4+T cells was detected by flow cytometry(FCM).Ten mice underwent intraperitoneal injection of ovalbumin(OVA)to be sensitized and tIIen divided into 2 groups to inhale 1,25(OH)2 D3-treated DC suspension and PBS-DC suspension respectively for 6 successive days.Then the micc were killed.Bronchoalveolar lavage fluid was obtained to detect tlle eosinophil count and the levels ofinterleukin(IL)-4,IL-6,IL-13,and interferon(IFN)-γ,and pathological examination of lung was conducted.Spleens were taken out to isolate the CD4+T cells,and immunolabeling and FCM were used to detect the percentage of CD4+CD25+Foxp3+T ceils.Results The mRNA and protein expression levels of Jaggedl and Jagged2 in the 1,25(OH)2D3-treated DCs were(0.376±0.029)and(0.786±0.034),and (0.564±0.018)and(0.632±0.026)respectively,all significantly higher than those of the control group [(0.146.±0.032)and(0.124±0.025),and(0.267±0.012)and(0.098±0.012)respectively,all P<0.01)].The percentage of CD4+CD25+Foxp3+T cells in the CD4+T cells cultured with 1,25 (OH)2D3-treated DCs was(22.49%±0.56%),significantly higher than that of the a PBS control group [(6.67%±0.50%),P<0.01].The percentage of CD4+cD25+Foxp3+T cells in CD4+T cells after cultured with 1,25(OH)2D3.treated DC blocked by polyclone antibody of Jagged2 was(6.56%±1.89%),significantly lower than that of the un.blocked control group[(20.37%±1.64%),P<0.01].The levels of IL-4,IL-5,IL-13,and IFN-γ,and eosinophil count in the BALF of the 1,25(OH)2D3-treated DC group were(33±5)pg/ml,(134±23)pg/ml,(91

  14. Multiscale Vessel-guided Airway Tree Segmentation

    DEFF Research Database (Denmark)

    Lo, Pechin Chien Pau; Sporring, Jon; de Bruijne, Marleen

    2009-01-01

    that is trained to differentiate between airway and non-airway voxels. Vessel and airway orientation information are used in the form of a vessel orientation similarity measure, which indicates how similar the orientation of the an airway candidate is to the orientation of the neighboring vessel. The method...... is evaluated within EXACT’09 on a diverse set of CT scans. Results show a favorable combination of a relatively large portion of the tree detected correctly with very few false positives....

  15. Pharmacogenetics, pharmacogenomics and airway disease

    Directory of Open Access Journals (Sweden)

    Hall Ian P

    2001-11-01

    Full Text Available Abstract The availability of a draft sequence for the human genome will revolutionise research into airway disease. This review deals with two of the most important areas impinging on the treatment of patients: pharmacogenetics and pharmacogenomics. Considerable inter-individual variation exists at the DNA level in targets for medication, and variability in response to treatment may, in part, be determined by this genetic variation. Increased knowledge about the human genome might also permit the identification of novel therapeutic targets by expression profiling at the RNA (genomics or protein (proteomics level. This review describes recent advances in pharmacogenetics and pharmacogenomics with regard to airway disease.

  16. Functional phenotype of airway myocytes from asthmatic airways

    NARCIS (Netherlands)

    Wright, David B.; Trian, Thomas; Siddiqui, Sana; Pascoe, Chris D.; Ojo, Oluwaseun O.; Johnson, Jill R.; Dekkers, Bart G. J.; Dakshinamurti, Shyamala; Bagchi, Rushita; Burgess, Janette K.; Kanabar, Varsha

    2013-01-01

    In asthma, the airway smooth muscle (ASM) cell plays a central role in disease pathogenesis through cellular changes which may impact on its microenvironment and alter ASM response and function. The answer to the long debated question of what makes a 'healthy' ASM cell become 'asthmatic' still remai

  17. The role of the small airways in the pathophysiology of asthma and chronic obstructive pulmonary disease.

    Science.gov (United States)

    Bonini, Matteo; Usmani, Omar S

    2015-12-01

    Chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), represent a major social and economic burden for worldwide health systems. During recent years, increasing attention has been directed to the role of small airways in respiratory diseases, and their exact contribution to the pathophysiology of asthma and COPD continues to be clarified. Indeed, it has been suggested that small airways play a distinct role in specific disease phenotypes. Besides providing information on small airways structure and diagnostic procedures, this review therefore aims to present updated and evidence-based findings on the role of small airways in the pathophysiology of asthma and COPD. Most of the available information derives from either pathological studies or review articles and there are few data on the natural history of small airways disease in the onset or progression of asthma and COPD. Comparisons between studies on the role of small airways are hard to draw because both asthma and COPD are highly heterogeneous conditions. Most studies have been performed in small population samples, and different techniques to characterize aspects of small airways function have been employed in order to assess inflammation and remodelling. Most methods of assessing small airways dysfunction have been largely confined to research purposes, but some data are encouraging, supporting the utilization of certain techniques into daily clinical practice, particularly for early-stage diseases, when subjects are often asymptomatic and routine pulmonary function tests may be within normal ranges. In this context further clinical trials and real-life feedback on large populations are desirable.

  18. The human airway epithelial basal cell transcriptome.

    Directory of Open Access Journals (Sweden)

    Neil R Hackett

    Full Text Available BACKGROUND: The human airway epithelium consists of 4 major cell types: ciliated, secretory, columnar and basal cells. During natural turnover and in response to injury, the airway basal cells function as stem/progenitor cells for the other airway cell types. The objective of this study is to better understand human airway epithelial basal cell biology by defining the gene expression signature of this cell population. METHODOLOGY/PRINCIPAL FINDINGS: Bronchial brushing was used to obtain airway epithelium from healthy nonsmokers. Microarrays were used to assess the transcriptome of basal cells purified from the airway epithelium in comparison to the transcriptome of the differentiated airway epithelium. This analysis identified the "human airway basal cell signature" as 1,161 unique genes with >5-fold higher expression level in basal cells compared to differentiated epithelium. The basal cell signature was suppressed when the basal cells differentiated into a ciliated airway epithelium in vitro. The basal cell signature displayed overlap with genes expressed in basal-like cells from other human tissues and with that of murine airway basal cells. Consistent with self-modulation as well as signaling to other airway cell types, the human airway basal cell signature was characterized by genes encoding extracellular matrix components, growth factors and growth factor receptors, including genes related to the EGF and VEGF pathways. Interestingly, while the basal cell signature overlaps that of basal-like cells of other organs, the human airway basal cell signature has features not previously associated with this cell type, including a unique pattern of genes encoding extracellular matrix components, G protein-coupled receptors, neuroactive ligands and receptors, and ion channels. CONCLUSION/SIGNIFICANCE: The human airway epithelial basal cell signature identified in the present study provides novel insights into the molecular phenotype and biology of

  19. Incidence of unanticipated difficult airway using an objective airway score versus a standard clinical airway assessment

    DEFF Research Database (Denmark)

    Nørskov, Anders Kehlet; Rosenstock, Charlotte Valentin; Wetterslev, Jørn

    2013-01-01

    the examination and registration of predictors for difficult mask ventilation with a non-specified clinical airway assessment on prediction of difficult mask ventilation.Method/Design: We cluster-randomized 28 Danish departments of anaesthesia to airway assessment either by the SARI or by usual non...... reduction equalling a number needed to treat of 180. Sample size estimation is adjusted for the study design and based on standards for randomization on cluster-level. With an average cluster size of 2,500 patients, 70,000 patients will be enrolled over a 1-year trial period. The database is programmed so...

  20. Vessel-guided Airway Tree Segmentation

    DEFF Research Database (Denmark)

    Lo, P.; Sporring, J.; Ashraf, H.;

    2010-01-01

    This paper presents a method for airway tree segmentation that uses a combination of a trained airway appearance model, vessel and airway orientation information, and region growing. We propose a voxel classification approach for the appearance model, which uses a classifier that is trained...... method is evaluated on 250 low dose computed tomography images from a lung cancer screening trial. Our experiments showed that applying the region growing algorithm on the airway appearance model produces more complete airway segmentations, leading to on average 20% longer trees, and 50% less leakage...

  1. Inflammatory bowel disease and airway diseases

    Science.gov (United States)

    Vutcovici, Maria; Brassard, Paul; Bitton, Alain

    2016-01-01

    Airway diseases are the most commonly described lung manifestations of inflammatory bowel disease (IBD). However, the similarities in disease pathogenesis and the sharing of important environmental risk factors and genetic susceptibility suggest that there is a complex interplay between IBD and airway diseases. Recent evidence of IBD occurrence among patients with airway diseases and the higher than estimated prevalence of subclinical airway injuries among IBD patients support the hypothesis of a two-way association. Future research efforts should be directed toward further exploration of this association, as airway diseases are highly prevalent conditions with a substantial public health impact. PMID:27678355

  2. Mucus hypersecretion in the airway

    Institute of Scientific and Technical Information of China (English)

    WANG Ke; WEN Fu-qiang; XU Dan

    2008-01-01

    @@ Mucus hypersecretion is a distinguishing feature of Chronic intlammation diseases,such as asthma,1chronic bronchitis.2 bronchiectasis3 and cystic fibrosis.4Mucus hypersecretion leads to impairment of mucociliary clearance,abnormal bacterial plantation,mucus plug in the airway,and dysfunction of gas exchange.5

  3. Nasal continuous positive airway pressure

    DEFF Research Database (Denmark)

    Scholze, Alexandra; Lamwers, Stephanie; Tepel, Martin;

    2012-01-01

    Obstructive sleep apnoea (OSA) is linked to increased cardiovascular risk. This risk can be reduced by nasal continuous positive airway pressure (nCPAP) treatment. As OSA is associated with an increase of several vasoconstrictive factors, we investigated whether nCPAP influences the digital volum...

  4. Airway nerves: in vitro electrophysiology.

    Science.gov (United States)

    Fox, Alyson

    2002-06-01

    Recording the activity of single airway sensory fibres or neuronal cell bodies in vitro has allowed detailed characterisation of fibre types and membrane properties. Fibre types can be identified by their conduction velocities and further studied by the application of drugs to their receptive field. C-fibres are sensitive to mechanical stimuli and a range of irritant chemicals (bradykinin, capsaicin, low pH, platelet-activating factor), whereas Adelta-fibres are relatively insensitive to chemical stimuli and appear to correlate to the rapidly adapting receptors identified in airways in vivo. Their site of origin also differs: upper airway C-fibres arise predominantly from the jugular ganglion and Adelta-fibres from the jugular and nodose ganglia. Intracellular recording from cell bodies in the ganglia has revealed a calcium-dependent potassium current common to many putative C-fibre cell bodies. This slow after hyperpolarisation current may be inhibited by stimuli that excite and sensitise C-fibres - this could be an important mechanism underlying the sensitisation of C-fibres in airway irritability.

  5. Divergent Inhibitor Susceptibility among Airway Lumen-Accessible Tryptic Proteases.

    Directory of Open Access Journals (Sweden)

    Shilpa Nimishakavi

    Full Text Available Tryptic serine proteases of bronchial epithelium regulate ion flux, barrier integrity, and allergic inflammation. Inhibition of some of these proteases is a strategy to improve mucociliary function in cystic fibrosis and asthmatic inflammation. Several inhibitors have been tested in pre-clinical animal models and humans. We hypothesized that these inhibitors inactivate a variety of airway protease targets, potentially with bystander effects. To establish relative potencies and modes of action, we compared inactivation of human prostasin, matriptase, airway trypsin-like protease (HAT, and β-tryptase by nafamostat, camostat, bis(5-amidino-2-benzimidazolylmethane (BABIM, aprotinin, and benzamidine. Nafamostat achieved complete, nearly stoichiometric and very slowly reversible inhibition of matriptase and tryptase, but inhibited prostasin less potently and was weakest versus HAT. The IC50 of nafamostat's leaving group, 6-amidino-2-naphthol, was >104-fold higher than that of nafamostat itself, consistent with suicide rather than product inhibition as mechanisms of prolonged inactivation. Stoichiometric release of 6-amidino-2-naphthol allowed highly sensitive fluorometric estimation of active-site concentration in preparations of matriptase and tryptase. Camostat inactivated all enzymes but was less potent overall and weakest towards matriptase, which, however was strongly inhibited by BABIM. Aprotinin exhibited nearly stoichiometric inhibition of prostasin and matriptase, but was much weaker towards HAT and was completely ineffective versus tryptase. Benzamidine was universally weak. Thus, each inhibitor profile was distinct. Nafamostat, camostat and aprotinin markedly reduced tryptic activity on the apical surface of cystic fibrosis airway epithelial monolayers, suggesting prostasin as the major source of such activity and supporting strategies targeting prostasin for inactivation.

  6. Acrolein stimulates eicosanoid release from bovine airway epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Doupnik, C.A.; Leikauf, G.D. (Univ. of Cincinnati College of Medicine, OH (USA))

    1990-10-01

    Injury to the airway mucosa after exposure to environmental irritants is associated with pulmonary inflammation and bronchial hyperresponsiveness. To better understand the relationships between mediator release and airway epithelial cell injury during irritant exposures, we studied the effects of acrolein, a low-molecular-weight aldehyde found in cigarette smoke, on arachidonic acid metabolism in cultured bovine tracheal epithelial cells. Confluent airway epithelial cell monolayers, prelabeled with (3H)arachidonic acid, released significant levels of 3H activity when exposed (20 min) to 100 microM acrolein. (3H)arachidonic acid products were resolved using reverse-phase high-performance liquid chromatography. Under control conditions the released 3H activity coeluted predominantly with the cyclooxygenase product, prostaglandin (PG) E2. After exposure to acrolein, significant peaks in 3H activity coeluted with the lipoxygenase products 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE, as well as with PGE2, PGF2 alpha, and 6-keto-PGF1 alpha. Dose-response relationships for acrolein-induced release of immunoreactive PGF2 alpha and PGE2 from unlabeled epithelial monolayers demonstrated 30 microM acrolein as the threshold dose, with 100 microM acrolein inducing nearly a fivefold increase in both PGF2 alpha and PGE2. Cellular viability after exposure to 100 microM acrolein, determined by released lactate dehydrogenase activity, was not affected until exposure periods were greater than or equal to 2 h. These results implicate the airway epithelial cell as a possible source of eicosanoids after exposure to acrolein.

  7. Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Borst Mathias M

    2009-12-01

    Full Text Available Abstract Background In idiopathic pulmonary arterial hypertension (IPAH, peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1, to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH. We hypothesized that bosentan might affect airway obstruction. Methods In 32 IPAH-patients (19 female, WHO functional class II (n = 10, III (n = 22; (data presented as mean ± standard deviation pulmonary vascular resistance (11 ± 5 Wood units, lung function, 6 minute walk test (6-MWT; 364 ± 363.7 (range 179.0-627.0 m, systolic pulmonary artery pressure, sPAP, 79 ± 19 mmHg, and NT-proBNP serum levels (1427 ± 2162.7 (range 59.3-10342.0 ng/L were measured at baseline, after 3 and 12 months of oral bosentan (125 mg twice per day. Results and Discussion At baseline, maximal expiratory flow at 50 and 25% vital capacity were reduced to 65 ± 25 and 45 ± 24% predicted. Total lung capacity was 95.6 ± 12.5% predicted and residual volume was 109 ± 21.4% predicted. During 3 and 12 months of treatment, 6-MWT increased by 32 ± 19 and 53 ± 69 m, respectively; p Conclusion This study gives first evidence in IPAH, that during long-term bosentan, improvement of hemodynamics, functional parameters or serum biomarker occur independently from persisting peripheral airway obstruction.

  8. Distinct microRNA Expression in Human Airway Cells of Asthmatic Donors Identifies a Novel Asthma-associated Gene

    Science.gov (United States)

    Airway inflammation is the hallmark of asthma and suggests a dysregulation of homeostatic mechanisms. MicroRNAs (miRNAs) are key regulators of gene expression, necessary for the proper function of cellular processes. Here, we tested the hypothesis that differences between healthy...

  9. The involvement of glycosaminoglycans in airway disease associated with cystic fibrosis.

    LENUS (Irish Health Repository)

    Reeves, Emer P

    2012-02-01

    Individuals with cystic fibrosis (CF) present with severe airway destruction and extensive bronchiectasis. It has been assumed that these structural airway changes have occurred secondary to infection and inflammation, but recent studies suggest that glycosaminoglycan (GAG) remodelling may be an important independent parallel process. Evidence is accumulating that not only the concentration, but also sulphation of GAGs is markedly increased in CF bronchial cells and tissues. Increased expression of GAGs and, in particular, heparan sulphate, has been linked to a sustained inflammatory response and neutrophil recruitment to the CF airways. This present review discusses the biological role of GAGs in the lung, as well as their involvement in CF respiratory disease, and their potential as therapeutic targets.

  10. Microfibrillar-associated protein 4 modulates airway smooth muscle cell phenotype in experimental asthma

    DEFF Research Database (Denmark)

    Pilecki, Bartosz; Schlosser, Anders; Wulf-Johansson, Helle

    2015-01-01

    . In the current study