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Sample records for decreases airway hyperresponsiveness

  1. Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation

    PubMed Central

    Downie, Sue R; Salome, Cheryl M; Verbanck, Sylvia; Thompson, Bruce; Berend, Norbert; King, Gregory G

    2007-01-01

    Background Airway hyperresponsiveness is the ability of airways to narrow excessively in response to inhaled stimuli and is a key feature of asthma. Airway inflammation and ventilation heterogeneity have been separately shown to be associated with airway hyperresponsiveness. A study was undertaken to establish whether ventilation heterogeneity is associated with airway hyperresponsiveness independently of airway inflammation in subjects with asthma and to determine the effect of inhaled corticosteroids on this relationship. Methods Airway inflammation was measured in 40 subjects with asthma by exhaled nitric oxide, ventilation heterogeneity by multiple breath nitrogen washout and airway hyperresponsiveness by methacholine challenge. In 18 of these subjects with uncontrolled symptoms, measurements were repeated after 3 months of treatment with inhaled beclomethasone dipropionate. Results At baseline, airway hyperresponsiveness was independently predicted by airway inflammation (partial r2 = 0.20, p<0.001) and ventilation heterogeneity (partial r2 = 0.39, p<0.001). Inhaled corticosteroid treatment decreased airway inflammation (p = 0.002), ventilation heterogeneity (p = 0.009) and airway hyperresponsiveness (p<0.001). After treatment, ventilation heterogeneity was the sole predictor of airway hyperresponsiveness (r2 = 0.64, p<0.001). Conclusions Baseline ventilation heterogeneity is a strong predictor of airway hyperresponsiveness, independent of airway inflammation in subjects with asthma. Its persistent relationship with airway hyperresponsiveness following anti‐inflammatory treatment suggests that it is an important independent determinant of airway hyperresponsiveness. Normalisation of ventilation heterogeneity is therefore a potential goal of treatment that may lead to improved long‐term outcomes. PMID:17311839

  2. SPONTANEOUS AIRWAY HYPERRESPONSIVENESS IN ESTROGEN RECEPTOR-A DEFICIENT MICE

    EPA Science Inventory

    Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans. Objectives: To examine the role of estrogen receptors in modulat...

  3. SPONTANEOUS AIRWAY HYPERRESPONSIVENESS IN ESTROGEN RECEPTOR-A DEFICIENT MICE

    EPA Science Inventory

    Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans. Objectives: To examine the role of estrogen receptors in modulat...

  4. [Mechanisms of non-specific airway hyperresponsiveness: Methacholine-induced alterations in airway architecture].

    PubMed

    Plantier, L; Pradel, A; Delclaux, C

    2016-10-01

    Multiple mechanisms drive non-specific airway hyperresponsiveness in asthma. At the organ level, methacholine inhalation induces a complex bronchomotor response involving both bronchoconstriction and, to some extent, paradoxical bronchodilatation. This response is heterogeneous both serially, along a single bronchial axis, and in parallel, among lung regions. The bronchomotor response to methacholine induces contraction of distal airways as well as focal airway closure in select lung territories, leading to anatomically defined ventilation defects and decreased vital capacity. In addition, loss of the bronchoprotector and bronchodilator effects of deep inspirations is a key contributor to airway hyperresponsiveness in asthma. Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  5. Effect of ozone exposure on antigen-induced airway hyperresponsiveness in guinea pigs

    SciTech Connect

    Vargas, M.H.; Segura, P.; Campos, M.G.; Hong, E.; Montano, L.M.

    1994-12-31

    Airway hyperresponsiveness can be induced by several stimuli including antigen and ozone, both of which may be present in the air of polluted cities. Though the effect of ozone on the bronchoconstrictor response to antigen has been well described, the combined effect of these stimuli on airway hyperresponsiveness has not yet been studied. Sensitized guinea pigs with or without ozone exposure for 1 h at 3 ppm, 18 h prior to study, were challenged with a dose-response curve to histamine (0.01-1.8 {mu}g/kg, iv), and then by a second histamine dose-response curve 1 h later. Airway responses were measured as the increase in pulmonary insufflation pressure. In sensitized guinea pigs, the histamine ED50 significantly decreased after antigen challenge, demonstrating the development of airway hyperresponsiveness. Sensitized guinea pigs exposed to ozone showed airway hyperresponsiveness to histamine when compared with nonexposed animals, and such hyperresponsiveness was further enhanced after antigen challenge. We conclude that in this guinea pig model of acute allergic bronchoconstriction both antigen challenge and ozone induce airway hyperresponsiveness, while ozone exposure does not modify the development of antigen-induced hyperresponsiveness. 25 refs., 1 fig., 1 tab.

  6. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice

    PubMed Central

    1995-01-01

    Allergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a murine model that antigen- induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4+ T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mRNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration of IL-12 (1 microgram/d x 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) gamma and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-gamma, because concurrent treatment with IL-12 and anti-IFN-gamma monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel

  7. A fungal protease allergen provokes airway hyperresponsiveness in asthma

    PubMed Central

    Balenga, Nariman A.; Klichinsky, Michael; Xie, Zhihui; Chan, Eunice C.; Zhao, Ming; Jude, Joseph; Laviolette, Michel; Panettieri, Reynold A.; Druey, Kirk M.

    2015-01-01

    Asthma, a common disorder that affects more than 250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine, bradykinin, and histamine—also termed airway hyper-responsiveness Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with IgE sensitization to ubiquitous fungi, typically Aspergillus fumigatus. Here we show that a major Aspergillus fumigatus allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle cell-extracellular matrix interactions. Alp 1-mediated extracellular matrix degradation evokes pathophysiological RhoA-dependent Ca2+ sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby airway smooth muscle cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness. PMID:25865874

  8. Mitochondrial Transplantation Attenuates Airway Hyperresponsiveness by Inhibition of Cholinergic Hyperactivity

    PubMed Central

    Su, Yuan; Zhu, Liping; Yu, Xiangyuan; Cai, Lei; Lu, Yankai; Zhang, Jiwei; Li, Tongfei; Li, Jiansha; Xia, Jingyan; Xu, Feng; Hu, Qinghua

    2016-01-01

    Increased cholinergic activity has been highlighted in the pathogenesis of airway hyperresponsiveness, and alternations of mitochondrial structure and function appear to be involved in many lung diseases including airway hyperresponsiveness. It is crucial to clarify the cause-effect association between mitochondrial dysfunction and cholinergic hyperactivity in the pathogenesis of airway hyperresponsiveness. Male SD rats and cultured airway epithelial cells were exposed to cigarette smoke plus lipopolysaccharide administration; mitochondria isolated from airway epithelium were delivered into epithelial cells in vitro and in vivo. Both the cigarette smoke plus lipopolysaccharide-induced cholinergic hyperactivity in vitro and the airway hyperresponsiveness to acetylcholine in vivo were reversed by the transplantation of exogenous mitochondria. The rescue effects of exogenous mitochondria were imitated by the elimination of excessive reactive oxygen species or blockage of muscarinic M3 receptor, but inhibited by M receptor enhancer. Mitochondrial transplantation effectively attenuates cigarette smoke plus lipopolysaccharide-stimulated airway hyperresponsiveness through the inhibition of ROS-enhanced epithelial cholinergic hyperactivity. PMID:27279915

  9. Immunomodulatory Effects of Ambroxol on Airway Hyperresponsiveness and Inflammation

    PubMed Central

    Miyahara, Nobuaki; Matsubara, Shigeki; Taube, Christian; Kitamura, Kenichi; Hirano, Astushi; Tanimoto, Mitsune; Gelfand, Erwin W.

    2016-01-01

    Ambroxol is used in COPD and asthma to increase mucociliary clearance and regulate surfactant levels, perhaps through anti-oxidant and anti-inflammatory activities. To determine the role and effect of ambroxol in an experimental model of asthma, BALB/c mice were sensitized to ovalbumin (OVA) followed by 3 days of challenge. Airway hyperresponsiveness (AHR), lung cell composition and histology, and cytokine and protein carbonyl levels in bronchoalveolar lavage (BAL) fluid were determined. Ambroxol was administered either before the first OVA challenge or was begun after the last allergen challenge. Cytokine production levels from lung mononuclear cells (Lung MNCs) or alveolar macrophages (AM) were also determined. Administration of ambroxol prior to challenge suppressed AHR, airway eosinophilia, goblet cell metaplasia, and reduced inflammation in subepithelial regions. When given after challenge, AHR was suppressed but without effects on eosinophil numbers. Levels of IL-5 and IL-13 in BAL fluid were decreased when the drug was given prior to challenge; when given after challenge, increased levels of IL-10 and IL-12 were detected. Decreased levels of protein carbonyls were detected in BAL fluid following ambroxol treatment after challenge. In vitro, ambroxol increased levels of IL-10, IFN-γ, and IL-12 from Lung MNCs and AM, whereas IL-4, IL-5, and IL-13 production was not altered. Taken together, ambroxol was effective in preventing AHR and airway inflammation through upregulation of Th1 cytokines and protection from oxidative stress in the airways. PMID:27340385

  10. Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury

    PubMed Central

    Lazrak, Ahmed; Creighton, Judy; Yu, Zhihong; Komarova, Svetlana; Doran, Stephen F.; Aggarwal, Saurabh; Emala, Charles W.; Stober, Vandy P.; Trempus, Carol S.; Garantziotis, Stavros

    2015-01-01

    Chlorine (Cl2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular-weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-α-trypsin-inhibitor (IαI), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against IαI post-Cl2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl2 (100 ppm, 10 min) or incubation with Cl2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca2+, and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca2+, blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca2+ channels of airway smooth muscle cells, increasing their contractility and thus causing AHR. PMID:25747964

  11. Glutathione redox regulates airway hyperresponsiveness and airway inflammation in mice.

    PubMed

    Koike, Yoko; Hisada, Takeshi; Utsugi, Mitsuyoshi; Ishizuka, Tamotsu; Shimizu, Yasuo; Ono, Akihiro; Murata, Yukie; Hamuro, Junji; Mori, Masatomo; Dobashi, Kunio

    2007-09-01

    Glutathione is the major intracellular redox buffer. We have shown that glutathione redox status, which is the balance between intracellular reduced (GSH) and oxidized (GSSG) glutathione, in antigen-presenting cells (APC) regulates the helper T cell type 1 (Th1)/Th2 balance due to the production of IL-12. Bronchial asthma is a typical Th2 disease. Th2 cells and Th2 cytokines are characteristic of asthma and trigger off an inflammation. Accordingly, we studied the effects of the intracellular glutathione redox status on airway hyperresponsiveness (AHR) and allergen-induced airway inflammation in a mouse model of asthma. We used gamma-Glutamylcysteinylethyl ester (gamma-GCE), which is a membrane-permeating GSH precursor, to elevate the intracellular GSH level and GSH/GSSG ratio of mice. In vitro, gamma-GCE pretreatment of human monocytic THP-1 cells elevated the GSH/GSSG ratio and enhanced IL-12(p70) production induced by LPS. In the mouse asthma model, intraperitoneal injection of gamma-GCE elevated the GSH/GSSG ratio of lung tissue and reduced AHR. gamma-GCE reduced levels of IL-4, IL-5, IL-10, and the chemokines eotaxin and RANTES (regulated on activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid, whereas it enhanced the production of IL-12 and IFN-gamma. Histologically, gamma-GCE suppressed eosinophils infiltration. Interestingly, we also found that gamma-GCE directly inhibited chemokine-induced eosinophil chemotaxis without affecting eotaxin receptor chemokine receptor 3 (CCR3) expressions. Taken together, these findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio by gamma-GCE, ameliorate bronchial asthma by altering the Th1/Th2 imbalance through IL-12 production from APC and suppressing chemokine production and eosinophil migration itself.

  12. Role of the parasympathetic nervous system in airway hyperresponsiveness after ozone inhalation

    SciTech Connect

    Jones, G.L.; Lane, C.G.; Manning, P.J.; O'Byrne, P.M.

    1987-09-01

    Airway hyperresponsiveness develops in dogs after ozone inhalation. This study examined the role of the parasympathetic nervous system in ozone-induced airway hyperresponsiveness in dogs. Dose-response curves to acetylcholine (n = 8) and histamine (n = 4) were measured before and after exposure to ozone (3 ppm for 30 min). The provocative concentration of each agonist was measured on two randomly assigned days separated by at least 1 wk. On one day a control experiment was performed, and on the other day the dogs were pretreated with the ganglionic blocker hexamethonium bromide in doses that block ganglionic transmission. The acetylcholine provocative concentration decreased on the control day from 5.5 mg/ml (%SE 1.8) before ozone to 0.5 mg/ml (%SE 2.0) after ozone (P less than 0.0001). After pretreatment with hexamethonium the acetylcholine provocative concentration decreased from 9.0 mg/ml (%SE 1.8) before ozone to 1.0 mg/ml (%SE 2.0) after ozone (P = 0.002). The results were similar when histamine was used as the agonist. Therefore, ganglionic blockade does not prevent airway hyperresponsiveness after ozone inhalation, and a parasympathetic reflex mechanism is not responsible for airway hyperresponsiveness after ozone inhalation in dogs.

  13. Omega-3 Fatty acids and airway hyperresponsiveness in asthma.

    PubMed

    Mickleborough, Timothy D; Ionescu, Alina A; Rundell, Kenneth W

    2004-12-01

    Despite the progress that has been made in the treatment of asthma, the prevalence and burden of this disease has continued to increase. Exercise is a powerful trigger of asthma symptoms and reversible airflow obstruction and may result in the avoidance of physical activity by patients with asthma, resulting in detrimental consequences to their health. Approximately 90% of patients with asthma are hyperresponsive to exercise and experience exercise-induced bronchoconstriction (EIB). While pharmacologic treatment of asthma is usually highly effective, medications often have significant side-effects or exhibit tachyphylaxis. Alternative therapies for treatment (complementary medicine) that reduce the dose requirements of pharmacologic interventions would be beneficial, and could potentially reduce the public health burden of this disease. There is accumulating evidence that dietary modification has potential to influence the severity of asthma and reduce the prevalence and incidence of this condition. A possible contributing factor to the increased incidence of asthma in Western societies may be the consumption of a proinflammatory diet. In the typical Western diet, 20- to 25-fold more omega- 6 polyunsaturated fatty acids (PUFA) than omega-3 PUFA are consumed, which causes the release of proinflammatory arachidonic acid metabolites (leukotrienes and prostanoids). This review analyzes the existing literature on omega-3 PUFA supplementation as a potential modifier of airway hyperresponsiveness in asthma and includes studies concerning the efficacy of omega-3 PUFA supplementation in EIB. While clinical data evaluating the effect of omega-3 PUFA supplementation in asthma has been equivocal, it has recently been shown that pharmaceutical-grade fish oil (omega-3 PUFA) supplementation reduces airway hyperresponsiveness after exercise, medication use, and proinflammatory mediator generation in nonatopic elite athletes with EIB. These findings are provocative and suggest that

  14. Extrathoracic airway hyperresponsiveness as a mechanism of post infectious cough: case report

    PubMed Central

    Ryan, Nicole M; Gibson, Peter G

    2008-01-01

    Post-infectious cough is a common diagnosis in people with chronic cough. However, the specific infectious aetiology and cough mechanisms are seldom identified. We report a case of chronic cough after Mycoplasma pneumoniae lower respiratory tract infection with extrathoracic airway hyperresponsiveness as the cough mechanism. Extrathoracic airway hyperresponsiveness may be a common mechanism in post-infectious cough which may be useful both diagnostically and therapeutically since chronic cough with extrathoracic airway hyperresponsiveness responds to speech pathology treatment. PMID:18673583

  15. Strain-Dependent Genomic Factors Affect Allergen-Induced Airway Hyperresponsiveness in Mice

    PubMed Central

    Kelada, Samir N. P.; Wilson, Mark S.; Tavarez, Urraca; Kubalanza, Kari; Borate, Bhavesh; Whitehead, Greg S.; Maruoka, Shuichiro; Roy, Michelle G.; Olive, Michelle; Carpenter, Danielle E.; Brass, David M.; Wynn, Thomas A.; Cook, Donald N.; Evans, Christopher M.; Schwartz, David A.

    2011-01-01

    Asthma is etiologically and clinically heterogeneous, making the genomic basis of asthma difficult to identify. We exploited the strain-dependence of a murine model of allergic airway disease to identify different genomic responses in the lung. BALB/cJ and C57BL/6J mice were sensitized with the immunodominant allergen from the Dermatophagoides pteronyssinus species of house dust mite (Der p 1), without exogenous adjuvant, and the mice then underwent a single challenge with Der p 1. Allergic inflammation, serum antibody titers, mucous metaplasia, and airway hyperresponsiveness were evaluated 72 hours after airway challenge. Whole-lung gene expression analyses were conducted to identify genomic responses to allergen challenge. Der p 1–challenged BALB/cJ mice produced all the key features of allergic airway disease. In comparison, C57BL/6J mice produced exaggerated Th2-biased responses and inflammation, but exhibited an unexpected decrease in airway hyperresponsiveness compared with control mice. Lung gene expression analysis revealed genes that were shared by both strains and a set of down-regulated genes unique to C57BL/6J mice, including several G-protein–coupled receptors involved in airway smooth muscle contraction, most notably the M2 muscarinic receptor, which we show is expressed in airway smooth muscle and was decreased at the protein level after challenge with Der p 1. Murine strain–dependent genomic responses in the lung offer insights into the different biological pathways that develop after allergen challenge. This study of two different murine strains demonstrates that inflammation and airway hyperresponsiveness can be decoupled, and suggests that the down-modulation of expression of G-protein–coupled receptors involved in regulating airway smooth muscle contraction may contribute to this dissociation. PMID:21378263

  16. Prevention of allergic airway hyperresponsiveness and remodeling in mice by Astragaliradix Antiasthmatic decoction

    PubMed Central

    2013-01-01

    Background Astragali radix Antiasthmatic Decoction (AAD), a traditional Chinese medication, is found effective in treating allergic diseases and chronic cough. The purpose of this study is to determine whether this medication could suppress allergen-induced airway hyperresponsiveness (AHR) and remodeling in mice, and its possible mechanisms. Methods A mouse model of chronic asthma was used to investigate the effects of AAD on the airway lesions. Mice were sensitized and challenged with ovalbumin (OVA), and the extent of AHR and airway remodeling were characterized. Cells and cytokines in the bronchoalveolar lavage fluid (BALF) were examined. Results AAD treatment effectively decreased OVA-induced AHR, eosinophilic airway inflammation, and collagen deposition around the airway. It significantly reduced the levels of IL-13 and TGF-β1, but exerted inconsiderable effect on INF-γ and IL-10. Conclusions AAD greatly improves the symptoms of allergic airway remodeling probably through inhibition of Th2 cytokines and TGF-β1. PMID:24367979

  17. Physiological Mechanisms of Airway Hyperresponsiveness in Obese Asthma.

    PubMed

    Bates, Jason H T

    2016-05-01

    Obesity affects the incidence and severity of asthma in at least two major phenotypes: an early-onset allergic (EOA) form that is complicated by obesity and a late-onset nonallergic (LONA) form that occurs only in the setting of obesity. Both groups exhibit airway hyperresponsiveness to methacholine challenge but exhibit differential effects of weight loss. Measurements of lung function in patients with LONA obese asthma suggest that this group of individuals may simply be those unlucky enough to have airways that are more compliant than average, and that this leads to airway hyperresponsiveness at the reduced lung volumes caused by excess adipose tissue around the chest wall. In contrast, the frequent exacerbations in those with EOA obese asthma can potentially be explained by episodic inflammatory thickening of the airway wall synergizing with obesity-induced reductions in lung volume. These testable hypotheses are based on the strong likelihood that LONA and EOA obese asthma are distinct diseases. Both, however, may benefit from targeted therapeutics that impose elevations in lung volume.

  18. Syk Regulates Neutrophilic Airway Hyper-Responsiveness in a Chronic Mouse Model of Allergic Airways Inflammation

    PubMed Central

    Juvet, Stephen; Scott, Jeremy A.; Chow, Chung-Wai

    2017-01-01

    Background Asthma is a chronic inflammatory disease characterized by airways hyper-responsiveness (AHR), reversible airway obstruction, and airway inflammation and remodeling. We previously showed that Syk modulates methacholine-induced airways contractility in naïve mice and in mice with allergic airways inflammation. We hypothesize that Syk plays a role in the pathogenesis of AHR; this was evaluated in a chronic 8-week mouse model of house dust mite (HDM)-induced allergic airways inflammation. Methods We used the Sykflox/flox//rosa26CreERT2 conditional Syk knock-out mice to assess the role of Syk prior to HDM exposure, and treated HDM-sensitized mice with the Syk inhibitor, GSK143, to evaluate its role in established allergic airways inflammation. Respiratory mechanics and methacholine (MCh)-responsiveness were assessed using the flexiVent® system. Lungs underwent bronchoalveolar lavage to isolate inflammatory cells or were frozen for determination of gene expression in tissues. Results MCh-induced AHR was observed following HDM sensitization in the Syk-intact (Sykflox/flox) and vehicle-treated BALB/c mice. MCh responsiveness was reduced to control levels in HDM-sensitized Sykdel/del mice and in BALB/c and Sykflox/flox mice treated with GSK143. Both Sykdel/del and GSK143-treated mice mounted appropriate immune responses to HDM, with HDM-specific IgE levels that were comparable to Sykflox/flox and vehicle-treated BALB/c mice. HDM-induced increases in bronchoalveolar lavage cell counts were attenuated in both Sykdel/del and GSK143-treated mice, due primarily to decreased neutrophil recruitment. Gene expression analysis of lung tissues revealed that HDM-induced expression of IL-17 and CXCL-1 was significantly attenuated in both Sykdel/del and GSK143-treated mice. Conclusion Syk inhibitors may play a role in the management of neutrophilic asthma. PMID:28107345

  19. [The research on the airway hyperresponsiveness and IOS airway resistance index of industrial area resident].

    PubMed

    Xu, Jin; Wang, Zhen; Sun, Hongcun

    2015-09-01

    To study airway reactivity and impulse oscillation (IOS)-measured airway resistance indicators of residents of Zhenhai industrial area in Ningbo city. In the form of follow-up, both. airway reactivity and respiratory functions of populations in Zhenhai industrial zone (n = 215) and urban (n = 203) were measured, comparing difference degree between different regions. Ninty-five of 215 cases in industrial area were identified as suspected airway hyperresponsiveness, but only 43 of 203 cases were in urban areas. Forty-seven of 95 cases (49.5%) in industrial zone were positive, while only 14 cases (32.6%) in urban. The proportions of people in the two regions on different types of airway hyperresponsiveness were significantly different (P < 0.01). All airway resistance indexes of urban populations were significantly lower than that of industrial zone (P < 0.05). The prevalence of airway hyperresponsiveness and IOS airway resistance aspects of industrial area residents was higher than that of urban residents. Monitoring and evaluating the airway diseases, inflammatory lesions and respiratory function in the region were good for understanding the severe pollution in the local area in certain significance.

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

    PubMed Central

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

    2010-01-01

    The use of silver in the past demonstrated the certain antimicrobial activity, though this has been replaced by other treatments. However, nanotechnology has provided a way of producing pure silver nanoparticles, and it shows cytoprotective activities and possible pro-healing properties. But, the mechanism of silver nanoparticles remains unknown. This study was aimed to investigate the effects of silver nanoparticles on bronchial inflammation and hyperresponsiveness. We used ovalbumin (OVA)-inhaled female C57BL/6 mice to evaluate the roles of silver nanoparticles and the related molecular mechanisms in allergic airway disease. In this study with an OVA-induced murine model of allergic airway disease, we found that the increased inflammatory cells, airway hyperresponsiveness, increased levels of IL-4, IL-5, and IL-13, and the increased NF-κB levels in lungs after OVA inhalation were significantly reduced by the administration of silver nanoparticles. In addition, we have also found that the increased intracellular reactive oxygen species (ROS) levels in bronchoalveolar lavage fluid after OVA inhalation were decreased by the administration of silver nanoparticles. These results indicate that silver nanoparticles may attenuate antigen-induced airway inflammation and hyperresponsiveness. And antioxidant effect of silver nanoparticles could be one of the molecular bases in the murine model of asthma. These findings may provide a potential molecular mechanism of silver nanoparticles in preventing or treating asthma. PMID:20957173

  1. Airway Hyperresponsiveness in Children With Sickle Cell Anemia

    PubMed Central

    Field, Joshua J.; Stocks, Janet; Kirkham, Fenella J.; Rosen, Carol L.; Dietzen, Dennis J.; Semon, Trisha; Kirkby, Jane; Bates, Pamela; Seicean, Sinziana; DeBaun, Michael R.; Redline, Susan

    2011-01-01

    Background: The high prevalence of airway hyperresponsiveness (AHR) among children with sickle cell anemia (SCA) remains unexplained. Methods: To determine the relationship between AHR, features of asthma, and clinical characteristics of SCA, we conducted a multicenter, prospective cohort study of children with SCA. Dose response slope (DRS) was calculated to describe methacholine responsiveness, because 30% of participants did not achieve a 20% decrease in FEV1 after inhalation of the highest methacholine concentration, 25 mg/mL. Multiple linear regression analysis was done to identify independent predictors of DRS. Results: Methacholine challenge was performed in 99 children with SCA aged 5.6 to 19.9 years (median, 12.8 years). Fifty-four (55%) children had a provocative concentration of methacholine producing a 20% decrease in FEV1 < 4 mg/mL. In a multivariate analysis, independent associations were found between increased methacholine responsiveness and age (P < .001), IgE (P = .009), and lactate dehydrogenase (LDH) levels (P = .005). There was no association between methacholine responsiveness and a parent report of a doctor diagnosis of asthma (P = .986). Other characteristics of asthma were not associated with methacholine responsiveness, including positive skin tests to aeroallergens, exhaled nitric oxide, peripheral blood eosinophil count, and pulmonary function measures indicating airflow obstruction. Conclusions: In children with SCA, AHR to methacholine is prevalent. Younger age, serum IgE concentration, and LDH level, a marker of hemolysis, are associated with AHR. With the exception of serum IgE, no signs or symptoms of an allergic diathesis are associated with AHR. Although the relationship between methacholine responsiveness and LDH suggests that factors related to SCA may contribute to AHR, these results will need to be validated in future studies. PMID:20724735

  2. Arsenic trioxide, a potent inhibitor of NF-κB, abrogates allergen-induced airway hyperresponsiveness and inflammation

    PubMed Central

    Zhou, Lin-Fu; Zhu, Yi; Cui, Xue-Fan; Xie, Wei-Ping; Hu, Ai-Hua; Yin, Kai-Sheng

    2006-01-01

    Background Overactivation of nuclear factor κB (NF-κB) orchestrates airway eosinophilia, but does not dampen airway hyperresponsiveness in asthma. NF-κB repression by arsenic trioxide (As2O3) contributes to apoptosis of eosinophils (EOS) in airways. Here we provide evidence that As2O3 abrogates allergen (OVA)-induced airway eosinophilia by modulating the expression of IκBα, an NF-κB inhibitory protein, and decreases the airway hyperresponsiveness. Methods Using a murine model of asthma, the airway hyperresponsiveness was conducted by barometric whole-body plethysmography. Airway eosinophilia, OVA-specific IgE in serum, and chemokine eotaxin and RANTES (regulated upon activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid were measured by lung histology, Diff-Quick staining, and ELISA. Chemokine-induced EOS chemotactic activity was evaluated using EOS chemotaxis assay. Electrophoretic mobility shift assay and Western blot analysis were performed to assess pulmonary NF-κB activation and IκBα expression, respectively. Results As2O3 attenuated the allergen-induced serum IgE, chemokine expression of eotaxin and RANTES, and the EOS recruitment in bronchoalveolar lavage fluid, which is associated with an increased IκBα expression as well as a decreased NF-κB activation. Also, As2O3 suppressed the chemotaxis of EOS dose-dependently in vitro. Additionally, As2O3 significantly ameliorated the allergen-driven airway hyperresponsiveness, the cardinal feature underlying asthma. Conclusion These findings demonstrate an essential role of NF-κB in airway eosinophilia, and illustrate a potential dissociation between airway inflammation and hyperresponsiveness. As2O3 likely exerts its broad anti-inflammatory effects by suppression of NF-κB activation through augmentation of IκBα expression in asthma. PMID:17178007

  3. Arsenic trioxide, a potent inhibitor of NF-kappaB, abrogates allergen-induced airway hyperresponsiveness and inflammation.

    PubMed

    Zhou, Lin-Fu; Zhu, Yi; Cui, Xue-Fan; Xie, Wei-Ping; Hu, Ai-Hua; Yin, Kai-Sheng

    2006-12-20

    Overactivation of nuclear factor kappaB (NF-kappaB) orchestrates airway eosinophilia, but does not dampen airway hyperresponsiveness in asthma. NF-kappaB repression by arsenic trioxide (As2O3) contributes to apoptosis of eosinophils (EOS) in airways. Here we provide evidence that As2O3 abrogates allergen (OVA)-induced airway eosinophilia by modulating the expression of IkappaBalpha, an NF-kappaB inhibitory protein, and decreases the airway hyperresponsiveness. Using a murine model of asthma, the airway hyperresponsiveness was conducted by barometric whole-body plethysmography. Airway eosinophilia, OVA-specific IgE in serum, and chemokine eotaxin and RANTES (regulated upon activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid were measured by lung histology, Diff-Quick staining, and ELISA. Chemokine-induced EOS chemotactic activity was evaluated using EOS chemotaxis assay. Electrophoretic mobility shift assay and Western blot analysis were performed to assess pulmonary NF-kappaB activation and IkappaBalpha expression, respectively. As2O3 attenuated the allergen-induced serum IgE, chemokine expression of eotaxin and RANTES, and the EOS recruitment in bronchoalveolar lavage fluid, which is associated with an increased IkappaBalpha expression as well as a decreased NF-kappaB activation. Also, As2O3 suppressed the chemotaxis of EOS dose-dependently in vitro. Additionally, As2O3 significantly ameliorated the allergen-driven airway hyperresponsiveness, the cardinal feature underlying asthma. These findings demonstrate an essential role of NF-kappaB in airway eosinophilia, and illustrate a potential dissociation between airway inflammation and hyperresponsiveness. As2O3 likely exerts its broad anti-inflammatory effects by suppression of NF-kappaB activation through augmentation of IkappaBalpha expression in asthma.

  4. Airway hyperresponsiveness; smooth muscle as the principal actor

    PubMed Central

    Lauzon, Anne-Marie; Martin, James G.

    2016-01-01

    Airway hyperresponsiveness (AHR) is a defining characteristic of asthma that refers to the capacity of the airways to undergo exaggerated narrowing in response to stimuli that do not result in comparable degrees of airway narrowing in healthy subjects. Airway smooth muscle (ASM) contraction mediates airway narrowing, but it remains uncertain as to whether the smooth muscle is intrinsically altered in asthmatic subjects or is responding abnormally as a result of the milieu in which it sits. ASM in the trachea or major bronchi does not differ in its contractile characteristics in asthmatics, but the more pertinent peripheral airways await complete exploration. The mass of ASM is increased in many but not all asthmatics and therefore cannot be a unifying hypothesis for AHR, although when increased in mass it may contribute to AHR. The inability of a deep breath to reverse or prevent bronchial narrowing in asthma may reflect an intrinsic difference in the mechanisms that lead to softening of contracted ASM when subjected to stretch. Cytokines such as interleukin-13 and tumor necrosis factor-α promote a more contractile ASM phenotype. The composition and increased stiffness of the matrix in which ASM is embedded promotes a more proliferative and pro-inflammatory ASM phenotype, but the expected dedifferentiation and loss of contractility have not been shown. Airway epithelium may drive ASM proliferation and/or molecular remodeling in ways that may lead to AHR. In conclusion, AHR is likely multifactorial in origin, reflecting the plasticity of ASM properties in the inflammatory environment of the asthmatic airway. PMID:26998246

  5. Airway hyperresponsiveness in asthma: mechanisms, clinical significance, and treatment.

    PubMed

    Brannan, John D; Lougheed, M Diane

    2012-01-01

    Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of asthma. Bronchial provocation tests (BPTs) are objective tests for AHR that are clinically useful to aid in the diagnosis of asthma in both adults and children. BPTs can be either "direct" or "indirect," referring to the mechanism by which a stimulus mediates bronchoconstriction. Direct BPTs refer to the administration of pharmacological agonist (e.g., methacholine or histamine) that act on specific receptors on the airway smooth muscle. Airway inflammation and/or airway remodeling may be key determinants of the response to direct stimuli. Indirect BPTs are those in which the stimulus causes the release of mediators of bronchoconstriction from inflammatory cells (e.g., exercise, allergen, mannitol). Airway sensitivity to indirect stimuli is dependent upon the presence of inflammation (e.g., mast cells, eosinophils), which responds to treatment with inhaled corticosteroids (ICS). Thus, there is a stronger relationship between indices of steroid-sensitive inflammation (e.g., sputum eosinophils, fraction of exhaled nitric oxide) and airway sensitivity to indirect compared to direct stimuli. Regular treatment with ICS does not result in the complete inhibition of responsiveness to direct stimuli. AHR to indirect stimuli identifies individuals that are highly likely to have a clinical improvement with ICS therapy in association with an inhibition of airway sensitivity following weeks to months of treatment with ICS. To comprehend the clinical utility of direct or indirect stimuli in either diagnosis of asthma or monitoring of therapeutic intervention requires an understanding of the underlying pathophysiology of AHR and mechanisms of action of both stimuli.

  6. Bronchial hyperresponsiveness in the assessment of asthma control: Airway hyperresponsiveness in asthma: its measurement and clinical significance.

    PubMed

    Brannan, John D

    2010-08-01

    The two key pathophysiologic features of asthma are bronchial hyperresponsiveness (BHR) and airway inflammation. Symptoms and lung function are the most accessible clinical markers for the diagnosis of asthma as well as for assessing asthma control using the most effective treatment of asthma, inhaled corticosteroids (ICS). However, BHR and inflammation usually take longer to resolve using ICS compared with symptoms and lung function. BHR can be assessed using "direct" stimuli that act on the airway smooth muscle (eg, methacholine) or "indirect" stimuli that require the presence of airway inflammation (eg, exercise, osmotic stimuli). Although there are practical limitations in using BHR to assess asthma control, efforts have been made to make BHR more accessible and standardized. Some studies have demonstrated that treatment aimed to decrease BHR with direct stimuli can lead to improved asthma control; however, it often results in the use of higher doses of ICS. Furthermore, BHR to direct stimuli does not usually resolve using ICS because of a fixed component. By contrast, BHR with an indirect stimulus indicates a responsive smooth muscle that occurs only in the presence of inflammation sensitive to ICS (eg, mast cells, eosinophils). BHR to indirect stimuli does resolve using ICS. Because ICS target both key pathophysiologic features of asthma, assessing indirect BHR in the presence of ICS will identify resolution or persistence of BHR and airway inflammation. This may provide a more clinically relevant marker for asthma control that may also lead to improving the clinical usefulness of ICS.

  7. Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness

    PubMed Central

    Song, Weifeng; Yu, Zhihong; Doran, Stephen F.; Ambalavanan, Namasivayam; Steele, Chad; Garantziotis, Stavros

    2015-01-01

    Exposure to chlorine (Cl2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1β, IL-10, IFN-γ, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl2 exposure. Cl2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl2-induced AHR was mitigated by treatment with inter-α-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl2-induced injury. These data emphasize the necessity for further research on the effects of Cl2 in vulnerable populations and the development of appropriate treatments. PMID:26071553

  8. ROCK insufficiency attenuates ozone-induced airway hyperresponsiveness in mice.

    PubMed

    Kasahara, David I; Mathews, Joel A; Park, Chan Y; Cho, Youngji; Hunt, Gabrielle; Wurmbrand, Allison P; Liao, James K; Shore, Stephanie A

    2015-10-01

    Ozone causes airway hyperresponsiveness (AHR) and pulmonary inflammation. Rho kinase (ROCK) is a key regulator of smooth muscle cell contraction and inflammatory cell migration. To determine the contribution of the two ROCK isoforms ROCK1 and ROCK2 to ozone-induced AHR, we exposed wild-type, ROCK1(+/-), and ROCK2(+/-) mice to air or ozone (2 ppm for 3 h) and evaluated mice 24 h later. ROCK1 or ROCK2 haploinsufficiency did not affect airway responsiveness in air-exposed mice but significantly reduced ozone-induced AHR, with a greater reduction in ROCK2(+/-) mice despite increased bronchoalveolar lavage (BAL) inflammatory cells in ROCK2(+/-) mice. Compared with wild-type mice, ozone-induced increases in BAL hyaluronan, a matrix protein implicated in ozone-induced AHR, were lower in ROCK1(+/-) but not ROCK2(+/-) mice. Ozone-induced increases in other inflammatory moieties reported to contribute to ozone-induced AHR (IL-17A, osteopontin, TNFα) were not different in wild-type vs. ROCK1(+/-) or ROCK2(+/-) mice. We also observed a dose-dependent reduction in ozone-induced AHR after treatment with the ROCK1/ROCK2 inhibitor fasudil, even though fasudil was administered after induction of inflammation. Ozone increased pulmonary expression of ROCK2 but not ROCK1 or RhoA. A ROCK2 inhibitor, SR3677, reduced contractile forces in primary human airway smooth muscle cells, confirming a role for ROCK2 in airway smooth muscle contraction. Our results demonstrate that ozone-induced AHR requires ROCK. Whereas ROCK1-dependent changes in hyaluronan may contribute to ROCK1's role in O3-induced AHR, the role of ROCK2 is downstream of inflammation, likely at the level of airway smooth muscle contraction. Copyright © 2015 the American Physiological Society.

  9. ROCK insufficiency attenuates ozone-induced airway hyperresponsiveness in mice

    PubMed Central

    Mathews, Joel A.; Park, Chan Y.; Cho, Youngji; Hunt, Gabrielle; Wurmbrand, Allison P.; Liao, James K.; Shore, Stephanie A.

    2015-01-01

    Ozone causes airway hyperresponsiveness (AHR) and pulmonary inflammation. Rho kinase (ROCK) is a key regulator of smooth muscle cell contraction and inflammatory cell migration. To determine the contribution of the two ROCK isoforms ROCK1 and ROCK2 to ozone-induced AHR, we exposed wild-type, ROCK1+/−, and ROCK2+/− mice to air or ozone (2 ppm for 3 h) and evaluated mice 24 h later. ROCK1 or ROCK2 haploinsufficiency did not affect airway responsiveness in air-exposed mice but significantly reduced ozone-induced AHR, with a greater reduction in ROCK2+/− mice despite increased bronchoalveolar lavage (BAL) inflammatory cells in ROCK2+/− mice. Compared with wild-type mice, ozone-induced increases in BAL hyaluronan, a matrix protein implicated in ozone-induced AHR, were lower in ROCK1+/− but not ROCK2+/− mice. Ozone-induced increases in other inflammatory moieties reported to contribute to ozone-induced AHR (IL-17A, osteopontin, TNFα) were not different in wild-type vs. ROCK1+/− or ROCK2+/− mice. We also observed a dose-dependent reduction in ozone-induced AHR after treatment with the ROCK1/ROCK2 inhibitor fasudil, even though fasudil was administered after induction of inflammation. Ozone increased pulmonary expression of ROCK2 but not ROCK1 or RhoA. A ROCK2 inhibitor, SR3677, reduced contractile forces in primary human airway smooth muscle cells, confirming a role for ROCK2 in airway smooth muscle contraction. Our results demonstrate that ozone-induced AHR requires ROCK. Whereas ROCK1-dependent changes in hyaluronan may contribute to ROCK1's role in O3-induced AHR, the role of ROCK2 is downstream of inflammation, likely at the level of airway smooth muscle contraction. PMID:26276827

  10. Effect of Dexamethasone and Fluticasone on Airway Hyperresponsiveness in Horses With Inflammatory Airway Disease.

    PubMed

    Léguillette, R; Tohver, T; Bond, S L; Nicol, J A; McDonald, K J

    2017-07-01

    Airway hyperresponsiveness (AWHR), expressed as hypersensitivity (PC75 RL ) or hyperreactivity (slope of the histamine dose-response curve), is a feature of inflammatory airway disease (IAD) or mild equine asthma in horses. Glucocorticoids are used empirically to treat IAD. To determine whether dexamethasone (DEX) (0.05 mg/kg IM q24h) and inhaled fluticasone (FLUT) (3,000 μg q12h) administered by inhalation are effective in decreasing AWHR, lung inflammation, and clinical signs in horses with IAD. A randomized crossover study design was used. Eight horses with IAD were assigned to a treatment group with either DEX or FLUT. Measured outcomes included lung mechanics during bronchoprovocative challenges, bronchoalveolar lavage fluid (BALF) cytology, and scoring of clinical signs during exercise. Dexamethasone and FLUT abolished the increase in RL by 75% at any histamine bronchoprovocative dose in all horses after the first week of treatment. However, after 2 weeks of FLUT treatment, 1 horse redeveloped hypersensitivity. There was a significant decrease in the number of lymphocytes after treatment with both DEX and FLUT (P = .039 for both) but no significant differences in other BALF cell types or total cell counts (P > .05). There was no difference in the scoring of the clinical signs during each treatment and washout period (P > .05). Both DEX and FLUT treatments significantly inhibit airway hypersensitivity and hyperreactivity in horses with IAD. There are no significant effects on the clinical signs or the number of inflammatory cells (except lymphocytes) in BALF. The treatments have no residual effect 3 weeks after discontinuation. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  11. Acid aspiration-induced airways hyperresponsiveness in mice

    PubMed Central

    Leclair, Timothy R.; von Reyn, Jessica; Larrabee, Yuna C.; Cloutier, Mary E.; Irvin, Charles G.; Bates, Jason H. T.

    2009-01-01

    The role of gastroesophageal reflux and micro-aspiration as a trigger of airways hyperresponsiveness (AHR) in patients with asthma is controversial. The role of acid reflux and aspiration as a direct cause of AHR in normal subjects is also unclear. We speculated that aspiration of a weak acid with a pH (1.8) equivalent to the upper range of typical gastric contents would lead to AHR in naive mice. We further speculated that modest reductions in aspirate acidity to a level expected during gastric acid suppression therapy (pH 4.0) would impede aspiration-induced AHR. BALB/c female mice were briefly anesthetized with isoflurane and allowed to aspirate 75 μl of saline with HCl (pH 1.8, 4.0, or 7.4) or underwent sham aspiration. Mice were re-anesthetized 2 or 24 h later, underwent tracheostomy, and were coupled to a mechanical ventilator. Forced oscillations were used to periodically measure respiratory impedance (Zrs) following aerosol delivery of saline and increasing doses of methacholine to measure for AHR. Values for elastance (H), airways resistance (RN), and tissue damping (G) were derived from Zrs. Aspirate pH of 1.8 led to a significant overall increase in peak RN, G, and H compared with pH 4.0 and 7.4 at 2 and 24 h. Differences between pH 7.4 and 4.0 were not significant. In mice aspirating pH 1.8 compared with controls, airway lavage fluid contained more neutrophils, higher protein, and demonstrated higher permeability. We conclude that acid aspiration triggers an acute AHR, driven principally by breakdown of epithelial barrier integrity within the airways. PMID:19797689

  12. Clinical implications of airway hyper-responsiveness in COPD

    PubMed Central

    Scichilone, Nicola; Battaglia, Salvatore; La Sala, Alba; Bellia, Vincenzo

    2006-01-01

    COPD represents one of the leading causes of mortality in the general population. This study aimed at evaluating the relationship between airway hyperresponsiveness (AHR) and COPD and its relevance for clinical practice. We performed a MEDLINE search that yielded a total of 1919 articles. Eligible studies were defined as articles that addressed specific aspects of AHR in COPD, such as prevalence, pathogenesis, or prognosis. AHR appears to be present in at least one out of two individuals with COPD. The occurrence of AHR in COPD is influenced by multiple mechanisms, among which impairment of factors that oppose airway narrowing plays an important role. The main determinants of AHR are reduction in lung function and smoking status. We envision a dual role of AHR: in suspected COPD, specific determinants of AHR, such as reactivity and the plateau response, may help the physician to discriminate COPD from asthma; in definite COPD, AHR may be relevant for the prognosis. Indeed, AHR is an independent predictor of mortality in COPD patients. Smoking cessation has been shown to reduce AHR. Further studies are needed to elucidate whether this functional change is associated with improvement in lung function and respiratory symptoms. PMID:18046902

  13. Proximity to major roadways is a risk factor for airway hyper-responsiveness in adults

    PubMed Central

    Riley, Shannon; Wallace, Julie; Nair, Parameswaran

    2012-01-01

    BACKGROUND: Proximity to major roads is reported to be associated with asthma and airway hyper-responsiveness in children. Similar studies using objective measurements in adults are not available in Canada. OBJECTIVE: To test the hypothesis that adult asthmatic patients who live close to major roads and highways in an urban environment are at a risk of moderate to severe airway hyper-responsiveness. METHODS: Airway responsiveness was determined using methacholine bronchial provocation (PC20) tests in a cohort of 2625 patients who attended an outpatient clinic in Hamilton, Ontario. Patient addresses were geocoded in a geographic information system to determine proximity to major roads and highways. Multivariate linear and multinomial regression analyses were used to assess whether proximity to roads was a risk factor for airway hyper-responsiveness as measured by PC20 methacholine. RESULTS: Patients who lived within 200 m of a major road had increased odds (OR 1.38 [95% CI 1.04 to 1.85]) of having moderate airway hyper-responsiveness (0.25 mg/mL 16 mg/mL). Spatial analysis also revealed that the majority of patients with severe airway hyper-responsiveness lived within the urban core of the city while those with moderate to mild hyper-responsiveness were also dispersed in rural areas. CONCLUSIONS: In an adult population of patients attending an outpatient respiratory clinic in Hamilton, living close to major roadways was associated with an increased risk of moderate airway hyper-responsiveness. This correlation suggests that exposure to traffic emissions may provoke the pathology of airway hyper-responsiveness leading to variable airflow obstruction. PMID:22536577

  14. Dose-response relationship of ozone-induced airway hyperresponsiveness in unanesthetized guinea pigs

    SciTech Connect

    Nishikawa, M.; Suzuki, S.; Ikeda, H.; Fukuda, T.; Suzuki, J.; Okubo, T. )

    1990-06-01

    The effect of ozone dose (the product of ozone concentration and exposure time) on airway responsiveness was examined in unanesthetized, spontaneously breathing guinea pigs. Airway responsiveness was assessed by measuring specific airway resistance (sRaw) as a function of increasing concentration of inhaled methacholine (Mch) aerosol (the concentration of Mch required in order to double the baseline sRaw: PC200Mch). The airway responsiveness was measured before and at 5 min, 5 h, and 24 h after exposure. A 30-min exposure to 1 ppm ozone (dose 30 ppm.min) did not change PC200Mch at any time after exposure. Both a 90-min exposure to 1 ppm ozone and a 30-min exposure to 3 ppm ozone, which are identical in terms of ozone dose (90 ppm.min), decreased PC200Mch to a similar degree. A 120-min exposure to 3 ppm ozone (360 ppm.min) produced a much greater decrease of PC200Mch at 5 min and 5 h after exposure, compared with low-dose exposure. There was a significant correlation between ozone dose and the change in airway responsiveness. In all groups, the baseline sRaw was increased by approximately 50% at 5 min after exposure, but there was no correlation between the changes in PC200Mch and the baseline sRaw. This study suggests that ozone-induced airway hyperresponsiveness in guinea pigs is closely related to ozone dose.

  15. Water-soluble cooling lubricants induce airway hyperresponsiveness in rabbits.

    PubMed

    Marek, W; Mensing, T; Fricke, H; Baur, X

    1998-01-01

    Airway hyperresponsiveness (AHR) to water-soluble cooling lubricants (CL) induced by aerosol administered by tracheal tube was studied in a rabbit model of occupational lung disease. Two commercial CL were examined: the first was of the boric acid amine ester type without biozide (CL-BAE), the second was of the sulfonate type with biozide (CL-SB). 50, 5.0 or 0.5 mg/m3 CL was administered over a period of twice 2 h to six different groups of rabbits. Airway responsiveness (AR) to aerosols of 0.2% and 2.0% acetylcholine solution (ACH) was measured before and after each exposure to CL. A control group A of nine animals not exposed to CL showed no significant respiratory responses following inhalation of 0.2% ACH for 1 min. Conversely, inhalation of 2.0% ACH almost doubled the dynamic elastance (Edyn) in the ACH challenge test in this animal group. Airway resistance (RI), Edyn, slope of inspiratory pressure generation (delta Pes/tI), arterial pressure (Pa) and arterial blood gas tensions (PaO2, PaCO2) were not significantly altered during and after exposures to CL. However, after CL-BAE inhalation of 50 and 5 mg/m3 over 4 h, the amplitude of the ACH-induced airway obstruction indicated by the changes in Edyn rose significantly to almost five times the control response before exposure (group C, D, p < 0.005). Similar changes in RI and delta Pes/tI were obtained. After inhalation of 0.5 mg/m3 CL-BAE (group D), no significant changes in AR were observed. Similar to CL-BAE inhalation of 50 mg/m3, CL-SB caused enlarged AR in the ACH challenge test (group E), whereas no significant changes were found after exposure to 5.0 and 0.5 mg/m3 in groups F and G. In summary, CL aerosols with and without biozide in the range of 50 and 5 mg/m3 applied via tracheal tubes increased AR to ACH within 4 h of exposure in a time- and concentration-dependent manner. It has to be assumed that this augmented AR indicates an increased risk of developing lubricant-induced obstructive lung diseases.

  16. Pituitary Adenylate Cyclase-Activating Polypeptide Reverses Ammonium Metavanadate-Induced Airway Hyperresponsiveness in Rats

    PubMed Central

    Tlili, Mounira; Rouatbi, Sonia; Sriha, Badreddine; Ben Rhouma, Khémais; Sakly, Mohsen; Vaudry, David; Wurtz, Olivier; Tebourbi, Olfa

    2015-01-01

    The rate of atmospheric vanadium is constantly increasing due to fossil fuel combustion. This environmental pollution favours vanadium exposure in particular to its vanadate form, causing occupational bronchial asthma and bronchitis. Based on the well admitted bronchodilator properties of the pituitary adenylate cyclase-activating polypeptide (PACAP), we investigated the ability of this neuropeptide to reverse the vanadate-induced airway hyperresponsiveness in rats. Exposure to ammonium metavanadate aerosols (5 mg/m3/h) for 15 minutes induced 4 hours later an array of pathophysiological events, including increase of bronchial resistance and histological alterations, activation of proinflammatory alveolar macrophages, and increased oxidative stress status. Powerfully, PACAP inhalation (0.1 mM) for 10 minutes alleviated many of these deleterious effects as demonstrated by a decrease of bronchial resistance and histological restoration. PACAP reduced the level of expression of mRNA encoding inflammatory chemokines (MIP-1α, MIP-2, and KC) and cytokines (IL-1α and TNF-α) in alveolar macrophages and improved the antioxidant status. PACAP reverses the vanadate-induced airway hyperresponsiveness not only through its bronchodilator activity but also by counteracting the proinflammatory and prooxidative effects of the metal. Then, the development of stable analogs of PACAP could represent a promising therapeutic alternative for the treatment of inflammatory respiratory disorders. PMID:26199679

  17. Involvement of PTEN in airway hyperresponsiveness and inflammation in bronchial asthma.

    PubMed

    Kwak, Yong-Geun; Song, Chang H; Yi, Ho K; Hwang, Pyoung H; Kim, Jong-Suk; Lee, Kyung S; Lee, Yong C

    2003-04-01

    Phosphatase and tensin homologue deleted on chromosome ten (PTEN) is part of a complex signaling system that affects a variety of important cell functions. PTEN blocks the action of PI3K by dephosphorylating the signaling lipid phosphatidylinositol 3,4,5-triphosphate. We have used a mouse model for asthma to determine the effect of PI3K inhibitors and PTEN on allergen-induced bronchial inflammation and airway hyperresponsiveness. PI3K activity increased significantly after allergen challenge. PTEN protein expression and PTEN activity were decreased in OVA-induced asthma. Immunoreactive PTEN localized in epithelial layers around the bronchioles in control mice. However, this immunoreactive PTEN dramatically disappeared in allergen-induced asthmatic lungs. The increased IL-4, IL-5, and eosinophil cationic protein levels in bronchoalveolar lavage fluids after OVA inhalation were significantly reduced by the intratracheal administration of PI3K inhibitors or adenoviruses carrying PTEN cDNA (AdPTEN). Intratracheal administration of PI3K inhibitors or AdPTEN remarkably reduced bronchial inflammation and airway hyperresponsiveness. These findings indicate that PTEN may play a pivotal role in the pathogenesis of the asthma phenotype.

  18. Hyperresponsiveness in the human nasal airway: new targets for the treatment of allergic airway disease.

    PubMed Central

    Turner, P J; Foreman, J C

    1999-01-01

    Allergic rhinitis is a condition which affects over 15% of the population in the United Kingdom. The pathological process involves two stages: nasal inflammation, and the development of nasal airway hyperresponsiveness (AHR) to allergen and a number of other stimuli. This results in the amplification of any subsequent allergic reaction, contributing to the chronic allergic state. A number of different hypotheses have been proposed to explain the underlying mechanism of AHR, including a role for eosinophil-derived proteins, free radicals and neuropeptides. While there may be a number of independent pathways which can result in AHR, evidence obtained from both animal models and in vivo experiments in humans indicate that some mediators may interact with one another, resulting in AHR. Further research into these interactions may open new avenues for the pharmacological treatment of chronic allergic rhinitis, and possibly other allergic airway diseases. PMID:10704051

  19. Nebulized lidocaine blunts airway hyper-responsiveness in experimental feline asthma.

    PubMed

    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 <0.05 significant). No adverse effects were noted. In healthy cats, lidocaine did not significantly alter BALF eosinophilia or the EC200Raw. There was no difference in %BALF 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.

  20. Does the length dependency of airway smooth muscle force contribute to airway hyperresponsiveness?

    PubMed

    Lee-Gosselin, Audrey; Pascoe, Chris D; Couture, Christian; Paré, Peter D; Bossé, Ynuk

    2013-11-01

    Airway wall remodeling and lung hyperinflation are two typical features of asthma that may alter the contractility of airway smooth muscle (ASM) by affecting its operating length. The aims of this study were as follows: 1) to describe in detail the "length dependency of ASM force" in response to different spasmogens; and 2) to predict, based on morphological data and a computational model, the consequence of this length dependency of ASM force on airway responsiveness in asthmatic subjects who have both remodeled airway walls and hyperinflated lungs. Ovine tracheal ASM strips and human bronchial rings were isolated and stimulated to contract in response to increasing concentrations of spasmogens at three different lengths. Ovine tracheal strips were more sensitive and generated greater force at longer lengths in response to acetylcholine (ACh) and K(+). Equipotent concentrations of ACh were approximately a log less for ASM stretched by 30% and approximately a log more for ASM shortened by 30%. Similar results were observed in human bronchi in response to methacholine. Morphometric and computational analyses predicted that the ASM of asthmatic subjects may be elongated by 6.6-10.4% (depending on airway generation) due to remodeling and/or hyperinflation, which could increase ACh-induced force by 1.8-117.8% (depending on ASM length and ACh concentration) and enhance the increased resistance to airflow by 0.4-4,432.8%. In conclusion, elongation of ASM imposed by airway wall remodeling and/or hyperinflation may allow ASM to operate at a longer length and to consequently generate more force and respond to lower concentration of spasmogens. This phenomenon could contribute to airway hyperresponsiveness.

  1. Role of TNF-α in virus-induced airway hyperresponsiveness and neuronal M2 muscarinic receptor dysfunction

    PubMed Central

    Nie, Zhenying; Scott, Gregory D; Weis, Patrick D; Itakura, Asako; Fryer, Allison D; Jacoby, David B

    2011-01-01

    BACKGROUND AND PURPOSE Infections with respiratory viruses induce exacerbations of asthma, increase acetylcholine release and potentiate vagally mediated bronchoconstriction by blocking inhibitory M2 muscarinic receptors on parasympathetic neurons. Here we test whether virus-induced M2 receptor dysfunction and airway hyperresponsiveness are tumour necrosis factor-alpha (TNF-α) dependent. EXPERIMENTAL APPROACH Guinea pigs were pretreated with etanercept or phosphate-buffered saline 24 h before intranasal infection with parainfluenza. Four days later, pulmonary inflation pressure, heart rate and blood pressure were measured. M2 receptor function was assessed by the potentiation by gallamine (an M2 receptor antagonist) of bronchoconstriction caused by electrical stimulation of the vagus nerves and measured as increased pulmonary inflation pressure. Human airway epithelial cells were infected with influenza and TNF-α concentration in supernatant was measured before supernatant was applied to human neuroblastoma cells. M2 receptor expression in these neuroblastoma cells was measured by qRT-PCR. KEY RESULTS Influenza-infected animals were hyperresponsive to vagal stimulation but not to intravenous ACh. Gallamine did not potentiate vagally induced bronchoconstriction in virus-infected animals, indicating M2 receptor dysfunction. Etanercept prevented virus-induced airway hyperresponsiveness and M2 receptor dysfunction, without changing lung viral titres. Etanercept caused a non-significant decrease in total cells, macrophages and neutrophils in bronchoalveolar lavage. Influenza infection significantly increased TNF-α release from isolated epithelial cells, sufficient to decrease M2 receptors in neuroblastoma cells. This ability of supernatants from infected epithelial cells to inhibit M2 receptor expression was blocked by etanercept. CONCLUSIONS AND IMPLICATIONS TNF-α is a key mediator of virus-induced M2 muscarinic receptor dysfunction and airway hyperresponsiveness

  2. The effect of ozone on inflammatory cell infiltration and airway hyperresponsiveness in the guinea pig lung

    SciTech Connect

    Schultheis, A.J.H.

    1993-01-01

    Inflammatory cells may contribute to the development of exaggerated bronchoconstrictor responses since a persistent link has been noted between pulmonary inflammation and airway hyperresponsiveness. In these studies guinea pigs were exposed to 2.0 ppm ozone for 4 hours, then immediately sacrificed or allowed to breathe filtered air for up to 14 days. Following ozone exposure there was an immediate massive neutrophil infiltration into the lung. Neutrophils in lung digest dropped to control values within 3-12 hours post-ozone but remained elevated in BAL fluid for 3 days. There was probable eosinophil degranulation within the first 24 hours post-ozone. Guinea pigs were hyperresponsive to vigal stimulation through 3 days post-ozone. Although they were also hyperresponsive to ACh, responses to MCh were unchanged. Neuronal M[sub 2] receptors were dysfunctional through 3 days post-ozone. There was resolution of inflammation, airway responsiveness, and neuronal M[sub 2] receptor function by 14 days post-exposure. This investigation has (1) confirmed an immediate lung inflammation following acute ozone exposure; (2) established that cells in BAL give a distorted reflection of inflammatory events in lung digest; (3) demonstrated that ozone-induced hyperresponsiveness is at least partially due to efferent cholinergic mechanisms without functional changes of muscarinic receptors on airway smooth muscle; (4) shown that ACh may not be an appropriate agent to test ozone-induced airway hyperresponsiveness; and (5) demonstrated that inhibitory neuronal M[sub 2] receptors are dysfunctional following ozone exposure. There was close linkage between these events, suggesting that they may be causally related. This investigation proposes a specific mechanism, dysfunction of neuronal M[sub 2] receptors, by which inflammatory cells could cause airway hyperresponsiveness following acute ozone exposure.

  3. Streptomycin treatment alters the intestinal microbiome, pulmonary T cell profile and airway hyperresponsiveness in a cystic fibrosis mouse model

    PubMed Central

    Bazett, Mark; Bergeron, Marie-Eve; Haston, Christina K.

    2016-01-01

    Cystic fibrosis transmembrane conductance regulator deficient mouse models develop phenotypes of relevance to clinical cystic fibrosis (CF) including airway hyperresponsiveness, small intestinal bacterial overgrowth and an altered intestinal microbiome. As dysbiosis of the intestinal microbiota has been recognized as an important contributor to many systemic diseases, herein we investigated whether altering the intestinal microbiome of BALB/c Cftrtm1UNC mice and wild-type littermates, through treatment with the antibiotic streptomycin, affects the CF lung, intestinal and bone disease. We demonstrate that streptomycin treatment reduced the intestinal bacterial overgrowth in Cftrtm1UNC mice and altered the intestinal microbiome similarly in Cftrtm1UNC and wild-type mice, principally by affecting Lactobacillus levels. Airway hyperresponsiveness of Cftrtm1UNC mice was ameliorated with streptomycin, and correlated with Lactobacillus abundance in the intestine. Additionally, streptomycin treated Cftrtm1UNC and wild-type mice displayed an increased percentage of pulmonary and mesenteric lymph node Th17, CD8 + IL-17+ and CD8 + IFNγ+ lymphocytes, while the CF-specific increase in respiratory IL-17 producing γδ T cells was decreased in streptomycin treated Cftrtm1UNC mice. Bone disease and intestinal phenotypes were not affected by streptomycin treatment. The airway hyperresponsiveness and lymphocyte profile of BALB/c Cftrtm1UNC mice were affected by streptomycin treatment, revealing a potential intestinal microbiome influence on lung response in BALB/c Cftrtm1UNC mice. PMID:26754178

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

    PubMed Central

    Spaziano, Giuseppe; Piegari, Elena; Matteis, Maria; Cappetta, Donato; Esposito, Grazia; Russo, Rosa; Tartaglione, Gioia; De Palma, Raffaele; Rossi, Francesco; D’Agostino, Bruno

    2016-01-01

    Background 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. Objectives To elucidate the mechanisms by which local administration of MSCs interferes with pathophysiological features of airway hyperresponsiveness in an animal model. Methods 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. Results 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. Conclusion 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

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

    PubMed

    Urbanek, Konrad; De Angelis, Antonella; Spaziano, Giuseppe; Piegari, Elena; Matteis, Maria; Cappetta, Donato; Esposito, Grazia; Russo, Rosa; Tartaglione, Gioia; De Palma, Raffaele; Rossi, Francesco; D'Agostino, Bruno

    2016-01-01

    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 remodeling.

  6. CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models.

    PubMed

    Guedes, Alonso G P; Deshpande, Deepak A; Dileepan, Mythili; Walseth, Timothy F; Panettieri, Reynold A; Subramanian, Subbaya; Kannan, Mathur S

    2015-02-01

    Asthma is an inflammatory disease in which altered calcium regulation, contractility, and airway smooth muscle (ASM) proliferation contribute to airway hyper-responsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g., TNF-α) that requires the activation of MAP kinases and the transcription factors, NF-κB and AP-1, and is post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3' Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in Cd38 exhibit reduced airway responsiveness to inhaled methacholine relative to the response in wild-type mice. Intranasal challenge of Cd38-deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared with wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyper-responsiveness to inhaled methacholine in the Cd38-deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyper-responsiveness; a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and (or) activity are warranted.

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

    PubMed

    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.

  8. Involvement of superoxide in ozone-induced airway hyperresponsiveness in anesthetized cats

    SciTech Connect

    Takahashi, T.; Miura, M.; Katsumata, U.; Ichinose, M.; Kimura, K.; Inoue, H.; Takishima, T.; Shirato, K. )

    1993-07-01

    To determine whether oxygen radical scavengers inhibit ozone-induced airway hyperresponsiveness, we examined the protective effect of polyethylene glycol-superoxide dismutase (PEG-SOD) and PEG-catalase (PEG-CAT) on ozone-induced airway hyperresponsiveness in cat airways. Twenty-five cats divided into five groups were anesthetized and mechanically ventilated. There was no difference between the groups in baseline airway responsiveness to inhaled acetylcholine (ACh). In the control group, AChPC, the concentration required to produce a doubling increase in baseline pulmonary resistance, was significantly reduced by ozone exposure (2.0 ppm for 2 h); the ratios of AChPC before ozone exposure to after ozone exposure (AChPC ratio) were 14.8 +/- 5.7 (p < 0.001) and 4.80 +/- 1.6 (p < 0.01) 30 and 120 min after exposure, respectively. Local administration of PEG-SOD (2,000 U/kg) into airways partially but significantly prevented ozone-induced airway hyperresponsiveness. The AChPC ratios were 6.2 +/- 1.4 and 1.5 +/- 0.2 30 and 120 min after exposure, respectively, which were significantly different from those of the control group (p < 0.05), whereas PEG-CAT pretreatment (6,000 U/kg) was without effect. Combined pretreatment with PEG-SOD and PEG-CAT had no additional protective effect compared with PEG-SOD alone. PEG-SOD had no direct effect on airway responsiveness to ACh. These results suggest that superoxide may be involved in ozone-induced airway hyperresponsiveness.

  9. New Role of Adult Lung c-kit+ Cells in a Mouse Model of Airway Hyperresponsiveness

    PubMed Central

    Cappetta, Donato; Urbanek, Konrad; Esposito, Grazia; Matteis, Maria; Sgambato, Manuela; Tartaglione, Gioia; Rossi, Francesco

    2016-01-01

    Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Emerging evidence points to the involvement of c-kit+ cells in lung homeostasis, although their potential role in asthma is unknown. Our aim was to isolate c-kit+ cells from normal mouse lungs and to test whether these cells can interfere with hallmarks of asthma in an animal model. Adult mouse GFP-tagged c-kit+ cells, intratracheally delivered in the ovalbumin-induced airway hyperresponsiveness, positively affected airway remodeling and improved airway function. In bronchoalveolar lavage fluid of cell-treated animals, a reduction in the number of inflammatory cells and in IL-4, IL-5, and IL-13 release, along with an increase of IL-10, was observed. In MSC-treated mice, the macrophage polarization to M2-like subset may explain, at least in part, the increment in the level of anti-inflammatory cytokine IL-10. After in vitro stimulation of c-kit+ cells with proinflammatory cytokines, the indoleamine 2,3-dioxygenase and TGFβ were upregulated. These data, together with the increased apoptosis of inflammatory cells in vivo, indicate that c-kit+ cells downregulate immune response in asthma by influencing local environment, possibly by cell-to-cell contact combined to paracrine action. In conclusion, intratracheally administered c-kit+ cells reduce inflammation, positively modulate airway remodeling, and improve function. These data document previously unrecognized properties of c-kit+ cells, able to impede pathophysiological features of experimental airway hyperresponsiveness. PMID:28090152

  10. Acute exposure to hair bleach causes airway hyperresponsiveness in a rabbit model.

    PubMed

    Mensing, T; Marek, W; Raulf-Heimsoth, M; Baur, X

    1998-12-01

    Ammonium persulphate (APS) and hydrogen peroxide (H2O2) are used as oxidants in many industrial processes and are the main constituents of standard hair bleaching products. In a previous study, it was demonstrated that aerosols of APS induce alterations in airway responsiveness. The present study examined whether exposure for 4 h to a hair bleach composition (containing APS, potassium persulphate and H2O2) or H2O2 could induce airway hyperresponsiveness and/or an obstructive ventilation pattern in a rabbit model. Exposure to the aerosols altered neither baseline airway resistance, dynamic elastance, slope of inspiratory pressure generation nor arterial blood pressure and blood gas measurements. Similarly to APS, hair bleach aerosols containing > or =10.9 mg x m(-3) persulphate (ammonium and potassium salt) in air and > or =1.36 mg x m(-3) H2O2 in air caused airway hyperresponsiveness to acetylcholine after 4 h of exposure. Aerosolized H2O2 (> or =37 mg x m(-3) in air) did not influence airway responsiveness to acetylcholine. The results demonstrate that hair bleaching products containing persulphates dissolved in H2O2 cause airway hyperresponsiveness to acetylcholine in rabbits.

  11. O3-induced airway hyperresponsiveness to noncholinergic system and other stimuli

    SciTech Connect

    Campos, M.G.; Segura, P.; Vargas, M.H.; Vanda, B.; Ponce-Monter, H.; Selman, M.; Montano, L.M. )

    1992-07-01

    The effect of O3 exposure (3 ppm, 1 h) on the in vivo and in vitro airway responsiveness, as well as the changes in cell contents in bronchoalveolar lavage (BAL) fluid, were evaluated 16-18 h after O3 exposure in sensitized and nonsensitized male guinea pigs. The sensitization procedure was performed through repeated inhalation of ovalbumin for 3 wk. Increase in pulmonary insufflation pressure produced by the excitatory nonadrenergic noncholinergic (eNANC) system, histamine, and antigen were assessed in in vivo conditions, whereas airway responsiveness to histamine and substance P was evaluated in in vitro conditions by use of tracheal chains with or without epithelium and lung parenchymal strips. The authors found that O3 exposure (1) increased the neutrophil content in BAL fluids in both sensitized and nonsensitized guinea pigs, (2) caused hyperresponsiveness to eNANC stimulation in nonsensitized guinea pigs (although combination of sensitization and O3 exposure paradoxically abolished the hyperresponsiveness to eNANC stimulation), (3) increased the in vivo bronchoconstrictor responses to histamine and antigen, (4) caused hyperresponsiveness to substance P in nonsensitized tracheae with or without epithelium and in sensitized tracheae with epithelium, (5) did not modify the responsiveness to histamine in tracheae with or without epithelium (and in addition, epithelium removal caused hyperresponsiveness to histamine even in those tracheae exposed to O3), and (6) produced hyperresponsiveness to histamine in lung parenchymal strips either from sensitized or nonsensitized guinea pigs.

  12. 20-HETE Mediates Ozone-Induced, Neutrophil-Independent Airway Hyper-Responsiveness in Mice

    PubMed Central

    Cooper, Philip R.; Mesaros, A. Clementina; Zhang, Jie; Christmas, Peter; Stark, Christopher M.; Douaidy, Karim; Mittelman, Michael A.; Soberman, Roy J.; Blair, Ian A.; Panettieri, Reynold A.

    2010-01-01

    Background Ozone, a pollutant known to induce airway hyper-responsiveness (AHR), increases morbidity and mortality in patients with obstructive airway diseases and asthma. We postulate oxidized lipids mediate in vivo ozone-induced AHR in murine airways. Methodology/Principal Findings Male BALB/c mice were exposed to ozone (3 or 6 ppm) or filtered air (controls) for 2 h. Precision cut lung slices (PCLS; 250 µm thickness) containing an intrapulmonary airway (∼0.01 mm2 lumen area) were prepared immediately after exposure or 16 h later. After 24 h, airways were contracted to carbachol (CCh). Log EC50 and Emax values were then calculated by measuring the airway lumen area with respect to baseline. In parallel studies, dexamethasone (2.5 mg/kg), or 1-aminobenzotriazol (ABT) (50 mg/kg) were given intraperitoneal injection to naïve mice 18 h prior to ozone exposure. Indomethacin (10 mg/kg) was administered 2 h prior. Cell counts, cytokine levels and liquid chromatography-mass spectrometry (LC-MS) for lipid analysis were assessed in bronchoalveolar lavage (BAL) fluid from ozone exposed and control mice. Ozone acutely induced AHR to CCh. Dexamethasone or indomethacin had little effect on the ozone-induced AHR; while, ABT, a cytochrome P450 inhibitor, markedly attenuated airway sensitivity. BAL fluid from ozone exposed animals, which did not contain an increase in neutrophils or interleukin (IL)-6 levels, increased airway sensitivity following in vitro incubation with a naïve PCLS. In parallel, significant increases in oxidized lipids were also identified using LC-MS with increases of 20-HETE that were decreased following ABT treatment. Conclusions/Significance These data show that ozone acutely induces AHR to CCh independent of inflammation and is insensitive to steroid treatment or cyclooxygenase (COX) inhibition. BAL fluid from ozone exposed mice mimicked the effects of in vivo ozone exposure that were associated with marked increases in oxidized lipids. 20-HETE plays

  13. Gene-environment interactions in a mutant mouse kindred with native airway constrictor hyperresponsiveness.

    PubMed

    Pinto, Lawrence H; Eaton, Emily; Chen, Bohao; Fleisher, Jonah; Shuster, Dmitry; McCauley, Joel; Kedainis, Dalius; Siepka, Sandra M; Shimomura, Kazuhiro; Song, Eun-Joo; Husain, Aliya; Lakser, Oren J; Mitchell, Richard W; Dowell, Maria L; Brown, Melanie; Camoretti-Mercado, Blanca; Naclerio, Robert; Sperling, Anne I; Levin, Stephen I; Turek, Fred W; Solway, Julian

    2008-01-01

    We mutagenized male BTBR mice with N-ethyl-N-nitrosourea and screened 1315 of their G3 offspring for airway hyperresponsiveness. A phenovariant G3 mouse with exaggerated methacholine bronchoconstrictor response was identified and his progeny bred in a nonspecific-pathogen-free (SPF) facility where sentinels tested positive for minute virus of mice and mouse parvovirus and where softwood bedding was used. The mutant phenotype was inherited through G11 as a single autosomal semidominant mutation with marked gender restriction, with males exhibiting almost full penetrance and very few females phenotypically abnormal. Between G11 and G12, facility infection eradication was undertaken and bedding was changed to hardwood. We could no longer detect airway hyperresponsiveness in more than 37 G12 offspring of 26 hyperresponsive G11 males. Also, we could not identify the mutant phenotype among offspring of hyperresponsive G8-G10 sires rederived into an SPF facility despite 21 attempts. These two observations suggest that both genetic and environmental factors were needed for phenotype expression. We suspect that rederivation into an SPF facility or altered exposure to pathogens or other unidentified substances modified environmental interactions with the mutant allele, and so resulted in disappearance of the hyperresponsive phenotype. Our experience suggests that future searches for genes that confer susceptibility for airway hyperresponsiveness might not be able to identify some genes that confer susceptibility if the searches are performed in SPF facilities. Experimenters are advised to arrange for multigeneration constancy of mouse care in order to clone mutant genes. Indeed, we were not able to map the mutation before losing the phenotype.

  14. Alpha 4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep.

    PubMed Central

    Abraham, W M; Sielczak, M W; Ahmed, A; Cortes, A; Lauredo, I T; Kim, J; Pepinsky, B; Benjamin, C D; Leone, D R; Lobb, R R

    1994-01-01

    Eosinophils and T lymphocytes are thought to be involved in allergic airway inflammation. Both cells express the alpha 4 beta 1-integrin, very late antigen-4 (VLA-4, CD49d/CD29); alpha 4-integrins can promote cellular adhesion and activation. Therefore, we examined the in vivo effects of a blocking anti-alpha 4 monoclonal antibody, HP 1/2, on antigen-induced early and late bronchial responses, airway hyperresponsiveness, inflammatory cell influx, and peripheral leukocyte counts in allergic sheep. Sheep blood lymphocytes, monocytes, and eosinophils expressed alpha 4 and bound HP 1/2. In control sheep, Ascaris antigen challenge produced early and late increases in specific lung resistance of 380 +/- 42% and 175 +/- 16% over baseline immediately and 7 h after challenge, respectively, as well as airway hyperresponsiveness continuing for 14 d after antigen challenge. Treatment with HP 1/2 (1 mg/kg, i.v.) 30 min before antigen challenge did not affect the early increase in specific lung resistance but inhibited the late-phase increase at 5-8 h by 75% (P < 0.05) and inhibited the post-antigen-induced airway hyperresponsiveness at 1, 2, 7, and 14 d (P < 0.05, for each time). Intravenous HP 1/2 given 2 h after antigen challenge likewise blocked late-phase airway changes and postchallenge airway hyperresponsiveness. Airway administration of HP 1/2 (16-mg dose) was also effective in blocking these antigen-induced changes. Response to HP 1/2 was specific since an isotypic monoclonal antibody, 1E6, was ineffective by intravenous and aerosol administration. Inhibition of leukocyte recruitment did not totally account for the activity of anti-alpha 4 antibody since HP 1/2 neither diminished the eosinopenia or lymphopenia that followed antigen challenge nor consistently altered the composition of leukocytes recovered by bronchoalveolar lavage. Because airway administration of HP 1/2 was also active, HP 1/2 may have inhibited cell activation. Reduction of platelet-activating factor

  15. Anti-inflammatory drug (BW755C) inhibits airway hyperresponsiveness induced by ozone in dogs

    SciTech Connect

    Fabbri, L.M.; Aizawa, H.; O'Byrne, P.M.; Bethel, R.A.; Walters, E.H.; Holtzman, M.J.; Nadel, J.A.

    1985-08-01

    To follow up a previous observation that airway hyperresponsiveness induced by ozone is linked to airway inflammation, the authors investigated the effect of BW755C, an anti-inflammatory drug, on ozone-induced hyperresponsiveness in dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance in two sets of experiments. In one set (placebo treatment), five dogs were given only saline solution treatment and were studied before treatment or ozone exposure and then after treatment both before and after ozone (3.0 ppm, 2 hours); in another set (BW755C treatment), the same dogs were studied before BW755C treatment or ozone and then after treatment (10 mg/kg intravenously) both before and after ozone. When the dogs were given no BW755C treatment, ozone induced a marked increase in airway responsiveness to acetylcholine. When the dogs were given BW755C, responsiveness was no different during treatment than before treatment but, more importantly, responsiveness did not increase significantly after ozone. The authors conclude that BW755C markedly inhibits ozone-induced airway hyperresponsiveness in dogs, probably by inhibiting the formation of oxygenation products of arachidonic acid.

  16. O3-induced mucosa-linked airway muscle hyperresponsiveness in the guinea pig

    SciTech Connect

    Murlas, C.G.; Murphy, T.P.; Chodimella, V. )

    1990-07-01

    We investigated the effects of ozone exposure (3.0 ppm, 2 h) on the responsiveness of guinea pig airway muscle in vitro from animals developing bronchial hyperreactivity. Muscarinic reactivity in vivo was determined by measuring specific airway resistance (sRaw) in response to increasing concentrations of aerosolized acetylcholine (ACh) administered before and 30 min after exposure. Immediately after reactivity testing, multiple tracheal rings from ozone- and air-exposed animals were prepared and the contractile responses to increasing concentrations of substance P, ACh, or KCl were assessed in the presence of 10 microM indomethacin with or without 1 microM phosphoramidon, an inhibitor of neutral endopeptidase. Isometric force generation in vitro was measured on stimulation by cumulative concentrations of the agonists, and force generation (in g/cm2) was calculated after determination of muscle cross-sectional area. The smooth muscle of mucosa-intact airways from guinea pigs with ozone-induced bronchial hyper-reactivity proved to be hyperresponsive in vitro to substance P and ACh but not to KCl. Pretreatment with phosphoramidon abolished the increase in substance P responsiveness but had no effect on muscarinic hyperresponsiveness after ozone exposure. Furthermore, substance P responsiveness was not augmented in ozone-exposed airways in which the mucosa had been removed before testing in vitro. Likewise, muscarinic hyperresponsiveness was not present in ozone-exposed airways without mucosa. Our data indicate that airway smooth muscle responsiveness is increased in guinea pigs with ozone-induced bronchial hyperreactivity and suggest that this hyperresponsiveness may be linked to non-cyclooxygenase mucosa-derived factors.

  17. Arachidonic acid metabolites do not mediate toluene diisocyanate-induced airway hyperresponsiveness in guinea pigs

    SciTech Connect

    Gordon, T.; Thompson, J.E.; Sheppard, D.

    1988-05-01

    Arachidonic acid metabolites have previously been demonstrated to mediate the airway hyperresponsiveness observed in guinea pigs and dogs after exposure to ozone. Guinea pigs were treated with indomethacin (a cyclooxygenase inhibitor), U-60,257 (piriprost, a 5-lipoxygenase inhibitor), or BW775c (a lipoxygenase and cyclooxygenase inhibitor) and exposed to air or 3 ppm TDI. Airway responsiveness to acetylcholine aerosol was examined 2 h after exposure. In control animals, the provocative concentration of acetylcholine which caused a 200% increase in pulmonary resistance over baseline (PC200) was significantly less (p less than 0.05) after exposure to TDI (8.6 +/- 2.0 mg/ml, geometric mean + geometric SE, n = 10) than after exposure to air (23.9 + 2.5 mg/ml, n = 14). The airway responsiveness to acetylcholine in animals treated with indomethacin or piriprost and exposed to TDI was not different from that of control animals exposed to TDI. Treatment with BW755c enhanced the airway hyperresponsiveness observed in animals exposed to TDI without altering the PC200 of animals exposed to air. The PC200 of animals treated with BW755c and exposed to TDI (2.3 + 0.8 mg/ml, n = 8) was significantly lower than the PC200 of control animals exposed to TDI (p less than 0.025). These results suggest that products of arachidonic acid metabolism are not responsible for TDI-induced airway hyperresponsiveness in guinea pigs. BW755c, however, appears to potentiate the TDI-induced airway hyperresponsiveness to acetylcholine by an as yet unidentified mechanism.

  18. Arachidonic acid metabolites do not mediate toluene diisocyanate-induced airway hyperresponsiveness in guinea pigs.

    PubMed

    Gordon, T; Thompson, J E; Sheppard, D

    1988-05-01

    Arachidonic acid metabolites have previously been demonstrated to mediate the airway hyperresponsiveness observed in guinea pigs and dogs after exposure to ozone. Guinea pigs were treated with indomethacin (a cyclooxygenase inhibitor), U-60,257 (piriprost, a 5-lipoxygenase inhibitor), or BW775c (a lipoxygenase and cyclooxygenase inhibitor) and exposed to air or 3 ppm TDI. Airway responsiveness to acetylcholine aerosol was examined 2 h after exposure. In control animals, the provocative concentration of acetylcholine which caused a 200% increase in pulmonary resistance over baseline (PC200) was significantly less (p less than 0.05) after exposure to TDI (8.6 +/- 2.0 mg/ml, geometric mean + geometric SE, n = 10) than after exposure to air (23.9 + 2.5 mg/ml, n = 14). The airway responsiveness to acetylcholine in animals treated with indomethacin or piriprost and exposed to TDI was not different from that of control animals exposed to TDI. Treatment with BW755c enhanced the airway hyperresponsiveness observed in animals exposed to TDI without altering the PC200 of animals exposed to air. The PC200 of animals treated with BW755c and exposed to TDI (2.3 + 0.8 mg/ml, n = 8) was significantly lower than the PC200 of control animals exposed to TDI (p less than 0.025). These results suggest that products of arachidonic acid metabolism are not responsible for TDI-induced airway hyperresponsiveness in guinea pigs. BW755c, however, appears to potentiate the TDI-induced airway hyperresponsiveness to acetylcholine by an as yet unidentified mechanism.

  19. The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough.

    PubMed

    Makwana, Raj; Venkatasamy, Radhakrishnan; Spina, Domenico; Page, Clive

    2015-04-01

    of airway smooth muscle in response to nerve stimulation by enhancing postganglionic acetylcholine release. Δ(9)-Tetrahydrocannabinol and CP55940 inhibited the TNF-α-enhanced acetylcholine release, and hence contraction and bronchoconstriction, through activation of presynaptic CB(1) and CB(2) receptors. The other cannabinoids did not influence cholinergic transmission, and only Δ(9)-THC demonstrated effects on airway hyper-responsiveness, anti-inflammatory activity, and antitussive activity in the airways. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  20. Effectiveness of carbocysteine lysine salt monohydrate on models of airway inflammation and hyperresponsiveness.

    PubMed

    Asti, C; Melillo, G; Caselli, G F; Daffonchio, L; Hernandez, A; Clavenna, G; Omini, C

    1995-06-01

    We investigated the possible effects of the mucoactive drug Carbocysteine lysine salt monohydrate (CLS.H2O) on experimentally-induced airway inflammation and hyperresponsiveness. CLS.H2O given by the oral route (300 mg kg(-1)) significantly reduced neutrophil infiltration into the airway lumen induced by intratracheal injection of IL-1 beta in rats. In addition, CLS.H2O inhibited dose-dependently (100-300 mg kg(-1) p.o.) the formation of pleural exudate and leukocyte recruitment induced by intrapleural injection of carrageenan in rats. Because of the close interaction between the inflammatory process and the development of airway hyperresponsiveness we also tested CLS.H2O on cigarette-smoke-induced inflammation and hyperreactivity in anaesthetized guinea-pigs. The drug, given either by oral (300 mg kg(-1)) or aerosol route (30-100 mg ml(-1)), was able to reduce the increase in airway responsiveness induced by smoke and the associated cell recruitment detected in the bronchoalveolar lavage (BAL) fluids. These results suggest that CLS.H2O can exert an anti-inflammatory action in addition to its mucoregulatory activity. The anti-inflammatory and anti-hyperreactivity effect of the drug within the airways may be of advantage in the treatment of inflammatory lung diseases where mucus secretion together with airway inflammation and hyperreactivity contribute to airway obstruction.

  1. Effects of combination therapy with montelukast and carbocysteine in allergen-induced airway hyperresponsiveness and airway inflammation

    PubMed Central

    Takeda, K; Shiraishi, Y; Matsubara, S; Miyahara, N; Matsuda, H; Okamoto, M; Joetham, A; Gelfand, EW

    2010-01-01

    Background and purpose: Montelukast and S-carbocysteine have been used in asthmatic patients as an anti-inflammatory or mucolytic agent respectively. S-carbocysteine also exhibits anti-inflammatory properties. Experimental approach: Ovalbumin (OVA) sensitized BALB/c mice were challenged with OVA for 3 days followed by single OVA re-challenge (secondary challenge) 2 weeks later. Forty-eight hours after secondary challenge, mice were assessed for airway hyperresponsiveness (AHR) and cell composition in bronchoalveolar lavage (BAL) fluid. Suboptimal doses of 10 mg·kg−1 of S-carbocysteine by intraperitoneal injection (ip), 20 mg·kg−1 of montelukast by gavage, the combination of S-carbocysteine and montelukast or 3 mg·kg−1 of dexamethasone as a control were administered from 1 day before the secondary challenge to the last experimental day. Isolated lung cells were cultured with OVA and montelukast to determine the effects on cytokine production. Key results: Treatment with S-carbocysteine or montelukast reduced both AHR and the numbers of eosinophils in BAL fluid. Neutralizing IFN-γ abolished the effects of S-carbocysteine on these airway responses. Combination of the two drugs showed further decreases in both AHR and eosinophils in the BAL fluid. Goblet cell metaplasia and Th2-type cytokines, interleukin (IL)-4, IL-5 and IL-13, in BAL fluid were decreased with montelukast treatment. Conversely, S-carbocysteine increased Th1-type cytokines, IFN-γ and IL-12 in BAL fluid. Conclusions and inplications: The combination of two agents, montelukast and S-carbocysteine, demonstrated additive effects on AHR and airway inflammation in a secondary allergen model most likely through independent mechanisms of action. PMID:20590630

  2. Effects of combination therapy with montelukast and carbocysteine in allergen-induced airway hyperresponsiveness and airway inflammation.

    PubMed

    Takeda, K; Shiraishi, Y; Matsubara, S; Miyahara, N; Matsuda, H; Okamoto, M; Joetham, A; Gelfand, E W

    2010-07-01

    Montelukast and S-carbocysteine have been used in asthmatic patients as an anti-inflammatory or mucolytic agent respectively. S-carbocysteine also exhibits anti-inflammatory properties. Ovalbumin (OVA) sensitized BALB/c mice were challenged with OVA for 3 days followed by single OVA re-challenge (secondary challenge) 2 weeks later. Forty-eight hours after secondary challenge, mice were assessed for airway hyperresponsiveness (AHR) and cell composition in bronchoalveolar lavage (BAL) fluid. Suboptimal doses of 10 mg.kg(-1) of S-carbocysteine by intraperitoneal injection (ip), 20 mg.kg(-1) of montelukast by gavage, the combination of S-carbocysteine and montelukast or 3 mg.kg(-1) of dexamethasone as a control were administered from 1 day before the secondary challenge to the last experimental day. Isolated lung cells were cultured with OVA and montelukast to determine the effects on cytokine production. Treatment with S-carbocysteine or montelukast reduced both AHR and the numbers of eosinophils in BAL fluid. Neutralizing IFN-gamma abolished the effects of S-carbocysteine on these airway responses. Combination of the two drugs showed further decreases in both AHR and eosinophils in the BAL fluid. Goblet cell metaplasia and Th2-type cytokines, interleukin (IL)-4, IL-5 and IL-13, in BAL fluid were decreased with montelukast treatment. Conversely, S-carbocysteine increased Th1-type cytokines, IFN-gamma and IL-12 in BAL fluid. The combination of two agents, montelukast and S-carbocysteine, demonstrated additive effects on AHR and airway inflammation in a secondary allergen model most likely through independent mechanisms of action.

  3. Ozone at high-pollution urban levels causes airway hyperresponsiveness to substance P but not to other agonists.

    PubMed

    Segura, P; Montaño, L M; Bazán-Perkins, B; Gustin, P; Vargas, M H

    1997-06-06

    Ozone (O(3)) causes airway hyperresponsiveness, but few studies have evaluated this effect at urban concentrations. In this work dose-response curves to intravenous acetylcholine, histamine or substance P were performed in guinea pigs with or without previous exposure to O(3) (0.15, 0.3, 0.6 or 1.2 ppm for 4 h, 16-18 h before the studies). We found airway hyperresponsiveness to histamine, but not to acetylcholine, only after 1.2 ppm O(3). By contrast, airway hyperresponsiveness to substance P was developed at O(3) levels encountered in highly-polluted cities (0.3 ppm). These results suggest that excitatory non-adrenergic non-cholinergic responses could be affected by air pollution, and that substance P is a useful pharmacological tool for evaluating the airway hyperresponsiveness induced by low O(3) concentrations.

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

    PubMed

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

    2011-12-15

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

  5. IL-17A Modulates Oxidant Stress-Induced Airway Hyperresponsiveness but Not Emphysema

    PubMed Central

    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. PMID:23505509

  6. IL-17A modulates oxidant stress-induced airway hyperresponsiveness but not emphysema.

    PubMed

    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.

  7. A Phosphorylatable Sphingosine Analog Induces Airway Smooth Muscle Cytostasis and Reverses Airway Hyperresponsiveness in Experimental Asthma

    PubMed Central

    Gendron, David R.; Lecours, Pascale B.; Lemay, Anne-Marie; Beaulieu, Marie-Josée; Huppé, Carole-Ann; Lee-Gosselin, Audrey; Flamand, Nicolas; Don, Anthony S.; Bissonnette, Élyse; Blanchet, Marie-Renée; Laplante, Mathieu; Bourgoin, Sylvain G.; Bossé, Ynuk; Marsolais, David

    2017-01-01

    In asthma, excessive bronchial narrowing associated with thickening of the airway smooth muscle (ASM) causes respiratory distress. Numerous pharmacological agents prevent experimental airway hyperresponsiveness (AHR) when delivered prophylactically. However, most fail to resolve this feature after disease is instated. Although sphingosine analogs are primarily perceived as immune modulators with the ability to prevent experimental asthma, they also influence processes associated with tissue atrophy, supporting the hypothesis that they could interfere with mechanisms sustaining pre-established AHR. We thus assessed the ability of a sphingosine analog (AAL-R) to reverse AHR in a chronic model of asthma. We dissected the pharmacological mechanism of this class of agents using the non-phosphorylatable chiral isomer AAL-S and the pre-phosphorylated form of AAL-R (AFD-R) in vivo and in human ASM cells. We found that a therapeutic course of AAL-R reversed experimental AHR in the methacholine challenge test, which was not replicated by dexamethasone or the non-phosphorylatable isomer AAL-S. AAL-R efficiently interfered with ASM cell proliferation in vitro, supporting the concept that immunomodulation is not necessary to interfere with cellular mechanisms sustaining AHR. Moreover, the sphingosine-1-phosphate lyase inhibitor SM4 and the sphingosine-1-phosphate receptor antagonist VPC23019 failed to inhibit proliferation, indicating that intracellular accumulation of sphingosine-1-phosphate or interference with cell surface S1P1/S1P3 activation, are not sufficient to induce cytostasis. Potent AAL-R-induced cytostasis specifically related to its ability to induce intracellular AFD-R accumulation. Thus, a sphingosine analog that possesses the ability to be phosphorylated in situ interferes with cellular mechanisms that beget AHR. PMID:28270767

  8. Could an increase in airway smooth muscle shortening velocity cause airway hyperresponsiveness?

    PubMed

    Bullimore, Sharon R; Siddiqui, Sana; Donovan, Graham M; Martin, James G; Sneyd, James; Bates, Jason H T; Lauzon, Anne-Marie

    2011-01-01

    Airway hyperresponsiveness (AHR) is a characteristic feature of asthma. It has been proposed that an increase in the shortening velocity of airway smooth muscle (ASM) could contribute to AHR. To address this possibility, we tested whether an increase in the isotonic shortening velocity of ASM is associated with an increase in the rate and total amount of shortening when ASM is subjected to an oscillating load, as occurs during breathing. Experiments were performed in vitro using 27 rat tracheal ASM strips supramaximally stimulated with methacholine. Isotonic velocity at 20% isometric force (Fiso) was measured, and then the load on the muscle was varied sinusoidally (0.33 ± 0.25 Fiso, 1.2 Hz) for 20 min, while muscle length was measured. A large amplitude oscillation was applied every 4 min to simulate a deep breath. We found that: 1) ASM strips with a higher isotonic velocity shortened more quickly during the force oscillations, both initially (P < 0.001) and after the simulated deep breaths (P = 0.002); 2) ASM strips with a higher isotonic velocity exhibited a greater total shortening during the force oscillation protocol (P < 0.005); and 3) the effect of an increase in isotonic velocity was at least comparable in magnitude to the effect of a proportional increase in ASM force-generating capacity. A cross-bridge model showed that an increase in the total amount of shortening with increased isotonic velocity could be explained by a change in either the cycling rate of phosphorylated cross bridges or the rate of myosin light chain phosphorylation. We conclude that, if asthma involves an increase in ASM velocity, this could be an important factor in the associated AHR.

  9. Complete Resolution of Airway Hyperresponsiveness in Aspirin-sensitive Asthmatic Patients

    PubMed Central

    Park, Hae-Sim

    1996-01-01

    Appreciable numbers of aspirin-sensitive asthmatic patients have chronic steroid-dependent severe asthmatic symptoms. We report four cases of aspirin-sensitive asthmatics who had mild to severe asthmatic symptoms, whose methacholine PC20 level ranged from 0.6 to 22 mg/ml at the first visit. The aspirin sensitivity was confirmed by lysine-aspirin bronchoprovocation. After anti-asthmatic medications and avoidance of salicylate-containing agents, airway hyperresponsiveness and respiratory symptoms disappeared for two to 30 months. These results suggest that early detection and careful avoidance of salicylate-containing agents may have a beneficial effect resulting in the resolution of airway hyperresponsiveness in aspirin-sensitive asthmatic patients. PMID:8854653

  10. Role of leukotrienes in airway hyperresponsiveness in guinea-pigs.

    PubMed Central

    Ishida, K.; Thomson, R. J.; Schellenberg, R. R.

    1993-01-01

    1. Repeated aerosolization of leukotriene C4 (LTC4) to guinea-pigs produced leftward shift in their pulmonary resistance (RL) dose-response curves to inhaled acetylcholine (ACh) without increasing the maximum responses. 2. Repeated LTC4 aerosolization did not increase airway eosinophils. 3. The 5-lipoxygenase-activating protein (FLAP) inhibitor, MK-886, prevented the leftward shift in RL dose-response curves to ACh following repeated antigen challenge in guinea-pigs. 4. MK-886 did not inhibit the increased maximal RL produced by repeated antigen challenge, nor inhibit the airway eosinophilia induced by repeated antigen challenge. 5. Our findings suggest that leukotrienes may account for the leftward shift in pulmonary resistance responses caused by antigen but do not cause the airway eosinophilia nor enhanced maximum broncho-constrictor response to antigen. PMID:8467358

  11. Airway Microbiota and Bronchial Hyperresponsiveness in Patients with Sub-optimally Controlled Asthma

    PubMed Central

    Huang, Yvonne J.; Nelson, Craig E.; Brodie, Eoin L.; DeSantis, Todd Z.; Baek, Marshall S.; Liu, Jane; Woyke, Tanja; Allgaier, Martin; Bristow, Jim; Wiener-Kronish, Jeanine P.; Sutherland, E. Rand; King, Tonya S.; Icitovic, Nikolina; Martin, Richard J.; Calhoun, William J.; Castro, Mario; Denlinger, Loren C.; DiMango, Emily; Kraft, Monica; Peters, Stephen P.; Wasserman, Stephen I.; Wechsler, Michael E.; Boushey, Homer A.; Lynch, Susan V.

    2010-01-01

    Background Improvement in lung function following macrolide antibiotic therapy has been attributed to reduction in bronchial infection due to specific bacteria. However, the airway may be populated by a more diverse microbiota, and clinical features of asthma may be associated with characteristics of the airway microbiota present. Objective To determine if relationships exist between the composition of the airway bacterial microbiota and clinical features of asthma, using culture-independent tools capable of detecting the presence and relative abundance of most known bacteria. Methods In this pilot study, bronchial epithelial brushings were collected from sixty-five adults with sub-optimally controlled asthma participating in a multicenter study of the effects of clarithromycin on asthma control, and ten healthy subjects. A combination of high-density 16S rRNA microarray and parallel clone library-sequencing analysis was used to profile the microbiota and examine relationships with clinical measurements. Results Compared to controls, 16S rRNA amplicon concentrations (a proxy for bacterial burden) and bacterial diversity were significantly higher among asthmatic patients. In multivariate analyses, airway microbiota composition and diversity were significantly correlated with bronchial hyperresponsiveness. Specifically, the relative abundance of particular phylotypes, including members of the Comamonadaceae, Sphingomonadaceae, Oxalobacteraceae and other bacterial families, were highly correlated with the degree of bronchial hyperresponsiveness. Conclusion The composition of bronchial airway microbiota is associated with the degree of bronchial hyperresponsiveness among patients with sub-optimally controlled asthma. These findings support the need for further functional studies to examine the potential contribution of members of the airway microbiota in asthma pathogenesis. PMID:21194740

  12. Streptomycin treatment alters the intestinal microbiome, pulmonary T cell profile and airway hyperresponsiveness in a cystic fibrosis mouse model.

    PubMed

    Bazett, Mark; Bergeron, Marie-Eve; Haston, Christina K

    2016-01-12

    Cystic fibrosis transmembrane conductance regulator deficient mouse models develop phenotypes of relevance to clinical cystic fibrosis (CF) including airway hyperresponsiveness, small intestinal bacterial overgrowth and an altered intestinal microbiome. As dysbiosis of the intestinal microbiota has been recognized as an important contributor to many systemic diseases, herein we investigated whether altering the intestinal microbiome of BALB/c Cftr(tm1UNC) mice and wild-type littermates, through treatment with the antibiotic streptomycin, affects the CF lung, intestinal and bone disease. We demonstrate that streptomycin treatment reduced the intestinal bacterial overgrowth in Cftr(tm1UNC) mice and altered the intestinal microbiome similarly in Cftr(tm1UNC) and wild-type mice, principally by affecting Lactobacillus levels. Airway hyperresponsiveness of Cftr(tm1UNC) mice was ameliorated with streptomycin, and correlated with Lactobacillus abundance in the intestine. Additionally, streptomycin treated Cftr(tm1UNC) and wild-type mice displayed an increased percentage of pulmonary and mesenteric lymph node Th17, CD8 + IL-17+ and CD8 + IFNγ+ lymphocytes, while the CF-specific increase in respiratory IL-17 producing γδ T cells was decreased in streptomycin treated Cftr(tm1UNC) mice. Bone disease and intestinal phenotypes were not affected by streptomycin treatment. The airway hyperresponsiveness and lymphocyte profile of BALB/c Cftr(tm1UNC) mice were affected by streptomycin treatment, revealing a potential intestinal microbiome influence on lung response in BALB/c Cftr(tm1UNC) mice.

  13. Airways Hyperresponsiveness Following a Single Inhalation Exposure to Doxorubicin-Induced Heart Failure Prevents Airways Transition Metal-Rich Particulate Matter in Hypertensive Rats

    EPA Science Inventory

    Exposure to particulate matter (PM) air pollution results in airways hyperresponsiveness (AHR), however it also results in adverse cardiovascular effects, particularly in individuals with underlying cardiovascular disease. The impact of pre-existing cardiac deficit on PM-induced ...

  14. Airways Hyperresponsiveness Following a Single Inhalation Exposure to Doxorubicin-Induced Heart Failure Prevents Airways Transition Metal-Rich Particulate Matter in Hypertensive Rats

    EPA Science Inventory

    Exposure to particulate matter (PM) air pollution results in airways hyperresponsiveness (AHR), however it also results in adverse cardiovascular effects, particularly in individuals with underlying cardiovascular disease. The impact of pre-existing cardiac deficit on PM-induced ...

  15. Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness.

    PubMed

    Hoffman, Sidra M; Chapman, David G; Lahue, Karolyn G; Cahoon, Jonathon M; Rattu, Gurkiranjit K; Daphtary, Nirav; Aliyeva, Minara; Fortner, Karen A; Erzurum, Serpil C; Comhair, Suzy A A; Woodruff, Prescott G; Bhakta, Nirav; Dixon, Anne E; Irvin, Charles G; Janssen-Heininger, Yvonne M W; Poynter, Matthew E; Anathy, Vikas

    2016-03-01

    Evidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown. Here we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma. We examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57. Lung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis. Here we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier

  16. Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness

    PubMed Central

    Li, Shanru; Koziol-White, Cynthia; Jude, Joseph; Jiang, Meiqi; Zhao, Hengjiang; Cao, Gaoyuan; Yoo, Edwin; Jester, William; Morley, Michael P.; Zhou, Su; Wang, Yi; Lu, Min Min; Panettieri, Reynold A.

    2016-01-01

    Asthma is one of the most common chronic diseases globally and can be divided into presenting with or without an immune response. Current therapies have little effect on nonimmune disease, and the mechanisms that drive this type of asthma are poorly understood. Here, we have shown that loss of the transcription factors forkhead box P1 (Foxp1) and Foxp4, which are critical for lung epithelial development, in the adult airway epithelium evokes a non-Th2 asthma phenotype that is characterized by airway hyperresponsiveness (AHR) without eosinophilic inflammation. Transcriptome analysis revealed that loss of Foxp1 and Foxp4 expression induces ectopic expression of neuropeptide Y (Npy), which has been reported to be present in the airways of asthma patients, but whose importance in disease pathogenesis remains unclear. Treatment of human lung airway explants with recombinant NPY increased airway contractility. Conversely, loss of Npy in Foxp1- and Foxp4-mutant airway epithelium rescued the AHR phenotype. We determined that NPY promotes AHR through the induction of Rho kinase activity and phosphorylation of myosin light chain, which induces airway smooth muscle contraction. Together, these studies highlight the importance of paracrine signals from the airway epithelium to the underlying smooth muscle to induce AHR and suggest that therapies targeting epithelial induction of this phenotype may prove useful in treatment of noneosinophilic asthma. PMID:27088802

  17. Linking Ventilation Heterogeneity Quantified via Hyperpolarized 3He MRI to Dynamic Lung Mechanics and Airway Hyperresponsiveness.

    PubMed

    Lui, Justin K; Parameswaran, Harikrishnan; Albert, Mitchell S; Lutchen, Kenneth R

    2015-01-01

    Advancements in hyperpolarized helium-3 MRI (HP 3He-MRI) have introduced the ability to render and quantify ventilation patterns throughout the anatomic regions of the lung. The goal of this study was to establish how ventilation heterogeneity relates to the dynamic changes in mechanical lung function and airway hyperresponsiveness in asthmatic subjects. In four healthy and nine mild-to-moderate asthmatic subjects, we measured dynamic lung resistance and lung elastance from 0.1 to 8 Hz via a broadband ventilation waveform technique. We quantified ventilation heterogeneity using a recently developed coefficient of variation method from HP 3He-MRI imaging. Dynamic lung mechanics and imaging were performed at baseline, post-challenge, and after a series of five deep inspirations. AHR was measured via the concentration of agonist that elicits a 20% decrease in the subject's forced expiratory volume in one second compared to baseline (PC20) dose. The ventilation coefficient of variation was correlated to low-frequency lung resistance (R = 0.647, P < 0.0001), the difference between high and low frequency lung resistance (R = 0.668, P < 0.0001), and low-frequency lung elastance (R = 0.547, P = 0.0003). In asthmatic subjects with PC20 values <25 mg/mL, the coefficient of variation at baseline exhibited a strong negative trend (R = -0.798, P = 0.02) to PC20 dose. Our findings were consistent with the notion of peripheral rather than central involvement of ventilation heterogeneity. Also, the degree of AHR appears to be dependent on the degree to which baseline airway constriction creates baseline ventilation heterogeneity. HP 3He-MRI imaging may be a powerful predictor of the degree of AHR and in tracking the efficacy of therapy.

  18. Linking Ventilation Heterogeneity Quantified via Hyperpolarized 3He MRI to Dynamic Lung Mechanics and Airway Hyperresponsiveness

    PubMed Central

    Lui, Justin K.; Parameswaran, Harikrishnan; Albert, Mitchell S.; Lutchen, Kenneth R.

    2015-01-01

    Advancements in hyperpolarized helium-3 MRI (HP 3He-MRI) have introduced the ability to render and quantify ventilation patterns throughout the anatomic regions of the lung. The goal of this study was to establish how ventilation heterogeneity relates to the dynamic changes in mechanical lung function and airway hyperresponsiveness in asthmatic subjects. In four healthy and nine mild-to-moderate asthmatic subjects, we measured dynamic lung resistance and lung elastance from 0.1 to 8 Hz via a broadband ventilation waveform technique. We quantified ventilation heterogeneity using a recently developed coefficient of variation method from HP 3He-MRI imaging. Dynamic lung mechanics and imaging were performed at baseline, post-challenge, and after a series of five deep inspirations. AHR was measured via the concentration of agonist that elicits a 20% decrease in the subject’s forced expiratory volume in one second compared to baseline (PC20) dose. The ventilation coefficient of variation was correlated to low-frequency lung resistance (R = 0.647, P < 0.0001), the difference between high and low frequency lung resistance (R = 0.668, P < 0.0001), and low-frequency lung elastance (R = 0.547, P = 0.0003). In asthmatic subjects with PC20 values <25 mg/mL, the coefficient of variation at baseline exhibited a strong negative trend (R = -0.798, P = 0.02) to PC20 dose. Our findings were consistent with the notion of peripheral rather than central involvement of ventilation heterogeneity. Also, the degree of AHR appears to be dependent on the degree to which baseline airway constriction creates baseline ventilation heterogeneity. HP 3He-MRI imaging may be a powerful predictor of the degree of AHR and in tracking the efficacy of therapy. PMID:26569412

  19. MAG-DPA curbs inflammatory biomarkers and pharmacological reactivity in cytokine-triggered hyperresponsive airway models.

    PubMed

    Khaddaj-Mallat, Rayan; Hiram, Roddy; Sirois, Chantal; Sirois, Marco; Rizcallah, Edmond; Marouan, Sofia; Morin, Caroline; Rousseau, Éric

    2016-12-01

    Bronchial inflammation contributes to a sustained elevation of airway hyperresponsiveness (AHR) in asthma. Conversely, omega-3 fatty acid derivatives have been shown to resolve inflammation in various tissues. Thus, the effects of docosapentaenoic acid monoacylglyceride (MAG-DPA) were assessed on inflammatory markers and reactivity of human distal bronchi as well as in a cultured model of guinea pig tracheal rings. Human bronchi were dissected and cultured for 48 h with 10 ng/mL TNF-α or IL-13. Guinea pig tracheas were maintained in organ culture for 72 h which was previously shown to trigger spontaneous AHR. All tissues were treated with increasing concentrations of MAG-DPA (0.1, 0.3, and 1 μmol/L). Pharmacomechanical reactivity, Ca(2+) sensitivity, and western blot analysis for specific phosphoproteins and transcription factors were performed to assess the effects of both cytokines, alone or in combination with MAG-DPA, on human and guinea pig airway preparations. Although 0.1 μmol/L MAG-DPA did not significantly reduce inflammatory biomarkers, the higher concentrations of MAG-DPA (0.3 and 1 μmol/L) blunted the activation of the TNF-α/NF κB pathway and abolished COX-2 expression in human and guinea pig tissues. Moreover, 0.3 and 1 μmol/L MAG-DPA consistently decreased the Ca(2+) sensitivity and pharmacological reactivity of cultured bronchial explants. Furthermore, in human bronchi, IL-13-stimulated phosphorylation of CPI-17 was reversed by 1 μmol/L MAG-DPA. This effect was further amplified in the presence of 100 μmol/L aspirin. MAG-DPA mediates antiphlogistic effects by increasing the resolution of inflammation, while resetting Ca(2+) sensitivity and contractile reactivity.

  20. Graphene Oxide Attenuates Th2-Type Immune Responses, but Augments Airway Remodeling and Hyperresponsiveness in a Murine Model of Asthma

    PubMed Central

    2015-01-01

    Several lines of evidence indicate that exposure to nanoparticles (NPs) is able to modify airway immune responses, thus facilitating the development of respiratory diseases. Graphene oxide (GO) is a promising carbonaceous nanomaterial with unique physicochemical properties, envisioned for a multitude of medical and industrial applications. In this paper, we determined how exposure to GO modulates the allergic pulmonary response. Using a murine model of ovalbumin (OVA)-induced asthma, we revealed that GO, given at the sensitization stage, augmented airway hyperresponsiveness and airway remodeling in the form of goblet cell hyperplasia and smooth muscle hypertrophy. At the same time, the levels of the cytokines IL-4, IL-5, and IL-13 were reduced in broncho-alveolar lavage (BAL) fluid in GO-exposed mice. Exposure to GO during sensitization with OVA decreased eosinophil accumulation and increased recruitment of macrophages in BAL fluid. In line with the cytokine profiles, sensitization with OVA in the presence of GO stimulated the production of OVA-specific IgG2a and down-regulated the levels of IgE and IgG1. Moreover, exposure to GO increased the macrophage production of the mammalian chitinases, CHI3L1 and AMCase, whose expression is associated with asthma. Finally, molecular modeling has suggested that GO may directly interact with chitinase, affecting AMCase activity, which has been directly proven in our studies. Thus, these data show that GO exposure attenuates Th2 immune response in a model of OVA-induced asthma, but leads to potentiation of airway remodeling and hyperresponsiveness, with the induction of mammalian chitinases. PMID:24847914

  1. Fenretinide prevents inflammation and airway hyperresponsiveness in a mouse model of allergic asthma.

    PubMed

    Kanagaratham, Cynthia; Kalivodová, Alžběta; Najdekr, Lukáš; Friedecký, David; Adam, Tomáš; Hajduch, Marian; De Sanctis, Juan Bautista; Radzioch, Danuta

    2014-12-01

    Arachidonic acid (AA) and docosahexaenoic acid (DHA) play important roles in inflammation and disease progression, where AA is viewed as proinflammatory and DHA as antiinflammatory. We observe in our model of allergic asthma that the AA/DHA ratio is significantly skewed in a proinflammatory direction. Fenretinide, a vitamin A derivative, has been shown to correct fatty acid imbalances in other diseases. Therefore, we explored if fenretinide can have a protective effect in allergic asthma. To accomplish this, we measured the levels of AA and DHA in the lungs of nonallergic, ovalbumin-induced allergic, and fenretinide-treated allergic mice. We also investigated the effect of allergic asthma and fenretinide treatment on markers of oxidative stress, levels of metabolites, IgE production, airway hyperresponsiveness, and histological changes. Our data demonstrate that treatment of allergen-sensitized mice with fenretinide before allergen challenge prevents ovalbumin-induced changes in the AA/DHA ratio. The levels of several metabolites, such as serotonin, and markers of cellular stress, which are increased after ovalbumin challenge, are also controlled by fenretinide treatment. We observed the protective effect of fenretinide against ovalbumin-induced airway hyperresponsiveness and inflammation in the lungs, illustrated by a complete block in the infiltration of inflammatory cells to the airways and dramatically diminished goblet cell proliferation, even though IgE remained high. Our results demonstrate that fenretinide is an effective agent targeting inflammation, oxidation, and lung pathology observed in allergic asthma.

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

    PubMed Central

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

    1998-01-01

    The complex pathophysiology of lung allergic inflammation and bronchial hyperresponsiveness (BHR) that characterize asthma is achieved by the regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes correlate with the coordinated production of chemokines. Here, we have assessed the role that different chemokines play in lung allergic inflammation and BHR by blocking their activities in vivo. Our results show that blockage of each one of these chemokines reduces both lung leukocyte infiltration and BHR in a substantially different way. Thus, eotaxin neutralization reduces specifically BHR and lung eosinophilia transiently after each antigen exposure. Monocyte chemoattractant protein (MCP)-5 neutralization abolishes BHR not by affecting the accumulation of inflammatory leukocytes in the airways, but rather by altering the trafficking of the eosinophils and other leukocytes through the lung interstitium. Neutralization of RANTES (regulated upon activation, normal T cell expressed and secreted) receptor(s) with a receptor antagonist decreases significantly lymphocyte and eosinophil infiltration as well as mRNA expression of eotaxin and RANTES. In contrast, neutralization of one of the ligands for RANTES receptors, macrophage-inflammatory protein 1α, reduces only slightly lung eosinophilia and BHR. Finally, MCP-1 neutralization diminishes drastically BHR and inflammation, and this correlates with a pronounced decrease in monocyte- and lymphocyte-derived inflammatory mediators. These results suggest that different chemokines activate different cellular and molecular pathways that in a coordinated fashion contribute to the complex pathophysiology of asthma, and that their individual blockage results in intervention at different levels of these processes. PMID:9653092

  3. Inhalation of diesel exhaust enhances allergen-related eosinophil recruitment and airway hyperresponsiveness in mice.

    PubMed

    Takano, H; Ichinose, T; Miyabara, Y; Shibuya, T; Lim, H B; Yoshikawa, T; Sagai, M

    1998-06-01

    We have previously shown that intratracheal instillation of suspension of diesel exhaust particles enhances allergen-related eosinophilic airway inflammation, airway hyperresponsiveness, and local expression of interleukin (IL)-5 and granulocyte macrophage-colony stimulating factor (GM-CSF) in mice. The present study was designed to elucidate the effects of daily inhalation of diesel exhaust (DE) on the allergen-related respiratory disease. ICR mice were exposed for 40 weeks to clean air or DE at a soot concentration of 0.3, 1.0, or 3.0 mg/m3 with aerosol allergen challenges (1% ovalbumin in isotonic saline for 6 min) at 3-week intervals during the last 24 weeks of exposures. Exposure to DE enhanced allergen-related eosinophil recruitment to the submucosal layers of the airways and to the bronchoalveolar space, and increased protein levels of GM-CSF and IL-5 in the lung in a dose-dependent manner compared to exposure to clean air. There were strong correlations between the number of eosinophils in bronchoalveolar lavage (BAL) fluid and IL-5 concentrations in BAL supernatants and lung tissue supernatants. In addition, the increases in eosinophil recruitment and local cytokine expression were accompanied by goblet cell proliferation in the bronchial epithelium and airway hyperresponsiveness to inhaled acetylcholine. In contrast, the control mice exposed for 40 weeks to clean air or DE at a soot concentration of 0.3, 1.0, or 3.0 mg/m3 without allergen provocation showed no eosinophil recruitment to the submucosal layers of the airways nor to the bronchoalveolar space and few goblet cells in the bronchial epithelium. The present study provides experimental evidence that daily inhalation of DE can enhance allergen-related respiratory diseases such as allergic asthma. This effect may be mediated by the enhanced local expression of IL-5 and GM-CSF. Increased ambient levels of DE may be implicated in the increasing prevalence of bronchial asthma in recent years.

  4. Induction of transient airway hyperresponsiveness by exposure to 4 ppm nitrogen dioxide in guinea pigs

    SciTech Connect

    Kobayashi, T.; Shinozaki, Y. )

    1992-11-01

    In the present study, we investigated (1) whether airway responsiveness to inhaled histamine-aerosol could be induced during 7-d exposure of guinea pigs to 4 ppm NO[sub 2] and, if so, (2) whether thromboxane A2 may be involved in such increase. Female Hartley guinea pigs were divided into 6 groups (n = 15/group). Three groups were exposed to filtered air and the other 3 groups were exposed to NO[sub 2] for 1, 3, or 7 d (24 h/d). Baseline specific airway resistance (SRaw) did not change significantly after exposure to 4 ppm NO[sub 2] or air. Airway responsiveness was determined 1 wk before the beginning of exposure and on the day of termination of the exposure. Prior to exposure to NO[sub 2], the EC200His, the concentrations of inhaled histamine necessary to double SRawNaCl (SRaw after inhalation of 0.9% NaCl), were 1.07 [plus minus] 0.20, 1.30 [plus minus] 0.20, and 1.01 [plus minus] 0.18 mM for the 3 groups later given NO[sub 2] for 1, 3, and 7 d, respectively. Following exposure to NO[sub 2] for 1, 3, or 7 d, EC200His values were 1.42 [plus minus] 0.25, 0.66 [plus minus] 0.10 (p < .05), and 1.05 [plus minus] 0.22 mM, respectively. These results show that 7-d exposure to 4 ppm NO[sub 2] induced a significant increase in airway responsiveness on d 3. Exposure to air had no significant effect on the airway responsiveness. This transient hyperresponsiveness was inhibited by a specific inhibitor of thromboxane synthetase, OKY 046. These results indicated that (1) a lower concentration (4 ppm) of NO[sub 2] than that previously reported can induce transient hyperresponsiveness in guinea pigs during appropriate long-term exposure, and (2) thromboxane A2 may play an important role in this transient airway hyperresponsiveness.

  5. Concomitant Exposure to Ovalbumin and Endotoxin Augments Airway Inflammation but Not Airway Hyperresponsiveness in a Murine Model of Asthma

    PubMed Central

    Mac Sharry, John; Shalaby, Karim H.; Marchica, Cinzia; Farahnak, Soroor; Chieh-Li, Tien; Lapthorne, Susan; Qureshi, Salman T.; Shanahan, Fergus; Martin, James G.

    2014-01-01

    Varying concentrations of lipopolysaccharide (LPS) in ovalbumin (OVA) may influence the airway response to allergic sensitization and challenge. We assessed the contribution of LPS to allergic airway inflammatory responses following challenge with LPS-rich and LPS-free commercial OVA. BALB/c mice were sensitized with LPS-rich OVA and alum and then underwent challenge with the same OVA (10 µg intranasally) or an LPS-free OVA. Following challenge, bronchoalveolar lavage (BAL), airway responsiveness to methacholine and the lung regulatory T cell population (Treg) were assessed. Both OVA preparations induced BAL eosinophilia but LPS-rich OVA also evoked BAL neutrophilia. LPS-free OVA increased interleukin (IL)-2, IL-4 and IL-5 whereas LPS-rich OVA additionally increased IL-1β, IL-12, IFN-γ, TNF-α and KC. Both OVA-challenged groups developed airway hyperresponsiveness. TLR4-deficient mice challenged with either OVA preparation showed eosinophilia but not neutrophilia and had increased IL-5. Only LPS-rich OVA challenged mice had increased lung Tregs and LPS-rich OVA also induced in vitro Treg differentiation. LPS-rich OVA also induced a Th1 cytokine response in human peripheral blood mononuclear cells.We conclude that LPS-rich OVA evokes mixed Th1, Th2 and innate immune responses through the TLR-4 pathway, whereas LPS-free OVA evokes only a Th2 response. Contaminating LPS is not required for induction of airway hyperresponsiveness but amplifies the Th2 inflammatory response and is a critical mediator of the neutrophil, Th1 and T regulatory cell responses to OVA. PMID:24968337

  6. Usefulness of impulse oscillometry for the assessment of airway hyperresponsiveness in mild-to-moderate adult asthma.

    PubMed

    Short, Philip M; Anderson, William J; Manoharan, Arvind; Lipworth, Brian J

    2015-07-01

    Impulse oscillometry (IOS) is a novel method of assessing airway resistance. IOS is rarely used in assessing airway resistance after bronchoprovocation in adult asthma. To ascertain the degree of change in IOS measurements seen in patients with asthma undergoing bronchial challenge testing. Patients 18 to 65 years old with mild to moderate asthma, forced expiratory volume in 1 second (FEV1) greater than 80% predicted, and diurnal FEV1 variation less than 30% and taking inhaled corticosteroid (≤1,000 μg/day of beclomethasone dipropionate equivalent dose) were recruited. Sequential spirometry and IOS results were measured during bronchial challenge testing to inhaled methacholine and histamine. The magnitude of percentage of change demonstrated in total airway resistance at 5 Hz was greater than that observed for FEV1 in the 2 bronchial challenge tests. For example, at a methacholine provocation concentration that caused a decrease in FEV1 of 20%, a 43.5% change (95% confidence interval 29.4-57.5) was seen in total airway resistance at 5 Hz as measured by IOS compared with a 23.3% change (95% confidence interval 18.7-27.9) in FEV1. The magnitude of change seen with other IOS outcomes, including peripheral airway resistance, area under the curve, and resonant frequency, also was greater compared with spirometry. The potential application of IOS in the assessment of airway hyperresponsiveness in adult asthma has been demonstrated. Further population studies are required. www.clinicaltrials.gov (NCT01074853). Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  7. Ozone-induced airway hyperresponsiveness and loss of neuronal M2 muscarinic receptor function.

    PubMed

    Schultheis, A H; Bassett, D J; Fryer, A D

    1994-03-01

    The effect of acute ozone exposure on the function of efferent parasympathetic nerves, M3 muscarinic receptors on airway smooth muscle, and inhibitory M2 muscarinic receptors on the parasympathetic nerves was studied. Immediately after exposure to 2.0 ppm ozone for 4 h, guinea pigs became hyperresponsive to electrical stimulation of the vagus nerves. The normal airway response to intravenous cholinergic agonists at this time demonstrates normal M3 receptor function. M2 muscarinic receptors on the nerves, which normally inhibit release of acetylcholine, were dysfunctional after ozone exposure, as demonstrated by the failure of the muscarinic agonist pilocarpine to inhibit, and the failure of the M2 antagonist gallamine to potentiate, vagally mediated bronchoconstriction. Thus, loss of inhibitory M2 muscarinic receptor function after ozone exposure potentiates release of acetylcholine from the vagus nerves, increasing vagally mediated bronchoconstriction. By 14 days, postozone responses to vagal nerve stimulation were not different from those of air-exposed animals and the function of the neuronal M2 muscarinic receptor was normal, confirming that ozone-induced hyperresponsiveness is reversible.

  8. Prophylactic Supplementation of Bifidobacterium longum 51A Protects Mice from Ovariectomy-Induced Exacerbated Allergic Airway Inflammation and Airway Hyperresponsiveness

    PubMed Central

    Mendes, Eduardo; Acetturi, Beatriz G.; Thomas, Andrew M.; Martins, Flaviano dos S.; Crisma, Amanda R.; Murata, Gilson; Braga, Tárcio T.; Camâra, Niels O. S.; Franco, Adriana L. dos S.; Setubal, João C.; Ribeiro, Willian R.; Valduga, Claudete J.; Curi, Rui; Dias-Neto, Emmanuel; Tavares-de-Lima, Wothan; Ferreira, Caroline M.

    2017-01-01

    Asthma is a chronic inflammatory disease that affects more females than males after puberty, and its symptoms and severity in women change during menstruation and menopause. Recently, evidence has demonstrated that interactions among the microbiota, female sex hormones, and immunity are associated with the development of autoimmune diseases. However, no studies have investigated if therapeutic gut microbiota modulation strategies could affect asthma exacerbation during menstruation and menopause. Here we aimed to examine the preventive effects of a probiotic, Bifidobacterium longum 51A, on airway inflammation exacerbation in allergic ovariectomized mice. We first evaluated the gut microbiota composition and diversity in mice 10 days after ovariectomy. Next, we examined whether re-exposure of ovariectomized allergic mice to antigen (ovalbumin) would lead to exacerbation of lung inflammation. Finally, we evaluated the preventive and treatment effect of B. longum 51A on lung inflammation and airway hyperresponsiveness. Our results showed that whereas ovariectomy caused no alterations in the gut microbiota composition and diversity in this animal model, 10 days after ovariectomy, preventive use administration of B. longum 51A, rather than its use after surgery was capable of attenuate the exacerbated lung inflammation and hyperresponsiveness in ovariectomized allergic mice. This prophylactic effect of B. longum 51A involves acetate production, which led to increased fecal acetate levels and, consequently, increased Treg cells in ovariectomized allergic mice. PMID:28959241

  9. Abrogation of airway hyperresponsiveness but not inflammation by rho kinase insufficiency.

    PubMed

    Kasahara, David I; Ninin, Fernanda M C; Wurmbrand, Alison P; Liao, James K; Shore, Stephanie A

    2015-02-01

    Major features of allergic asthma include airway hyperresponsiveness (AHR), eosinophilic inflammation, and goblet cell metaplasia. Rho kinase (ROCK) is a serine/threonine protein kinase that regulates the actin cytoskeleton. By doing so, it can modulate airway smooth muscle cell contraction and leucocyte migration and proliferation. This study was designed to determine the contributions of the two ROCK isoforms, ROCK1 and ROCK2, to AHR, inflammation and goblet cell metaplasia in a mast cell-dependent model of allergic airways disease. Repeated intranasal challenges with OVA caused AHR, eosinophilic inflammation, and goblet cell hyperplasia in wild-type (WT) mice. OVA-induced AHR was partially or completely abrogated in mice haploinsufficient for ROCK2 (ROCK2(+/-) ) or ROCK1 (ROCK1(+/-) ), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK1 and ROCK2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK1(+/-) vs. WT mice. However, in ROCK2(+/-) mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine-induced force generation was reduced in tracheal rings from ROCK1(+/-) and ROCK2(+/-) vs. WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA-challenged mice, without affecting inflammatory responses. In a mast cell model of allergic airways disease, ROCK1 and ROCK2 both contribute to AHR, likely through direct effects on smooth muscle cell and effects on mast cell degranulation. In addition, ROCK2 but not ROCK1 plays a role in allergen-induced goblet cell hyperplasia. © 2014 John Wiley & Sons Ltd.

  10. Inhibitory effects of a standardized extract of Justicia pectoralis in an experimental rat model of airway hyper-responsiveness.

    PubMed

    Moura, Carlos T M; Batista-Lima, Francisco J; Brito, Teresinha S; Silva, Alfredo A V; Ferreira, Luan C; Roque, Cássia R; Aragão, Karoline S; Havt, Alexandre; Fonseca, Francisco N; Leal, Luzia K A M; Magalhães, Pedro J C

    2017-06-01

    Justicia pectoralis is a plant useful for the treatment of respiratory diseases. Here, we studied the antiasthmatic properties of a standardized extract of J. pectoralis (Jp). Ovalbumin (OVA)-sensitized rats were actively challenged with saline or OVA to study airway hyper-responsiveness after oral treatment with saline or Jp. The ability of Jp to inhibit hyper-reactivity was evaluated in isolated trachea mounted in isolated organ bath chamber. Using KCl or carbachol as contractile agents, tracheal rings of OVA-challenged rats contracted with higher magnitude than trachea of rats challenged with saline. Such hyper-responsive phenotype of OVA-challenged tissues decreased with Jp administration. In Ca(+) -free medium, Jp or its major constituent coumarin inhibited preferentially the contractions induced by Ca(2+) addition in tissues of OVA-challenged rats stimulated with KCl or acetylcholine. In tissues depleted of their internal Ca(+) stores in the presence of thapsigargin, Jp inhibited the contraction induced by capacitative Ca(2+) entry. By gavage, Jp abolished the increase caused by challenge with OVA on the levels of IL-1β and TNF-α in the bronchoalveolar fluid and also impaired the changes in gene expression of canonical transient receptor proteins. Jp has antiasthmatic properties in an experimental model that reproduces tracheal hyper-reactivity. © 2017 Royal Pharmaceutical Society.

  11. G Protein βγ-subunit signaling mediates airway hyperresponsiveness and inflammation in allergic asthma.

    PubMed

    Nino, Gustavo; Hu, Aihua; Grunstein, Judith S; McDonough, Joseph; Kreiger, Portia A; Josephson, Maureen B; Choi, John K; Grunstein, Michael M

    2012-01-01

    Since the Gβγ subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gβγ signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gβγ blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gβγ-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease.

  12. G Protein βγ-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

    PubMed Central

    Grunstein, Judith S.; McDonough, Joseph; Kreiger, Portia A.; Josephson, Maureen B.; Choi, John K.; Grunstein, Michael M.

    2012-01-01

    Since the Gβγ subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gβγ signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gβγ blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gβγ-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease. PMID:22384144

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

    NASA Astrophysics Data System (ADS)

    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.

  14. Chronic exposure to ozone causes tolerance to airway hyperresponsiveness in guinea pigs: lack of SOD role.

    PubMed

    Vargas, M H; Romero, L; Sommer, B; Zamudio, P; Gustin, P; Montaño, L M

    1998-05-01

    Tolerance to respiratory effects of O3 has been demonstrated for anatomic and functional changes, but information about tolerance to O3-induced airway hyperresponsiveness (AHR) is scarce. In guinea pigs exposed to air or O3 (0.3 parts/million, 4 h/day, for 1, 3, 6, 12, 24, or 48 days, studied 16-18 h later), pulmonary insufflation pressure changes induced by intravenous substance P (SP, 0.032-3.2 micro ug/kg) were measured, then the animals were subjected to bronchoalveolar lavage (BAL). Bronchial rings with or without phosphoramidon were also evaluated 3 h after air or a single O3 exposure. O3 caused in vivo AHR (increased sensitivity) to SP after 1, 3, 6, 12, and 24 days of exposure compared with control. However, after 48 days of exposure, O3 no longer caused AHR. Total cell, macrophage, neutrophil, and eosinophil counts in BAL were increased in most O3-exposed groups. When data from all animals were pooled, we found a highly significant correlation between degree of airway responsiveness and total cells (r = 0.55), macrophages (r = 0.54), neutrophils (r = 0.47), and eosinophils (r = 0.53), suggesting that airway inflammation is involved in development of AHR to SP. Superoxide dismutase (SOD) levels in BAL fluids were increased (P < 0.05) after 1, 3, 6, and 12 days of O3 exposure and returned to basal levels after 24 and 48 days of exposure. O3 failed to induce hyperresponsiveness to SP in bronchial rings, and phosphoramidon increased responses to SP in air- and O3-exposed groups, suggesting that neutral endopeptidase inactivation was not involved in O3-induced AHR to SP in vivo. We conclude that chronic exposure to 0. 3 ppm O3, a concentration found in highly polluted cities, resulted in tolerance to AHR to SP in guinea pigs by an SOD-independent mechanism.

  15. Airway hyperresponsiveness induced by repeated esophageal infusion of HCl in guinea pigs.

    PubMed

    Cheng, Yan-Mei; Cao, Ai-Li; Zheng, Jian-Pu; Wang, Hong-Wei; Sun, Yong-Shun; Liu, Chun-Fang; Zhang, Bei-Bei; Wang, Yi; Zhu, Sheng-Liang; Wu, Da-Zheng

    2014-11-01

    Gastroesophageal reflux is a common disorder closely related to chronic airway diseases, such as chronic cough, asthma, chronic bronchitis, and chronic obstructive disease. Indeed, gastroesophageal acid reflux into the respiratory tract causes bronchoconstriction, but the underlying mechanisms have still not been clarified. This study aimed to elucidate functional changes of bronchial smooth muscles (BSMs) isolated from guinea pigs in an animal model of gastroesophageal reflux. The marked airway inflammation, hyperresponsiveness and remodeling were observed after guinea pigs were exposed to intraesophageal HCl infusion for 14 days. In addition, contractile responses to acetylcholine (ACh), KCl, electrical field stimulation, and extracellular Ca(2+) were greater in guinea pigs infused with HCl compared with control groups. The L-type voltage-dependent Ca(2+) channels (L-VDCC) blocker, nicardipine, significantly inhibited ACh- and Ca(2+)-enhanced BSM contractions in guinea pigs infused with HCl. The Rho-kinase inhibitor, Y27632, attenuated ACh-enhanced BSM contractions in guinea pigs infused with HCl. Moreover, mRNA and protein expressions for muscarinic M2 and M3 receptors, RhoA, and L-VDCC in BSM were detected by real-time PCR and Western blot. Expressions of mRNA and protein for muscarinic M3 receptors, RhoA, and L-VDCC were greater than in BSM of HCl-infused guinea pigs, whereas levels of muscarinic M2 receptors were unchanged. We demonstrate that acid infusion to the lower esophagus and, subsequently, microaspiration into the respiratory tract in guinea pigs leads to airway hyperresponsiveness and overactive BSM. Functional and molecular results indicate that overactive BSM is the reason for enhancement of extracellular Ca(2+) influx via L-VDCC and Ca(2+) sensitization through Rho-kinase signaling.

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

    SciTech Connect

    Jonasson, Sofia; Wigenstam, Elisabeth; Koch, Bo; Bucht, Anders

    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

  17. OVA-induced airway hyperresponsiveness alters murine heart rate variability and body temperature.

    PubMed

    Domnik, N J; Seaborn, G; Vincent, S G; Akl, S G; Redfearn, D P; Fisher, J T

    2012-01-01

    Altered autonomic (ANS) tone in chronic respiratory disease is implicated as a factor in cardiovascular co-morbidities, yet no studies address its impact on cardiovascular function in the presence of murine allergic airway (AW) hyperresponsiveness (AHR). Since antigen (Ag)-induced AHR is used to model allergic asthma (in which ANS alterations have been reported), we performed a pilot study to assess measurement feasibility of, as well as the impact of allergic sensitization to ovalbumin (OVA) on, heart rate variability (HRV) in a murine model. Heart rate (HR), body temperature (T(B)), and time- and frequency-domain HRV analyses, a reflection of ANS control, were obtained in chronically instrumented mice (telemetry) before, during and for 22 h after OVA or saline aerosolization in sensitized (OVA) or Alum adjuvant control exposed animals. OVA mice diverged significantly from Alum mice with respect to change in HR during aerosol challenge (P < 0.001, Two-Way ANOVA; HR max change Ctrl = +80 ± 10 bpm vs. OVA = +1 ± 23 bpm, mean ± SEM), and displayed elevated HR during the subsequent dark cycle (P = 0.006). Sensitization decreased the T(B) during aerosol challenge (P < 0.001). Sensitized mice had decreased HRV prior to challenge (SDNN: P = 0.038; Low frequency (LF) power: P = 0.021; Low/high Frequency (HF) power: P = 0.042), and increased HRV during Ag challenge (RMSSD: P = 0.047; pNN6: P = 0.039). Sensitized mice displayed decreased HRV subsequent to OVA challenge, primarily in the dark cycle (RMSSD: P = 0.018; pNN6: P ≤ 0.001; LF: P ≤ 0.001; HF: P = 0.040; LF/HF: P ≤ 0.001). We conclude that implanted telemetry technology is an effective method to assess the ANS impact of allergic sensitization. Preliminary results show mild sensitization is associated with reduced HRV and a suppression of the acute T(B)-response to OVA challenge. This approach to assess altered ANS control in the acute OVA model may also be beneficial in chronic AHR models.

  18. Effects of (±)-praeruptorin A on airway inflammation, airway hyperresponsiveness and NF-κB signaling pathway in a mouse model of allergic airway disease.

    PubMed

    Xiong, Youyi; Wang, Junsong; Wu, Feihua; Li, Juan; Zhou, Linfu; Kong, Lingyi

    2012-05-15

    The root of Peucedanum praeruptorum Dunn is a traditional Chinese medicine commonly used to treat asthma in China. (±)-praeruptorin A (PA) is the most abundant constituent of P. praeruptorum Dunn, the effects of which on asthma were investigated using a murine model of allergic airway disease. BALB/c mice were sensitized and challenged by ovalbumin to induce airway inflammation. PA was administered intragastrically before every OVA challenge. Airway responsiveness was measured by a lung function analysis system. The number of total leukocytes in bronchoalveolar lavage fluid was counted using a hemocytometer, and differential cell counts were determined using Diff-Quick-stained smears. Histopathology of lung tissue was analyzed by hematoxylin-eosin and Congo red staining. Levels of inflammatory mediators in bronchoalveolar lavage fluid and immunoglobulins in serum were measured by enzyme-linked immunosorbent assay. The expression of pulmonary eotaxin was detected by immunohistochemistry and reverse transcription polymerase chain reaction. The activation of NF-κB was evaluated by electrophoretic mobility shift assay and western blot analysis. Compared with model group, PA significantly reduced airway hyperresponsiveness and airway eosinophilic inflammation, improved pathologic lesion of the lungs, reduced levels of interleukin (IL)-4, IL-5, IL-13 and LTC₄ in bronchoalveolar lavage fluid and immunoglobulin (Ig) E in serum, and inhibited eotaxin protein and mRNA expression, IκBα degradation, NF-κB nuclear translocation, NF-κB DNA-binding activity and RelA/p65 phosphorylation in lung, which suggested that PA can significantly suppress OVA-induced airway inflammation and airway hyperresponsiveness in mice, showing great therapeutic potential for the treatment of allergic asthma. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Eight-year follow-up of airway hyperresponsiveness in patients with primary Sjögren’s syndrome

    PubMed Central

    Ludviksdottir, Dora; Valtysdottir, Sigridur Th.; Hedenström, Hans; Hällgren, Roger; Gudbjörnsson, Björn

    2017-01-01

    Objective To evaluate in a longitudinal study the influence of airway hyperresponsiveness (AHR) on lung function in patients with primary Sjögren’s syndrome (pSS). Methods Lung function was studied over an eight-year period in 15 patients who fulfilled the Copenhagen criteria for primary Sjögren’s syndrome and who were covered in our earlier published study on AHR in patients with Sjögren’s syndrome. Standard spirometry and measurements of lung volumes, diffusing capacity (DLCO), and AHR to methacholine were performed. Results A significant decline over time was found in total lung capacity (TLC), vital capacity (VC), forced vital capacity (FVC), functional residual capacity (FRC), and expiratory midflows (FEF50). A sign of small airway obstruction (decrease in FEF50) at entry correlated with VC at follow-up (r = .8, P < .003), and the individual change in FEF50 during the observation period correlated with the individual change in VC (r = .6, P < .05). Six patients had increased AHR, and three of them had decreased DLCO. Six of the patients progressively reduced DLCO over time, and five of them had spirometric signs of increased small airway obstruction. Conclusions During this eight-year follow-up we observed that one-third of the patients with pSS developed a significant reduction in lung function. Our findings suggest that small airways obstruction and AHR are associated with reduction of VC and development of impaired DLCO as a sign of interstitial lung disease in this group of patients. PMID:27849141

  20. The antidiabetic agent glibenclamide protects airway hyperresponsiveness and inflammation in mice.

    PubMed

    Cui, Wei; Zhang, Shufang; Cai, Zhijian; Hu, Xinlei; Zhang, Ruifeng; Wang, Yong; Li, Na; Chen, Zhihua; Zhang, Gensheng

    2015-04-01

    Glibenclamide has a newly discovered role in inflammation regulation besides its antidiabetic effect. As an inhibitor of ATP-sensitive potassium (KATP) channel, glibenclamide antagonizes the relaxation of the tracheal smooth muscle. This indicates that glibenclamide might attenuate airway inflammation while aggravate airway hyperresponsiveness (AHR) in asthmatics. Clinically, many diabetics with asthma are prescribed with glibenclamide to control blood glucose. However, whether glibenclamide could exert any effects on asthmatic inflammation remains unknown. Using an ovalbumin (OVA)-induced mouse model of asthma, we evaluated the effects of glibenclamide on the AHR and inflammation. Interestingly, glibenclamide reduced all the cardinal features of asthma in OVA-challenged mice, including AHR, airway inflammation, and T-helper type 2 (Th2) cytokines. Glibenclamide also downregulated OVA-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and phosphorylated signal transducer and activator of transcription 6 (p-STAT6) in the lung. In addition, increased sulfonylurea receptor 1 (SUR1) expression in the lung was observed after the OVA challenge. These findings suggest that the classic sulfonylurea glibenclamide plays an important protective role in the development of asthma, which not only provides the evidence for the safety of prescribed glibenclamide in diabetics combined with asthma but also indicates a possible new therapeutic for asthma via targeting glibenclamide-related pathways.

  1. Are mouse models of asthma appropriate for investigating the pathogenesis of airway hyper-responsiveness?

    PubMed Central

    Kumar, Rakesh K.; Foster, Paul S.

    2012-01-01

    Whether mouse models of chronic asthma can be used to investigate the relationship between airway inflammation/remodeling and airway hyper-responsiveness (AHR) is a vexed question. It raises issues about the extent to which such models replicate key features of the human disease. Here, we review some of the characteristic pathological features of human asthma and their relationship to AHR and examine some limitations of mouse models that are commonly used to investigate these relationships. We compare these conventional models with our mouse model of chronic asthma involving long-term low-level inhalational challenge and review studies of the relationship between inflammation/remodeling and AHR in this model and its derivatives, including models of an acute exacerbation of chronic asthma and of the induction phase of childhood asthma. We conclude that while extrapolating from studies in mouse models to AHR in humans requires cautious interpretation, such experimental work can provide significant insights into the pathogenesis of airway responsiveness and its molecular and cellular regulation. PMID:23060800

  2. Murine lung responses to ambient particulate matter: genomic analysis and influence on airway hyperresponsiveness.

    PubMed

    Wang, Ting; Moreno-Vinasco, Liliana; Huang, Yong; Lang, Gabriel D; Linares, Jered D; Goonewardena, Sascha N; Grabavoy, Alayna; Samet, Jonathan M; Geyh, Alison S; Breysse, Patrick N; Lussier, Yves A; Natarajan, Viswanathan; Garcia, Joe G N

    2008-11-01

    Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) and chronic airway inflammation. Epidemiologic studies have demonstrated that exposures to environmental factors such as ambient particulate matter (PM), a major air pollutant, contribute to increased asthma prevalence and exacerbations. We investigated pathophysiologic responses to Baltimore, Maryland, ambient PM (median diameter, 1.78 mum) in a murine model of asthma and attempted to identify PM-specific genomic/molecular signatures. We exposed ovalbumin (OVA)-sensitized A/J mice intratracheally to PM (20 mg/kg), and assayed both AHR and bronchoalveolar lavage (BAL) on days 1, 4, and 7 after PM exposure. Lung gene expression profiling was analyzed in OVA- and PM-challenged mice. Consistent with this murine model of asthma, we observed significant increases in airway responsiveness in OVA-treated mice, with PM exposure inducing significant changes in AHR in both naive mice and OVA-induced asthmatic mice. PM evoked eosinophil and neutrophil infiltration into airways, elevated BAL protein content, and stimulated secretion of type 1 T helper (T(H)1) cytokines [interferon-gamma, interleukin-6 (IL-6), tumor necrosis factor-alpha] and T(H)2 cytokines (IL-4, IL-5, eotaxin) into murine airways. Furthermore, PM consistently induced expression of genes involved in innate immune responses, chemotaxis, and complement system pathways. This study is consistent with emerging epidemiologic evidence and indicates that PM exposure evokes proinflammatory and allergic molecular signatures that may directly contribute to the asthma susceptibility in naive subjects and increased severity in affected asthmatics.

  3. Epigenetic alterations by DNA methylation in house dust mite-induced airway hyperresponsiveness.

    PubMed

    Shang, Yan; Das, Sandhya; Rabold, Richard; Sham, James S K; Mitzner, Wayne; Tang, Wan-yee

    2013-08-01

    Asthma is one of the most prevalent chronic lung diseases, affecting 235 million individuals around the world, with its related morbidity and mortality increasing steadily over the last 20 years. Exposure to the environmental allergen, house dust mite (HDM), results in airway inflammation with a variable degree of airway obstruction. Although there has been much experimental work in the past using HDM challenge models to understand mechanistic details in allergic inflammation and airway hyperresponsiveness (AHR), there has been no study on reprogramming of lung or airways mediated through epigenetic mechanisms in response to an acute HDM exposure. Male mice, 6 weeks of age, were administrated HDM extracts or saline at Days 1, 14, and 21. Exposure of mice to HDM extracts caused significant airway inflammation and increased AHR. These HDM-challenged mice also exhibited a change in global DNA methylation as compared with saline-exposed (control) mice. Next, by employing methylation-sensitive restriction fingerprinting, we identified a set of genes, showing aberrant methylation status, associated with the HDM-induced AHR. These candidate genes are known to be involved in cAMP signaling (pde4 d), Akt-signaling (akt1 s1), ion transport (tm6 sf1, pom121l2, and slc8a3), and fatty acid metabolism (acsl3). Slc8a3 and acsl3 were down-regulated, whereas pde4 d, akt1 s1, tm6 sf1, and pom121l2 were up-regulated in the mice exposed to HDM. Hence, our results suggest that HDM exposure induces a series of aberrant methylated genes that are potentially important for the development of allergic AHR.

  4. Airway hyperresponsiveness, prevalence of chronic respiratory symptoms, and lung function in workers exposed to irritants.

    PubMed Central

    Kremer, A M; Pal, T M; Boleij, J S; Schouten, J P; Rijcken, B

    1994-01-01

    The association between occupational exposure to airway irritants and the prevalence of chronic respiratory symptoms and level of lung function, and whether these associations were modified by airway hyperresponsiveness, smoking, and a history of allergy were studied in 668 workers from synthetic fibre plants. Respiratory symptoms were recorded with a self administered Dutch version of the British Medical Research Council questionnaire, with additional questions on allergy. Airway responsiveness was measured by a 30 second tidal breathing histamine challenge test. On the basis of job titles and working department, the current state of exposure of all workers was characterised as (1) no exposure, reference group; (2) white collar workers; (3) SO2 HCl, SO4(2); (4) polyester vapour; (5) oil mist and vapour; (6) polyamide and polyester vapour; (7) multiple exposure. Workers exposed to airway irritants were not simultaneously exposed to airborne dust. Airway hyperresponsiveness (AHR), defined as a 20% fall in forced expiratory volume in one second (FEV1) at < or = 32 mg/ml histamine, was present in 23% of the subjects. The association between exposure groups and prevalence of symptoms was estimated by means of multiple logistic regression; the association with level of lung function (forced vital capacity (FVC), FEV1, maximum mid-expiratory flow rate (MMEF)) was estimated by means of multiple linear regression. Both methods allow simultaneous adjustment for potential confounding factors. The exposure groups were associated with a higher prevalence of chronic respiratory symptoms. Lower prevalence of symptoms was found for workers exposed to SO2, HCl, and SO4(2-), most likely due to pre-employment selection procedures. Current smoking, AHR, and a history of allergy were significantly associated with a higher prevalence of chronic respiratory symptoms, independent of each other, and independent of irritant exposure. The association between exposure and prevalence of

  5. Airway hyperresponsiveness, prevalence of chronic respiratory symptoms, and lung function in workers exposed to irritants.

    PubMed

    Kremer, A M; Pal, T M; Boleij, J S; Schouten, J P; Rijcken, B

    1994-01-01

    The association between occupational exposure to airway irritants and the prevalence of chronic respiratory symptoms and level of lung function, and whether these associations were modified by airway hyperresponsiveness, smoking, and a history of allergy were studied in 668 workers from synthetic fibre plants. Respiratory symptoms were recorded with a self administered Dutch version of the British Medical Research Council questionnaire, with additional questions on allergy. Airway responsiveness was measured by a 30 second tidal breathing histamine challenge test. On the basis of job titles and working department, the current state of exposure of all workers was characterised as (1) no exposure, reference group; (2) white collar workers; (3) SO2 HCl, SO4(2); (4) polyester vapour; (5) oil mist and vapour; (6) polyamide and polyester vapour; (7) multiple exposure. Workers exposed to airway irritants were not simultaneously exposed to airborne dust. Airway hyperresponsiveness (AHR), defined as a 20% fall in forced expiratory volume in one second (FEV1) at < or = 32 mg/ml histamine, was present in 23% of the subjects. The association between exposure groups and prevalence of symptoms was estimated by means of multiple logistic regression; the association with level of lung function (forced vital capacity (FVC), FEV1, maximum mid-expiratory flow rate (MMEF)) was estimated by means of multiple linear regression. Both methods allow simultaneous adjustment for potential confounding factors. The exposure groups were associated with a higher prevalence of chronic respiratory symptoms. Lower prevalence of symptoms was found for workers exposed to SO2, HCl, and SO4(2-), most likely due to pre-employment selection procedures. Current smoking, AHR, and a history of allergy were significantly associated with a higher prevalence of chronic respiratory symptoms, independent of each other, and independent of irritant exposure. The association between exposure and prevalence of

  6. Vitamin D deficiency causes airway hyperresponsiveness, increases airway smooth muscle mass, and reduces TGF-β expression in the lungs of female BALB/c mice.

    PubMed

    Foong, Rachel E; Shaw, Nicole C; Berry, Luke J; Hart, Prue H; Gorman, Shelley; Zosky, Graeme R

    2014-01-01

    Abstract Vitamin D deficiency is associated with disease severity in asthma. We tested whether there is a causal association between vitamin D deficiency, airway smooth muscle (ASM) mass, and the development of airway hyperresponsiveness (AHR). A physiologically relevant mouse model of vitamin D deficiency was developed by raising BALB/c mice on vitamin D-deficient or -replete diets. AHR was assessed by measuring lung function responses to increasing doses of inhaled methacholine. Five-micron sections from formalin-fixed lungs were used for ASM measurement and assessment of lung structure using stereological methods. Transforming growth factor (TGF)-β levels were measured in bronchoalveolar lavage fluid (BALF). Lungs were dissected from embryonic day (E) 17.5 vitamin D-deficient and -replete fetal mice for quantification of ASM density and relative gene expression of TGF-β signaling pathway molecules. Eight-week-old adult vitamin D-deficient female mice had significantly increased airway resistance and ASM in the large airways compared with controls. Vitamin D-deficient female mice had a smaller lung volume, volume of parenchyma, and alveolar septa. Both vitamin D-deficient male and female mice had reduced TGF-β levels in BALF. Vitamin D deficiency did not have an effect on ASM density in E17.5 mice, however, expression of TGF-β1 and TGF-β receptor I was downregulated in vitamin D-deficient female fetal mice. Decreased expression of TGF-β1 and TGF-β receptor I during early lung development in vitamin D-deficient mice may contribute to airway remodeling and AHR in vitamin D-deficient adult female mice. This study provides a link between vitamin D deficiency and respiratory symptoms in chronic lung disease.

  7. Chronic Low Dose Chlorine Exposure Aggravates Allergic Inflammation and Airway Hyperresponsiveness and Activates Inflammasome Pathway

    PubMed Central

    Kim, Sae-Hoon; Park, Da-Eun; Lee, Hyun-Seung; Kang, Hye-Ryun; Cho, Sang-Heon

    2014-01-01

    Background Epidemiologic clinical studies suggested that chronic exposure to chlorine products is associated with development of asthma and aggravation of asthmatic symptoms. However, its underlying mechanism was not clearly understood. Studies were undertaken to define the effects and mechanisms of chronic low-dose chlorine exposure in the pathogenesis of airway inflammation and airway hyperresponsiveness (AHR). Methods Six week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low dose chlorine exposure of naturally vaporized gas of 5% sodium hypochlorite solution. Airway inflammation and AHR were evaluated by bronchoalveolar lavage (BAL) cell recovery and non-invasive phlethysmography, respectively. Real-time qPCR, Western blot assay, and ELISA were used to evaluate the mRNA and protein expressions of cytokines and other inflammatory mediators. Human A549 and murine epithelial (A549 and MLE12) and macrophage (AMJ2-C11) cells were used to define the responses to low dose chlorine exposure in vitro. Results Chronic low dose chlorine exposure significantly augmented airway inflammation and AHR in OVA-sensitized and challenged mice. The expression of Th2 cytokines IL-4 and IL-5 and proinflammatory cytokine IL-1β and IL-33 were significantly increased in OVA/Cl group compared with OVA group. The chlorine exposure also activates the major molecules associated with inflammasome pathway in the macrophages with increased expression of epithelial alarmins IL-33 and TSLP in vitro. Conclusion Chronic low dose exposure of chlorine aggravates allergic Th2 inflammation and AHR potentially through activation of inflammasome danger signaling pathways. PMID:25202911

  8. Chronic low dose chlorine exposure aggravates allergic inflammation and airway hyperresponsiveness and activates inflammasome pathway.

    PubMed

    Kim, Sae-Hoon; Park, Da-Eun; Lee, Hyun-Seung; Kang, Hye-Ryun; Cho, Sang-Heon

    2014-01-01

    Epidemiologic clinical studies suggested that chronic exposure to chlorine products is associated with development of asthma and aggravation of asthmatic symptoms. However, its underlying mechanism was not clearly understood. Studies were undertaken to define the effects and mechanisms of chronic low-dose chlorine exposure in the pathogenesis of airway inflammation and airway hyperresponsiveness (AHR). Six week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low dose chlorine exposure of naturally vaporized gas of 5% sodium hypochlorite solution. Airway inflammation and AHR were evaluated by bronchoalveolar lavage (BAL) cell recovery and non-invasive phlethysmography, respectively. Real-time qPCR, Western blot assay, and ELISA were used to evaluate the mRNA and protein expressions of cytokines and other inflammatory mediators. Human A549 and murine epithelial (A549 and MLE12) and macrophage (AMJ2-C11) cells were used to define the responses to low dose chlorine exposure in vitro. Chronic low dose chlorine exposure significantly augmented airway inflammation and AHR in OVA-sensitized and challenged mice. The expression of Th2 cytokines IL-4 and IL-5 and proinflammatory cytokine IL-1β and IL-33 were significantly increased in OVA/Cl group compared with OVA group. The chlorine exposure also activates the major molecules associated with inflammasome pathway in the macrophages with increased expression of epithelial alarmins IL-33 and TSLP in vitro. Chronic low dose exposure of chlorine aggravates allergic Th2 inflammation and AHR potentially through activation of inflammasome danger signaling pathways.

  9. Do individuals with asthma experience airway hyper-responsiveness after exposure to nitrogen dioxide?

    PubMed

    Goodman, Julie E; Kennedy, Erin M; Seeley, Mara

    2017-10-01

    The current 100 ppb short-term National Ambient Air Quality Standard for NO2, and EPA's determination of a causal association for respiratory effects, are based in part on controlled human exposure studies evaluating airway hyper-responsiveness (AHR). A meta-analysis by Goodman et al. (2009) found increased AHR at 100 ppb NO2 but no clear concentration-response relationship up to 600 ppb, and an overall lack of an AHR effect for studies involving exercise or exposure to allergens. Several factors have been suggested to explain why effects on AHR are observed while people are at rest, but not during exercise or after exposure to allergens. These include an exercise-induced refractory period; partial reversal of bronchospasm from use of forced expiration maneuvers; and greater airway responsiveness of participants exposed to NO2 at rest. We reviewed the scientific evidence to determine whether there is biological support for these factors and found that none sufficiently explained the lack of an effect during exercise or after exposure to allergens. In the absence of either a consistent concentration-response or a plausible explanation for the paradoxical AHR findings, the biological significance of these findings is uncertain and provides equivocal support for NO2 as a causal factor of AHR at these exposure levels. Copyright © 2017 Gradient. Published by Elsevier Inc. All rights reserved.

  10. PM2.5-induced airway inflammation and hyperresponsiveness in NC/Nga mice.

    PubMed

    Ogino, Keiki; Nagaoka, Kenjiro; Okuda, Tomoaki; Oka, Akira; Kubo, Masayuki; Eguchi, Eri; Fujikura, Yoshihisa

    2017-03-01

    The allergic inflammatory effects of particulate matter (PM) 2.5, collected with the cyclone system in Yokohama city in Japan, were investigated in NC/Nga mice, which are hypersensitive to mite allergens. PM2.5 with alum was injected intraperitoneally for sensitization. Five days later, 200 μg of PM2.5 in 25 μL of saline was administered to mice intranasally five times for further sensitization. On the 11th day, PM2.5 was administered as a challenge. On the 12th day, mice were examined for airway hyperresponsiveness (AHR), the bronchoalveolar lavage fluid (BALF) cell count, mRNA expression of Th1 , Th2 cytokines, and metallothioneins in lung tissue, and histopathology. PM2.5 increased AHR, total cell numbers including eosinophils in BALF, and mRNA levels of IL-5, IL-22, eotaxin, eotaxin 2, and metallothionein 3. In PM2.5-induced lungs, inflammation was observed around the bronchus. These results demonstrate that PM2.5 alone, collected with the cyclone system in Yokohama city in Japan, induces asthma-like airway inflammation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1047-1054, 2017.

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

    SciTech Connect

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

    2013-11-15

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

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

    PubMed

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

    2010-11-01

    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. We sought to compare AHR to mannitol and methacholine and exhaled nitric oxide (eNO) levels in a nonselected population sample. In 238 young adults randomly drawn from the nationwide civil registration list in Copenhagen, Denmark, AHR to mannitol and methacholine, as well as levels of eNO, were determined, and the association with asthma was analyzed. In diagnosing asthma the specificity of methacholine and mannitol was 80.2% (95% CI, 77.1% to 82.9%) and 98.4% (95% CI, 96.2% to 99.4%), respectively, with a positive predictive value of 48.6% versus 90.4%, whereas the sensitivity was 68.6% (95% CI, 57.1% to 78.4%) and 58.8% (95% CI, 50.7% to 62.6%), respectively. In asthmatic subjects AHR to mannitol was associated with increased eNO levels (positive AHR to mannitol: median, 47 ppb [interquartile range, 35-68 ppb]; negative AHR to mannitol: median, 19 ppb [interquartile range, 13-30 ppb]; P = .001), whereas this was not the case for AHR to methacholine (median of 37 ppb [interquartile range, 26-51 ppb] vs 24 ppb [interquartile range, 15-39 ppb], P = .13). In this random population sample, AHR to mannitol was less sensitive but more specific than methacholine in the diagnosis of asthma. Furthermore, AHR to mannitol was more closely associated with ongoing airway inflammation in terms of increased eNO levels. Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  13. Ingestion of milk containing the Dp2 peptide, a dust mite allergen, protects mice from allergic airway inflammation and hyper-responsiveness

    PubMed Central

    2013-01-01

    Background Allergen-specific immunotherapy has been demonstrated to have potential for the treatment of allergic diseases. Transgenic animals are currently the best available bioreactors to produce recombinant proteins, which can be secreted in milk. It has not been clearly demonstrated whether milk from transgenic animals expressing recombinant allergens has immunomodulatory effects on allergic asthma. Methods We aimed to determine whether the oral administration of milk containing a mite allergen can down-regulate allergen-specific airway inflammation. Transgenic CD-1 mice that express a recombinant group 2 allergen from Dermatophagoides pteronyssinus (Dp2) in their milk were generated using an embryonic gene-microinjection technique. Mouse pups were fed transgenic Dp2-containing milk or wild-type milk. Subsequently, these mice were sensitized and challenged with Dp2 to induce allergic airway inflammation. Results Upon sensitization and challenge, mice fed transgenic Dp2 milk had decreased T-helper 2 (Th2) and increased T-helper 1 (Th1) responses in the airway compared with mice fed wild-type milk. Moreover, pre-treatment with transgenic Dp2 milk attenuated airway inflammation and decreased airway hyper-responsiveness. Conclusions This study provides new evidence that oral administration of transgenic milk containing the Dp2 allergen down-regulated and moderately protected against allergic airway inflammation. Milk from transgenic animals expressing allergens may have potential use in the prevention of allergic asthma. PMID:23763898

  14. Inhalation of inactivated‑Mycobacterium phlei prevents asthma‑mediated airway hyperresponsiveness and airway eosinophilia in mice by reducing IL‑5 and IL‑13 levels.

    PubMed

    Ming, Moyu; Luo, Zhixi; Lv, Shengqiu; Li, Chaoqian

    2016-12-01

    The present study aimed to investigate whether inhalation of inactivated‑Mycobacterium phlei could prevent airway hyperresponsiveness and airway eosinophilia. A total of 24 male Balb/c mice were randomly divided into three groups: Normal control group (group A), asthma model group (group B) and the intervention group (group C), (8 mice/group). Group A mice were sensitized and with challenged saline and group B with ovalbumin (OVA). Group C mice were administered with aerosol Mycobacterium phlei once daily prior to the allergen challenge. Airway responsiveness in each group was assessed. All the animals were sacrificed and lung tissues, blood samples and bronchoalveolar lavage fluid (BALF) were harvested. Cell fractionation and differential cells were counted in serum and BALF. HE staining and alcian blue/periodic acid Schiff staining were used to measure airway eosinophilic inflammation and mucus production. The levels of the cytokines IL‑5, IL‑13 and IgE were measured in lung and BALF as determined by ELISA and reverse transcription‑quantitative polymerase chain reaction assays. The results indicated that inactivated‑Mycobacterium phlei suppressed the airway hyperresponsiveness and mitigated airway eosinophilia induced by a methacholine challenge, and significantly reduced the levels of cytokines IL‑5 and IL‑13 in lung tissue and IgE level in BALF when compared with the OVA‑sensitized mice. In conclusion, inhalation of inactivated‑Mycobacterium phlei could reduce OVA‑induced airway hyperresponsiveness and may be a potential alternative therapy for allergic airway diseases.

  15. Stimulation of protease-activated receptor-2 inhibits airway eosinophilia, hyperresponsiveness and bronchoconstriction in a murine model of allergic inflammation

    PubMed Central

    De Campo, Benjamin A; Henry, Peter J

    2005-01-01

    An emerging body of evidence indicates that PGE2 has a privileged anti-inflammatory role within the airways. Stimulants of protease-activated receptor-2 (PAR2) inhibit airway smooth muscle tone in vitro and in vivo predominantly via cyclooxygenase (COX)-dependent generation of prostaglandin E2 (PGE2). Thus, the current study tested the hypothesis that PAR2-induced generation of PGE2 inhibits the development of allergic airways inflammation and hyperresponsiveness. Bronchoalveolar lavage (BAL) fluid recovered from ovalbumin (OVA)-sensitised and -challenged (allergic) mice contained elevated numbers of eosinophils, which peaked at 48 h postchallenge. Intranasal (i.n.) administration of a PAR2-activating peptide (PAR2-AP) SLIGRL (25 mg kg−1, at the time of OVA challenge) caused a 70% reduction in the numbers of BAL eosinophils (compared to the scrambled peptide LSIGRL, 25 mg kg−1). Pretreatment of allergic mice with either indomethacin (1 mg kg−1, dual COX inhibitor) or nimesulide (3 mg kg−1, COX-2-selective inhibitor) blocked SLIGRL-induced reductions in BAL eosinophils. I.n. SLIGRL, but not LSIGRL, inhibited the development of antigen-induced airways hyperresponsiveness. The inhibitory effect of SLIGRL was blocked by indomethacin. Exposure of isolated tracheal preparations from allergic mice to 100 μM SLIGRL was associated with a 5.0-fold increase in PGE2 levels (P<0.05, compared to 100 μM LSIGRL). SLIGRL induced similar increases in PGE2 levels in control mice (OVA-sensitised, saline-challenged). I.n. administration of PGE2 (0.15 mg kg−1) to allergic mice significantly inhibited eosinophilia and airways hyperresponsiveness to methacholine. In anaesthetised, ventilated allergic mice, SLIGRL (5 mg kg−1, i.v.) inhibited methacholine-induced increases in airways resistance. Consistent with this bronchodilator effect, SLIGRL induced pronounced relaxation responses in isolated tracheal preparations obtained from allergic mice

  16. Accumulating evidence for increased velocity of airway smooth muscle shortening in asthmatic airway hyperresponsiveness.

    PubMed

    Ijpma, Gijs; Matusovsky, Oleg; Lauzon, Anne-Marie

    2012-01-01

    It remains unclear whether airway smooth muscle (ASM) mechanics is altered in asthma. While efforts have originally focussed on contractile force, some evidence points to an increased velocity of shortening. A greater rate of airway renarrowing after a deep inspiration has been reported in asthmatics compared to controls, which could result from a shortening velocity increase. In addition, we have recently shown in rats that increased shortening velocity correlates with increased muscle shortening, without increasing muscle force. Nonetheless, establishing whether or not asthmatic ASM shortens faster than that of normal subjects remains problematic. Endobronchial biopsies provide excellent tissue samples because the patients are well characterized, but the size of the samples allows only cell level experiments. Whole human lungs from transplant programs suffer primarily from poor patient characterization, leading to high variability. ASM from several animal models of asthma has shown increased shortening velocity, but it is unclear whether this is representative of human asthma. Several candidates have been suggested as responsible for increased shortening velocity in asthma, such as alterations in contractile protein expression or changes in the contractile apparatus structure. There is no doubt that more remains to be learned about the role of shortening velocity in asthma.

  17. The effect of platelet activating factor antagonist on ozone-induced airway inflammation and bronchial hyperresponsiveness in guinea pigs

    SciTech Connect

    Tan, W.C.; Bethel, R.A. )

    1992-10-01

    We investigated the role of platelet-activating factor (PAF) in ozone-induced airway responses by examining the effects of L659,989, a potent PAF antagonist, on bronchial hyperresponsiveness and airway inflammation. Twenty-four male guinea pigs were studied in four equal groups. Total lung resistance (RL) in intubated and spontaneously breathing animals was measured in a constant-volume body plethysmograph. Dose-response curves to methacholine were determined in all animals at the start of the experiment. These were repeated on a separate day after the following types of treatments: air exposure in Group 1, intraperitoneally administered alcohol and air exposure in Group 2; intraperitoneally administered alcohol and ozone exposure in Group 3, and intraperitoneally administered L659,989 (a specific PAF antagonist), 5 mg/kg dissolved in alcohol, and ozone exposure in Group 4. Bronchoalveolar lavage (BAL) was performed after the second methacholine challenge, and the bronchial mucosa was also examined for inflammatory cells. Exposure to 3 ppm ozone for 2 h resulted in a three-doubling concentration increase in bronchial responsiveness, which was not significantly inhibited by prior treatment with L659,989. Ozone induced a 1.8-fold increase in BAL total cell count, increased eosinophilic influx into the airways, and increased eosinophilic infiltration in the bronchial mucosa, which were all not inhibited by L659,989 pretreatment. The results suggest that PAF may not have an essential role in ozone-induced airway hyperresponsiveness and nonallergic airway inflammation.

  18. Interaction of ozone exposure with airway hyperresponsiveness and inflammation induced by trimellitic anhydride in sensitized guinea pigs

    SciTech Connect

    Sun, Jian; Chung, K.Fan

    1997-09-01

    The effect of prior ozone (O{sub 3}) exposure on airway hyperresponsiveness and inflammation induced by trimellitic anhydride (TMA) has been investigated in TMA-sensitized guinea pigs. Airway responsiveness was measured as the concentration of acetylcholine needed to increase baseline lung resistance (RL) by 300% (PC300). Ozone (3 ppm, for 3 h) caused an increase in-log PC300 at 1 h after exposure, with return of -log PC300 to control levels at 8 h. Ozone also increased baseline RL at 8 h. TMA challenge increase -log PC300 in TMA-sensitized guinea pigs at 8 h after challenge from 3.85 {+-} 0.09 to 4.11 {+-} 0.09. Ozone exposure prior to TMA challenge prevented the induction of airway hyperresponsiveness with a mean -log PC300 of 3.51 {+-} 0.20, which was not different from that of control TMA-Sensitized group. Baseline RL was significantly higher in ozone-pretreated animals after TMA challenge when compared to those of either control or challenged with TMA alone. Ozone had no effect on TMA challenge-induced BAL eosinophilia and neutrophilia. We conclude that a single exposure to ozone inhibits the increase in airway responsiveness, but increases the bronchoconstrictor response induced by TMA in TMA-Sensitized guinea pigs; however, the inflammatory airway response to TMA is unchanged by preexposure to ozone. 29 refs., 2 figs., 1 tab.

  19. Effects of fluticasone vs. fluticasone/salmeterol on airway calibre and airway hyperresponsiveness in mild persistent asthma

    PubMed Central

    Currie, Graeme P; Stenback, Suvi; Lipworth, Brian J

    2003-01-01

    Aims Inhaled corticosteroids alone or in combination with long acting β2-agonists are indicated for use in mild persistent asthmatics. We set out to evaluate effects on airway hyperresponsiveness (AHR) and airway calibre using hydrofluoroalkane fluticasone/salmeterol (FP/SM) vs. double the dose of fluticasone alone (FP). Methods Fourteen mild persistent asthmatics completed a randomized double-blind crossover study with 1-week run-in and washout periods prior to treatments. Subjects received 3 weeks of FP 250 µg or FP 125 µg/SM 25 µg as 1 puff twice daily. Methacholine PD20 and lung function were measured after both baseline and treatment periods. Results There were no significant differences in baseline values prior to randomized treatments. Compared with pooled baseline, FP/SM and FP conferred improvements (P < 0.05) on methacholine PD20: 2.5 (95% confidence interval 1.7, 3.2) and 1.6 (0.8–2.3) doubling dose improvements, respectively; between FP/SM vs. FP there was a 0.9 (0.4, 1.4) doubling dose difference (P < 0.05). For forced expiratory volume in 1 s (FEV1), forced mid-expiratory flow (FEF25−75) and morning peak expiratory flow (PEF), FP/SM but not FP conferred improvements (P < 0.05) compared with pooled baseline, with FP/SM being greater than FP (P < 0.05): differences in FEV1 of 7.2% (3.8, 10.6) predicted, FEF25−75 of 11.2% (6.3, 16.1) predicted, and morning PEF of 17 L min−1(1–32). Conclusions FP/SM conferred improvements on AHR and airway calibre, while twice the dose of FP improved only AHR in patients with mild asthma. The differential effects of FP/SM and FP suggest separate but complementary actions of the two moieties on airway inflammation and smooth muscle stabilization. This may explain the beneficial effects of combination inhalers on exacerbations. PMID:12848770

  20. Bronchial hyperresponsiveness to mannitol, airway inflammation and Asthma Control Test in atopic asthmatic children.

    PubMed

    Attanasi, Marina; Consilvio, Nicola P; Rapino, Daniele; Nicola, Marta Di; Scaparrotta, Alessandra; Cingolani, Anna; Petrosino, Marianna I; Filippo, Paola Di; Di Pillo, Sabrina; Chiarelli, Francesco

    2016-02-01

    The aim of this study was to evaluate the relationship between airway hyperresponsiveness (AHR) to mannitol and bronchial inflammation measured as exhaled nitric oxide (FeNO) and to assess whether asthma control correlates with AHR to mannitol and FeNO in atopic asthmatic children. Allergy evaluation, the mannitol challenge test, FeNO levels and the Asthma Control Test (ACT) questionnaire were assessed in 40 children with intermittent and mild persistent allergic asthma. All the subjects showed positive AHR to mannitol. Pearson's correlation test revealed a significant inverse correlation between AHR (mannitol PD15) and FeNO (p = 0.020). There was also a significant positive correlation between ACT and PD15 (p = 0.020) and a significant negative correlation between ACT and FeNO levels (p = 0.003). The study population was divided into two groups according to FeNO levels (group A ≥ 16 ppb vs. group B < 16 ppb). In group A mannitol PD15 was significantly lower (p = 0.040) and ACT score values were significantly lower (p = 0.001) compared to group B. In group A, the ACT showed that 13.3% of subjects had well-controlled asthma, 80% had partially controlled asthma and 6.7% had uncontrolled asthma. In group B, the ACT showed that 72% of subjects had well-controlled asthma and 28% had partially controlled asthma. Our findings indicate that the degree of AHR to mannitol correlates with the degree of airway inflammation in asthmatic atopic children; moreover, better control of asthma correlates with a lower degree of AHR to both mannitol and FeNO.

  1. Bronchial hyperresponsiveness to mannitol, airway inflammation and Asthma Control Test in atopic asthmatic children

    PubMed Central

    Consilvio, Nicola P.; Rapino, Daniele; Nicola, Marta Di; Scaparrotta, Alessandra; Cingolani, Anna; Petrosino, Marianna I.; Filippo, Paola Di; Pillo, Sabrina Di; Chiarelli, Francesco

    2016-01-01

    Introduction The aim of this study was to evaluate the relationship between airway hyperresponsiveness (AHR) to mannitol and bronchial inflammation measured as exhaled nitric oxide (FeNO) and to assess whether asthma control correlates with AHR to mannitol and FeNO in atopic asthmatic children. Material and methods Allergy evaluation, the mannitol challenge test, FeNO levels and the Asthma Control Test (ACT) questionnaire were assessed in 40 children with intermittent and mild persistent allergic asthma. Results All the subjects showed positive AHR to mannitol. Pearson's correlation test revealed a significant inverse correlation between AHR (mannitol PD15) and FeNO (p = 0.020). There was also a significant positive correlation between ACT and PD15 (p = 0.020) and a significant negative correlation between ACT and FeNO levels (p = 0.003). The study population was divided into two groups according to FeNO levels (group A ≥ 16 ppb vs. group B < 16 ppb). In group A mannitol PD15 was significantly lower (p = 0.040) and ACT score values were significantly lower (p = 0.001) compared to group B. In group A, the ACT showed that 13.3% of subjects had well-controlled asthma, 80% had partially controlled asthma and 6.7% had uncontrolled asthma. In group B, the ACT showed that 72% of subjects had well-controlled asthma and 28% had partially controlled asthma. Conclusions Our findings indicate that the degree of AHR to mannitol correlates with the degree of airway inflammation in asthmatic atopic children; moreover, better control of asthma correlates with a lower degree of AHR to both mannitol and FeNO. PMID:26925129

  2. Dietary omega-3 polyunsaturated fatty acid supplementation and airway hyperresponsiveness in asthma.

    PubMed

    Mickleborough, Timothy D

    2005-06-01

    Asthma prevalence continues to increase despite the progress that has been made in the treatment options for asthma. Alternative treatment therapies that reduce the dose requirements of pharmacological interventions would be beneficial, and could potentially reduce the public health burden of this disease. There is accumulating evidence that dietary modification has potential to influence the severity of asthma and reduce the prevalence and incidence of this condition. A possible contributing factor to the increased incidence of asthma in Western societies may the consumption of a pro-inflammatory diet. In the typical Western diet, 20-25-fold more omega (n)-6 polyunsaturated fatty acids (PUFA) than n-3 PUFA are consumed, which results in the release of pro-inflammatory arachidonic acid metabolites. Eicosapentaenoic acid and docosahexaenoic acid are n-3 PUFA derived from fish oil that competitively inhibit n-6 PUFA arachidonic acid (AA) metabolism and this reduce the generation of pro-inflammatory 4-series leukotrienes (LTs) and 2-series prostaglandins (PGs) and production of cytokines from inflammatory cells. These data are consistent with the proposed pathway by which dietary intake of n-3 PUFA modulates lung disease. This article will review the existing information concerning the relationship between n-3 PUFA supplementation and airway hyperresponsiveness in asthma. It includes studies assessing the efficacy of n-3 PUFA supplementation in exercise-induced bronchoconstriction. This review will also address the question as to whether supplementing the diet with n-3 PUFA represents a viable alternative treatment regimen for asthma.

  3. Relationship of non-specific airway hyperresponsiveness (AHR) to measures of peak expiratory flow (PEF) variability.

    PubMed

    Kolbe, J; Richards, G; Mercer-Fenwick, J; Rea, H

    1996-02-01

    The relationship between airway hyper-responsiveness (AHR) and clinical asthma remains controversial and unclear. To test the hypothesis that serial measures of variability of peak expiratory flow rate (PEF) correlate with serial measures of AHR, and to determine which mathematical expression of variability provides the best correlation. A longitudinal study over 180 days of 20 atopic, moderately severe asthmatics was undertaken. A diary of medication use and morning and evening PEFR before and after beta agonist was kept and AHR (PD20 histamine) was measured at three-weekly intervals. Using group data (128 sets) in PD20 was correlated with various measures of PEF variability over 9 days. [Table: see text] Within the group there was a weak but highly statistically significant correlation between AHR and measures of PEF variability--the strongest correlation being with mean morning PEF. Within individual subjects, however, the correlation was not a consistent finding and only four patients had a statistically significant relationship (p < 0.05) between AHR and mean morning PEF. These results suggest that while PEF variability may reflect AHR for the purposes of epidemiologic studies, it is unlikely to be useful as a simple 'non-invasive' means of assessing AHR in individual patients. More complex measures of PEF variability do not have an advantage over simpler measures such as mean morning PEF.

  4. Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma

    PubMed Central

    Abdala-Valencia, Hiam; Earwood, Julie; Bansal, Shelly; Jansen, Michael; Babcock, George; Garvy, Beth; Wills-Karp, Marsha; Cook-Mills, Joan M.

    2009-01-01

    Pulmonary eosinophilia is one of the most consistent hallmarks of asthma. Infiltration of eosinophils into the lung in experimental asthma is dependent on the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. Ligation of VCAM-1 activates endothelial cell NADPH oxidase, which is required for VCAM-1-dependent leukocyte migration in vitro. To examine whether endothelial-derived NADPH oxidase modulates eosinophil recruitment in vivo, mice deficient in NADPH oxidase (CYBB mice) were irradiated and received wild-type hematopoietic cells to generate chimeric CYBB mice. In response to ovalbumin (OVA) challenge, the chimeric CYBB mice had increased numbers of eosinophils bound to the endothelium as well as reduced eosinophilia in the lung tissue and bronchoalveolar lavage. This occurred independent of changes in VCAM-1 expression, cytokine/chemokine levels (IL-5, IL-10, IL-13, IFNγ, or eotaxin), or numbers of T cells, neutrophils, or mononuclear cells in the lavage fluids or lung tissue of OVA-challenged mice. Importantly, the OVA-challenged chimeric CYBB mice had reduced airway hyperresponsiveness (AHR). The AHR in OVA-challenged chimeric CYBB mice was restored by bypassing the endothelium with intratracheal administration of eosinophils. These data suggest that VCAM-1 induction of NADPH oxidase in the endothelium is necessary for the eosinophil recruitment during allergic inflammation. Moreover, these studies provide a basis for targeting VCAM-1-dependent signaling pathways in asthma therapies. PMID:17293377

  5. Antibody to very late activation antigen 4 prevents interleukin-5-induced airway hyperresponsiveness and eosinophil infiltration in the airways of guinea pigs.

    PubMed

    Kraneveld, A D; van Ark, I; Van Der Linde, H J; Fattah, D; Nijkamp, F P; Van Oosterhout, A J

    1997-08-01

    This study examines the effect of monoclonal antibody to very late activation antigen-4 (VLA-4) on IL5-induced airway hyperresponsiveness in vivo and eosinophil accumulation into guinea pig airways. IL5 has been shown to be important in the development of airway hyperresponsiveness and eosinophil accumulation in the guinea pig. Eosinophils, unlike neutrophils, express VLA-4 which mediates the adhesion to vascular cell adhesion molecule-1 on endothelial cells. Thus VLA-4 seems to be an important adhesion molecule in the infiltration of eosinophils from the vasculature into the airway tissue. In addition, it has been shown that IL5 activates VLA-4 on eosinophils to facilitate their adhesion. In the present study, IL5 (1 microg, twice on one day) or vehicle were administered intranasally. Monoclonal antibody (mAb) to VLA-4 (HP1/2) or the isotype-matched control mAb (1E6) were injected 1 hour before each IL5 or vehicle treatment at a dose of 2.5 mg/kg body weight. The next day in vivo bronchial reactivity, eosinophil number in bronchoalveolar lavage (BAL) fluid, and eosinophil peroxidase (EPO) activity in cell-free BAL fluid were determined. IL5 induces an increase in bronchial reactivity to histamine, which is associated with an accumulation of eosinophils into BAL fluid (control: 12 (5 to 42) x 10(5) cells and IL5: 69 (11 to 99) x 10(5) cells, p < 0.05) and an increase of 35% +/- 14% in EPO activity in cell-free BAL fluid. Intravenous administration of anti-VLA-4 mAb, but not of the control antibody, completely inhibits the bronchial hyperresponsiveness as well as the airway eosinophilia found after intraairway application of IL5. HP1/2 also suppresses the IL5-induced increase in EPO activity in cell-free BAL fluid. In conclusion, for the development of IL5-induced airway hyperresponsiveness in the guinea pig, the VLA-4-dependent infiltration and activation of eosinophils in the bronchial tissue seems to be essential.

  6. Amb a 1-linked CpG oligodeoxynucleotides reverse established airway hyperresponsiveness in a murine model of asthma.

    PubMed

    Santeliz, Joanna V; Van Nest, Gary; Traquina, Paula; Larsen, Elizabeth; Wills-Karp, Marsha

    2002-03-01

    Recently, it has been demonstrated that immunostimulatory DNA sequences (ISS) containing CpG motifs prevent the development of allergic airway responses in murine models of disease. However, few studies have addressed the issue of whether these agents will reverse established Tm(H)2-driven allergic airway responses. The aim of this study was to determine whether intradermal delivery of an immunogenic protein of ragweed pollen linked to an immunostimulatory DNA sequence could reverse an established allergic response in the mouse lung. Mice sensitized and challenged with ragweed pollen extract were treated intradermally twice at 1-week intervals with an ISS chemically linked to Amb a 1 (Amb a 1-ISS). One week after the Amb a 1-ISS treatment, mice were rechallenged intratracheally with ragweed extract, and airway responses were assessed. Amb a 1-ISS treatment of ragweed-sensitized and ragweed-challenged mice significantly reversed allergen-induced airway hyperresponsiveness and suppressed the total number of eosinophils in bronchoalveolar lavage fluid. The inhibitory effect of Amb a 1-ISS was associated with a marked increase in IFN-gamma levels by Amb a 1-stimulated splenocytes and a shift in the antibody profile from a T(H)2-directed IgG1 response to a T(H)1-directed IgG2a response. Interestingly, the inhibitory effect of Amb a 1-ISS on allergen-driven airway hyperresponsiveness was independent of suppression of T(H)2 cytokine production. These results demonstrate that intradermal delivery of allergen-specific DNA conjugates can reverse established allergic responses in the murine lung, supporting their potential use in the treatment of human asthma.

  7. Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection

    PubMed Central

    Zang, Na; Zhuang, Jianguo; Deng, Yu; Yang, Zhimei; Ye, Zhixu; Xie, Xiaohong; Ren, Luo; Fu, Zhou; Luo, Zhengxiu; Xu, Fadi

    2015-01-01

    ABSTRACT Children with acute respiratory syncytial virus (RSV) infection often develop sequelae of persistent airway inflammation and wheezing. Pulmonary C fibers (PCFs) are involved in the generation of airway inflammation and resistance; however, their role in persistent airway diseases after RSV is unexplored. Here, we elucidated the pathogenesis of PCF activation in RSV-induced persistent airway disorders. PCF-degenerated and intact mice were used in the current study. Airway inflammation and airway resistance were evaluated. MMP408 and FSLLRY-NH2 were the selective antagonists for MMP-12 and PAR2, respectively, to investigate the roles of MMP-12 and PAR2 in PCFs mediating airway diseases. As a result, PCF degeneration significantly reduced the following responses to RSV infection: augmenting of inflammatory cells, especially macrophages, and infiltrating of inflammatory cells in lung tissues; specific airway resistance (sRaw) response to methacholine; and upregulation of MMP-12 and PAR2 expression. Moreover, the inhibition of MMP-12 reduced the total number of cells and macrophages in bronchiolar lavage fluid (BALF), as well infiltrating inflammatory cells, and decreased the sRaw response to methacholine. In addition, PAR2 was upregulated especially at the later stage of RSV infection. Downregulation of PAR2 ameliorated airway inflammation and resistance following RSV infection and suppressed the level of MMP-12. In all, the results suggest that PCF involvement in long-term airway inflammation and airway hyperresponsiveness occurred at least partially via modulating MMP-12, and the activation of PAR2 might be related to PCF-modulated MMP-12 production. Our initial findings indicated that the inhibition of PCF activity would be targeted therapeutically for virus infection-induced long-term airway disorders. IMPORTANCE The current study is critical to understanding that PCFs are involved in long-term airway inflammation and airway resistance after RSV infection

  8. Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

    PubMed Central

    Lanza, Gregory M.; Jenkins, John; Schmieder, Anne H.; Moldobaeva, Aigul; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Zhong, Qiong; Keupp, Jochen; Sergin, Ismail; Paranandi, Krishna S.; Eldridge, Lindsey; Allen, John S.; Williams, Todd; Scott, Michael J.; Razani, Babak; Wagner, Elizabeth M.

    2017-01-01

    Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvβ3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of αvβ3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous 19F/1H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvβ3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvβ3-No-Drug micelles while αvβ3-Dxtl-PD or αvβ3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvβ3+ macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvβ3-Dxtl-PD micelles. Additionally, αvβ3-Dxtl-PD decreased BAL eosinophil and αvβ3+ CD45+ leukocytes relative to αvβ3-No-Drug micelles, whereas αvβ3-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in a

  9. Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat.

    PubMed

    Lanza, Gregory M; Jenkins, John; Schmieder, Anne H; Moldobaeva, Aigul; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Zhong, Qiong; Keupp, Jochen; Sergin, Ismail; Paranandi, Krishna S; Eldridge, Lindsey; Allen, John S; Williams, Todd; Scott, Michael J; Razani, Babak; Wagner, Elizabeth M

    2017-01-01

    Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvβ3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of αvβ3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous (19)F/(1)H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvβ3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvβ3-No-Drug micelles while αvβ3-Dxtl-PD or αvβ3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvβ3(+) macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvβ3-Dxtl-PD micelles. Additionally, αvβ3-Dxtl-PD decreased BAL eosinophil and αvβ3(+) CD45(+) leukocytes relative to αvβ3-No-Drug micelles, whereas αvβ3-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in

  10. Transient receptor potential melastatin 8 gene polymorphism is associated with cold-induced airway hyperresponsiveness in bronchial asthma.

    PubMed

    Naumov, Denis E; Perelman, Juliy M; Kolosov, Victor P; Potapova, Tatyana A; Maksimov, Vladimir N; Zhou, Xiangdong

    2015-11-01

    Cold-induced airway hyperresponsiveness (CAH) is common in bronchial asthma (BA) patients and represents a problem for those living in cold climate. Transient receptor potential melastatin 8 (TRPM8) channel is the main cold temperature sensor in humans that could mediate cold response in asthmatics with CAH. No associations between TRPM8 gene polymorphisms and CAH have been reported. The present study involved 123 BA patients. CAH was assessed by 3-min isocapnic (5% CO2 ) cold air (-20°C) hyperventilation challenge. The c.750G > C (rs11562975), c.1256G > A (rs7593557), c.3048C > T (rs11563208) and c.3174C > G (rs11563071) polymorphisms of TRPM8 gene were genotyped by allele-specific polymerase chain reaction (PCR) and PCR with subsequent restriction fragment length polymorphism analysis. GC genotype and C allele carriers of the c.750G > C (rs11562975) polymorphism were more frequently observed to exhibit CAH. The estimated odds ratio for the GC genotype was 3.73 95%CI (1.48; 9.37), P = 0.005. Furthermore, GC heterozygotes had a prominent decrease in forced expiratory volume in 1 s after the challenge as compared to GG homozygotes (-12% (-16; -8.1) vs -6.45% (-11; -2.1), P < 0.001). GC carriers also had a marked reduction in other spirometric parameters. The GC variant of the TRPM8:c.750G > C (rs11562975) polymorphism is associated with CAH in patients with BA, which suggests a potential role of TRPM8 in CAH development. © 2015 Asian Pacific Society of Respirology.

  11. AIRWAY HYPERRESPONSIVENESS IN MICE FOLLOWING ANTIGEN AND PARTICULATE MATTER EXPOSURE IS VAGALLY MEDIATED

    EPA Science Inventory

    Sensory nerves within the airways can initiate a variety of protective reflexes. We hypothesized that insults such as exposure to antigen and particulate matter (PM) might dysregulate airway sensory nerve function, thereby contributing to enhanced airway inflammation and hyperre...

  12. AIRWAY HYPERRESPONSIVENESS IN MICE FOLLOWING ANTIGEN AND PARTICULATE MATTER EXPOSURE IS VAGALLY MEDIATED

    EPA Science Inventory

    Sensory nerves within the airways can initiate a variety of protective reflexes. We hypothesized that insults such as exposure to antigen and particulate matter (PM) might dysregulate airway sensory nerve function, thereby contributing to enhanced airway inflammation and hyperre...

  13. Airway hyperresponsiveness with chest strapping: A matter of heterogeneity or reduced lung volume?

    PubMed

    Pellegrino, Riccardo; Pompilio, Pasquale P; Bruni, Giulia Innocenti; Scano, Giorgio; Crimi, Claudia; Biasco, Luigi; Coletta, Giuseppe; Cornara, Giuseppe; Torchio, Roberto; Brusasco, Vito; Dellacà, Raffaele L

    2009-03-31

    Chest wall strapping has been recently shown to be associated with an increase in airway responsiveness to methacholine. To investigate whether this is the result of the decreased lung volume or an increased heterogeneity due to chest wall distortion, ten healthy volunteers underwent a methacholine challenge at control conditions and after selective strapping of the rib cage, the abdomen or the whole chest wall resulting in similar decrements of functional residual capacity and total lung capacity but causing different distribution of the bronchoconstrictor. Methacholine during strapping reduced forced expiratory flow, dynamic compliance, and reactance at 5Hz and increased pulmonary resistance and respiratory resistance at 5Hz that were significantly greater than at control and associated with a blunted bronchodilator effect of the deep breath. However, no significant differences were observed between selective and total chest wall strapping, suggesting that the major mechanism for increasing airway responsiveness with chest wall strapping is the breathing at low lung volume rather than regional heterogeneities.

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

    PubMed Central

    Nguyen, Thi Hiep; Maltby, Steven; Eyers, Fiona; Foster, Paul S.; Yang, Ming

    2016-01-01

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

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

    PubMed

    Nguyen, Thi Hiep; Maltby, Steven; Eyers, Fiona; Foster, Paul S; Yang, Ming

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

  16. Use of a novel one-nostril mask-spacer device to evaluate airway hyperresponsiveness (AHR) in horses after chronic administration of albuterol

    PubMed Central

    Mazan, Melissa R.; Lascola, Kara; Bruns, Susan J.; Hoffman, Andrew M.

    2014-01-01

    Inflammatory airway disease (IAD) is very common in stabled horses. Short-acting beta agonist (SABA) drugs are often used to relieve clinical signs, although long-term exposure to these drugs may result in rebound bronchoconstriction. The purpose of this study was twofold: i) to describe the deposition of radiolabeled drugs using a novel one-nostril design mask-spacer combination with a breath-activated inhaler (BAI), and ii) to determine whether treatment for 10 d with inhaled albuterol using this device would impair the ability of albuterol to prevent bronchospasm during a histamine challenge test. The percentage of radio-aerosol deposited in the total lung was 12.39% ± 5.05%. All study horses demonstrated airway hyperresponsiveness (AHR) before enrollment in the study [mean provocative concentration eliciting 35% increase in delta flow (PC35) < 6 mg/mL histamine]. There was no significant difference in airway hyperresponsiveness to post-albuterol histamine challenge before or after treatment with albuterol. A 10-d treatment with placebo, however, caused a significant increase in airway hyperresponsiveness in all horses (P < 0.001). The results of this study show that the novel mask-spacer device was effective in delivering radiolabeled aerosolized drug to the lung and that delivery of a SABA for 10 d using this device did not result in increased airway hyperresponsiveness. PMID:24982553

  17. Use of a novel one-nostril mask-spacer device to evaluate airway hyperresponsiveness (AHR) in horses after chronic administration of albuterol.

    PubMed

    Mazan, Melissa R; Lascola, Kara; Bruns, Susan J; Hoffman, Andrew M

    2014-07-01

    Inflammatory airway disease (IAD) is very common in stabled horses. Short-acting beta agonist (SABA) drugs are often used to relieve clinical signs, although long-term exposure to these drugs may result in rebound bronchoconstriction. The purpose of this study was twofold: i) to describe the deposition of radiolabeled drugs using a novel one-nostril design mask-spacer combination with a breath-activated inhaler (BAI), and ii) to determine whether treatment for 10 d with inhaled albuterol using this device would impair the ability of albuterol to prevent bronchospasm during a histamine challenge test. The percentage of radio-aerosol deposited in the total lung was 12.39% ± 5.05%. All study horses demonstrated airway hyperresponsiveness (AHR) before enrollment in the study [mean provocative concentration eliciting 35% increase in delta flow (PC35) < 6 mg/mL histamine]. There was no significant difference in airway hyperresponsiveness to post-albuterol histamine challenge before or after treatment with albuterol. A 10-d treatment with placebo, however, caused a significant increase in airway hyperresponsiveness in all horses (P < 0.001). The results of this study show that the novel mask-spacer device was effective in delivering radiolabeled aerosolized drug to the lung and that delivery of a SABA for 10 d using this device did not result in increased airway hyperresponsiveness.

  18. Airway response to chlorine inhalation (bleach) among cleaning workers with and without bronchial hyperresponsiveness.

    PubMed

    Sastre, Joaquín; Madero, Mauro F; Fernández-Nieto, Mar; Sastre, Beatriz; del Pozo, Victoria; Potro, Manuela García-del; Quirce, Santiago

    2011-04-01

    Symptoms of obstructive lung disease in domestic cleaning staff have been related to the use of bleach and other irritant cleaning products. Included in the study were thirteen cleaning employees with work-related asthma-like symptoms, three asthmatic controls and three atopic subjects without bronchial hyperresponsiveness (BHR) who had no exposure to cleaning products. The study protocol consisted of a methacholine test, sputum induction and fraction of exhaled nitric oxide measurement (FENO) both at baseline and 24 hr after a 1-hr inhalation challenge with either placebo or bleach at a concentration of 0.4 ppm of chlorine. The inhalation of the placebo caused no bronchial reactions. Mean maximum fall in FEV(1) during challenge testing with bleach was significantly higher than the values obtained during the placebo challenge. Inhalation challenge with bleach elicited two isolated late asthmatic reactions and one dual asthmatic reaction. Of all the patients who underwent challenge testing with bleach, only one had a ≥2-fold decrease in methacholine PC(20) 24 hr after the challenge. No significant correlation was found between maximum fall in FEV(1) and PC(20) methacholine. Following challenge testing with bleach, no clinically significant changes in sputum cell counts or FENO were detected. These results suggest that bleach inhalation at a concentration of 0.4 ppm-a concentration below 8-hr permissible occupational exposure level-brings about a substantial decrease in FEV1 in subjects with and without BHR. Some subjects have a positive challenge response to bleach inhalation. Copyright © 2010 Wiley-Liss, Inc.

  19. Oral administration of Lactobacillus paracasei L9 attenuates PM2.5-induced enhancement of airway hyperresponsiveness and allergic airway response in murine model of asthma.

    PubMed

    Wang, Xifan; Hui, Yan; Zhao, Liang; Hao, Yanling; Guo, Huiyuan; Ren, Fazheng

    2017-01-01

    This study investigated allergy immunotherapy potential of Lactobacillus paracasei L9 to prevent or mitigate the particulate matter 2.5 (PM2.5) enhanced pre-existing asthma in mice. Firstly, we used a mouse model of asthma (a 21-day ovalbumin (OVA) sensitization and challenge model) followed by PM2.5 exposure twice on the same day of the last challenge. PM2.5 was collected from the urban area of Beijing and underwent analysis for metals and polycyclic aromatic hydrocarbon contents. The results showed that PM2.5 exposure enhanced airway hyper-responsiveness (AHR) and lead to a mixed Th2/ IL-17 response in asthmatic mice. Secondly, the PM2.5 exposed asthmatic mice were orally administered with L9 (4×107, 4×109 CFU/mouse, day) from the day of first sensitization to the endpoint, for 20 days, to investigate the potential mitigative effect of L9 on asthma. The results showed that L9 ameliorated PM2.5 exposure enhanced AHR with an approximate 50% decrease in total airway resistance response to methacholine (48 mg/ml). L9 also prevented the exacerbated eosinophil and neutrophil infiltration in bronchoalveolar lavage fluid (BALF), and decreased the serum level of total IgE and OVA-specific IgG1 by 0.44-fold and 0.3-fold, respectively. Additionally, cytokine production showed that L9 significantly decreased T-helper cell type 2 (Th2)-related cytokines (IL-4, -5, -13) and elevated levels of Th1 related IFN-γ in BALF. L9 also reduced the level of IL-17A and increased the level of TGF-β. Taken together, these results indicate that L9 may exert the anti-allergic benefit, possibly through rebalancing Th1/Th2 immune response and modulating IL-17 pro-inflammatory immune response. Thus, L9 is a promising candidate for preventing PM exposure enhanced pre-existing asthma.

  20. Oral administration of Lactobacillus paracasei L9 attenuates PM2.5-induced enhancement of airway hyperresponsiveness and allergic airway response in murine model of asthma

    PubMed Central

    Zhao, Liang; Hao, Yanling; Guo, Huiyuan; Ren, Fazheng

    2017-01-01

    This study investigated allergy immunotherapy potential of Lactobacillus paracasei L9 to prevent or mitigate the particulate matter 2.5 (PM2.5) enhanced pre-existing asthma in mice. Firstly, we used a mouse model of asthma (a 21-day ovalbumin (OVA) sensitization and challenge model) followed by PM2.5 exposure twice on the same day of the last challenge. PM2.5 was collected from the urban area of Beijing and underwent analysis for metals and polycyclic aromatic hydrocarbon contents. The results showed that PM2.5 exposure enhanced airway hyper-responsiveness (AHR) and lead to a mixed Th2/ IL-17 response in asthmatic mice. Secondly, the PM2.5 exposed asthmatic mice were orally administered with L9 (4×107, 4×109 CFU/mouse, day) from the day of first sensitization to the endpoint, for 20 days, to investigate the potential mitigative effect of L9 on asthma. The results showed that L9 ameliorated PM2.5 exposure enhanced AHR with an approximate 50% decrease in total airway resistance response to methacholine (48 mg/ml). L9 also prevented the exacerbated eosinophil and neutrophil infiltration in bronchoalveolar lavage fluid (BALF), and decreased the serum level of total IgE and OVA-specific IgG1 by 0.44-fold and 0.3-fold, respectively. Additionally, cytokine production showed that L9 significantly decreased T-helper cell type 2 (Th2)–related cytokines (IL-4, -5, -13) and elevated levels of Th1 related IFN-γ in BALF. L9 also reduced the level of IL-17A and increased the level of TGF-β. Taken together, these results indicate that L9 may exert the anti-allergic benefit, possibly through rebalancing Th1/Th2 immune response and modulating IL-17 pro-inflammatory immune response. Thus, L9 is a promising candidate for preventing PM exposure enhanced pre-existing asthma. PMID:28199353

  1. Anisakis pegreffii-induced airway hyperresponsiveness is mediated by gamma interferon in the absence of interleukin-4 receptor alpha responsiveness.

    PubMed

    Kirstein, Frank; Horsnell, William G C; Nieuwenhuizen, Natalie; Ryffel, Bernhard; Lopata, Andreas L; Brombacher, Frank

    2010-09-01

    Infection with the fish parasite Anisakis following exposure to contaminated fish can lead to allergic reactions in humans. The present study examined the immunological mechanisms underlying the development of allergic airway inflammation in mice after different routes of sensitization to Anisakis. Wild-type and interleukin-4 receptor alpha (IL-4Ralpha)-deficient BALB/c mice were sensitized intraperitoneally with live or heat-killed Anisakis larvae or by intranasal administration of an Anisakis extract and were subsequently challenged intranasally with an Anisakis extract. Both routes of sensitization induced IL-4Ralpha-dependent allergic airway responses, whereas allergen-specific antibody responses developed only when mice were sensitized intraperitoneally. Intranasal sensitization induced airway hyperresponsiveness (AHR) in wild-type mice only, showing that AHR was IL-4/IL-13 dependent. Unexpectedly, infection with Anisakis larvae induced AHR in both wild-type and IL-4Ralpha-deficient mice. IL-4Ralpha-independent AHR was mediated by gamma interferon (IFN-gamma), as evidenced by the fact that in vivo neutralization of IFN-gamma abrogated AHR. Together, these results demonstrate that both infection with larvae and inhalational exposure to Anisakis proteins are potent routes of allergic sensitization to Anisakis, explaining food- and work-related allergies in humans. Importantly for diagnosis, allergic airway inflammation can be independent of detectable Anisakis-specific antibodies. Moreover, depending on the route of sensitization, AHR can be induced either by IL-4/IL-13 or by IFN-gamma.

  2. Anisakis pegreffii-Induced Airway Hyperresponsiveness Is Mediated by Gamma Interferon in the Absence of Interleukin-4 Receptor Alpha Responsiveness▿

    PubMed Central

    Kirstein, Frank; Horsnell, William G. C.; Nieuwenhuizen, Natalie; Ryffel, Bernhard; Lopata, Andreas L.; Brombacher, Frank

    2010-01-01

    Infection with the fish parasite Anisakis following exposure to contaminated fish can lead to allergic reactions in humans. The present study examined the immunological mechanisms underlying the development of allergic airway inflammation in mice after different routes of sensitization to Anisakis. Wild-type and interleukin-4 receptor alpha (IL-4Rα)-deficient BALB/c mice were sensitized intraperitoneally with live or heat-killed Anisakis larvae or by intranasal administration of an Anisakis extract and were subsequently challenged intranasally with an Anisakis extract. Both routes of sensitization induced IL-4Rα-dependent allergic airway responses, whereas allergen-specific antibody responses developed only when mice were sensitized intraperitoneally. Intranasal sensitization induced airway hyperresponsiveness (AHR) in wild-type mice only, showing that AHR was IL-4/IL-13 dependent. Unexpectedly, infection with Anisakis larvae induced AHR in both wild-type and IL-4Rα-deficient mice. IL-4Rα-independent AHR was mediated by gamma interferon (IFN-γ), as evidenced by the fact that in vivo neutralization of IFN-γ abrogated AHR. Together, these results demonstrate that both infection with larvae and inhalational exposure to Anisakis proteins are potent routes of allergic sensitization to Anisakis, explaining food- and work-related allergies in humans. Importantly for diagnosis, allergic airway inflammation can be independent of detectable Anisakis-specific antibodies. Moreover, depending on the route of sensitization, AHR can be induced either by IL-4/IL-13 or by IFN-γ. PMID:20605987

  3. Suhuang antitussive capsule at lower doses attenuates airway hyperresponsiveness, inflammation, and remodeling in a murine model of chronic asthma

    PubMed Central

    Zhang, Chao; Zhang, Lan-Hong; Wu, Yin-Fang; Lai, Tian-Wen; Wang, Hai-Sheng; Xiao, Hui; Che, Luan-Qing; Ying, Song-Min; Li, Wen; Chen, Zhi-Hua; Shen, Hua-Hao

    2016-01-01

    Suhuang antitussive capsule (Suhuang), a traditional Chinese medication, is found effective in treating chronic cough and cough variant asthma (CVA). This study aimed to determine the possible effects and underlying mechanisms of Suhuang on chronic ovalbumin (OVA)-induced airway hyperresponsiveness (AHR), inflammation, and remodeling in mice. Mice were randomly assigned to six experimental groups: control, OVA model with or without Suhuang (low dose: 3.5 g/kg, middle dose: 7.0 g/kg, high dose: 14.0 g/kg), or dexamethasone (2.5 mg/kg). AHR, inflammatory cells, cytokines in bronchoalveolar lavage fluid (BALF), lung pathology, mucus production, and airway remodeling were examined. We found Suhuang treated at lower doses effectively inhibited OVA-induced AHR, airway inflammation, mucus production and collagen deposition around the airway. High dose of Suhuang reduced most of the inflammatory hallmarks while exerted inconsiderable effects on the number of macrophages in BALF and AHR. At all doses, Suhuang significantly reduced the levels of interlukin (IL) -13 and transforming growth factor (TGF)-β1, but had little effects on IL-4, IL-5, IL-17A and interferon (IFN)-γ. Thus, Suhuang administration alleviates the pathological changes of chronic asthma likely through inhibition of IL-13 and TGF-β1. Suhuang might be a promising therapy for patients with allergic asthma in the future. PMID:26861679

  4. Inhibition of the 5-lipoxygenase pathway with piriprost (U-60,257) protects normal primates from ozone-induced methacholine hyperresponsive small airways

    SciTech Connect

    Johnson, H.G.; Stout, B.K.; Ruppel, P.L.

    1988-03-01

    Weekly exposure to ozone in seven normal Rhesus monkeys led to induction of methacholine hypersensitive airways (RL increases 242 +/- 60% and Cdyn decreases 68 +/- 13% of baseline methacholine responses). It took 19 weeks to establish this hyperresponse that persisted for greater than 15 weeks once ozone was stopped. A second exposure led to similar response peaks in 6 weeks. At the peak of the second response, weekly 1% piriprost exposure before ozone led to a return to baseline that was not different between placebo and piriprost treated animals (9.4 +/- 1.0 and 4.3 +/- 2.9 weeks, placebo and treated, respectively P = 0.09 NS). A statistical difference in the mecholyl response in placebo and piriprost treated groups while on ozone was shown only in the Cdyn measurement (Cdyn% change 68 +/- 13 vs 24 +/- 14, placebo and piriprost, respectively P = 0.03). Off ozone (or return to baseline), a statistical difference could be detected both in RL and Cdyn (RL% changed 151 +/- 41 vs 31.1 +/- 49, P = 0.03, and for Cdyn 62.7 +/- 8 vs 9 +/- 10, P = 0.0006, placebo and piriprost, respectively). We conclude tha the primate provides a chronic model of airways reactivity in which the role of lipoxygenase is implicated because of the beneficial role of piriprost, and further that the ozone lesion is primarily in the smaller airways (possibly and alveolitis).

  5. The role of airway hyperresponsiveness measured by methacholine challenge test in defining asthma severity in asthma-obesity syndrome.

    PubMed

    Charron, Catherine B; Pakhalé, Smita

    2016-06-01

    Asthma is a complex disease defined by chronic inflammation of the airways. In research and clinical practice measures used for diagnosis, an assessment of control and severity of asthma are varied and there exists no gold standard. To date, several studies have explored the link between obesity and asthma although the exact mechanism is not yet fully understood. A study undertaken by our research group in 2015, on the effects of weight loss on asthma severity in obese asthmatics, demonstrated that an improvement in airway hyperresponsiveness could be achieved after significant weight reduction with a weight loss program. The objective of this article is to review the current literature for the primary and secondary outcomes studied to estimate the effects of weight loss on asthma severity in adults with obesity and asthma. A review of the most recent research conducted since 2014 demonstrates that effects of weight loss on asthma severity in adults with obesity and asthma has not been the focus of majority of the studies. Apart from our study published in 2015, very few studies used airway hyperresponsiveness as the primary or secondary outcome measure. The literature reveals that significant weight loss does, however, lead to improvement in asthma severity and control in adults with obesity and asthma. The current literature suggests that improvement in lung function requires moderate to significant (5-10%) weight loss in adults with obesity and asthma. However, with a few exceptions, the majority of these studies were small and used variable and questionable asthma severity outcome measures. There is an urgent need for standardization of diagnosis of asthma, study inclusion criteria, and outcome measures to assess asthma severity in research setting. Long-term effects of weight loss interventions on asthma severity and control, in adults with obesity and asthma, also remain unanswered.

  6. Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness.

    PubMed

    Taniguchi, Akihiko; Miyahara, Nobuaki; Waseda, Koichi; Kurimoto, Etsuko; Fujii, Utako; Tanimoto, Yasushi; Kataoka, Mikio; Yamamoto, Yasuhiko; Gelfand, Erwin W; Yamamoto, Hiroshi; Tanimoto, Mitsune; Kanehiro, Arihiko

    2015-10-15

    The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE-/-) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE-/- mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE+/+ mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE-/- mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses. Copyright © 2015 the American Physiological Society.

  7. Augmented acetylcholine-induced, Rho-mediated Ca2+ sensitization of bronchial smooth muscle contraction in antigen-induced airway hyperresponsive rats

    PubMed Central

    Chiba, Yoshihiko; Takada, Yuka; Miyamoto, Shigeki; Mitsui-Saito, Minori; Karaki, Hideaki; Misawa, Miwa

    1999-01-01

    Treatment with acetylcholine (ACh) of a β-escin-permeabilized intrapulmonary bronchial smooth muscle of the rat induced force when the Ca2+ concentration was clamped at 1 μM. The ACh-induced Ca2+ sensitization of myofilaments was significantly greater in antigen-induced airway hyperresponsive rats than in control rats. The ACh-induced Ca2+ sensitization was completely blocked by treatment with Clostridium botulinum C3 exoenzyme, an inactivator of Rho family of proteins. Moreover, the protein level of RhoA in the intrapulmonary bronchi was significantly increased in the airway hyperresponsive rats. Thus, increased airway smooth muscle contractility observed in asthmatics may be related to augmented agonist-induced, Rho-mediated Ca2+ sensitization of myofilaments. PMID:10401547

  8. Weight Loss Decreases Inherent and Allergic Methacholine Hyperresponsiveness in Mouse Models of Diet-Induced Obese Asthma.

    PubMed

    Ather, Jennifer L; Chung, Michael; Hoyt, Laura R; Randall, Matthew J; Georgsdottir, Anna; Daphtary, Nirav A; Aliyeva, Minara I; Suratt, Benjamin T; Bates, Jason H T; Irvin, Charles G; Russell, Sheila R; Forgione, Patrick M; Dixon, Anne E; Poynter, Matthew E

    2016-08-01

    Obese asthma presents with inherent hyperresponsiveness to methacholine or augmented allergen-driven allergic asthma, with an even greater magnitude of methacholine hyperresponsiveness. These physiologic parameters and accompanying obese asthma symptoms can be reduced by successful weight loss, yet the underlying mechanisms remain incompletely understood. We implemented mouse models of diet-induced obesity, dietary and surgical weight loss, and environmental allergen exposure to examine the mechanisms and mediators of inherent and allergic obese asthma. We report that the methacholine hyperresponsiveness in these models of inherent obese asthma and obese allergic asthma manifests in distinct anatomical compartments but that both are amenable to interventions that induce substantial weight loss. The inherent obese asthma phenotype, with characteristic increases in distal airspace tissue resistance and tissue elastance, is associated with elevated proinflammatory cytokines that are reduced with dietary weight loss. Surprisingly, bariatric surgery-induced weight loss further elevates these cytokines while reducing methacholine responsiveness to levels similar to those in lean mice or in formerly obese mice rendered lean through dietary intervention. In contrast, the obese allergic asthma phenotype, with characteristic increases in central airway resistance, is not associated with increased adaptive immune responses, yet diet-induced weight loss reduces methacholine hyperresponsiveness without altering immunological variables. Diet-induced weight loss is effective in models of both inherent and allergic obese asthma, and our examination of the fecal microbiome revealed that the obesogenic Firmicutes/Bacteroidetes ratio was normalized after diet-induced weight loss. Our results suggest that structural, immunological, and microbiological factors contribute to the manifold presentations of obese asthma.

  9. Weight Loss Decreases Inherent and Allergic Methacholine Hyperresponsiveness in Mouse Models of Diet-Induced Obese Asthma

    PubMed Central

    Ather, Jennifer L.; Chung, Michael; Hoyt, Laura R.; Randall, Matthew J.; Georgsdottir, Anna; Daphtary, Nirav A.; Aliyeva, Minara I.; Suratt, Benjamin T.; Bates, Jason H. T.; Irvin, Charles G.; Russell, Sheila R.; Forgione, Patrick M.; Dixon, Anne E.

    2016-01-01

    Obese asthma presents with inherent hyperresponsiveness to methacholine or augmented allergen-driven allergic asthma, with an even greater magnitude of methacholine hyperresponsiveness. These physiologic parameters and accompanying obese asthma symptoms can be reduced by successful weight loss, yet the underlying mechanisms remain incompletely understood. We implemented mouse models of diet-induced obesity, dietary and surgical weight loss, and environmental allergen exposure to examine the mechanisms and mediators of inherent and allergic obese asthma. We report that the methacholine hyperresponsiveness in these models of inherent obese asthma and obese allergic asthma manifests in distinct anatomical compartments but that both are amenable to interventions that induce substantial weight loss. The inherent obese asthma phenotype, with characteristic increases in distal airspace tissue resistance and tissue elastance, is associated with elevated proinflammatory cytokines that are reduced with dietary weight loss. Surprisingly, bariatric surgery–induced weight loss further elevates these cytokines while reducing methacholine responsiveness to levels similar to those in lean mice or in formerly obese mice rendered lean through dietary intervention. In contrast, the obese allergic asthma phenotype, with characteristic increases in central airway resistance, is not associated with increased adaptive immune responses, yet diet-induced weight loss reduces methacholine hyperresponsiveness without altering immunological variables. Diet-induced weight loss is effective in models of both inherent and allergic obese asthma, and our examination of the fecal microbiome revealed that the obesogenic Firmicutes/Bacteroidetes ratio was normalized after diet-induced weight loss. Our results suggest that structural, immunological, and microbiological factors contribute to the manifold presentations of obese asthma. PMID:27064658

  10. Colchicine decreases airway hyperreactivity after phosgene exposure.

    PubMed

    Ghio, Andrew; Lehmann, James; Winsett, Darrell; Richards, Judy; Costa, Daniel

    2005-05-01

    Phosgene (COCl(2)) exposure affects an influx of inflammatory cells into the lung, which can be reduced in an animal model by pretreatment with colchicine. Inflammation in the respiratory tract can be associated with an increase in airway hyperreactivity. We tested the hypotheses that (1) phosgene exposure increases airway reactivity and (2) colchicine can decrease this elevation. Sprague Dawley rats (70 d old; male) were exposed to 1 ppm COCl(2) for 1 h. Airway reactivity was tested at 0, 4, and 24 h postexposure by infusing anesthetized animals intravenously with acetylcholine and assessing expiratory resistance and dynamic compliance. Immediately and 4 h postexposure, a significant change in expiratory resistance and dynamic compliance was observed in those animals exposed to COCl(2), while at 24 h this response was greater. A second experiment was performed in rats pretreated with colchicine (1 mg/kg) or saline given intraperitoneally, exposed to 1 ppm COCl(2) for 1 h, with both expiratory resistance and dynamic compliance assessed at 24 h. After exposure, cell differentials and protein in lavage were also quantitated. The results indicate that colchicine decreased neutrophil influx, protein accumulation, and changes in both expiratory resistance and dynamic compliance after COCl(2) exposure. Colchicine may affect injury and changes in expiratory resistance and dynamic compliance by diminishing the incursion of inflammatory cells, but other properties of this medication may also be responsible for the observed results.

  11. Airway hyperresponsiveness and inflammation induced by toluene diisocyanate in guinea pigs

    SciTech Connect

    Gordon, T.; Sheppard, D.; McDonald, D.M.; Distefano, S.; Scypinski, L.

    1985-11-01

    The authors examined the changes in airway responsiveness to increasing doses of an acetylcholine aerosol in anesthetized and ventilated guinea pigs 2, 6, or 24 h after exposure to 2 ppm toluene diisocyanate (TDI) or 2 h after exposure to air or 1 ppm TDI. The concentration of acetylcholine calculated to cause a 200% increase in RL was significantly lower for animals studied at 2 h (0.68%) or at 6 h (0.77%), but not at 24 h (2.39%), after TDI than for air animals (3.07%). The increase in airway responsiveness in the TDI-exposed animals was associated with histologic changes in the trachea and intrapulmonary airways. Exposure to 2 ppm TDI caused a patchy loss of cilia, shedding of epithelial cells into the airway lumen, and an influx of inflammatory cells into the trachea and other airways. In the lamina propria of the trachea, the concentration of extravascular polymorphonuclear leukocytes (PMN) was 13- to 26-fold greater in animals studied 2 or 6 h after exposure to 2 ppm TDI or at 2 h after 1 ppm TDI than in animals exposed to air. The concentration of PMN in the epithelium was significantly increased only in animals examined 2 h after 2 ppm TDI. These results indicate that a single exposure to TDI can cause an increase in airway responsiveness that is associated with epithelial injury and acute airway inflammation.

  12. Leukotriene receptor antagonist attenuated airway inflammation and hyperresponsiveness in a double-stranded RNA-induced asthma exacerbation model.

    PubMed

    Ujino, Mariko; Sugimoto, Naoya; Koizumi, Yuta; Ro, Shoki; Kojima, Yasuhiro; Asae, Kamiyama-Hara; Yamashita, Naomi; Ohta, Ken; Nagase, Hiroyuki

    2017-09-01

    Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic-polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration. A/J mice were immunized with ovalbumin (OVA) + alum (days 0, 28, 42, and 49), followed by intranasal challenge with OVA (phase 1: days 50-52) and poly I:C (phase 2: days 53-55). Montelukast was administered during poly I:C challenge (phase 2) in the reliever model or throughout the OVA and poly I:C challenges (phases 1 and 2) in the controller model. Airway responsiveness to acetylcholine chloride was assessed, and bronchoalveolar lavage (BAL) was performed on day 56. Administration of poly I:C to OVA-sensitized and -challenged mice increased the number of eosinophils and levels of IL-13, IL-9, CCL3, and CXCL1 in BAL fluid (BALF) and tended to increase airway responsiveness. Montelukast significantly attenuated the poly I:C-induced increase in the number of eosinophils and levels of IL-13, IL-9, and CCL3 in BALF and airway hyperresponsiveness in both the reliever and controller models. This is the first report showing that LTRA functionally suppressed the pathophysiology of a virus-induced asthma exacerbation model, suggesting the importance of cysLTs as a potential treatment target. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  13. The allergen-induced airway hyperresponsiveness in a human-mouse chimera model of asthma is T cell and IL-4 and IL-5 dependent.

    PubMed

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

    2001-06-01

    The cellular and molecular mechanisms involved in the airway hyperresponsiveness (AHR) of patients with allergic asthma remain unclear. A role for Th2 inflammatory cells was suggested based on murine asthma models. No direct evidence exists on the role of these cells in human asthma. The development of a mouse-human chimera might be useful, allowing the in vivo study of the components of the human immune system relevant to asthma. We investigated the role of allergen-reactive T lymphocytes in a human-mouse SCID model. SCID mice were reconstituted intratracheally with human PBMC from healthy, nonallergic, nonasthmatic donors and exposed to an aerosol of house dust mite allergen after i.p. injection with Dermatophagoides pteronyssinus I Ag and alum. The donor T lymphocytes had a Th1 cytokine phenotype. The reconstituted and allergen-challenged mice developed AHR to carbachol. The mouse airways and lungs were infiltrated with human T lymphocytes. No eosinophils or increases in human IgE were observed. The intrapulmonary human T lymphocytes demonstrated an increase in intracytoplasmic IL-4 and IL-5 and a decrease in IFN-gamma after exposure to allergen adjuvant. Antagonizing human IL-4/IL-13 or IL-5 resulted in a normalization of the airway responsiveness, despite a sustained intracellular Th2 cytokine production. These results provide evidence that the activated human allergen-reactive Th2 cells producing IL-4 or IL-5 are pivotal in the induction of AHR, whereas no critical role for eosinophils or IgE could be demonstrated. They also demonstrate that human allergen-specific Th1 lymphocytes can be driven to a Th2 phenotype.

  14. Airway hyperresponsiveness and inflammation induced by toluene diisocyanate in guinea pigs.

    PubMed

    Gordon, T; Sheppard, D; McDonald, D M; Distefano, S; Scypinski, L

    1985-11-01

    We examined the changes in airway responsiveness to increasing doses of an acetylcholine aerosol in anesthetized and ventilated guinea pigs 2, 6, or 24 h after exposure to 2 ppm toluene diisocyanate (TDI) or 2 h after exposure to air or 1 ppm TDI. Pulmonary resistance (RL) after the animals inhaled a buffered saline aerosol was used as baseline and was similar for air and TDI groups. The concentration of acetylcholine calculated to cause a 200% increase in RL was significantly lower for animals studied at 2 h (0.68%) or at 6 h (0.77%), but not at 24 h (2.39%), after TDI than for air animals (3.07%). The increase in airway responsiveness in the TDI-exposed animals was associated with histologic changes in the trachea and intrapulmonary airways. Exposure to 2 ppm TDI caused a patchy loss of cilia, shedding of epithelial cells into the airway lumen, and an influx of inflammatory cells into the trachea and other airways. In the lamina propria of the trachea, the concentration of extravascular polymorphonuclear leukocytes (PMN) was 13- to 26-fold greater in animals studied 2 or 6 h after exposure to 2 ppm TDI or at 2 h after 1 ppm TDI than in animals exposed to air. The concentration of PMN in the epithelium was significantly increased only in animals examined 2 h after 2 ppm TDI. Exposure to TDI also caused an influx of eosinophils into the tracheal mucosa. This influx occurred later and was more persistent than the influx of PMN. These results indicate that a single exposure to TDI can cause an increase in airway responsiveness that is associated with epithelial injury and acute airway inflammation.

  15. Airway Hyperresponsiveness in Asthma Model Occurs Independently of Secretion of β1 Integrins in Airway Wall and Focal Adhesions Proteins Down Regulation.

    PubMed

    Álvarez-Santos, Mayra; Carbajal, Verónica; Tellez-Jiménez, Olivia; Martínez-Cordero, Erasmo; Ruiz, Victor; Hernández-Pando, Rogelio; Lascurain, Ricardo; Santibañez-Salgado, Alfredo; Bazan-Perkins, Blanca

    2016-10-01

    The extracellular domains of some membrane proteins can be shed from the cell. A similar phenomenon occurs with β1 integrins (α1β1 and α2β1) in guinea pig. The putative role of β1 integrin subunit alterations due to shedding in airway smooth muscle (ASM) in an allergic asthma model was evaluated. Guinea pigs were sensitized and challenged with antigen. Antigenic challenges induced bronchoobstruction and hyperresponsiveness at the third antigenic challenge. Immunohistochemistry and immunoelectronmicroscopy studies showed that the cytosolic and extracellular domains of the β1 integrin subunit shared the same distribution in airway structures in both groups. Various polypeptides with similar molecular weights were detected with both the cytosolic and extracellular β1 integrin subunit antibodies in isolated airway myocytes and the connective tissue that surrounds the ASM bundle. Flow cytometry and Western blot studies showed that the expression of cytosolic and extracellular β1 integrin subunit domains in ASM was similar between groups. An increment of ITGB1 mRNA in ASM was observed in the asthma model group. RACE-PCR of ITGB1 in ASM did not show splicing variants. The expression levels of integrin-linked kinase (ILK) and paxillin diminished in the asthma model, but not talin. The levels of phosphorylation of myosin phosphatase target subunit 1 (MYPT1) at Thr(696) increased in asthma model. Our work suggests that β1 integrin is secreted in guinea pig airway wall. This secretion is not altered in asthma model; nevertheless, β1 integrin cytodomain assembly proteins in focal cell adhesions in which ILK and paxillin are involved are altered in asthma model. J. Cell. Biochem. 117: 2385-2396, 2016. © 2016 Wiley Periodicals, Inc.

  16. Attenuated allergic airway hyperresponsiveness in C57BL/6 mice is associated with enhanced surfactant protein (SP)-D production following allergic sensitization

    PubMed Central

    Atochina, Elena N; Beers, Michael F; Tomer, Yaniv; Scanlon, Seth T; Russo, Scott J; Panettieri, Reynold A; Haczku, Angela

    2003-01-01

    Background C57BL/6 mice have attenuated allergic airway hyperresponsiveness (AHR) when compared with Balb/c mice but the underlying mechanisms remain unclear. SP-D, an innate immune molecule with potent immunosuppressive activities may have an important modulatory role in the allergic airway response and the consequent physiological changes. We hypothesized that an elevated SP-D production is associated with the impaired ability of C57BL/6 mice to develop allergic AHR. Methods SP-D mRNA and protein expression was investigated during development of allergic airway changes in a model of Aspergillus fumigatus (Af)-induced allergic inflammation. To study whether strain dependency of allergic AHR is associated with different levels of SP-D in the lung, Balb/c and C57BL/6 mice were compared. Results Sensitization and exposure to Af induced significant airway inflammation in both mouse strains in comparison with naïve controls. AHR to acetylcholine however was significantly attenuated in C57BL/6 mice in spite of increased eosinophilia and serum IgE when compared with Balb/c mice (p < 0.05). Af challenge of sensitized C57BL/6 mice induced a markedly increased SP-D protein expression in the SA surfactant fraction (1,894 ± 170% of naïve controls) that was 1.5 fold greater than the increase in Balb/c mice (1,234 ± 121% p < 0.01). These changes were selective since levels of the hydrophobic SP-B and SP-C and the hydrophilic SP-A were significantly decreased following sensitization and challenge with Af in both strains. Further, sensitized and exposed C57BL/6 mice had significantly lower IL-4 and IL-5 in the BAL fluid than that of Balb/c mice (p < 0.05). Conclusions These results suggest that enhanced SP-D production in the lung of C57BL/6 mice may contribute to an attenuated AHR in response to allergic airway sensitization. SP-D may act by inhibiting synthesis of Th2 cytokines. PMID:14748931

  17. Etanercept prevents airway hyperresponsiveness by protecting neuronal M2 muscarinic receptors in antigen-challenged guinea pigs

    PubMed Central

    Nie, Zhenying; Jacoby, David B; Fryer, Allison D

    2009-01-01

    Background and purpose Increased tumour necrosis factor-α (TNF-α) is associated with airway hyperreactivity in antigen-challenged animals. In human asthmatics, TNF-α is increased and blocking it prevents airway hyperreactivity in some asthmatic patients. However, the mechanisms by which TNF-α mediates hyperreactivity are unknown. Airway hyperreactivity can be caused by dysfunction of neuronal M2 muscarinic receptors that normally limit acetylcholine release from parasympathetic nerves. Here we test whether blocking TNF-α receptors with etanercept prevents M2 receptor dysfunction and airway hyperreactivity in antigen-challenged guinea pigs. Experimental approach Ovalbumin-sensitized guinea pigs were challenged by inhalation of antigen. Some animals received etanercept (3 mg kg−1 i.p.) 3 h before challenge. 24 h after challenge, airway hyperreactivity and M2 receptor function were tested. Inflammatory cells in bronchoalveolar lavage, blood and lung were counted. TNF-α and its receptors were detected by real-time RT-PCR and immunocytochemistry in parasympathetic nerves from humans and guinea pigs and in human neuroblastoma cells. Key results Antigen-challenged animals were hyperreactive to vagal stimulation and neuronal M2 receptors were dysfunctional. Both M2 receptor dysfunction and airway hyperreactivity were prevented by etanercept. Etanercept reduced eosinophils around airway nerves, and in blood, bronchoalveolar lavage and airway smooth muscle. Also, TNF-α decreased M2 receptor mRNA in human and guinea pig parasympathetic neurons. Conclusions and implications Tumour necrosis factor-α may contribute to M2 receptor dysfunction and airway hyperreactivity directly by decreasing receptor expression and indirectly by promoting recruitment of eosinophils, containing major basic protein, an M2 antagonist. This suggests that etanercept may be beneficial in treatment of allergic asthma. PMID:19134001

  18. Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model.

    PubMed

    Chen, Minyong; Hegde, Akhil; Choi, Yeon Ho; Theriot, Barbara S; Premont, Richard T; Chen, Wei; Walker, Julia K L

    2015-09-01

    β-Arrestin-2 (βarr2) is a ubiquitously expressed cytosolic protein that terminates G protein-coupled receptor signaling and transduces G protein-independent signaling. We previously showed that mice lacking βarr2 do not develop an asthma phenotype when sensitized to, and challenged with, allergens. The current study evaluates if an established asthma phenotype can be mitigated by deletion of βarr2 using an inducible Cre recombinase. We sensitized and challenged mice to ovalbumin (OVA) and demonstrated that on Day (d) 24 the allergic asthma phenotype was apparent in uninduced βarr2 and wild-type (WT) mice. In a second group of OVA-treated mice, tamoxifen was injected on d24 to d28 to activate Cre recombinase, and OVA aerosol challenge was continued through d44. The asthma phenotype was assessed using lung mechanics measurements, bronchoalveolar lavage cell analysis, and histological assessment of mucin and airway inflammation. Compared with their respective saline-treated controls, OVA-treated WT mice and mice expressing the inducible Cre recombinase displayed a significant asthma phenotype at d45. Whereas tamoxifen treatment had no significant effect on the asthma phenotype in WT mice, it inhibited βarr2 expression and caused a significant reduction in airway hyper-responsiveness (AHR) in Cre-inducible mice. These findings suggest that βarr2 is actively required for perpetuation of the AHR component of the allergic asthma phenotype. Our finding that βarr2 participates in the perpetuation of AHR in an asthma model means that targeting βarr2 may provide immediate and potentially long-term relief from daily asthma symptoms due to AHR irrespective of inflammation.

  19. Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model

    PubMed Central

    Chen, Minyong; Hegde, Akhil; Choi, Yeon Ho; Theriot, Barbara S.; Premont, Richard T.; Chen, Wei

    2015-01-01

    β-Arrestin-2 (βarr2) is a ubiquitously expressed cytosolic protein that terminates G protein–coupled receptor signaling and transduces G protein–independent signaling. We previously showed that mice lacking βarr2 do not develop an asthma phenotype when sensitized to, and challenged with, allergens. The current study evaluates if an established asthma phenotype can be mitigated by deletion of βarr2 using an inducible Cre recombinase. We sensitized and challenged mice to ovalbumin (OVA) and demonstrated that on Day (d) 24 the allergic asthma phenotype was apparent in uninduced βarr2 and wild-type (WT) mice. In a second group of OVA-treated mice, tamoxifen was injected on d24 to d28 to activate Cre recombinase, and OVA aerosol challenge was continued through d44. The asthma phenotype was assessed using lung mechanics measurements, bronchoalveolar lavage cell analysis, and histological assessment of mucin and airway inflammation. Compared with their respective saline-treated controls, OVA-treated WT mice and mice expressing the inducible Cre recombinase displayed a significant asthma phenotype at d45. Whereas tamoxifen treatment had no significant effect on the asthma phenotype in WT mice, it inhibited βarr2 expression and caused a significant reduction in airway hyper-responsiveness (AHR) in Cre-inducible mice. These findings suggest that βarr2 is actively required for perpetuation of the AHR component of the allergic asthma phenotype. Our finding that βarr2 participates in the perpetuation of AHR in an asthma model means that targeting βarr2 may provide immediate and potentially long-term relief from daily asthma symptoms due to AHR irrespective of inflammation. PMID:25569510

  20. Diet-induced obesity causes innate airway hyperresponsiveness to methacholine and enhances ozone-induced pulmonary inflammation.

    PubMed

    Johnston, Richard A; Theman, Todd A; Lu, Frank L; Terry, Raya D; Williams, Erin S; Shore, Stephanie A

    2008-06-01

    We previously reported that genetically obese mice exhibit innate airway hyperresponsiveness (AHR) and enhanced ozone (O(3))-induced pulmonary inflammation. Such genetic deficiencies in mice are rare in humans, and they may not be representative of human obesity. Thus the purpose of this study was to determine the pulmonary phenotype of mice with diet-induced obesity (DIO), which more closely mimics the cause of human obesity. Therefore, wild-type C57BL/6 mice were reared from the time of weaning until at least 30 wk of age on diets in which either 10 or 60% of the calories are derived from fat in the form of lard. Body mass was approximately 40% greater in mice fed 60 vs. 10% fat diets. Baseline airway responsiveness to intravenous methacholine, measured by forced oscillation, was greater in mice fed 60 vs. 10% fat diets. We also examined lung permeability and inflammation after exposure to room air or O(3) (2 parts/million for 3 h), an asthma trigger. Four hours after the exposure ended, O(3)-induced increases in bronchoalveolar lavage fluid protein, interleukin-6, KC, macrophage inflammatory protein-2, interferon-gamma-inducible protein-10, and eotaxin were greater in mice fed 60 vs. 10% fat diets. Innate AHR and augmented responses to O(3) were not observed in mice raised from weaning until 20-22 wk of age on a 60% fat diet. These results indicate that mice with DIO exhibit innate AHR and enhanced O(3)-induced pulmonary inflammation, similar to genetically obese mice. However, mice with DIO must remain obese for an extended period of time before this pulmonary phenotype is observed.

  1. Cyclooxygenase-1 overexpression decreases Basal airway responsiveness but not allergic inflammation.

    PubMed

    Card, Jeffrey W; Carey, Michelle A; Bradbury, J Alyce; Graves, Joan P; Lih, Fred B; Moorman, Michael P; Morgan, Daniel L; DeGraff, Laura M; Zhao, Yun; Foley, Julie F; Zeldin, Darryl C

    2006-10-01

    Pharmacological inhibition or genetic disruption of cyclooxygenase (COX)-1 or COX-2 exacerbates the inflammatory and functional responses of the lung to environmentally relevant stimuli. To further examine the contribution of COX-derived eicosanoids to basal lung function and to allergic lung inflammation, transgenic (Tr) mice were generated in which overexpression of human COX-1 was targeted to airway epithelium. Although no differences in basal respiratory or lung mechanical parameters were observed, COX-1 Tr mice had increased bronchoalveolar lavage fluid PGE(2) content compared with wild-type littermates (23.0 +/- 3.6 vs 8.4 +/- 1.4 pg/ml; p < 0.05) and exhibited decreased airway responsiveness to inhaled methacholine. In an OVA-induced allergic airway inflammation model, comparable up-regulation of COX-2 protein was observed in the lungs of allergic wild-type and COX-1 Tr mice. Furthermore, no genotype differences were observed in allergic mice in total cell number, eosinophil content (70 vs 76% of total cells, respectively), and inflammatory cytokine content of bronchoalveolar lavage fluid, or in airway responsiveness to inhaled methacholine (p > 0.05). To eliminate the presumed confounding effects of COX-2 up-regulation, COX-1 Tr mice were bred into a COX-2 null background. In these mice, the presence of the COX-1 transgene did not alter allergen-induced inflammation but significantly attenuated allergen-induced airway hyperresponsiveness, coincident with reduced airway leukotriene levels. Collectively, these data indicate that COX-1 overexpression attenuates airway responsiveness under basal conditions but does not influence allergic airway inflammation.

  2. Oral administration of allergen extracts from Dermatophagoides farinae desensitizes specific allergen-induced inflammation and airway hyperresponsiveness in rats.

    PubMed

    Xie, Qiang-min; Wu, Ximei; Wu, Hui-min; Deng, Yang-mei; Zhang, Shui-juan; Zhu, Jian-ping; Dong, Xin-wei

    2008-12-10

    Clinically sublingual immunotherapy (SLIT) by using allergen extracts effectively alleviates the symptoms of allergic rhinitis and asthma. Supposed that oral administration of high-dose of allergen extracts imitates SLIT and may prevent IgE-related responses in allergic diseases, we investigated the effects of oral administration of allergen extracts from Dermatophagoides farinae (Derf) on allergen-induced inflammation and airway hyperresponsiveness (AHR) in a model of asthmatic rat. After administration to the specific Derf-sensitized rats with Derfdrop solution containing Derf1 and Derf2 extracts derived from Derf, the effects of Derfdrop on AHR, inflammatory cell accumulation, cytokine production in the bronchoalveolar lavage fluid and lung tissue, as well as serum IgE and IgG levels were investigated. Results indicated that Derfdrop not only dose-dependently prevented the AHR in response to methacholine, but also significantly reduced the serum total and allergen-specific IgE levels, all the maximal effects were achieved at dose of 5 mg/kg/d, and were as comparable as those of dexamethasone at dose of 1.0 mg/kg/d. Furthermore, oral administration of Derfdrop not only dose-dependently elevated allergen-specific serum IgG levels and reduced total and allergen-specific IgE levels, but also normalized the imbalance between the Th1 cytokine, IFN-gamma and Th2 cytokine, IL-4. Finally, oral administration of Derfdrop significantly reduced Goblet cell hyperplasia and eosinophilia in the Derf-sensitized allergic rat model. These data suggest that Derfdrop effectively improves specific allergen-induced inflammation and AHR in Derf-sensitized and -challenged rats and provide with the rationale for clinical SLIT by using Derfdrop in a specific allergen-induced asthma.

  3. COLCHICINE DECREASES AIRWAY HYPERACTIVITY AFTER PHOSGENE EXPOSURE

    EPA Science Inventory

    Phosgene (COCl(2)) exposure affects an influx of inflammatory cells into the lung, which can be reduced in an animal model by pretreatment with colchicine. Inflammation in the respiratory tract can be associated with an increase in airway hyperreactivity. We tested the hypotheses...

  4. COLCHICINE DECREASES AIRWAY HYPERACTIVITY AFTER PHOSGENE EXPOSURE

    EPA Science Inventory

    Phosgene (COCl(2)) exposure affects an influx of inflammatory cells into the lung, which can be reduced in an animal model by pretreatment with colchicine. Inflammation in the respiratory tract can be associated with an increase in airway hyperreactivity. We tested the hypotheses...

  5. S-Petasin, the Main Sesquiterpene of Petasites formosanus, Inhibits Phosphodiesterase Activity and Suppresses Ovalbumin-Induced Airway Hyperresponsiveness

    PubMed Central

    Shih, Chung-Hung; Huang, Tzu-Jung; Chen, Chien-Ming; Lin, Yun-Lian; Ko, Wun-Chang

    2011-01-01

    S-Petasin is the main sesquiterpene of Petasites formosanus, a traditional folk medicine used to treat hypertension, tumors and asthma in Taiwan. The aim of the present study was to investigate its inhibitory effects on phosphodiesterase (PDE) 1–5, and on ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) in a murine model of allergic asthma. S-Petasin concentration-dependently inhibited PDE3 and PDE4 activities with 50% inhibitory concentrations (IC50) of 25.5, and 17.5 μM, respectively. According to the Lineweaver-Burk analysis, S-petasin competitively inhibited PDE3 and PDE4 activities with respective dissociation constants for inhibitor binding (Ki) of 25.3 and 18.1 μM, respectively. Both IC50 and Ki values for PDE3 were significantly greater than those for PDE4. S-Petasin (10–30 μmol/kg, administered subcutaneously (s.c.)) dose-dependently and significantly attenuated the enhanced pause (Penh) value induced by methacholine (MCh) in sensitized and challenged mice. It also significantly suppressed the increases in total inflammatory cells, lymphocytes, neutrophils, eosinophils and levels of cytokines, including interleukin (IL)-2, IL-4 and IL-5, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in bronchoalveolar lavage fluid (BALF) of these mice. In addition, S-petasin (10–30 μmol/kg, s.c.) dose-dependently and significantly attenuated total and OVA-specific immunoglobulin E (IgE) levels in the serum and BALF, and enhanced the IgG2a level in serum of these mice. The PDE4H value of S-petasin was >300 μM; therefore, its PDE4H/PDE4L value was calculated to be >17. In conclusion, the present results for S-petasin at least partially explain why Petasites formosanus is used as a folk medicine to treat asthma in Taiwan. PMID:19641087

  6. Pulmonary C-fiber degeneration downregulates IFN-γ receptor 1 via IFN-α induction to attenuate RSV-induced airway hyperresponsiveness.

    PubMed

    Ye, Zhixu; Ren, Luo; Tang, Zhengzhen; Deng, Yu; Xie, Xiaohong; Fu, Zhou; Luo, ZhengXiu; Xu, Fadi; Zang, Na; Liu, Enmei

    2017-10-01

    Respiratory syncytial virus (RSV) is a leading cause of respiratory infection in infants. Unfortunately, no effective vaccine or treatment against RSV is currently available. Pulmonary C-fibers (PCFs) are critical for regulating pulmonary inflammation and airway hyperresponsiveness (AHR). We previously reported that IFN-γ partially mediated RSV-induced airway disorders. In this study, we found that PCF degeneration alleviated RSV-induced airway inflammation, especially AHR by downregulating IFN-γ receptor 1 (IFNGR1), but had no effect on IFN-γ induction. In contrast, PCF degeneration actually increased IFN-α/β levels, as were the levels of STAT1 and phosphorylated STAT1 (pSTAT1). Exogenous IFN-α treatment induced STAT1 activation and downregulated IFNGR1 expression. These results suggest that PCFs affect IFNGR1 expression by inducing IFN-α to regulate IFN-γ-mediated airway inflammation and AHR. Thus, targeting PCFs activation may help control RSV-induced airway disorders, especially AHR, even with the presence of inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Macrophage/epithelial cell CCL2 contributes to rhinovirus-induced hyperresponsiveness and inflammation in a mouse model of allergic airways disease.

    PubMed

    Schneider, Dina; Hong, Jun Young; Bowman, Emily R; Chung, Yutein; Nagarkar, Deepti R; McHenry, Christina L; Goldsmith, Adam M; Bentley, J Kelley; Lewis, Toby C; Hershenson, Marc B

    2013-02-01

    Human rhinovirus (HRV) infections lead to exacerbations of lower airways disease in asthmatic patients but not in healthy individuals. However, underlying mechanisms remain to be completely elucidated. We hypothesized that the Th2-driven allergic environment enhances HRV-induced CC chemokine production, leading to asthma exacerbations. Ovalbumin (OVA)-sensitized and -challenged mice inoculated with HRV showed significant increases in the expression of lung CC chemokine ligand (CCL)-2/monocyte chemotactic protein (MCP)-1, CCL4/macrophage inflammatory protein (MIP)-1β, CCL7/MCP-3, CCL19/MIP-3β, and CCL20/MIP3α compared with mice treated with OVA alone. Inhibition of CCL2 with neutralizing antibody significantly attenuated HRV-induced airways inflammation and hyperresponsiveness in OVA-treated mice. Immunohistochemical stains showed colocalization of CCL2 with HRV in epithelial cells and CD68-positive macrophages, and flow cytometry showed increased CCL2(+), CD11b(+) cells in the lungs of OVA-treated, HRV-infected mice. Compared with lung macrophages from naïve mice, macrophages from OVA-exposed mice expressed significantly more CCL2 in response to HRV infection ex vivo. Pretreatment of mouse lung macrophages and BEAS-2B human bronchial epithelial cells with interleukin (IL)-4 and IL-13 increased HRV-induced CCL2 expression, and mouse lung macrophages from IL-4 receptor knockout mice showed reduced CCL2 expression in response to HRV, suggesting that exposure to these Th2 cytokines plays a role in the altered HRV response. Finally, bronchoalveolar macrophages from children with asthma elaborated more CCL2 upon ex vivo exposure to HRV than cells from nonasthmatic patients. We conclude that CCL2 production by epithelial cells and macrophages contributes to HRV-induced airway hyperresponsiveness and inflammation in a mouse model of allergic airways disease and may play a role in HRV-induced asthma exacerbations.

  8. Polygonum multiflorum Decreases Airway Allergic Symptoms in a Murine Model of Asthma.

    PubMed

    Lee, Chen-Chen; Lee, Yueh-Lun; Wang, Chien-N; Tsai, Hsing-Chuan; Chiu, Chun-Lung; Liu, Leroy F; Lin, Hung-Yun; Wu, Reen

    2016-01-01

    The root of Polygonum multiflorum (also called He-Shou-Wu in Chinese) is a common herb and medicinal food in Asia used for its anti-aging properties. Our study investigated the therapeutic potential of an extract of the root of Polygonum multiflorum (PME) in allergic asthma by using a mouse model. Feeding of 0.5 and 1 mg/mouse PME inhibited ovalbumin (OVA)-induced allergic asthma symptoms, including airway inflammation, mucus production, and airway hyper-responsiveness (AHR), in a dose-dependent manner. To discern PME's mechanism of action, we examined the profile and cytokine production of inflammatory cells in bronchial alveolar lavage fluid (BALF). We found that eosinophils, the main inflammatory cell infiltrate in the lung of OVA-immunized mice, significantly decreased after PME treatment. Th2 cytokine levels, including interleukin (IL)-4, IL-5, IL-13, eotaxin, and the proinflammatory cytokine tumor necrosis factor (TNF)-[Formula: see text], decreased in PME-treated mice. Elevated mRNA expression of Th2 transcription factor GATA-3 in the lung tissue was also inhibited after oral feeding of PME in OVA-immunized mice. Thus, we conclude that PME produces anti-asthma activity through the inhibition of Th2 cell activation.

  9. Activation of the Prostaglandin E2 receptor EP2 prevents house dust mite-induced airway hyperresponsiveness and inflammation by restraining mast cells' activity.

    PubMed

    Serra-Pages, M; Torres, R; Plaza, J; Herrerias, A; Costa-Farré, C; Marco, A; Jiménez, M; Maurer, M; Picado, C; de Mora, F

    2015-10-01

    Prostaglandin E2 (PGE2 ) has been proposed to exert antiasthmatic effects in patients, to prevent antigen-induced airway pathology in murine models, and to inhibit mast cells (MC) activity in vitro. To assess in a murine model whether the protective effect of PGE2 may be a consequence of its ability to activate the E-prostanoid (EP)2 receptor on airway MC. Either BALB/c or C57BL/6 mice were exposed intranasally (i.n.) to house dust mite (HDM) aeroallergens. Both strains were given PGE2 locally (0.3 mg/kg), but only BALB/c mice were administered butaprost (EP2 agonist: 0.3 mg/kg), or AH6809 (EP2 antagonist; 2.5 mg/kg) combined with the MC stabilizer sodium cromoglycate (SCG: 25 mg/kg). Airway hyperresponsiveness (AHR) and inflammation, along with lung MC activity, were evaluated. In addition, butaprost's effect was assessed in MC-mediated passive cutaneous anaphylaxis (PCA) in mice challenged with 2,4-dinitrophenol (DNP). Selective EP2 agonism attenuated aeroallergen-caused AHR and inflammation in HDM-exposed BALB/c mice, and this correlated with a reduced lung MC activity. Accordingly, the blockade of endogenous PGE2 by means of AH6809 worsened airway responsiveness in sensitive BALB/c mice, and such worsening was reversed by SCG. The relevance of MC to PGE2 -EP2 driven protection was further highlighted in MC-dependent PCA, where butaprost fully prevented MC-induced ear swelling. Unlike in BALB/c mice, PGE2 did not protect the airways of HDM-sensitized C57BL/6 animals, a strain in which we showed MC to be irrelevant to aeroallergen-driven AHR and inflammation. The beneficial effect of both exogenous and endogenous PGE2 in aeroallergen-sensitized mice may be attributable to the activation of the EP2 receptor, which in turn acts as a restrainer of airway MC activity. This opens a path towards the identification of therapeutic targets against asthma along the 'EP2 -MC-airway' axis. © 2015 John Wiley & Sons Ltd.

  10. Hyperresponse to Thyrotropin-Releasing Hormone Accompanying Small Decreases in Serum Thyroid Hormone Concentrations

    PubMed Central

    Vagenakis, Apostolos G.; Rapoport, Basil; Azizi, Fereidoun; Portnay, Gary I.; Braverman, Lewis E.; Ingbar, Sidney H.

    1974-01-01

    To determine whether pituitary thyrotropin (TSH) responsiveness to thyrotropin-releasing hormone (TRH) is enhanced by small decreases in serum thyroxine (T4) and triiodothyronine (T3), 12 euthyroid volunteers were given 190 mg iodide po daily for 10 days to inhibit T4 and T3 release from the thyroid. Basal serum T4, T3, and TSH concentrations and the serum T4 and TSH responses to 400 μg TRH i.v. were assessed before and at the end of iodide administration. Iodide induced small but highly significant decreases in basal serum T4 (8.0±1.6 vs. 6.6±1.7 μg/100 ml; mean ± SD) and T3 (128±15 vs. 110±22 ng/100 ml) and increases in basal serum TSH (1.3±0.9 vs. 2.1±1.0 μU/ml). During iodide administration, the TSH response to TRH was significantly increased at each of seven time points up to 120 min. The maximum increment in serum TSH after TRH increased from a control mean of 8.8±4.1 to a mean of 13.0±2.8 μU/ml during iodide administration. As evidence of the inhibitory effect of iodide on hormonal release, the increment in serum T3 at 120 min after TRH was significantly lessened during iodide administration (61±42 vs. 33±24 ng/100 ml). These findings demonstrate that small acute decreases in serum T4 and T3 concentrations, resulting in values well within the normal range, are associated both with slight increases in basal TSH concentrations and pronounced increases in the TSH response to TRH. These results demonstrate that a marked sensitivity of TSH secretion and responsiveness to TRH is applicable to decreasing, as well as increasing, concentrations of thyroid hormones. PMID:4214837

  11. Lymphocyte Gene Expression Characteristic of Immediate Airway Responses (IAR) and Methacholine (MCH) Hyperresponsiveness in Mice Sensitized and Challenged with Isocyanates

    EPA Science Inventory

    Exposure to isocyanates has been associated with occupational airway diseases, including asthma. Previously we reported on respiratory and immune responses following dermal sensitization and intranasal challenge of BALB/c mice with 6 different isocyanates. The purpose of this st...

  12. Lymphocyte Gene Expression Characteristic of Immediate Airway Responses (IAR) and Methacholine (MCH) Hyperresponsiveness in Mice Sensitized and Challenged with Isocyanates

    EPA Science Inventory

    Exposure to isocyanates has been associated with occupational airway diseases, including asthma. Previously we reported on respiratory and immune responses following dermal sensitization and intranasal challenge of BALB/c mice with 6 different isocyanates. The purpose of this st...

  13. Glutamine preferentially inhibits T-helper type 2 cell-mediated airway inflammation and late airway hyperresponsiveness through the inhibition of cytosolic phospholipase A(2) activity in a murine asthma model.

    PubMed

    Ko, H M; Kang, N I; Kim, Y S; Lee, Y M; Jin, Z W; Jung, Y J; Im, S Y; Kim, J H; Shin, Y H; Cho, B H; Lee, H K

    2008-02-01

    The non-essential amino acid, l-glutamine (Gln), is abundant in the human body. Gln exhibits beneficial effects on endotoxic shock through the inhibition of cytosolic phospholipase A(2) (cPLA(2)) activity. cPLA(2) has been reported to be implicated in the pathogenesis of asthma, but the effects of Gln on asthma have not yet been defined. To investigate the effects of Gln on allergic bronchial inflammation and airway hyperresponsiveness (AHR), and to determine the possible action mechanisms of Gln in a murine model of asthma. cPLA(2) phosphorylation was assessed by immunoprecipitation and Western blotting. Smears of bronchoalveolar lavage cells were stained with Diff-Quik solution for differential cell counting. Airway levels of the proteins [T-helper type-1 (Th1) and Th2 cytokines, and mucin] were measured by ELISA. mRNA expression of cytokines was assessed by real-time RT-PCR. AHR was assessed as a change in airway resistance (RL). Histological studies were performed to assess the levels of mucin and pulmonary inflammation. Systemic Gln administration inhibited cPLA(2) phosphorylation and its enzymatic activity in the lungs. Additionally, Gln effectively suppressed the key features of Th2-dependent asthmatic features, such as airway eosinophilia, mucus formation, and airway type 2 cytokine production, as well as late AHR. Gln was found to be effective in the suppression of Th2-dependent phenotypes and late AHR, and this effect of Gln appeared to be at least partially attributable to its ability to suppress cLPA(2) activity in the airway. Our results suggest that clinical use of Gln for patients with asthma may be beneficial.

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

    PubMed Central

    Russell, Kirsty E.; Chung, Kian Fan; Clarke, Colin J.; Durham, Andrew L.; Mallia, Patrick; Johnston, Sebastian L.; Barnes, Peter J.; Hall, Simon R.; Simpson, Karen D.; Starkey, Malcolm R.; Hansbro, Philip M.; Adcock, Ian M.; Wiegman, Coen H.

    2016-01-01

    Introduction 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. Methods 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. Results 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. Conclusion 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. PMID:26752192

  15. Dietary Acacetin Reduces Airway Hyperresponsiveness and Eosinophil Infiltration by Modulating Eotaxin-1 and Th2 Cytokines in a Mouse Model of Asthma

    PubMed Central

    Huang, Wen-Chung; Liou, Chian-Jiun

    2012-01-01

    A previous study found that eosinophil infiltration and Th2 cell recruitment are important causes of chronic lung inflammation in asthma. The plant flavonoid acacetin is known to have an anti-inflammatory effect in vitro. This study aims to investigate the anti-inflammatory effect of orally administered acacetin in ovalbumin- (OVA-) sensitized asthmatic mice and its underlying molecular mechanism. BALB/c mice were sensitized by intraperitoneal OVA injection. OVA-sensitized mice were fed acacetin from days 21 to 27. Acacetin treatment attenuated airway hyperresponsiveness and reduced eosinophil infiltration and goblet cell hyperplasia in lung tissue. Additionally, eotaxin-1- and Th2-associated cytokines were inhibited in bronchoalveolar lavage fluid and suppressed the level of OVA-IgE in serum. Human bronchial epithelial (BEAS-2B) cells were used to examine the effect of acacetin on proinflammatory cytokines, chemokines, and cell adhesion molecule production in vitro. At the molecular level, acacetin significantly reduced IL-6, IL-8, intercellular adhesion molecule-1, and eotaxin-1 in activated BEAS-2B cells. Acacetin also significantly suppressed the ability of eosinophils to adhere to inflammatory BEAS-2B cells. These results suggest that dietary acacetin may improve asthma symptoms in OVA-sensitized mice. PMID:23049614

  16. Potential of Inducible Nitric Oxide Synthase as a Therapeutic Target for Allergen-Induced Airway Hyperresponsiveness: A Critical Connection to Nitric Oxide Levels and PARP Activity

    PubMed Central

    Ghonim, Mohamed A.; Pyakurel, Kusma; Mishra, Anil

    2016-01-01

    Although expression of inducible NO synthase (iNOS) in the lungs of asthmatics and associated nitrosative damage are established, iNOS failed as a therapeutic target for blocking airway hyperresponsiveness (AHR) and inflammation in asthmatics. This dichotomy calls for better strategies with which the enzyme is adequately targeted. Here, we confirm iNOS expression in the asthmatic lung with concomitant protein nitration and poly(ADP-ribose) polymerase (PARP) activation. We show, for the first time, that iNOS is highly expressed in peripheral blood mononuclear cells (PBMCs) of asthmatics with uncontrolled disease, which did not correspond to protein nitration. Selective iNOS inhibition with L-NIL protected against AHR upon acute, but not chronic, exposure to ovalbumin or house dust mite (HDM) in mice. Supplementation of NO by nitrite administration significantly blocked AHR in chronically HDM-exposed mice that were treated with L-NIL. Protection against chronic HDM exposure-induced AHR by olaparib-mediated PARP inhibition may be associated with the partial but not the complete blockade of iNOS expression. Indeed, L-NIL administration prevented olaparib-mediated protection against AHR in chronically HDM-exposed mice. Our study suggests that the amount of iNOS and NO are critical determinants in the modulation of AHR by selective iNOS inhibitors and renews the potential of iNOS as a therapeutic target for asthma. PMID:27524861

  17. Oral Administration of Heat-Inactivated Lactobacillus plantarum K37 Modulated Airway Hyperresponsiveness in Ovalbumin-Sensitized BALB/c Mice

    PubMed Central

    Liu, Yen-Wenn; Liao, Tan-Wei; Chen, Yu-Han; Chiang, Yi-Chin; Tsai, Ying-Chieh

    2014-01-01

    This study aimed to investigate the anti-allergic effects of Lactobacillus plantarum K37 (K37) on airway hyperresponsiveness (AHR) and systemic allergic responses in ovalbumin (OVA)-sensitized and -challenged BALB/c mice. Heat-inactivated K37 (105, 107, and 109 CFU/mouse, day) were orally administered to OVA-sensitized BALB/c mice to investigate their effects on AHR, immunoglobulin (Ig) and cytokine production. The results showed that K37 dose-dependently lowered the serum levels of IgE, OVA-specific IgE and OVA-specific IgG1, ameliorated AHR induced by methacholine and suppressed eosinophil infiltration in bronchoalveolar lavage fluid (BALF). The cytokine production in spleen cells culture and BALF showed that K37 drove the immune responses toward T-helper cell type 1 (Th1) responses, elevated levels of IL-2 and IFN-γ, and reduced of IL-4, IL-5 and IL-13. K37 also improved cell infiltration in lung sections. Our results demonstrated that oral administration of K37 alleviated effectively the allergic responses in vivo. Thus, K37 can be a good source material and a promising candidate for prophylactic and therapeutic treatments of allergic diseases, like asthma. PMID:24936861

  18. Exposure to cigarette smoke impacts myeloid-derived regulatory cell function and exacerbates airway hyper-responsiveness

    PubMed Central

    Wang, Yong; Jin, Tong Huan; Farhana, Aisha; Freeman, Jason; Estell, Kim; Zmijewski, Jaroslaw; Gaggar, Amit; Thannickal, Victor J; Schwiebert, Lisa M; Steyn, Adrie JC; Deshane, Jessy S

    2014-01-01

    Cigarette smoking enhances oxidative stress and airway inflammation in asthma, the mechanisms of which are largely unknown. Myeloid-derived regulatory cells (MDRC) are free radical producing immature myeloid cells with immunoregulatory properties which have recently been demonstrated as critical regulators of allergic airway inflammation. NO (nitric oxide)-producing immunosuppressive MDRC suppress T cell proliferation and airway-hyper responsiveness (AHR), while the O2•− (superoxide)-producing MDRC are proinflammatory. We hypothesized that cigarette smoke (CS) exposure may impact MDRC function and contribute to exacerbations in asthma. Exposure of bone marrow (BM) derived NO-producing MDRC to CS reduced the production of NO and its metabolites and inhibited their potential to suppress T cell proliferation. Production of immunoregulatory cytokine IL-10 was significantly inhibited, while proinflammatory cytokines IL-6, IL-1β, TNF-α and IL-33 were enhanced in CS exposed BMMDRC. Additionally, CS exposure increased NF-κB activation and induced BM-MDRC-mediated production of O2•−, via NF-κB dependent pathway. Intratracheal transfer of smoke exposed MDRC producing proinflammatory cytokines increased NF-κB activation, reactive oxygen species and mucin production in vivo and exacerbated AHR in C57BL/6 mice, mice deficient in Type I IFNR and MyD88, both with reduced numbers of endogenous MDRC. Thus, CS exposure modulates MDRC function and contributes to asthma exacerbation and identifies MDRC as potential targets for asthma therapy. PMID:25365203

  19. Differential effects of formaldehyde exposure on airway inflammation and bronchial hyperresponsiveness in BALB/c and C57BL/6 mice

    PubMed Central

    He, Yafang

    2017-01-01

    Epidemiological evidence suggests that formaldehyde (FA) exposure may influence the prevalence and severity of allergic asthma. However, the role of genetic background in FA-induced asthma-like responses is poorly understood. In the present study, we investigated the nature and severity of asthma-like responses triggered by exposure to different doses of FA together with or without ovalbumin (OVA) in two genetically different mouse strains—BALB/c and C57BL/6. Both mouse strains were divided into two main groups: the non-sensitized group and the OVA-sensitized group. All the groups were exposed to 0, 0.5 or 3.0 mg/m3 FA for 6 h/day over 25 consecutive days. At 24 h after the final FA exposure, the pulmonary parameters were evaluated. We found that FA exposure induced Th2-type allergic responses in non-sensitized BALB/c and C57BL/6 mice. In addition, FA-induced allergic responses were significantly more prominent in BALB/c mice than in C57BL/6 mice. In sensitized BALB/c mice, however, FA exposure suppressed the development of OVA-induced allergic responses. Exposure to 3.0 mg/m3 FA in sensitized C57BL/6 mice also led to suppressed allergic responses, whereas exposure to 0.5 mg/m3 FA resulted in exacerbated allergic responses to OVA. Our findings suggest that FA exposure can induce differential airway inflammation and bronchial hyperresponsiveness in BALB/c and C57BL/6 mice. PMID:28591193

  20. Differential effects of formaldehyde exposure on airway inflammation and bronchial hyperresponsiveness in BALB/c and C57BL/6 mice.

    PubMed

    Li, Luanluan; Hua, Li; He, Yafang; Bao, Yixiao

    2017-01-01

    Epidemiological evidence suggests that formaldehyde (FA) exposure may influence the prevalence and severity of allergic asthma. However, the role of genetic background in FA-induced asthma-like responses is poorly understood. In the present study, we investigated the nature and severity of asthma-like responses triggered by exposure to different doses of FA together with or without ovalbumin (OVA) in two genetically different mouse strains-BALB/c and C57BL/6. Both mouse strains were divided into two main groups: the non-sensitized group and the OVA-sensitized group. All the groups were exposed to 0, 0.5 or 3.0 mg/m3 FA for 6 h/day over 25 consecutive days. At 24 h after the final FA exposure, the pulmonary parameters were evaluated. We found that FA exposure induced Th2-type allergic responses in non-sensitized BALB/c and C57BL/6 mice. In addition, FA-induced allergic responses were significantly more prominent in BALB/c mice than in C57BL/6 mice. In sensitized BALB/c mice, however, FA exposure suppressed the development of OVA-induced allergic responses. Exposure to 3.0 mg/m3 FA in sensitized C57BL/6 mice also led to suppressed allergic responses, whereas exposure to 0.5 mg/m3 FA resulted in exacerbated allergic responses to OVA. Our findings suggest that FA exposure can induce differential airway inflammation and bronchial hyperresponsiveness in BALB/c and C57BL/6 mice.

  1. Heat Shock–Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of β2-Adrenergic Receptor

    PubMed Central

    Banathy, Alex; Cheung-Flynn, Joyce; Goleniewska, Kasia; Boyd, Kelly L.; Newcomb, Dawn C.; Peebles, R. Stokes

    2016-01-01

    Severe bronchospasm refractory to β-agonists is a challenging aspect of asthma therapy, and novel therapeutics are needed. β-agonist–induced airway smooth muscle (ASM) relaxation is associated with increases in the phosphorylation of the small heat shock–related protein (HSP) 20. We hypothesized that a transducible phosphopeptide mimetic of HSP20 (P20 peptide) causes relaxation of human ASM (HASM) by interacting with target(s) downstream of the β2-adrenergic receptor (β2AR) pathway. The effect of the P20 peptide on ASM contractility was determined in human and porcine ASM using a muscle bath. The effect of the P20 peptide on filamentous actin dynamics and migration was examined in intact porcine ASM and cultured primary HASM cells. The efficacy of the P20 peptide in vivo on airway hyperresponsiveness (AHR) was determined in an ovalbumin (OVA) sensitization and challenge murine model of allergic airway inflammation. P20 peptide caused dose-dependent relaxation of carbachol-precontracted ASM and blocked carbachol-induced contraction. The β2AR inhibitor, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride (ICI 118,551), abrogated isoproterenol but not P20 peptide–mediated relaxation. The P20 peptide decreased filamentous actin levels in intact ASM, disrupted stress fibers, and inhibited platelet-derived growth factor–induced migration of HASM cells. The P20 peptide treatment reduced methacholine-induced AHR in OVA mice without affecting the inflammatory response. These results suggest that the P20 peptide decreased airway constriction and disrupted stress fibers through regulation of the actin cytoskeleton downstream of β2AR. Thus, the P20 peptide may be a potential therapeutic for asthma refractory to β-agonists. PMID:26909644

  2. BLUNTING AIRWAYS EOSINOPHILIC INFLAMMATION RESULTS IN A DECREASED AIRWAY NEUTROPHIL RESPONSE TO INHALED LPS IN ATOPIC ASTHMATICS A ROLE FOR CD-14

    EPA Science Inventory

    Recent data demonstrate that atopic inflammation might enhance airway responses to inhaled LPS in individuals with atopic asthma by increasing CD14 expression on airway macrophages. We sought to determine whether blunting airway eosinophilic inflammation decreases CD14 expressio...

  3. BLUNTING AIRWAYS EOSINOPHILIC INFLAMMATION RESULTS IN A DECREASED AIRWAY NEUTROPHIL RESPONSE TO INHALED LPS IN ATOPIC ASTHMATICS A ROLE FOR CD-14

    EPA Science Inventory

    Recent data demonstrate that atopic inflammation might enhance airway responses to inhaled LPS in individuals with atopic asthma by increasing CD14 expression on airway macrophages. We sought to determine whether blunting airway eosinophilic inflammation decreases CD14 expressio...

  4. Proof-of-concept evaluation of trough airway hyper-responsiveness following regular racemic or levosalbutamol in genotype-stratified steroid-treated persistent asthmatic patients.

    PubMed

    Anderson, William J; Short, Philip M; Williamson, Peter A; Morrison, Ashley E; Palmer, Colin; Tavendale, Roger; Lipworth, Brian J

    2014-01-01

    Asthmatic patients receiving ICSs (inhaled corticosteroids) may take frequent add-on therapy with salbutamol despite on-demand prescription. Frequent salbutamol use can be detrimental in asthma. The isomeric formulation of salbutamol and the B2ADR (β2 adrenoceptor) 16 genotype may also influence this phenomenon. We performed a randomized, double-blind, placebo-controlled, triple crossover, proof of concept trial comparing 2 weeks of regular therapy with inhaled racemic salbutamol [200 μg q.i.d. (four times daily)], levosalbutamol (100 μg q.i.d.) or placebo on trough methacholine PC20 [provocative concentration causing 20% fall in FEV1 (forced expiratory volume in 1 s)] 6 h post-dose (the primary outcome) in 30 persistent asthmatic patients (15 who were Arg16 homozygous and 15 who were Gly16 homozygous) all receiving ICSs. There was no worsening of AHR (airway hyper-responsiveness) at trough to methacholine after 2 weeks regular exposure to either racemic (P=0.53) or levosalbutamol (P=0.84) compared with placebo, nor between genotypes-as dd (doubling dilution) difference in methacholine PC20 from placebo [salbutamol/Arg16=0.36 dd [95% CI (confidence interval), -0.43, 1.15]; salbutamol/Gly16=0.01 dd (95% CI, -0.47, 0.49); levosalbutamol/Arg16=-0.01 dd (95% CI, -0.89, 0.87); and levosalbutamol/Gly16=0.28 dd (95% CI, -0.22, 0.77)]. Both active treatments improved morning PEF (peak expiratory flow) in Gly16 (P=0.04 overall) but not Arg16 (P=0.50 overall) patients, whereas evening PEF improved in both Gly16 (P<0.001 overall) and Arg16 (P=0.006 overall) patients. In conclusion, the regular exposure to either racemic or levosalbutamol for 2 weeks added to ICSs did not cause worsening of AHR at trough compared with placebo; with no difference seen between B2ADR 16 genotypes.

  5. EDU pretreatment decreases polymorphonuclear leukocyte migration into rat lung airways.

    PubMed

    Bassett, D J; Elbon, C L; Ishii, Y; Yang, H; Otterbein, L; Boswell, G A; Kerr, J S

    1994-07-01

    Pretreatment with the heterocyclic compound EDU (N-[2-(2-oxo-1-imidazolindinyl)ethyl]-N'-phenylurea) has previously been shown to reduce polymorphonuclear leukocyte (PMN) infiltration into the airways of ozone-exposed rats. The present study further examined the effects of 1 and 2 days EDU pretreatment on rat lung inflammatory responses by determining PMN infiltration in response to intratracheal instillation with the chemoattractant formyl-norleucine-leucine-phenylalanine (fNLP). Maximal recovery of PMNs by bronchoalveolar lavage was observed 4 hr after fNLP instillation with no alteration in the numbers of recoverable macrophages and lymphocytes. Although 1-day pretreatment with EDU did not affect PMN recovery from fNLP-instilled rat lungs, 2 days of EDU pretreatment prevented PMN infiltration as indicated by PMN recoveries that were similar to those obtained from saline-instilled lungs. Measurements of lung-marginated and interstitial pools of inflammatory cells using collagenase tissue digestion demonstrated no effect of 2 days EDU pretreatment. Although 2 days EDU pretreatment alone did not alter blood PMN content, lung permeability, and the lavage recoveries of inflammatory cells, blood PMN responses to chemotactic stimuli in vitro were impaired. In addition, EDU was shown to directly inhibit PMN chemotaxis and superoxide anion generation in vitro. These data demonstrated that EDU acts by interfering with PMN activation and migration rather than by decreasing PMN availability. EDU, by modulating the inflammatory response, represents a useful compound for preventing PMN-associated amplification of acute lung injuries.

  6. [Effect of dental arch length decrease during orthodontic treatment in the upper airway development. A review].

    PubMed

    Haddad, Stéphanie; Kerbrat, Jean-Baptiste; Schouman, Thomas; Goudot, Patrick

    2017-03-01

    A possible relation between an upper airway space decrease and the development of obstructive sleep apnea syndrom explains the importance to know the effect of the modification of dental arch length on the upper airway during orthodontic treatment. The aim of this article is to expose recent knowledge about upper airway development and dental arch length decrease factors, to determine the influence of this decrease on upper airway development. A review was done to determine the upper airway normal development, to define dental arch to specify if an ideal position of dental arch on apical base exists. All of the length dental arch decrease factors during orthodontic treatment (dental extraction, dental agenesis and dental malpositions) and their upper airway resounding were searched. Some authors found a diminution of upper airway space after premolars extractions while others didn't found this diminution after extractions premolars when incisor retraction is finished. A decrease of transversal maxillary diameter and nasal cavity may be due to absence of permanent teeth. The effect of dental arch length decrease during orthodontic treatment in the upper airway development was not scientifically proved. However we had to be vigilant and adapt our orthodontic treatment case by case to avoid an upper airway modification. © EDP Sciences, SFODF, 2017.

  7. Long-term exposure of adults to outdoor air pollution is associated with increased airway obstruction and higher prevalence of bronchial hyperresponsiveness

    SciTech Connect

    Jammres, Y.; Delpierre, S.; Burnet, H.; Delvolgo, M.J.; Humbert-Tena, C.

    1998-11-01

    The authors studied the association between long-term exposure to outdoor air pollution and the severity of obstructive pulmonary disease and prevalence of bronchial hyperreactivity to {beta}2 agonists in two groups of adult patients who were of similar ages and who had similar smoking habits. The subjects lived in downtown districts or in the outer suburbs of Marseilles, the neighborhood that contained air samplers. The regions were similar with respect to sulfur dioxide levels, but levels of nitric oxides and particulate matter were higher in the downtown area than the suburbs. The authors assessed airway obstruction, as determined by a decrease in forced expiratory volume in 1 s, mean forced expiratory flow measured between 25% and 75% of vital capacity, and an elevated value of central airway resistance. The authors tested the changes in these variables induced by inhalation of a {beta}2 agonist. Baseline lung function was altered more significantly in both male and female patients who lived in downtown Marseilles than in those who resided in the suburbs, and the differences persisted regardless of the season during which the study occurred. Prevalence of bronchial hyperreactivity and symptoms of asthma were higher in the downtown than suburban male subjects. The results of this study suggest that an association exists between actual environmental exposure to outdoor air pollution and respiratory effects in sensitive adults represented by patients with chronic obstructive pulmonary disease or asthma.

  8. Airway responsiveness to sulfur dioxide in an adult population sample.

    PubMed

    Nowak, D; Jörres, R; Berger, J; Claussen, M; Magnussen, H

    1997-10-01

    We determined the prevalence of airway hyperresponsiveness to sulfur dioxide (SO2) in an adult population sample of 790 subjects 20 to 44 yr of age. Subjects were drawn randomly from the population of Hamburg, Northern Germany, within the framework of the European Community Respiratory Health Survey. In addition, we analyzed the relationship between SO2 responsiveness and a number of risk factors, such as a history of respiratory symptoms, methacholine responsiveness, and atopy derived from skin-prick test results. SO2 inhalation challenges were performed during isocapnic hyperventilation at constant rate (40 L x min(-1), for 3 min) with doubling concentrations of SO2 up to a maximum concentration of 2.0 ppm. If subjects achieved a 20% decrease in FEV1 from baseline during the challenge, they were considered to be hyperresponsive to SO2. The raw prevalence of SO2 hyperresponsiveness within the population sample studied was 3.4% (95% confidence interval [CI]: 2.3 to 5.0%). Adjustment for nonparticipation led to an estimated prevalence of SO2 hyperresponsiveness of 5.4%. Among subjects with hyperresponsiveness to methacholine, 22.4% (95% CI: 20.1 to 25.3) demonstrated hyperresponsiveness to SO2. There was no significant correlation between the degrees of hyperresponsiveness to methacholine and SO2. Predictors of a positive SO2 response were hyperresponsiveness to methacholine (p < 0.0001), a positive history of respiratory symptoms (p < 0.05), and a positive skin-prick test to at least one common allergen (p < 0.05). We conclude from these data that airway hyperresponsiveness to SO2 can be found in about 20 to 25% of subjects within the 20- to 44-yr age range who are hyperresponsive to methacholine.

  9. Inhaled Bordetella pertussis vaccine decreases airway responsiveness in guinea pigs.

    PubMed

    Vargas, M H; Bazán-Perkins, B; Segura, P; Campos, M G; Selman, M; Montaño, L M

    1995-01-01

    Bordetella pertussis (BP) has been used as adjuvant for experimental animal immunization, but its effects on airway responsiveness are uncertain. Three groups of guinea pigs were used: animals with a single exposure to inhaled BP vaccine (strain 134, total dose 1.24 x 10(12) germs), animals submitted to a sensitization procedure through inhalation of ovalbumin plus BP, and healthy control animals. Four weeks after inhalation of BP or after the beginning of sensitization, dose- or concentration-response curves to histamine were constructed in vivo and in vitro (tracheal and parenchymal preparations). We found that BP alone produced lower responses to histamine than control guinea pigs in vivo (insufflation pressure, p = 0.0003) and in tracheal tissues (p = 0.04), but not in parenchymal preparations. Sensitization did not modify the responsiveness compared with their respective controls. These results suggest that some BP component(s), probably pertussis toxin, causes a long lasting airway hyporesponsiveness in guinea pigs.

  10. Pretreatment with antibody to eosinophil major basic protein prevents hyperresponsiveness by protecting neuronal M2 muscarinic receptors in antigen-challenged guinea pigs.

    PubMed Central

    Evans, C M; Fryer, A D; Jacoby, D B; Gleich, G J; Costello, R W

    1997-01-01

    In antigen-challenged guinea pigs there is recruitment of eosinophils into the lungs and to airway nerves, decreased function of inhibitory M2 muscarinic autoreceptors on parasympathetic nerves in the lungs, and airway hyperresponsiveness. A rabbit antibody to guinea pig eosinophil major basic protein was used to determine whether M2 muscarinic receptor dysfunction, and the subsequent hyperresponsiveness, are due to antagonism of the M2 receptor by eosinophil major basic protein. Guinea pigs were sensitized, challenged with ovalbumin and hyperresponsiveness, and M2 receptor function tested 24 h later with the muscarinic agonist pilocarpine. Antigen-challenged guinea pigs were hyperresponsive to electrical stimulation of the vagus nerves compared with controls. Likewise, loss of M2 receptor function was demonstrated since the agonist pilocarpine inhibited vagally-induced bronchoconstriction in control but not challenged animals. Pretreatment with rabbit antibody to guinea pig eosinophil major basic protein prevented hyperresponsiveness, and protected M2 receptor function in the antigen-challenged animals without inhibiting eosinophil accumulation in the lungs or around the nerves. Thus, hyperresponsiveness is a result of inhibition of neuronal M2 muscarinic receptor function by eosinophil major basic protein in antigen-challenged guinea pigs. PMID:9410903

  11. Triggers of airway inflammation.

    PubMed

    Kerrebijn, K F

    1986-01-01

    Most asthmatics have hyperresponsive airways. This makes them more sensitive than non-asthmatics to bronchoconstricting environmental exposures which, in their turn, may enhance responsiveness. Airway inflammation is considered to be a key determinant of airway hyperresponsiveness: the fact that chronic airway inflammation in cystic fibrosis does not lead to airway hyperresponsiveness of any importance indicates, however, that the role of airway inflammation is complex and incompletely elucidated. The main inducers of airway inflammation are viral infections, antigens, occupational stimuli and pollutants. Although exercise, airway cooling and hyper- or hypotonic aerosols are potent stimuli of bronchoconstriction, it is questionable if airway inflammation is involved in their mode of action. Each of the above-mentioned stimuli is discussed, with emphasis laid on the relation of symptoms to mechanisms.

  12. Prophylactic effects of omega-3 polyunsaturated fatty acids and luteolin on airway hyperresponsiveness and inflammation in cats with experimentally-induced asthma.

    PubMed

    Leemans, Jérôme; Cambier, Carole; Chandler, Tony; Billen, Frédéric; Clercx, Cécile; Kirschvink, Nathalie; Gustin, Pascal

    2010-04-01

    The aim of this study was to assess the preventive effects of omega-3 polyunsaturated fatty acids (omega3 PUFA) and luteolin supplementation on allergen-induced inflammation in eight Ascaris suum (AS)-sensitised cats. Airway responsiveness (AR) tests were performed and venous blood and bronchoalveolar lavage fluid (BALF) collected before and following a single (AS-stimulated) allergen exposure, as well as at the end of a 4-week treatment period, which was followed by a second AS-challenge. The omega6/omega3 fatty acid ratio in erythrocyte membranes, BALF cytology, AR to carbachol, and BALF lipoxin A(4) (LXA(4)), an endogenous inhibitor of inflammation, were assessed at each time point. Compared to respective unstimulated values, AS-challenged cats exhibited a significant rise in BALF eosinophil percentage and there was a trend to increased BALF total cell counts, increased AR and reduced BALF LXA(4) concentrations. The significant decrease in the blood omega6/omega3 ratio seen after supplementation demonstrated that omega3 PUFA were efficiently absorbed. No changes in BALF cytology were found between untreated and treated AS-stimulated cats, but BALF LXA(4) levels were significantly elevated and AR significantly decreased following supplement intake. The study suggests that omega3-luteolin supplementation may have some beneficial effects on AR through a LXA(4)-dependent pathway in cats with experimentally-induced asthma. Copyright 2009 Elsevier Ltd. All rights reserved.

  13. TNFα decreases mitochondrial movement in human airway smooth muscle.

    PubMed

    Delmotte, Philippe; Zavaletta, Vanessa A; Thompson, Michael A; Prakash, Y S; Sieck, Gary C

    2017-07-01

    In airway smooth muscle (ASM) cells, excitation-contraction coupling is accomplished via a cascade of events that connect an elevation of cytosolic Ca(2+) concentration ([Ca(2+)]cyt) with cross-bridge attachment and ATP-consuming mechanical work. Excitation-energy coupling is mediated by linkage of the elevation of [Ca(2+)]cyt to an increase in mitochondrial Ca(2+) concentration, which in turn stimulates ATP production. Proximity of mitochondria to the sarcoplasmic reticulum (SR) and plasma membrane is thought to be an important mechanism to facilitate mitochondrial Ca(2+) uptake. In this regard, mitochondrial movement in ASM cells may be key in establishing proximity. Mitochondria also move where ATP or Ca(2+) buffering is needed. Mitochondrial movement is mediated through interactions with the Miro-Milton molecular complex, which couples mitochondria to kinesin motors at microtubules. We examined mitochondrial movement in human ASM cells and hypothesized that, at basal [Ca(2+)]cyt levels, mitochondrial movement is necessary to establish proximity of mitochondria to the SR and that, during the transient increase in [Ca(2+)]cyt induced by agonist stimulation, mitochondrial movement is reduced, thereby promoting transient mitochondrial Ca(2+) uptake. We further hypothesized that airway inflammation disrupts basal mitochondrial movement via a reduction in Miro and Milton expression, thereby disrupting the ability of mitochondria to establish proximity to the SR and, thus, reducing transient mitochondrial Ca(2+) uptake during agonist activation. The reduced proximity of mitochondria to the SR may affect establishment of transient "hot spots" of higher [Ca(2+)]cyt at the sites of SR Ca(2+) release that are necessary for mitochondrial Ca(2+) uptake via the mitochondrial Ca(2+) uniporter. Copyright © 2017 the American Physiological Society.

  14. Decreased expression of intelectin 1 in the human airway epithelium of smokers compared to nonsmokers.

    PubMed

    Carolan, Brendan J; Harvey, Ben-Gary; De, Bishnu P; Vanni, Holly; Crystal, Ronald G

    2008-10-15

    Lectins are innate immune defense proteins that recognize bacterial cell wall components. Based on the knowledge that cigarette smoking is associated with an increased risk of infections, we hypothesized that cigarette smoking may modulate the expression of lectin genes in airway epithelium. Affymetrix microarrays were used to survey the expression of lectin genes in large airway epithelium from nine nonsmokers and 20 healthy smokers and in small airway epithelium from 13 nonsmokers and 20 healthy smokers. There were no changes (>2-fold change; p < 0.05) in lectin gene expression among healthy smokers compared with nonsmokers except for down-regulation of intelectin 1, a lectin that binds to galactofuranosyl residues in bacterial cell walls (large airway epithelium, p < 0.01; small airway epithelium, p < 0.01). This was confirmed by TaqMan RT-PCR in both large (p < 0.05) and small airway epithelium (p < 0.02). Immunohistochemistry assessment of airway biopsies demonstrated that intelectin 1 was expressed in secretory cells, while Western analysis confirmed the decreased expression of intelectin 1 in airway epithelium of healthy smokers compared with healthy nonsmokers (p < 0.02). Finally, compared with healthy nonsmokers, intelectin 1 expression was also decreased in small airway epithelium of smokers with lone emphysema and normal spirometry (n = 13, p < 0.01) and smokers with established chronic obstructive pulmonary disease (n = 14, p < 0.01). In the context that intelectin 1 plays a role in defense against bacteria, its down-regulation in response to cigarette smoking is another example of the immunomodulatory effects of smoking on the immune system and may contribute to the increase in susceptibility to infections observed in smokers.

  15. Decreased Expression of Intelectin 1 in the Human Airway Epithelium of Smokers Compared to Nonsmokers*

    PubMed Central

    Carolan, Brendan J.; Harvey, Ben-Gary; De, Bishnu P.; Vanni, Holly; Crystal, Ronald G.

    2009-01-01

    Summary Lectins are innate immune defense proteins that recognize specific bacterial cell wall components. Based on the knowledge that cigarette smoking is associated with increased risk of bacterial infections, we hypothesized that cigarette smoking may modulate the expression of lectin genes in airway epithelium. Affymetrix microarrays were used to survey expression of lectin genes in large airway epithelium from 9 nonsmokers and 20 healthy smokers and in small airway epithelium from 13 nonsmokers and 20 healthy smokers. There were no changes (>2-fold change, p<0.05) in lectin gene expression among healthy smokers compared to nonsmokers except for a striking down regulation of intelectin 1, a lectin that binds to galactofuranosyl residues in the cell walls of bacteria (large airway epithelium, p<0.01; small airway epithelium, p<0.01). This was confirmed by TaqMan RT-PCR in both large (p<0.05) and small airway epithelium (p<0.02). Immunohistochemistry assessment of airway biopsies demonstrated that intelectin 1 was expressed in secretory cells, while Western analysis confirmed the decreased expression of intelectin 1 in airway epithelium of healthy smokers compared to healthy nonsmokers (p<0.02). Finally, compared to healthy nonsmokers, intelectin 1 expression was also decreased in small airway epithelium of smokers with lone emphysema with normal spirometry (n= 13, p<0.01) and smokers with established COPD (n= 14, p<0.01). In the context that intelectin 1 is an epithelial molecule that likely plays a role in defense against bacteria, its down regulation in response to cigarette smoking is another example of the immunomodulatory effects of smoking on the immune system and may contribute to the increase in susceptibility to infections observed in smokers, including those with COPD. PMID:18832735

  16. Postexposure Administration of a β2-Agonist Decreases Chlorine-Induced Airway Hyperreactivity in Mice

    PubMed Central

    Song, Weifeng; Wei, Shipeng; Liu, Gang; Yu, Zhihong; Estell, Kim; Yadav, Amit K.; Schwiebert, Lisa M.; Matalon, Sadis

    2011-01-01

    Exposure to chlorine (Cl2) damages airway and alveolar epithelia, resulting in acute lung injury and reactive airway dysfunction syndrome. We evaluated the efficacy and mechanisms by which arformoterol, a long-term β2-agonist, administered after exposure, mitigated the extent of this injury. Exposure of C57BL/6 mice to 400 ppm Cl2 for 30 minutes increased respiratory system resistance and airway responsiveness to aerosolized methacholine (assessed by FlexiVent) up to 6 days after exposure, and decreased Na+-dependent alveolar fluid clearance (AFC). Inducible Nitric Oxide Synthase (iNOS) knockout mice developed similar degrees of airway hyperreactivity as wild-type controls after Cl2 exposure, indicating that reactive intermediates from iNOS do not contribute to Cl2-induced airway dysfunction in our model. Intranasal administration of arformoterol mitigated the Cl2 effects on airway reactivity and AFC, presumably by increasing lung cyclic AMP level. Arformoterol did not modify the inflammatory responses, as evidenced by the number of inflammatory cells and concentrations of IL-6 and TNF-α in the bronchoalveolar lavage. NF-κB activity (assessed by p65 Western blots and electrophoretic mobility shift assay) remained at control levels up to 24 hours after Cl2 exposure. Our results provide mechanistic insight into the effectiveness of long-term β2-agonists in reversing Cl2-induced reactive airway dysfunction syndrome and injury to distal lung epithelial cells. PMID:20855648

  17. Pinellia ternata, Citrus reticulata, and their combinational prescription inhibit eosinophil infiltration and airway hyperresponsiveness by suppressing CCR3+ and Th2 cytokines production in the ovalbumin-induced asthma model.

    PubMed

    Ok, In-Soo; Kim, Seung-Hyung; Kim, Bok-Kyu; Lee, Jang-Cheon; Lee, Young-Cheol

    2009-01-01

    This study was aimed to analyse the curative effects of Pinellia ternata, Citrus reticulata, and their combination on airway hyperresponsiveness (AHR) to inhaled methacholine, pulmonary eosinophilic infiltration, Th2 cytokine production, and IgE and histamine production in a murine model of asthma. For this purpose, BALB/c mice were systemically sensitized to ovalbumin (OVA) followed intratracheally, intraperitoneally, and by aerosol allergen challenges for 12 weeks. We examined the development of pulmonary eosinophilic accumulation, control of Th2 cytokine, immunoglobulin E (IgE), and histamine productions in a murine model of asthma. Our data suggest that the therapeutic mechanism by which Pinellia ternata, Citrus reticulata, and their combinational prescription effectively treats asthma is based on reductions of eosinophil infiltration, eotaxin receptor (CCR3), histamine, OVA-specific IgE productions in serum, and Th2 cytokines (IL-5, IL-13) by marked reductions of IL-5 and IL-13 mRNA expression in lung tissue. These findings provide evidence that Pinellia ternata, Citrus reticulata, and their combination play a regulatory role in allergic inflammation and offer therapeutic approaches as novel CCR3 antagonists for treatment asthma. However, it is not clear whether pharmacological activities of prescription composed of two herbs are potentiated due to synergistic effect or additive effect.

  18. Pinellia ternata, Citrus reticulata, and Their Combinational Prescription Inhibit Eosinophil Infiltration and Airway Hyperresponsiveness by Suppressing CCR3+ and Th2 Cytokines Production in the Ovalbumin-Induced Asthma Model

    PubMed Central

    Ok, In-Soo; Kim, Seung-Hyung; Kim, Bok-Kyu; Lee, Jang-Cheon; Lee, Young-Cheol

    2009-01-01

    Background and Objective. This study was aimed to analyse the curative effects of Pinellia ternata, Citrus reticulata, and their combination on airway hyperresponsiveness (AHR) to inhaled methacholine, pulmonary eosinophilic infiltration, Th2 cytokine production, and IgE and histamine production in a murine model of asthma. Methods. For this purpose, BALB/c mice were systemically sensitized to ovalbumin (OVA) followed intratracheally, intraperitoneally, and by aerosol allergen challenges for 12 weeks. We examined the development of pulmonary eosinophilic accumulation, control of Th2 cytokine, immunoglobulin E (IgE), and histamine productions in a murine model of asthma. Results. Our data suggest that the therapeutic mechanism by which Pinellia ternata, Citrus reticulata, and their combinational prescription effectively treats asthma is based on reductions of eosinophil infiltration, eotaxin receptor (CCR3), histamine, OVA-specific IgE productions in serum, and Th2 cytokines (IL-5, IL-13) by marked reductions of IL-5 and IL-13 mRNA expression in lung tissue. Conclusions. These findings provide evidence that Pinellia ternata, Citrus reticulata, and their combination play a regulatory role in allergic inflammation and offer therapeutic approaches as novel CCR3 antagonists for treatment asthma. However, it is not clear whether pharmacological activities of prescription composed of two herbs are potentiated due to synergistic effect or additive effect. PMID:19657453

  19. [Bronchial hyperresponsiveness and its importance for the clinician].

    PubMed

    Mihalache, A; Fitting, J-W

    2014-11-19

    Asthma is a chronic inflammatory airway disease, characterised by bronchial hyperresponsiveness causing bronchoconstriction, and thereby provoking typical symptoms (dyspnoea, cough, wheezing). Bronchial hyperres- ponsiveness indicates a temporary airflow limitation when exposed to a bronchoconstricting stimulus. Its measurement by challenge tests can be a valuable tool for confirming or excluding asthma, as well as for evaluating the efficacy of treatment. However, the origin of bronchial hyperresponsiveness is multifactorial and the different challenge tests are not equivalent. Direct challenge tests, like methacholine, mainly reflect chronic airway remo- delling, whereas indirect tests, like mannitol, better reflect bronchial inflammation.

  20. MAG-EPA and 17,18-EpETE target cytoplasmic signalling pathways to reduce short-term airway hyperresponsiveness.

    PubMed

    Khaddaj-Mallat, Rayan; Rousseau, Éric

    2015-07-01

    This study was aimed to investigate the role of eicosapentaenoic acid monoacylglyceride (MAG-EPA) and 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) on the regulation of contractile reactivity and nuclear protein expression in 72-h-cultured and TNF-α-treated guinea pig tracheal rings. Tension measurements performed on native tissues demonstrated that the cytochrome P-450 epoxygenase (CYP450)-dependent EPA metabolite, 17,18-EpETE, displayed a higher potency than MAG-EPA in inhibiting U-46619-induced tone. Calphostin C (a PKC inhibitor), whether in association or not with MAG-EPA or 17,18-EpETE, had no further effect, while 17,18-EpETE and Y-27632 (a Rho kinase inhibitor) yielded additive effects. Of note, MAG-EPA and 17,18-EpETE pre-treatments normalized the contractile responses to broncho-constrictive agents in 72-h-cultured trachea. The enhanced expression of TNF-α, P-p65-nuclear factor kappaB (NF)-κB, c-fos and c-Jun in 72-h-cultured tissues likely contributed to the hyperresponsiveness. β-Escin-permeabilized preparations demonstrated that 17,18-EpETE abolished Ca(2+) hypersensitivity, suggesting a blunting of PKC and/or Rho kinase activation. Lastly, activation of NF-κB and activating protein-1 (AP-1) signalling by exogenous TNF-α markedly increased the contractile response to MCh, through an increase in 17-kDa PKC-potentiated inhibitory protein of PP1 (CPI-17) phosphorylation and IκBα degradation. Dual incubation of 17,18-EpETE with calphostin C or Y-27632 induced cumulative inhibitory effects on MCh responses in TNF-α-incubated tracheal rings. 17,18-EpETE also reduced the detection level of P-p65-NF-κB and AP-1 subunits. The present data provide evidence that MAG-EPA, through its bioactive metabolite, represents a prospective pharmacological target in respiratory diseases.

  1. Can the use of HEPA cleaners in homes of asthmatic children and adolescents sensitized to cat and dog allergens decrease bronchial hyperresponsiveness and allergen contents in solid dust?

    PubMed

    Sulser, Claudia; Schulz, Gabriele; Wagner, Petra; Sommerfeld, Christine; Keil, Thomas; Reich, Andreas; Wahn, Ulrich; Lau, Susanne

    2009-01-01

    Exposure and sensitization to pet allergens are associated with allergic asthma in children. Conflicting data have emerged regarding the potential benefit of air cleaners with respect to a reduction of indoor pet allergens and bronchial hyperresponsiveness (BHR). In a randomized controlled trial 36 asthmatic children with sensitization to cat and/or dog and significant exposure to cat and/or dog allergen (Fel d 1 and/or Can f 1 >500 ng/g of carpet dust) were included in order to study the effect of high-efficiency particulate arresting (HEPA) air cleaners placed in the living room and bedroom compared with the effect of sham air cleaners. Patients were allocated to two groups: group 1 exposed to active filters and group 2 exposed to sham filters. At month 0, after 6 months and after 12 months, pulmonary function testing and cold air challenge were performed, serum eosinophil cationic protein (ECP) and specific IgE to seven aeroallergens were determined, and carpet dust samples and filters were collected. Major pet allergen concentrations (Fel d 1, Can f 1) were determined in filters and bulk dust samples. Thirty patients completed the study. After 6 and 12 months, there was no significant change in delta FEV(1) after cold air challenge, or in the use of medication and serum ECP levels. However, there was a trend in the active group towards an improvement of bronchial hyperresponsiveness, whereas the sham filter group showed a deterioration of BHR. Although HEPA air cleaners retained airborne pet allergens, no effect on disease activity or allergen concentrations in bulk dust samples was observed in this study. (c) 2008 S. Karger AG, Basel.

  2. Alcohol hyper-responsiveness in chronic rhinosinusitis with nasal polyps.

    PubMed

    De Schryver, Els; Derycke, Lara; Campo, Paloma; Gabriels, Eline; Joos, Guy F; Van Zele, Thibaut; Bachert, Claus; Hellings, Peter W; Gevaert, Philippe

    2017-02-01

    An important percentage of subjects diagnosed with chronic upper airway disease report alcohol-induced worsening of their symptoms. The prevalence and characteristics of respiratory reactions provoked by alcohol-containing drinks have not been fully investigated yet. The aim of this study was to estimate the prevalence and characteristics of alcohol hyper-responsiveness in patients with chronic airway disease and healthy controls. Furthermore, nasal inflammation was evaluated in nasal polyp patients with and without hyper-responsiveness. We evaluated the prevalence and characteristics of alcohol-induced respiratory complaints in 1281 subjects. Chronic rhinosinusitis with nasal polyps (CRSwNP) patients with and without NSAID exacerbated respiratory disease (NERD), chronic rhinosinusitis patients without nasal polyps (CRSsNP), allergic rhinitis (AR) patients and healthy controls were approached by means of a questionnaire. Inflammatory markers (eosinophilic cationic protein (ECP), IL-5, IgE, SAE-specific IgE, IL-17, TNFα and IFNγ) in tissue were then compared between alcohol hyper-responsive and non-hyper-responsive CRSwNP patients. The highest prevalence of nasal and bronchial alcohol hyper-responsiveness was observed in patients with NERD, followed by CRSwNP, and less frequent in CRSsNP, AR and healthy controls. Alcohol hyper-responsiveness is significantly more prevalent in CRSwNP patients suffering from recurrent disease and in patients with severe symptomatology. In nasal tissue of the hyper-responsive CRSwNP group, we observed significantly higher nasal levels of the eosinophilic biomarker ECP. Nasal hyper-responsiveness to alcohol is significantly more prevalent in severe eosinophilic upper airway disease. © 2016 John Wiley & Sons Ltd.

  3. CpG in Combination with an Inhibitor of Notch Signaling Suppresses Formalin-Inactivated Respiratory Syncytial Virus-Enhanced Airway Hyperresponsiveness and Inflammation by Inhibiting Th17 Memory Responses and Promoting Tissue-Resident Memory Cells in Lungs.

    PubMed

    Zhang, Lei; Li, Hongyong; Hai, Yan; Yin, Wei; Li, Wenjian; Zheng, Boyang; Du, Xiaomin; Li, Na; Zhang, Zhengzheng; Deng, Yuqing; Zeng, Ruihong; Wei, Lin

    2017-05-15

    Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations. The formalin-inactivated RSV (FI-RSV) vaccine-enhanced respiratory disease (ERD) has been an obstacle to the development of a safe and effective killed RSV vaccine. Agonists of Toll-like receptor (TLR) have been shown to regulate immune responses induced by FI-RSV. Notch signaling plays critical roles during the differentiation and effector function phases of innate and adaptive immune responses. Cross talk between TLR and Notch signaling pathways results in fine-tuning of TLR-triggered innate inflammatory responses. We evaluated the impact of TLR and Notch signaling on ERD in a murine model by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling during FI-RSV immunization. Activation with CpG or deficiency of MyD88-dependent TLR signaling did not alleviate airway inflammation in FI-RSV-immunized mice. Activation or inhibition of Notch signaling with Dll4, one of the Notch ligands, or L685,458 did not suppress FI-RSV-enhanced airway inflammation either. However, the CpG together with L685,458 markedly inhibited FI-RSV-enhanced airway hyperresponsiveness, weight loss, and lung inflammation. Interestingly, CpG plus L685,458 completely inhibited FI-RSV-associated Th17 and Th17-associated proinflammatory chemokine responses in lungs following RSV challenge but not Th1 or Th2, memory responses. In addition, FI-RSV plus CpG plus L685,458 promoted protective CD8(+) lung tissue-resident memory (TRM) cells. These results indicate that activation of TLR signaling combined with inhibition of Notch signaling prevent FI-RSV ERD, and the mechanism appears to involve suppressing proinflammatory Th17 memory responses and promoting protective TRM in lungs.IMPORTANCE RSV is the most important cause of lower respiratory tract infections in infants. The FI-RSV-enhanced respiratory disease (ERD) is a major impediment to the development of a safe and

  4. Nitric oxide induces airway smooth muscle cell relaxation by decreasing the frequency of agonist-induced Ca2+ oscillations

    PubMed Central

    Perez-Zoghbi, Jose F.; Bai, Yan

    2010-01-01

    Nitric oxide (NO) induces airway smooth muscle cell (SMC) relaxation, but the underlying mechanism is not well understood. Consequently, we investigated the effects of NO on airway SMC contraction, Ca2+ signaling, and Ca2+ sensitivity in mouse lung slices with phase-contrast and confocal microscopy. Airways that were contracted in response to the agonist 5-hydroxytryptamine (5-HT) transiently relaxed in response to the NO donor, NOC-5. This NO-induced relaxation was enhanced by zaprinast or vardenafil, two selective inhibitors of cGMP-specific phosphodiesterase-5, but blocked by ODQ, an inhibitor of soluble guanylyl cyclase, and by Rp-8-pCPT-cGMPS, an inhibitor of protein kinase G (PKG). Simultaneous measurements of airway caliber and SMC [Ca2+]i revealed that airway contraction induced by 5-HT correlated with the occurrence of Ca2+ oscillations in the airway SMCs. Airway relaxation induced by NOC-5 was accompanied by a decrease in the frequency of these Ca2+ oscillations. The cGMP analogues and selective PKG activators 8Br-cGMP and 8pCPT-cGMP also induced airway relaxation and decreased the frequency of the Ca2+ oscillations. NOC-5 inhibited the increase of [Ca2+]i and contraction induced by the photolytic release of inositol 1,4,5-trisphosphate (IP3) in airway SMCs. The effect of NO on the Ca2+ sensitivity of the airway SMCs was examined in lung slices permeabilized to Ca2+ by treatment with caffeine and ryanodine. Neither NOC-5 nor 8pCPT-cGMP induced relaxation in agonist-contracted Ca2+-permeabilized airways. Consequently, we conclude that NO, acting via the cGMP–PKG pathway, induced airway SMC relaxation by predominately inhibiting the release of Ca2+ via the IP3 receptor to decrease the frequency of agonist-induced Ca2+ oscillations. PMID:20176853

  5. Organophosphorus Pesticides Decrease M2 Muscarinic Receptor Function in Guinea Pig Airway Nerves via Indirect Mechanisms

    PubMed Central

    Proskocil, Becky J.; Bruun, Donald A.; Thompson, Charles M.; Fryer, Allison D.; Lein, Pamela J.

    2010-01-01

    Background Epidemiological studies link organophosphorus pesticide (OP) exposures to asthma, and we have shown that the OPs chlorpyrifos, diazinon and parathion cause airway hyperreactivity in guinea pigs 24 hr after a single subcutaneous injection. OP-induced airway hyperreactivity involves M2 muscarinic receptor dysfunction on airway nerves independent of acetylcholinesterase (AChE) inhibition, but how OPs inhibit neuronal M2 receptors in airways is not known. In the central nervous system, OPs interact directly with neurons to alter muscarinic receptor function or expression; therefore, in this study we tested whether the OP parathion or its oxon metabolite, paraoxon, might decrease M2 receptor function on peripheral neurons via similar direct mechanisms. Methodology/Principal Findings Intravenous administration of paraoxon, but not parathion, caused acute frequency-dependent potentiation of vagally-induced bronchoconstriction and increased electrical field stimulation (EFS)-induced contractions in isolated trachea independent of AChE inhibition. However, paraoxon had no effect on vagally-induced bradycardia in intact guinea pigs or EFS-induced contractions in isolated ileum, suggesting mechanisms other than pharmacologic antagonism of M2 receptors. Paraoxon did not alter M2 receptor expression in cultured cells at the mRNA or protein level as determined by quantitative RT-PCR and radio-ligand binding assays, respectively. Additionally, a biotin-labeled fluorophosphonate, which was used as a probe to identify molecular targets phosphorylated by OPs, did not phosphorylate proteins in guinea pig cardiac membranes that were recognized by M2 receptor antibodies. Conclusions/Significance These data indicate that neither direct pharmacologic antagonism nor downregulated expression of M2 receptors contributes to OP inhibition of M2 function in airway nerves, adding to the growing evidence of non-cholinergic mechanisms of OP neurotoxicity. PMID:20479945

  6. Increased airway responsiveness and decreased alveolar attachment points following in utero smoke exposure in the guinea pig.

    PubMed

    Elliot, J; Carroll, N; Bosco, M; McCrohan, M; Robinson, P

    2001-01-01

    Maternal smoking during pregnancy has been shown to result in abnormalities in lung function in newborn infants, including reduced expiratory flow and increased airway responsiveness to inhaled agonists. The mechanisms by which this occurs remain unclear. Using a guinea pig model of in utero smoke exposure, we measured airway responsiveness and lung morphology in a group of neonatal guinea pigs 21 d after delivery. Pregnant guinea pigs were exposed to cigarette smoke from Day 28 to term (Day 68 of gestation). After delivery newborn animals did not receive any smoke exposure. Airway wall thickness, smooth muscle area, and the number of points where the alveoli attached to the airway adventitia were measured. Airway responsiveness was increased (p < 0.05) and the mean distance between alveolar attachment points was increased (mean 0.052 +/- SE 0.001 mm versus 0.046 +/- 0.001, p = 0.001) in animals exposed to cigarette smoke in utero compared with nonexposed animals. Although not statistically significant, both the inner and outer airway wall and the smooth muscle area were greater in exposed animals compared with nonexposed animals. The increased mean distance between alveolar attachments in the smoke-exposed group was the result of a reduction in the number of attachments and an increase in the outer airway wall perimeter. These findings suggest that the increased airway responsiveness observed in postnatal animals, subsequent to in utero cigarette smoke exposure, may be the result of decreased alveolar attachment points to the airways and changes in airway dimensions.

  7. Mandibular advancement decreases pressures in the tissues surrounding the upper airway in rabbits.

    PubMed

    Kairaitis, Kristina; Stavrinou, Rosie; Parikh, Radha; Wheatley, John R; Amis, Terence C

    2006-01-01

    The pharyngeal airway can be considered as an airway luminal shape formed by surrounding tissues, contained within a bony enclosure formed by the mandible, skull base, and cervical vertebrae. Mandibular advancement (MA), a therapy for obstructive sleep apnea, is thought to increase the size of this bony enclosure and to decrease the pressure in the upper airway extraluminal tissue space (ETP). We examined the effect of MA on upper airway airflow resistance (Rua) and ETP in a rabbit model. We studied 11 male, supine, anesthetized, spontaneously breathing New Zealand White rabbits in which ETP was measured via pressure transducer-tipped catheters inserted into the tissues surrounding the lateral (ETPlat) and anterior (ETPant) pharyngeal wall. Airflow, measured via surgically inserted pneumotachograph in series with the trachea, and tracheal pressure were recorded while graded MA at 75 degrees and 100 degrees to the horizontal was performed using an external traction device. Data were analyzed using a linear mixed-effects statistical model. We found that MA at 100 degrees increased mouth opening from 4.7 +/- 0.4 to 6.6 +/- 0.4 (SE) mm (n = 7; P < 0.004), whereas mouth opening did not change from baseline (4.0 +/- 0.2 mm) with MA at 75 degrees . MA at both 75 degrees and 100 degrees decreased mean ETPlat and ETPant by approximately 0.1 cmH2O/mm MA (n = 7-11; all P < 0.0005). However, the fall in Rua (measured at 20 ml/s) with MA was greater for MA at 75 degrees (approximately 0.03 mmH2O.ml(-1).s.mm(-1)) than at 100 degrees (approximately 0.01 mmH2O.ml(-1).s.mm(-1); P < 0.02). From these findings, we conclude that MA decreases ETP and is more effective in reducing Rua without mouth opening.

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

    PubMed Central

    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.

    2014-01-01

    The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial 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. PMID:24958709

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

    PubMed

    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.

  10. Airway Peroxidases Catalyze Nitration of the β2-Agonist Salbutamol and Decrease Its Pharmacological Activity

    PubMed Central

    Sallans, Larry; Macha, Stephen; Brown, Kari; McGraw, Dennis W.; Kovacic, Melinda Butsch; Britigan, Bradley E.

    2011-01-01

    β2-Agonists are the most effective bronchodilators for the rapid relief of asthma symptoms, but for unclear reasons, their effectiveness may be decreased during severe exacerbations. Because peroxidase activity and nitrogen oxides are increased in the asthmatic airway, we examined whether salbutamol, a clinically important β2-agonist, is subject to potentially inactivating nitration. When salbutamol was exposed to myeloperoxidase, eosinophil peroxidase or lactoperoxidase in the presence of hydrogen peroxide (H2O2) and nitrite (NO2−), both absorption spectroscopy and mass spectrometry indicated formation of a new metabolite with features expected for the nitrated drug. The new metabolites showed an absorption maximum at 410 nm and pKa of 6.6 of the phenolic hydroxyl group. In addition to nitrosalbutamol (m/z 285.14), a salbutamol-derived nitrophenol, formed by elimination of the formaldehyde group, was detected (m/z 255.13) by mass spectrometry. It is noteworthy that the latter metabolite was detected in exhaled breath condensates of asthma patients receiving salbutamol but not in unexposed control subjects, indicating the potential for β2-agonist nitration to occur in the inflamed airway in vivo. Salbutamol nitration was inhibited in vitro by ascorbate, thiocyanate, and the pharmacological agents methimazole and dapsone. The efficacy of inhibition depended on the nitrating system, with the lactoperoxidase/H2O2/NO2− being the most affected. Functionally, nitrated salbutamol showed decreased affinity for β2-adrenergic receptors and impaired cAMP synthesis in airway smooth muscle cells compared with the native drug. These results suggest that under inflammatory conditions associated with asthma, phenolic β2-agonists may be subject to peroxidase-catalyzed nitration that could potentially diminish their therapeutic efficacy. PMID:20974700

  11. Putting the Squeeze on Airway Epithelia

    PubMed Central

    Park, Jin-Ah; Fredberg, Jeffrey J.

    2015-01-01

    Asthma is characterized by chronic inflammation, airway hyperresponsiveness, and progressive airway remodeling. The airway epithelium is known to play a critical role in the initiation and perpetuation of these processes. Here, we review how excessive epithelial stress generated by bronchoconstriction is sufficient to induce airway remodeling, even in the absence of inflammatory cells. PMID:26136543

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

    EPA Science Inventory

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

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

    EPA Science Inventory

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

  14. Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma.

    PubMed

    Sweerus, Kelly; Lachowicz-Scroggins, Marrah; Gordon, Erin; LaFemina, Michael; Huang, Xiaozhu; Parikh, Mihir; Kanegai, Cindy; Fahy, John V; Frank, James A

    2017-01-01

    Epithelial barrier dysfunction and increased permeability may contribute to antigen sensitization and disease progression in asthma. Claudin-18.1 is the only known lung-specific tight junction protein, but its contribution to airway barrier function or asthma is unclear. We sought to test the hypotheses that claudin-18 is a determinant of airway epithelial barrier function that is downregulated by IL-13 and that claudin-18 deficiency results in increased aeroantigen sensitization and airway hyperresponsiveness. Claudin-18.1 mRNA levels were measured in airway epithelial brushings from healthy controls and patients with asthma. In patients with asthma, claudin-18 levels were compared with a three-gene-mean marker of TH2 inflammation. Airway epithelial permeability changes due to claudin-18 deficiency were measured in 16HBE cells and claudin-18 null mice. The effect of IL-13 on claudin expression was determined in primary human airway epithelial cells and in mice. Airway hyperresponsiveness and serum IgE levels were compared in claudin-18 null and wild-type mice following aspergillus sensitization. Epithelial brushings from patients with asthma (n = 67) had significantly lower claudin-18 mRNA levels than did those from healthy controls (n = 42). Claudin-18 levels were lowest among TH2-high patients with asthma. Loss of claudin-18 was sufficient to impair epithelial barrier function in 16HBE cells and in mouse airways. IL-13 decreased claudin-18 expression in primary human cells and in mice. Claudin-18 null mice had significantly higher serum IgE levels and increased airway responsiveness following intranasal aspergillus sensitization. These data support the hypothesis that claudin-18 is an essential contributor to the airway epithelial barrier to aeroantigens. Furthermore, TH2 inflammation suppresses claudin-18 expression, potentially promoting sensitization and airway hyperresponsiveness. Published by Elsevier Inc.

  15. Continuous positive airway pressure (CPAP) decreases pulmonary shunt in anaesthetized horses.

    PubMed

    Mosing, Martina; MacFarlane, Paul; Bardell, David; Lüthi, Laura; Cripps, Peter J; Bettschart-Wolfensberger, Regula

    2016-11-01

    To evaluate the effects of continuous positive airway pressure (CPAP) on intrapulmonary shunt, cardiac output and oxygen delivery in horses subjected to a 6 hour period of general anaesthesia. Randomized, experimental, crossover study. Ten healthy adult horses. Following medetomidine, diazepam and ketamine administration, orotracheal intubation was performed and horses positioned in dorsal recumbency. Anaesthesia was maintained with isoflurane carried in an oxygen and air mix (FiO2 0.5) combined with a medetomidine infusion. Horses were anaesthetized twice and either CPAP (8 cmH2 O) or physiologic airway pressure (NO CPAP) was applied to the lungs for 6 hours; the order of treatments was randomly assigned. Following induction of anaesthesia, cardiovascular and respiratory variables (including arterial blood gas analysis) were recorded every 30 minutes, cardiac output was measured every 60 minutes using the lithium dilution technique and oxygen delivery calculated. If PaCO2 exceeded 100 mmHg (13.3 kPa), controlled ventilation was initiated and horses excluded from further data collection. Groups were compared using a general linear model. Data from eight horses were analysed. PaO2 was 15-56 mmHg (2.00-7.45 kPa) higher (p < 0.001) and shunt fraction 6-14% lower (p < 0.001) in the CPAP group. No differences were seen for cardiac output and oxygen delivery. The lack of difference in oxygen delivery was attributed to lower haemoglobin levels in the CPAP group than in the NO CPAP group. CPAP of 8 cmH2 O can be used in dorsally recumbent horses to decrease pulmonary shunt fraction without causing a decrease in cardiac output during longterm anaesthesia. © 2016 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  16. Congenital high airway obstruction syndrome without tracheoesophageal fistula and with in utero decrease in relative lung size.

    PubMed

    Furukawa, Rieko; Aihara, Toshinori; Tazuke, Yuko; Maeda, Kosaku; Kuwata, Tomoyuki

    2012-12-01

    Congenital high airway obstruction syndrome (CHAOS) is diagnosed by characteristic features on US and MRI including fetal upper airway occlusion, lung hyperinflation with an inverted diaphragm, and sometimes massive ascites and hydrops. We describe a case of CHAOS in which improvement in the fetal condition was observed on three sequential fetal MRIs. Such an improvement was thought to represent decrease in intrathoracic pressure caused by a spontaneous perforation such as a tracheoesophageal fistula. However, a fistula was not observed in the present case. Therefore, we suggest that imaging improvements in patients with CHAOS do not always correspond to the presence of a fistula and other factors might contribute to decreasing fetal intrathoracic pressure.

  17. Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

    PubMed Central

    Bracher, Andreas; Doran, Stephen F.; Squadrito, Giuseppe L.; Fernandez, Solana; Postlethwait, Edward M.; Bowen, Larry; Matalon, Sadis

    2012-01-01

    We assessed the safety and efficacy of combined intravenous and aerosolized antioxidant administration to attenuate chlorine gas–induced airway alterations when administered after exposure. Adult male Sprague-Dawley rats were exposed to air or 400 parts per million (ppm) chlorine (a concentration likely to be encountered in the vicinity of industrial accidents) in environmental chambers for 30 minutes, and returned to room air, and they then received a single intravenous injection of ascorbic acid and deferoxamine or saline. At 1 hour and 15 hours after chlorine exposure, the rats were treated with aerosolized ascorbate and deferoxamine or vehicle. Lung antioxidant profiles, plasma ascorbate concentrations, airway morphology, and airway reactivity were evaluated at 24 hours and 7 days after chlorine exposure. At 24 hours after exposure, chlorine-exposed rats had significantly lower pulmonary ascorbate and reduced glutathione concentrations. Treatment with antioxidants restored depleted ascorbate in lungs and plasma. At 7 days after exposure, in chlorine-exposed, vehicle-treated rats, the thickness of the proximal airways was 60% greater than in control rats, with twice the amount of mucosubstances. Airway resistance in response to methacholine challenge was also significantly elevated. Combined treatment with intravenous and aerosolized antioxidants restored airway morphology, the amount of airway mucosubstances, and airway reactivity to control levels by 7 days after chlorine exposure. Our results demonstrate for the first time, to the best of our knowledge, that severe injury to major airways in rats exposed to chlorine, as characterized by epithelial hyperplasia, mucus accumulation, and airway hyperreactivity, can be reversed in a safe and efficacious manner by the post-exposure administration of ascorbate and deferoxamine. PMID:22162906

  18. Down-regulation of 8-oxoguanine DNA glycosylase 1 expression in the airway epithelium ameliorates allergic lung inflammation.

    PubMed

    Bacsi, Attila; Aguilera-Aguirre, Leopoldo; Szczesny, Bartosz; Radak, Zsolt; Hazra, Tapas K; Sur, Sanjiv; Ba, Xueqing; Boldogh, Istvan

    2013-01-01

    Allergic airway inflammation is characterized by increased expression of pro-inflammatory mediators, inflammatory cell infiltration, mucus hypersecretion, and airway hyperresponsiveness, in parallel with oxidative DNA base and strand damage, whose etiological role is not understood. Our goal was to establish the role of 8-oxoguanine (8-oxoG), a common oxidatively damaged base, and its repair by 8-oxoguanine DNA glycosylase 1 (Ogg1) in allergic airway inflammatory processes. Airway inflammation was induced by intranasally administered ragweed (Ambrosia artemisiifolia) pollen grain extract (RWPE) in sensitized BALB/c mice. We utilized siRNA technology to deplete Ogg1 from airway epithelium; 8-oxoG and DNA strand break levels were quantified by Comet assays. Inflammatory cell infiltration and epithelial methaplasia were determined histologically, mucus and cytokines levels biochemically and enhanced pause was used as the main index of airway hyperresponsiveness. Decreased Ogg1 expression and thereby 8-oxoG repair in the airway epithelium conveyed a lower inflammatory response after RWPE challenge of sensitized mice, as determined by expression of Th2 cytokines, eosinophilia, epithelial methaplasia, and airway hyperresponsiveness. In contrast, 8-oxoG repair in Ogg1-proficient airway epithelium was coupled to an increase in DNA single-strand break (SSB) levels and exacerbation of allergen challenge-dependent inflammation. Decreased expression of the Nei-like glycosylases Neil1 and Neil2 that preferentially excise ring-opened purines and 5-hydroxyuracil, respectively, did not alter the above parameters of allergic immune responses to RWPE. These results show that DNA SSBs formed during Ogg1-mediated repair of 8-oxoG augment antigen-driven allergic immune responses. A transient modulation of OGG1 expression/activity in airway epithelial cells could have clinical benefits.

  19. Decreased levels of nitrosothiols in the lower airways of patients with cystic fibrosis and normal pulmonary function.

    PubMed

    Grasemann, H; Gaston, B; Fang, K; Paul, K; Ratjen, F

    1999-12-01

    Airway S-nitrosothiols (SNOs) are naturally occurring bronchodilators. SNOs, nitrate, and nitrite were measured in bronchoalveolar lavage fluid of 23 patients with cystic fibrosis (CF) and mild pulmonary disease (aged 6-16 years) and 13 healthy children (aged 8-15 years). Concentrations of SNOs were decreased in the lower airways of patients with CF and mild pulmonary disease (median, range: 0, 0-320 nmol/L vs 80, 0-970 nmol/L) despite normal levels of the inert nitric oxide metabolites nitrate and nitrite (mean +/- SEM: 3.7 +/- 0.5 micromol/L vs 4.8 +/- 0.9 micromol/L). S-nitrosolation- mediated bioreactivities may be impaired by depletion of the CF airway SNO reservoir.

  20. Differences between inhaled and intravenous bronchial challenge to detect O(3)-induced hyperresponsiveness.

    PubMed

    Sommer, B; Vargas, M H; Chavez, J; Carbajal, V; Segura, P; Montaño, L M

    2001-12-01

    Ozone (O(3))-induced airway hyperresponsiveness in laboratory animals is usually demonstrated through dose-response curves with inhaled or intravenous bronchoconstrictor agonists. However, comparability of these two routes has not been well documented. Thus guinea pig airway responsiveness to ACh and histamine was evaluated 16-18 h after O(3) (3 parts/million, 1 h) or air exposure by two plethysmographic methods (spontaneously breathing and mechanically ventilated) and by two administration routes (inhalatory or intravenous). We found that O(3) caused airway hyperresponsiveness to intravenous, but not to inhaled, agonists, independent of the plethysmographic method used. Suitability of the inhalatory route to detect airway hyperresponsiveness was corroborated with inhaled ACh after an antigen challenge or extending O(3) exposure to 3 h. Acetylcholinesterase activity was not modified after O(3) exposure in lung homogenates and blood samples. Thus inhaled agonists were less effective to reveal the airway hyperresponsiveness after an acute O(3) exposure than intravenous ones, at least for the 1-h exposure to 3 parts/million, and this difference seems not to be related to an O(3)-induced inhibition of the acetylcholinesterase activity.

  1. Hyperresponsive Sensory Patterns in Young Children with Autism, Developmental Delay, and Typical Development

    ERIC Educational Resources Information Center

    Baranek, Grace T.; Boyd, Brian A.; Poe, Michele D.; David, Fabian J.; Watson, Linda R.

    2007-01-01

    The nature of hyperresponsiveness to sensory stimuli in children with autism, using a new observational measure, the SPA, was examined. Three groups of young participants were assessed (autism, developmental delay, typical). Across all groups, MA was a predictor of hyperresponsiveness, such that aversion to multisensory toys decreased as MA…

  2. Hyperresponsive Sensory Patterns in Young Children with Autism, Developmental Delay, and Typical Development

    ERIC Educational Resources Information Center

    Baranek, Grace T.; Boyd, Brian A.; Poe, Michele D.; David, Fabian J.; Watson, Linda R.

    2007-01-01

    The nature of hyperresponsiveness to sensory stimuli in children with autism, using a new observational measure, the SPA, was examined. Three groups of young participants were assessed (autism, developmental delay, typical). Across all groups, MA was a predictor of hyperresponsiveness, such that aversion to multisensory toys decreased as MA…

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

    PubMed

    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.

  4. Immunization and challenge with toluene diisocyanate decrease tachykinin and calcitonin gene-related peptide immunoreactivity in guinea pig central airways.

    PubMed

    Mapp, C E; Lucchini, R E; Miotto, D; Chitano, P; Jovine, L; Saetta, M; Maestrelli, P; Springall, D R; Polak, J; Fabbri, L M

    1998-07-01

    Toluene diisocyanate (TDI) is a potent sensitizer that causes occupational asthma in a significant proportion of subjects exposed. We used an animal model to investigate whether neuropeptide changes occur in the airways of immunized and TDI-challenged guinea pigs. Animals were immunized by weekly intradermal injections, challenged with TDI (5 to 20 ppb) after the third injection, and killed 6 h after exposure. Control guinea pigs received injections of saline. Lung tissue was processed immediately and analyzed for nerves using the streptavidin-biotin complex peroxidase method with antisera to the neural marker protein gene product 9.5 (PGP 9.5), substance P (SP), and calcitonin gene- related peptide (CGRP). We also quantified the inflammatory infiltrate in the submucosa of central airways, and we measured the serum level of specific IgG and IgG1. Specific antibodies against TDI were present only in immunized animals. Immunized as compared with nonimmunized animals had a significant increase in eosinophils in the submucosa of central airways, and a further increase was observed 6 h after TDI challenge. Immunization and TDI challenge did not modify the number of mononuclear cells in the submucosa of central airways in both nonimmunized and immunized animals. TDI exposure did not change the overall innervation in both nonimmunized and immunized animals, but the density of PGP 9.5-positive nerves was significantly different between nonimmunized and immunized TDI-challenged animals. The density of SP-, and CGRP-immunostained nerves was significantly lower in immunized TDI-challenged than in nonimmunized animals. TDI exposure significantly decreased the density of SP-positive nerves in nonimmunized animals. A negative relationship was found between the presence of airway inflammation, as indexed by eosinophil cell infiltration, and the density of PGP 9.5-, SP-, and CGRP-immunostained nerves. In conclusion, TDI produces airway inflammation and neuropeptides changes in the

  5. Mechanical effects of obesity on airway responsiveness in otherwise healthy humans.

    PubMed

    Torchio, Roberto; Gobbi, Alessandro; Gulotta, Carlo; Dellacà, Raffaele; Tinivella, Marco; Hyatt, Robert E; Brusasco, Vito; Pellegrino, Riccardo

    2009-08-01

    We investigated whether obesity is associated with airway hyperresponsiveness in otherwise healthy humans and, if so, whether this correlates with a restrictive lung function pattern or a decreased number of sighs at rest and/or during walking. Lung function was studied before and after inhaling methacholine (MCh) in 41 healthy subjects with body mass index ranging from 20 to 56. Breathing pattern was assessed during a 60-min rest period and a 30-min walk. The dose of MCh that produced a 50% decrease in the maximum expiratory flow measured in a body plethysmograph (PD50MCh) was inversely correlated with body mass index (r2=0.32, P<0.001) and waist circumference (r2=0.25, P<0.001). Significant correlations with body mass index were also found with the maximum changes in respiratory resistance (r2=0.19, P<0.001) and reactance (r2=0.40, P<0.001) measured at 5 Hz. PD50MCh was also positively correlated with functional residual capacity (r2=0.56, P<0.001) and total lung capacity (r2=0.59, P<0.001) in men, but not in women. Neither PD50MCh nor body mass index correlated with number of sighs, average tidal volume, ventilation, or breathing frequency. In this study, airway hyperresponsiveness was significantly associated with obesity in otherwise healthy subjects. In obese men, but not in women, airway hyperresponsiveness was associated with the decreases in lung volumes.

  6. Exposure to Beta-(1,3)-D-Glucan in House Dust at Age 7–10 Is Associated with Airway Hyperresponsiveness and Atopic Asthma by Age 11–14

    PubMed Central

    Maheswaran, Dharini; Zeng, Yiye; Chan-Yeung, Moira; Scott, James; Osornio-Vargas, Alvaro; Becker, Allan B.; Kozyrskyj, Anita L.

    2014-01-01

    Background Mould exposure has been linked to childhood asthma and bronchial hyper-responsiveness. Few studies have assessed beta-(1,3)-d-glucan (beta-glucan), a significant fungal cell wall constituent, in relation to asthma in adolescence. Objective To determine whether house dust-derived beta-glucan exposure at age 7–10 is associated with the development and persistence of atopic and non-atopic asthma, and bronchial hyper-responsiveness (BHR) by age 11–14. Methods Dust samples were collected from the 1995 Study of Asthma, Genes, and Environment (SAGE) birth cohort. This cohort was derived from Manitoba provincial healthcare administrative records of children high and low risk for asthma. Samples were collected from the homes of 422 children at age 7–10 and analyzed using beta-glucan and endotoxin-specific Limulus Amoebocyte Lysate assays. Asthma, atopy, and BHR status of each child were also assessed at ages 7–10 and 11–14. Results At age 7–10, beta-glucan dust levels in the home were associated with persistent atopic asthma at age 11–14 (OR 1.79 for each unit increase in levels, 95% CI 1.14–2.81), independent of endotoxin exposure, and Alternaria or Cladosporium sensitization. The likelihood of BHR almost doubled with unit increases in dust beta-glucan in asthmatic children. In children without asthma, exposure to high beta-glucan levels at age 7–10 also elevated risk for BHR in adolescence (OR 1.74, 95% CI 1.05–2.89). New-onset atopic asthma was twice more likely following high beta-glucan exposure in children without asthma but the association did not reach statistical significance. No associations were evident with concurrent asthma phenotype at age 7–10 or non-atopic asthma at age 11–14. Conclusion These findings implicate home beta-glucan exposure at school-age as a risk factor for persistent atopic asthma and new-onset BHR. The higher prevalence of BHR in urban adolescents may be propagated by this home exposure. PMID:24905346

  7. A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha.

    PubMed

    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.

  8. Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease

    PubMed Central

    Siddesha, Jalahalli M.; Nakada, Emily M.; Mihavics, Bethany R.; Hoffman, Sidra M.; Rattu, Gurkiranjit K.; Chamberlain, Nicolas; Cahoon, Jonathon M.; Lahue, Karolyn G.; Daphtary, Nirav; Aliyeva, Minara; Chapman, David G.; Desai, Dhimant H.; Poynter, Matthew E.

    2016-01-01

    Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases. PMID:27154200

  9. Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation

    PubMed Central

    Juncadella, Ignacio J.; Kadl, Alexandra; Sharma, Ashish K.; Shim, Yun M.; Hochreiter-Hufford, Amelia; Borish, Larry; Ravichandran, Kodi S.

    2013-01-01

    Lung epithelial cells can influence immune responses to airway allergens1,2. Airway epithelial cells also undergo apoptosis after encountering environmental allergens3; yet, relatively little is known about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant anti-inflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyper-responsiveness, with decreased interleukin (IL)-10 in bronchial lavages. Rac1-deficient epithelial cells produced much higher IL-33 upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells1,4,5. Administration of exogenous IL-10 ‘rescued’ the airway inflammation phenotype in Rac1-deficient mice, with decreased IL-33. Collectively, these genetic and functional studies suggest a new role for Rac1-dependent engulfment by airway epithelial cells and in establishing the anti-inflammatory environment, and that defects in cell clearance in the airways could contribute to inflammatory responses towards common allergens. PMID:23235830

  10. Inhaled mannitol as a test for bronchial hyper-responsiveness.

    PubMed

    Brannan, John D; Porsbjerg, Celeste; Anderson, Sandra D

    2009-10-01

    Bronchial provocation tests (BPTs) are useful for identifying one of the key features of asthma: bronchial hyper-responsiveness (BHR). The symptoms of asthma are not always reflective of the underlying pathophysiology of asthma and there is a need for objective tests to identify the presence and severity of BHR. A new BPT, involving the inhalation of dry powder mannitol, has recently been approved to identify BHR and is now in use as a diagnostic tool for currently active asthma. Airway sensitivity to mannitol identifies BHR that is dependent upon the presence of airway inflammation and would probably benefit from treatment with inhaled corticosteroids. The mannitol BPT is available commercially as a (single-use) test kit (Aridol/Osmohale), with the only additional requirement to perform the test being a spirometer. Accordingly, the mannitol BPT provides a point-of-need tool to identify BHR to assist in the diagnosis of asthma.

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

    PubMed

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

    2012-01-15

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

  12. Relation of perceived nasal and bronchial hyperresponsiveness to FEV1, basophil counts, and methacholine response.

    PubMed Central

    Kauffmann, F; Neukirch, F; Annesi, I; Korobaeff, M; Doré, M F; Lellouch, J

    1988-01-01

    Perceived nasal and bronchial hyperresponsiveness to tobacco smoke and cold air were assessed in 912 working men in the Paris area. Baseline lung function measurements and peripheral leucocyte counts with standard differential counts were performed. At least one perceived nasal or bronchial hyperresponsiveness symptom was reported by 15.7%. Current smoking was significantly less frequent among those with cough induced by tobacco smoke. Rhinitis induced by cold air was associated with lower FEV1 (p less than 0.01) and the association remained after adjustment for smoking, asthma, and wheezing (p = 0.06). Symptoms induced by cold air were related to circulating basophils. Neither perceived nasal nor perceived bronchial hyperresponsiveness was significantly related to the airway response to methacholine in a sample of the group (n = 324) surveyed again five years later. The result suggest that the symptom of rhinitis provoked by cold air is a possible "new" risk factor or marker for chronic airflow limitation. PMID:3420556

  13. Decreased Staphylococcus aureus biofilm formation on nanomodified endotracheal tubes: a dynamic airway model

    PubMed Central

    Machado, Mary C; Tarquinio, Keiko M; Webster, Thomas J

    2012-01-01

    Ventilator-associated pneumonia (VAP) is a serious and costly clinical problem. Specifically, receiving mechanical ventilation for over 24 hours increases the risk of VAP and is associated with high morbidity, mortality, and medical costs. Cost-effective endotracheal tubes (ETTs) that are resistant to bacterial infections could help prevent this problem. The objective of this study was to determine differences in the growth of Staphylococcus aureus on nanomodified and unmodified polyvinyl chloride (PVC) ETTs under dynamic airway conditions simulating a ventilated patient. PVC ETTs were modified to have nanometer surface features by soaking them in Rhizopus arrhisus, a fungal lipase. Twenty-four-hour experiments (supported by computational models) showed that airflow conditions within the ETT influenced both the location and the concentration of bacterial growth on the ETTs, especially within areas of tube curvature. More importantly, experiments revealed a 1.5 log reduction in the total number of S. aureus on the novel nanomodified ETTs compared with the conventional ETTs after 24 hours of airflow. This dynamic study showed that lipase etching can create nanorough surface features on PVC ETTs that suppress S. aureus growth, and thus may provide clinicians with an effective and inexpensive tool to combat VAP. PMID:22904622

  14. Decreased Staphylococcus aureus biofilm formation on nanomodified endotracheal tubes: a dynamic airway model.

    PubMed

    Machado, Mary C; Tarquinio, Keiko M; Webster, Thomas J

    2012-01-01

    Ventilator-associated pneumonia (VAP) is a serious and costly clinical problem. Specifically, receiving mechanical ventilation for over 24 hours increases the risk of VAP and is associated with high morbidity, mortality, and medical costs. Cost-effective endotracheal tubes (ETTs) that are resistant to bacterial infections could help prevent this problem. The objective of this study was to determine differences in the growth of Staphylococcus aureus on nanomodified and unmodified polyvinyl chloride (PVC) ETTs under dynamic airway conditions simulating a ventilated patient. PVC ETTs were modified to have nanometer surface features by soaking them in Rhizopus arrhisus, a fungal lipase. Twenty-four-hour experiments (supported by computational models) showed that airflow conditions within the ETT influenced both the location and the concentration of bacterial growth on the ETTs, especially within areas of tube curvature. More importantly, experiments revealed a 1.5 log reduction in the total number of S. aureus on the novel nanomodified ETTs compared with the conventional ETTs after 24 hours of airflow. This dynamic study showed that lipase etching can create nanorough surface features on PVC ETTs that suppress S. aureus growth, and thus may provide clinicians with an effective and inexpensive tool to combat VAP.

  15. Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells.

    PubMed

    Goodale, Britton C; Rayack, Erica J; Stanton, Bruce A

    2017-09-15

    Arsenic contamination of drinking water and food threatens the health of hundreds of millions of people worldwide by increasing the risk of numerous diseases. Arsenic exposure has been associated with infectious lung disease in epidemiological studies, but it is not yet understood how ingestion of low levels of arsenic increases susceptibility to bacterial infection. Accordingly, the goal of this study was to examine the effect of arsenic on gene expression in primary human bronchial epithelial (HBE) cells and to determine if arsenic altered epithelial cell responses to Pseudomonas aeruginosa, an opportunistic pathogen. Bronchial epithelial cells line the airway surface, providing a physical barrier and serving critical roles in antimicrobial defense and signaling to professional immune cells. We used RNA-seq to define the transcriptional response of HBE cells to Pseudomonas aeruginosa, and investigated how arsenic affected HBE gene networks in the presence and absence of the bacterial challenge. Environmentally relevant levels of arsenic significantly changed the expression of genes involved in cellular redox homeostasis and host defense to bacterial infection, and decreased genes that code for secreted antimicrobial factors such as lysozyme. Using pathway analysis, we identified Sox4 and Nrf2-regulated gene networks that are predicted to mediate the arsenic-induced decrease in lysozyme secretion. In addition, we demonstrated that arsenic decreased lysozyme in the airway surface liquid, resulting in reduced lysis of Microccocus luteus. Thus, arsenic alters the expression of genes and proteins in innate host defense pathways, thereby decreasing the ability of the lung epithelium to fight bacterial infection. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Mechanisms of inflammation-mediated airway smooth muscle plasticity and airways remodeling in asthma.

    PubMed

    Halayko, Andrew J; Amrani, Yassine

    2003-09-16

    Recent evidence points to progressive structural change in the airway wall, driven by chronic local inflammation, as a fundamental component for development of irreversible airway hyperresponsiveness. Acute and chronic inflammation is orchestrated by cytokines from recruited inflammatory cells, airway myofibroblasts and myocytes. Airway myocytes exhibit functional plasticity in their capacity for contraction, proliferation, and synthesis of matrix protein and cytokines. This confers a principal role in driving different components of the airway remodeling process, and mediating constrictor hyperresponsiveness. Functional plasticity of airway smooth muscle (ASM) is regulated by an array of environmental cues, including cytokines, which mediate their effects through receptors and a number of intracellular signaling pathways. Despite numerous studies of the cellular effects of cytokines on cultured airway myocytes, few have identified how intracellular signaling pathways modulate or induce these cellular responses. This review summarizes current understanding of these concepts and presents a model for the effects of inflammatory mediators on functional plasticity of ASM in asthma.

  17. The importance of synergy between deep inspirations and fluidization in reversing airway closure.

    PubMed

    Donovan, Graham M; Sneyd, James; Tawhai, Merryn H

    2012-01-01

    Deep inspirations (DIs) and airway smooth muscle fluidization are two widely studied phenomena in asthma research, particularly for their ability (or inability) to counteract severe airway constriction. For example, DIs have been shown effectively to reverse airway constriction in normal subjects, but this is impaired in asthmatics. Fluidization is a connected phenomenon, wherein the ability of airway smooth muscle (ASM, which surrounds and constricts the airways) to exert force is decreased by applied strain. A maneuver which sufficiently strains the ASM, then, such as a DI, is thought to reduce the force generating capacity of the muscle via fluidization and hence reverse or prevent airway constriction. Understanding these two phenomena is considered key to understanding the pathophysiology of asthma and airway hyper-responsiveness, and while both have been extensively studied, the mechanism by which DIs fail in asthmatics remains elusive. Here we show for the first time the synergistic interaction between DIs and fluidization which allows the combination to provide near complete reversal of airway closure where neither is effective alone. This relies not just on the traditional model of airway bistability between open and closed states, but also the critical addition of previously-unknown oscillatory and chaotic dynamics. It also allows us to explore the types of subtle change which can cause this interaction to fail, and thus could provide the missing link to explain DI failure in asthmatics.

  18. Control of allergen-induced inflammation and hyperresponsiveness by the metalloproteinase ADAMTS-12.

    PubMed

    Paulissen, Geneviève; El Hour, Mehdi; Rocks, Natacha; Guéders, Maud M; Bureau, Fabrice; Foidart, Jean-Michel; Lopez-Otin, Carlos; Noel, Agnès; Cataldo, Didier D

    2012-10-15

    A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue remodeling associated with pathological processes. Among them, ADAMTS12 was identified as an asthma-associated gene in a human genome screening program. However, its functional implication in asthma is not yet documented. The present study aims at investigating potential ADAMTS-12 functions in experimental models of allergic airways disease. Two different in vivo protocols of allergen-induced airways disease were applied to the recently generated Adamts12-deficient mice and corresponding wild-type mice. In this study, we provide evidence for a protective effect of ADAMTS-12 against bronchial inflammation and hyperresponsiveness. In the absence of Adamts12, challenge with different allergens (OVA and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cell counts and ST2 receptor and IL-33 levels were higher in the lungs of allergen-challenged Adamts12-deficient mice. The present study provides, to our knowledge, the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in airways disease, interfering with immunological processes leading to inflammation and airway hyperresponsiveness.

  19. Astragalus extract attenuates allergic airway inflammation and inhibits nuclear factor κB expression in asthmatic mice.

    PubMed

    Yang, Zhao-Chuan; Qu, Zheng-Hai; Yi, Ming-Ji; Wang, Chong; Ran, Ni; Xie, Ning; Fu, Peng; Feng, Xue-Ying; Lv, Zhi-Dong; Xu, Lei

    2013-11-01

    Astragalus membranaceus from traditional Chinese herbal medicines previously showed that it possesses a strong anti-inflammatory activity. The purpose of this study was to elucidate the effect of astragalus on allergen-induced airway inflammation and airway hyperresponsiveness and investigate its possible molecular mechanisms. Female BALB/c mice sensitized and challenged with ovalbumin (OVA) developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts and cytokine and chemokine levels. In vivo airway responsiveness to increasing concentrations of methacholine was measured 24 hours after the last OVA challenge using whole-body plethysmography. The expression of inhibitory κB-α and p65 in lung tissues was measured by Western blotting. Astragalus extract attenuated lung inflammation, goblet cell hyperplasia and airway hyperresponsiveness in OVA-induced asthma and decreased eosinophils and lymphocytes in bronchoalveolar lavage fluid. In addition, astragalus extract treatment reduced expression of the key initiators of allergic T(H)2-associated cytokines (interleukin 4, interleukin 5) (P < 0.05). Furthermore, astragalus extract could inhibit nuclear factor κB (NF-κB) expression and suppress NF-κB translocation from the cytoplasm to the nucleus in lung tissue samples. Taken together, our current study demonstrated a potential therapeutic value of astragalus extract in the treatment of asthma and it may act by inhibiting the expression of the NF-κB pathway.

  20. S-carboxymethylcysteine normalises airway responsiveness in sensitised and challenged mice.

    PubMed

    Takeda, K; Miyahara, N; Kodama, T; Taube, C; Balhorn, A; Dakhama, A; Kitamura, K; Hirano, A; Tanimoto, M; Gelfand, E W

    2005-10-01

    S-carboxymethylcysteine (S-CMC) has been used as a mucoregulator in respiratory diseases. However, the mechanism of action of S-CMC on allergic airway inflammation has not yet been defined. In the present study, BALB/c mice were initially sensitised and challenged to ovalbumin (OVA) and, weeks later, re-challenged with OVA (secondary challenge). S-CMC (5-100 mg.kg-1) was administered from 2 days before the secondary challenge through to the day of assay. Mice developed airway hyperresponsiveness (AHR) 6 h after the secondary challenge and increased numbers of neutrophils were present in the bronchoalveolar lavage (BAL) fluid. At 72 h after secondary challenge, mice again developed AHR, but the BAL fluid contained large numbers of eosinophils. S-CMC treatment was found to reduce AHR and neutrophilia at 6 h, as well as eosinophilia and AHR at 72 h. These effects appeared to be dose dependent. Goblet cell hyperplasia, observed at 72 h, was reduced by S-CMC. In BAL fluid, increased levels of interferon-gamma, interleukin (IL)-12 and IL-10 and decreased levels of IL-5 and IL-13 were detected. In conclusion, the data indicate that S-carboxymethylcysteine is effective in reducing airway hyperresponsiveness and airway inflammation at two distinct phases of the response to the secondary allergen challenge in sensitised mice.

  1. Eosinophil recruitment to the airway nerves.

    PubMed

    Jacoby, D B; Costello, R M; Fryer, A D

    2001-02-01

    Increased vagal reflexes contribute to bronchoconstriction in asthma. Antigen challenge of sensitized animals induces vagal hyperresponsiveness. This review will discuss the evidence that eosinophils increase release of acetylcholine from the parasympathetic nerves. After antigen challenge, eosinophils are actively recruited to the airway nerves, possibly through expression of chemotactic substances and adhesion molecules by the nerves. Tachykinins acting on neurokinin 1 receptors activate the eosinophils. Activated eosinophils release eosinophil major basic protein (MBP), which is an endogenous antagonist for M2 muscarinic receptors. The M2 muscarinic receptors on the parasympathetic nerves in the lungs normally inhibit release of acetylcholine. When M2 receptors are blocked by MBP, acetylcholine release is increased, resulting in hyperresponsiveness. Neutralization of MBP with polyanionic substances restores M2 receptor function and eliminates hyperresponsiveness. Antibodies to MBP prevent M2 receptor dysfunction and hyperresponsiveness, as do antibodies to the adhesion molecule very late antigen 4, which prevent eosinophil migration. A low dose of dexamethasone, which does not affect total eosinophil influx into the lungs and airways, prevents eosinophils from clustering around the nerves and prevents antigen-induced M2 dysfunction and hyperresponsiveness. Furthermore, animal studies show that viral infections, which are important precipitants of asthma attacks, and exposure to air pollutants such as ozone can also activate airway eosinophils, leading to a chain of events similar to that seen after antigen challenge. Finally, a similar clustering of eosinophils around airway nerves, as well as release of MBP onto the nerves, is seen in fatal asthma, suggesting that similar mechanisms may be involved in human airway hyperresponsiveness.

  2. Hyaluronan and Layilin Mediate Loss of Airway Epithelial Barrier Function Induced by Cigarette Smoke by Decreasing E-cadherin*

    PubMed Central

    Forteza, Rosanna Malbran; Casalino-Matsuda, S. Marina; Falcon, Nieves S.; Valencia Gattas, Monica; Monzon, Maria E.

    2012-01-01

    Cigarette smoke (CigS) exposure is associated with increased bronchial epithelial permeability and impaired barrier function. Primary cultures of normal human bronchial epithelial cells exposed to CigS exhibit decreased E-cadherin expression and reduced transepithelial electrical resistance. These effects were mediated by hyaluronan (HA) because inhibition of its synthesis with 4-methylumbelliferone prevented these effects, and exposure to HA fragments of <70 kDa mimicked these effects. We show that the HA receptor layilin is expressed apically in human airway epithelium and that cells infected with lentivirus expressing layilin siRNAs were protected against increased permeability triggered by both CigS and HA. We identified RhoA/Rho-associated protein kinase (ROCK) as the signaling effectors downstream layilin. We conclude that HA fragments generated by CigS bind to layilin and signal through Rho/ROCK to inhibit the E-cadherin gene and protein expression, leading to a loss of epithelial cell-cell contact. These studies suggest that HA functions as a master switch protecting or disrupting the epithelial barrier in its high versus low molecular weight form and that its depolymerization is a first and necessary step triggering the inflammatory response to CigS. PMID:23048036

  3. Hyaluronan and layilin mediate loss of airway epithelial barrier function induced by cigarette smoke by decreasing E-cadherin.

    PubMed

    Forteza, Rosanna Malbran; Casalino-Matsuda, S Marina; Falcon, Nieves S; Valencia Gattas, Monica; Monzon, Maria E

    2012-12-07

    Cigarette smoke (CigS) exposure is associated with increased bronchial epithelial permeability and impaired barrier function. Primary cultures of normal human bronchial epithelial cells exposed to CigS exhibit decreased E-cadherin expression and reduced transepithelial electrical resistance. These effects were mediated by hyaluronan (HA) because inhibition of its synthesis with 4-methylumbelliferone prevented these effects, and exposure to HA fragments of <70 kDa mimicked these effects. We show that the HA receptor layilin is expressed apically in human airway epithelium and that cells infected with lentivirus expressing layilin siRNAs were protected against increased permeability triggered by both CigS and HA. We identified RhoA/Rho-associated protein kinase (ROCK) as the signaling effectors downstream layilin. We conclude that HA fragments generated by CigS bind to layilin and signal through Rho/ROCK to inhibit the E-cadherin gene and protein expression, leading to a loss of epithelial cell-cell contact. These studies suggest that HA functions as a master switch protecting or disrupting the epithelial barrier in its high versus low molecular weight form and that its depolymerization is a first and necessary step triggering the inflammatory response to CigS.

  4. Lysophosphatidylcholine plays critical role in allergic airway disease manifestation

    PubMed Central

    Bansal, Preeti; Gaur, Shailendera Nath; Arora, Naveen

    2016-01-01

    Phospholipase A2 (sPLA2), pivotal for allergic and inflammatory response, hydrolyses phosphatidylcholine (PC) to lysophosphatidylcholine (LPC). In present study, the role of LPC in allergic airway disease manifestation was studied using mouse model. Balb/c mice were immunized using cockroach extract (CE) and LPC release was blocked by sPLA2 inhibitor. Airway hyperresponse (AHR), lung-histology, total and differential leukocyte count (TLC&DLC), Th2 type cytokines, sPLA2 activity and LPC levels in bronchoalveolar lavage fluid (BALF) were measured. Exogenous LPC was given to the mice with or without CE sensitization, to demonstrate its role in allergic airway disease manifestation. Anti-CD1d antibody was given to study the involvement of natural killer T (NKT) cells in LPC induced response. AHR, lung-inflammation, TLC, DLC, Th2 type cytokines, sPLA2 activity and LPC levels were increased on CE challenge. sPLA2 activity and LPC release was blocked by sPLA2-inhibitor, which decreased AHR, and inflammatory parameters. Exogenous LPC with or without CE sensitization increased above parameters. CE challenge or LPC exposure increased LY49C+TCRβ+ NKT cells in BALF and spleen, which was reduced by anti-CD1d antibody, accompanied with reduction in AHR and allergic airway inflammation parameters. Conclusively, LPC induces allergic airway disease manifestation and it does so probably via CD1d-restricted LY49C+TCRβ+ NKT cells. PMID:27282246

  5. Expression of T-box transcription factors 2, 4 and 5 is decreased in the branching airway mesenchyme of nitrofen-induced hypoplastic lungs.

    PubMed

    Takahashi, Toshiaki; Friedmacher, Florian; Zimmer, Julia; Puri, Prem

    2017-02-01

    Pulmonary hypoplasia (PH), characterized by smaller lung size and reduced airway branching, remains a major therapeutic challenge in newborns with congenital diaphragmatic hernia (CDH). T-box transcription factors (Tbx) have been identified as key components of the gene network that regulates fetal lung development. Tbx2, Tbx4 and Tbx5 are expressed throughout the mesenchyme of the developing lung, regulating the process of lung branching morphogenesis. Furthermore, lungs of Tbx2-, Tbx4- and Tbx5-deficient mice are hypoplastic and exhibit decreased lung branching, similar to PH in human CDH. We hypothesized that the expression of Tbx2, Tbx4 and Tbx5 is decreased in the branching airway mesenchyme of hypoplastic rat lungs with nitrofen-induced CDH. Time-mated rats received either nitrofen or vehicle on gestational day 9 (D9). Fetuses were killed on D15, D18 and D21, and dissected lungs were divided into control and nitrofen-exposed specimens. Pulmonary gene expression of Tbx2, Tbx4 and Tbx5 was investigated by quantitative real-time polymerase chain reaction. Immunofluorescence double staining for Tbx2, Tbx4 and Tbx5 was combined with the mesenchymal marker Fgf10 to assess protein expression and localization in branching airway tissue. Relative mRNA levels of Tbx2, Tbx4 and Tbx5 were significantly reduced in lungs of nitrofen-exposed fetuses on D15, D18 and D21 compared to controls. Confocal laser scanning microscopy showed markedly diminished immunofluorescence of Tbx2, Tbx4 and Tbx5 in mesenchymal cells surrounding branching airways of nitrofen-exposed fetuses on D15, D18 and D21 compared to controls. Decreased expression of Tbx2, Tbx4 and Tbx5 in the pulmonary mesenchyme during fetal lung development may lead to a decrease or arrest of airway branching, thus contributing to PH in the nitrofen-induced CDH model.

  6. Autophagy plays a role in FSTL1-induced epithelial mesenchymal transition and airway remodeling in asthma.

    PubMed

    Liu, Tian; Liu, Yahui; Miller, Marina; Cao, Liuzhao; Zhao, Jiping; Wu, Jinxiang; Wang, Junfei; Liu, Lin; Li, Shuo; Zou, Minfang; Xu, Jiawei; Broide, David H; Dong, Liang

    2017-07-01

    Asthma is a chronic disease related to airway hyperresponsiveness and airway remodeling. Airway remodeling is the important reason of refractory asthma and is associated with differentiation of airway epithelia into myofibroblasts via epithelial-mesenchymal transition (EMT) to increase the process of subepithelial fibrosis. There is growing evidence that autophagy modulates remodeling. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we hypothesized that Follistatin-like 1 (FSTL1) promotes EMT and airway remodeling by intensifying autophagy. With the use of transmission electron microscopy (TEM), double-membrane autophagosomes were detected in the airways of patients and mice. More autophagosomes were in patients with asthma and OVA-challenged mice compared with healthy controls. The expression of FSTL1 and beclin-1 was upregulated in the airways of patients with asthma and OVA-challenged mice, accompanied by airway EMT and remodeling. In OVA-challenged Fstl1(+/-) mice, the degree of airway remodeling and autophagy was decreased compared with control mice. The effects of FSTL1 on autophagy and EMT were also tested in 16HBE cells in vitro. Additionally, inhibition of autophagy by using LY-294002 and siRNA-ATG5 reduced the FSTL1-induced EMT in 16HBE cells, as measured by E-cadherin, N-cadherin, and vimentin expression. In line herewith, administration of LY-294002 reduced the expression of autophagy, EMT, and airway remodeling markers in FSTL1-challenged WT mice. Taken together, our study suggests that FSTL1 may induce EMT and airway remodeling by activating autophagy. These findings may provide novel avenues for therapeutic research targeting the autophagy and FSTL1 pathway, which may be beneficial to patients with refractory asthma. Copyright © 2017 the American Physiological Society.

  7. Ozone-induced hyperresponsiveness and blockade of M2 muscarinic receptors by eosinophil major basic protein.

    PubMed

    Yost, B L; Gleich, G J; Fryer, A D

    1999-10-01

    Control of airway smooth muscle is provided by parasympathetic nerves that release acetylcholine onto M(3) muscarinic receptors. Acetylcholine release is limited by inhibitory M(2) muscarinic receptors. In antigen-challenged guinea pigs, hyperresponsiveness is due to blockade of neuronal M(2) receptors by eosinophil major basic protein (MBP). Because exposure of guinea pigs to ozone also causes M(2) dysfunction and airway hyperresponsiveness, the role of eosinophils in ozone-induced hyperresponsiveness was tested. Animals were exposed to filtered air or to 2 parts/million ozone for 4 h. Twenty-four hours later, the muscarinic agonist pilocarpine no longer inhibited vagally induced bronchoconstriction in ozone-exposed animals, indicating M(2) dysfunction. M(2) receptor function in ozone-exposed animals was protected by depletion of eosinophils with antibody to interleukin-5 and by pretreatment with antibody to guinea pig MBP. M(2) function was acutely restored by removal of MBP with heparin. Ozone-induced hyperreactivity was also prevented by antibody to MBP and was reversed by heparin. These data show that loss of neuronal M(2) receptor function after ozone is due to release of eosinophil MBP.

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

    PubMed

    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.

  9. Chrysin alleviates allergic inflammation and airway remodeling in a murine model of chronic asthma.

    PubMed

    Yao, Jing; Jiang, Mingzi; Zhang, Yunshi; Liu, Xing; Du, Qiang; Feng, Ganzhu

    2016-03-01

    Asthma is a chronic airway inflammatory disorder and progresses mainly due to airway remodeling. Chrysin, a natural flavonoid, has been reported to possess multiple biologic activities, including anti-inflammation, anti-oxidation and anti-proliferation. The present study aimed to investigate whether chrysin could relieve allergic airway inflammation and remodeling in a murine model of chronic asthma and the mechanism involved. The female BALB/c mice sensitized and challenged with ovalbumin (OVA) successfully developed airway hyperresponsiveness (AHR), inflammation and remodeling. The experimental data showed that chrysin could alleviate OVA-induced AHR. Chrysin could also reduce OVA-induced increases in the number of inflammatory cells, especially eosinophils, interleukin (IL) -4, and IL-13 in bronchoalveolar lavage fluid (BALF) and total IgE in serum. The decreased interferon-γ (IFN-γ) level in BALF was also upregulated by chrysin. In addition, inflammatory cell infiltration, goblet cell hyperplasia and the expression of α-smooth muscle actin (α-SMA) around bronchioles were suppressed by chrysin. Furthermore, the phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK) could be decreased by chrysin, which are associated with airway smooth muscle cell (ASMC) proliferation. These results indicate the promising therapeutic effect of chrysin on chronic asthma, especially the progression of airway remodeling.

  10. Changes of Airway Reactivity after Mycoplasma Pneumoniae Infection in Children: A Study for Early Precautions against Pediatric Asthma.

    PubMed

    Zhang, Han; Lv, Gaomei; Shang, Yunxiao; Liu, Liyun; Xiang, Yun; Feng, Jing; Wang, Zhijia

    2015-10-01

    The relationship between Mycoplasma pneumoniae (MP) infection and asthma has rarely been explored through examination of airway reactivity. The aim of this study was to determine airway reactivity changes after MP infection in children. First, 106 children were divided into four groups according to the existence of MP infection and/or asthma. Then children with only MP belonged to the MP group; children who had both MP infection and asthma belonged to the MP+A group; children with asthma but not MP infection belonged to the non-MP+A group; normal children were classified as normal control (NC) group. Each subject underwent a bronchial provocation test (BPT) after effectively controlling the symptoms. Airway hyperresponsiveness (AHR) parameters were compared among the groups. BPT positive rates were also calculated and compared. All AHR parameters decreased following MP infection, with a more significant decrease of small airway reactivity related indexes. The BPT-positive rate in the MP+A group was significantly higher than that in the MP group. Large airway reactivity showed no significant differences between the MP+A and non-MP+A groups, while the small airway reactivity augmented more significantly in the MP+A group. MP infection caused increased reactivity of both large and small airways in lungs, and BPT-positive identification in some patients.

  11. Decreased S100A9 Expression Promoted Rat Airway Smooth Muscle Cell Proliferation by Stimulating ROS Generation and Inhibiting p38 MAPK

    PubMed Central

    Yin, Lei-Miao; Han, Xiao-Jie; Duan, Ting-Ting; Xu, Yu-Dong; Ulloa, Luis

    2016-01-01

    Background. Asthma is a disease with a core abnormality in airway smooth muscle function, and the proliferation of airway smooth muscle cells (ASMCs) plays a pivotal role in asthma airway remodeling. Our previous study showed that S100A9 (S100 calcium-binding protein A9; 400 and 800 ng/mL) significantly inhibited rat ASMCs proliferation at 48 h, and 50–800 ng/mL S100A9 (50, 100, 200, 400, and 800 ng/mL) also induced a lasting effect by significantly inhibiting rat ASMCs proliferation at 72 h in a dose-dependent manner. However, the intracellular effects of S100A9 on ASMCs proliferation remain unknown. Methods. Rat ASMCs with stable S100A9 knockdown were generated using short hairpin RNA. The effects of decreased S100A9 expression on cellular proliferation, the production of reactive oxygen species (ROS), and p38 MAPK pathway protein expression were examined. Results. Decreased intracellular S100A9 expression significantly promoted platelet-derived growth factor-induced rat ASMCs proliferation and increased ROS production. The antioxidative agent N-acetylcysteine significantly inhibited rat ASMCs proliferation. Western blot results showed that the decreased intracellular S100A9 expression significantly inhibited p38 MAPK phosphorylation. Conclusion. Decreased S100A9 expression promoted rat ASMCs proliferation by stimulating ROS generation and inhibiting p38 MAPK. Our study may provide novel insights into the regulation of asthma airway remodeling. PMID:28050155

  12. Celastrol suppresses allergen-induced airway inflammation in a mouse allergic asthma model.

    PubMed

    Kim, Dae Yong; Park, Jung Won; Jeoung, Dooil; Ro, Jai Youl

    2009-06-10

    Celastrol has anti-inflammatory and immunomodulatory activities, but its anti-allergic effects remain poorly understood. Therefore, we aimed to investigate the ability of celastrol to inhibit asthmatic reactions in a mouse allergic asthma model. BALB/c mice were sensitized and challenged with ovalbumin to induce asthma. We measured the recruitment of inflammatory cells into the bronchoalveolar lavage fluid or lung tissues by Diff-Quik and hematoxylin and eosin staining, respectively, goblet cell hyperplasia by periodic acid-Schiff (PAS) staining, airway hyperresponsiveness by Flexvent system, mRNA and protein expression of cytokines, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) by reverse transcriptase polymerase chain reaction and ELISA, respectively, and the activities of mitogen-activated protein (MAP) kinases and nuclear factor-kappa B (NF-kappaB) in the bronchoalveolar lavage cells and lung tissues by Western blot and electrophoretic mobility shift assay (EMSA), respectively. Celastrol reduced the total number of inflammatory cells in the bronchoalveolar lavage fluid and in peribronchial areas, and decreased the airway hyperresponsiveness, mRNA and protein expression levels for inflammatory cytokines such as interleukin (IL)-4, IL-13, TNF-alpha and IFN-gamma, and for MMPs and TIMPs, MAP kinases and NF-kappaB activities in the bronchoalveolar lavage cells and in the lung tissues increased in ovalbumin-induced allergic asthma in mice. Our data suggest that oral administration of celastrol suppresses ovalbumin-induced airway inflammation, hyperresponsiveness, and tissue remodeling by regulating the imbalance of MMP-2/-9 and TIMP-1/-2 by inflammatory cytokines via MAP kinases/NF-kappaB in inflammatory cells. Based on our findings, we suggest that celastrol may be used as a therapeutic agent for allergy-induced asthma.

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

    PubMed Central

    de Freitas Alves, Claudiney; Angeli, Giovanna Natalia; Favarin, Daniely Cornélio; Lemos de Andrade, Edinéia; Lazo Chica, Javier Emilio; Faccioli, Lúcia Helena; Roberto da Silva, Paulo; de Paula Rogerio, Alexandre

    2013-01-01

    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. PMID:24376308

  14. Lung morphometry changes in prevention of airway remodeling by protocatechuic aldehyde in asthmatic mice

    PubMed Central

    Zhang, Jiankai; Ma, Mulan; Qin, Dongyun; Huang, Jianping; Cui, Xiaojun; Wu, Yongfu; Yang, Huiling; Fu, Hui; Liao, Cui

    2015-01-01

    Airway remodeling can lead to irreversible airflow obstruction and persistent airway hyper-responsiveness, which is the pathological basis of refractory asthma. To investigate the preventive effect of protocatechuic aldehyde on airway remodeling in asthmatic mice by lung morphometry methods. BALB/c mice were used to establish model of airway remodeling by ovalbumin (OVA) inhalation. Bronchoalveolar lavage fluid (BALF) were collected for eosinophils (EOS) count and detection of interleukin 4 (IL-4), interleukin-13 (IL-13) and interferon (IFN-γ) content. The left lung pathological sections were performed HE, AB-PAS and Masson staining. The epithelial lamina thickness of the left main bronchus (Re), the smooth muscle layer thickness (Rm), the number of goblet cells and goblet cell area percentage (%Ac) and gas side of the road and vascular collagen deposition (%Aco, %Avc) situation were measured. Protocatechuic aldehyde gavage made the reduction of BALF EOS count. IL-4 and IL-13 levels also decreased, while the IFN-γ level increased. The left main bronchus Re, Rm, goblet cell count, Ac% and Aco% and Avc% reduced. Protocatechuic aldehyde can significantly control airway inflammation and prevent airway remodeling. PMID:26221226

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

    PubMed

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

    2012-01-01

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

  16. Modulation of airway remodeling and airway inflammation by peroxisome proliferator-activated receptor gamma in a murine model of toluene diisocyanate-induced asthma.

    PubMed

    Lee, Kyung Sun; Park, Seoung Ju; Kim, So Ri; Min, Kyung Hoon; Jin, Sun Mi; Lee, Hern Ku; Lee, Yong Chul

    2006-10-15

    Toluene diisocyanate (TDI) is a leading cause of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is an inflammatory disease of the airways characterized by airway remodeling. Peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to play a critical role in the control of airway inflammatory responses. However, no data are available on the role of PPARgamma in TDI-induced asthma. We have used a mouse model for TDI-induced asthma to determine the effect of PPARgamma agonist, rosiglitazone, or pioglitazone, and PPARgamma on TDI-induced bronchial inflammation and airway remodeling. This study with the TDI-induced model of asthma revealed the following typical pathophysiological features: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased levels of Th2 cytokines (IL-4, IL-5, and IL-13), adhesion molecules (ICAM-1 and VCAM-1), chemokines (RANTES and eotaxin), TGF-beta1, and NF-kappaB in nuclear protein extracts. In addition, the mice exposed to TDI developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer, subepithelial collagen deposition, and increased airway mucus production. Administration of PPARgamma agonists or adenovirus carrying PPARgamma2 cDNA reduced the pathophysiological symptoms of asthma and decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, TGF-beta1, and NF-kappaB in nuclear protein extracts after TDI inhalation. In addition, inhibition of NF-kappaB activation decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, and TGF-beta1 after TDI inhalation. These findings demonstrate a protective role of PPARgamma in the pathogenesis of the TDI-induced asthma phenotype.

  17. Silibinin attenuates allergic airway inflammation in mice

    SciTech Connect

    Choi, Yun Ho; Jin, Guang Yu; Guo, Hui Shu; Piao, Hong Mei; Li, Liang chang; Li, Guang Zhao; Lin, Zhen Hua; Yan, Guang Hai

    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.

  18. Leukotrienes and airway inflammation

    PubMed Central

    Okunishi, Katsuhide; Peters-Golden, Marc

    2011-01-01

    Asthma is a common chronic inflammatory disease of the airways characterized by airway obstruction and hyperresponsiveness. Leukotrienes (LTs) are lipid mediators that contribute to many aspects of asthma pathogenesis. As the LT pathway is relatively steroid-resistant, its blockade by alternative strategies is a desirable component of asthma management. Cysteinyl LT receptor 1 antagonists have been utilized worldwide for more than 10 years, and while their efficacy in asthma is well accepted, their limitations are also evident. In this review, we summarize the biological effects of LTs in asthma, review recent advances in LT receptors, and consider possible new therapeutic targets in the LT pathway that offer the potential to achieve better control of asthma in the future. PMID:21352897

  19. The effects of in utero vitamin D deficiency on airway smooth muscle mass and lung function.

    PubMed

    Foong, Rachel E; Bosco, Anthony; Jones, Anya C; Gout, Alex; Gorman, Shelley; Hart, Prue H; Zosky, Graeme R

    2015-11-01

    We have previously demonstrated increased airway smooth muscle (ASM) mass and airway hyperresponsiveness in whole-life vitamin D-deficient female mice. In this study, we aimed to uncover the molecular mechanisms contributing to altered lung structure and function. RNA was extracted from lung tissue of whole-life vitamin D-deficient and -replete female mice, and gene expression patterns were profiled by RNA sequencing. The data showed that genes involved in embryonic organ development, pattern formation, branching morphogenesis, Wingless/Int signaling, and inflammation were differentially expressed in vitamin D-deficient mice. Network analysis suggested that differentially expressed genes were connected by the hubs matrix metallopeptidase 9; NF-κ light polypeptide gene enhancer in B cells inhibitor, α; epidermal growth factor receptor; and E1A binding protein p300. Given our findings that developmental pathways may be altered, we investigated if the timing of vitamin D exposure (in utero vs. postnatal) had an impact on lung health outcomes. Gene expression was measured in in utero or postnatal vitamin D-deficient mice, as well as whole-life vitamin D-deficient and -replete mice at 8 weeks of age. Baseline lung function, airway hyperresponsiveness, and airway inflammation were measured and lungs fixed for lung structure assessment using stereological methods and quantification of ASM mass. In utero vitamin D deficiency was sufficient to increase ASM mass and baseline airway resistance and alter lung structure. There were increased neutrophils but decreased lymphocytes in bronchoalveolar lavage. Expression of inflammatory molecules S100A9 and S100A8 was mainly increased in postnatal vitamin D-deficient mice. These observations suggest that in utero vitamin D deficiency can alter lung structure and function and increase inflammation, contributing to symptoms in chronic diseases, such as asthma.

  20. Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased β1-integrin signaling and delayed wound repair

    PubMed Central

    Itokazu, Yutaka; Pagano, Richard E.; Schroeder, Andreas S.; O'Grady, Scott M.; Limper, Andrew H.

    2014-01-01

    Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function reduces chloride secretion and increases sodium uptake, but it is not clear why CFTR mutation also results in progressive lung inflammation and infection. We previously demonstrated that CFTR-silenced airway cells migrate more slowly during wound repair than CFTR-expressing controls. In addition, CFTR-deficient cells and mouse models have been reported to have altered sphingolipid levels. Here, we investigated the hypothesis that reduced migration in CFTR-deficient airway epithelial cells results from altered sphingolipid composition. We used cell lines derived from a human airway epithelial cell line (Calu-3) stably transfected with CFTR short hairpin RNA (CFTR-silenced) or nontargeting short hairpin RNA (controls). Cell migration was measured by electric cell substrate impedance sensing (ECIS). Lipid analyses, addition of exogenous glycosphingolipids, and immunoblotting were performed. We found that levels of the glycosphingolipid, GM1 ganglioside, were ∼60% lower in CFTR-silenced cells than in controls. CFTR-silenced cells exhibited reduced levels of activated β1-integrin, phosphorylated tyrosine 576 of focal adhesion kinase (pFAK), and phosphorylation of Crk-associated substrate (pCAS). Addition of GM1 (but not GM3) ganglioside to CFTR-silenced cells restored activated β1-integrin, pFAK, and pCAS to near control levels and partially restored (∼40%) cell migration. Our results suggest that decreased GM1 in CFTR-silenced cells depresses β1-integrin signaling, which contributes to the delayed wound repair observed in these cells. These findings have implications for the pathology of cystic fibrosis, where altered sphingolipid levels in airway epithelial cells could result in a diminished capacity for wound repair after injury. PMID:24500283

  1. Bronchial hyperresponsiveness to methacholine in patients with primary Sjögren's syndrome.

    PubMed Central

    Gudbjörnsson, B; Hedenström, H; Stålenheim, G; Hällgren, R

    1991-01-01

    The prevalence of bronchial hyperresponsiveness (BHR) to methacholine inhalation in a consecutive series of 21 patients with primary Sjögren's syndrome was studied prospectively. Slight to severe BHR was seen in 12/20 (60%) of the patients. Ten of 12 patients with BHR (83%) had a non-productive cough, wheezing, or intermittent breathlessness. Bronchial hyperresponsiveness was more common in patients with extraglandular symptoms (10/14, 71%) than in those with only glandular symptoms (29%). Spirometrically 29% (6/21) of the patients had 'small airways' disease', and all those had BHR. Of 6/21 (29%) who had diffuse interstitial lung disease, two had BHR. Three of the four patients with obstructive lung function were challenged with methacholine and two of them had BHR. Only two patients with BHR had normal spirometry findings. The data showed that respiratory disease--mostly mild or moderate but even severe bronchial hyperresponsiveness--is commonly seen in patients with primary Sjögren's syndrome. PMID:1994866

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

    PubMed

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

    2015-01-15

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

  3. New supraglottic airway with built-in pressure indicator decreases postoperative pharyngolaryngeal symptoms: a randomized controlled trial.

    PubMed

    Wong, David T; Tam, Amanda D; Mehta, Vanita; Raveendran, Raviraj; Riad, Waleed; Chung, Frances F

    2013-12-01

    Excessive supraglottic airway cuff pressure increases postoperative pharyngolaryngeal symptoms such as sore throat, dysphonia, and dysphagia. A new supraglottic airway, AES Ultra CPV™ (CPV), has a built-in intracuff pressure indicator. We hypothesized that using the CPV would reduce postoperative symptoms when compared with the LMA Classic™ (LMA) without intracuff pressure guidance. Ambulatory patients undergoing general anesthesia were randomized to either CPV or LMA. A size 3/4/5 was inserted according to manufacturer guidelines. Nitrous oxide was not used. In the LMA Group, the cuff was inflated according to manufacturer's guidelines. In the CPV Group, a CPV was inserted and the cuff inflated until the indicator was in the green zone (30-44 mmHg). Intracuff pressures were measured at five minutes and 20 min post-insertion in both groups. The primary outcome was the incidence of pharyngolaryngeal symptoms, defined as sore throat, dysphonia, and/or dysphagia at one, two, and/or 24 hr postoperatively. Continuous data were compared using Student's t test and categorical data were analyzed using Chi square analysis. The study included 170 patients, 85 per group. The mean (SD) intracuff pressure in the CPV group was significantly lower [44 (4) mmHg] than in the LMA Group [87 (37) mmHg]; P < 0.001. The incidence of pharyngolaryngeal symptoms was significantly lower in the CPV Group than in the LMA Group (26% vs 49%; P = 0.002). The absolute risk reduction was 24%, and the number-needed-to-treat was 4.3. The incidence of postoperative pharyngolaryngeal symptoms in the CPV Group with a cuff pressure-guided strategy was significantly lower than in the LMA Group with standard practice. ( NCT01800344).

  4. Inhibitory Effects of Resveratrol on Airway Remodeling by Transforming Growth Factor-β/Smad Signaling Pathway in Chronic Asthma Model

    PubMed Central

    Lee, Hwa Young; Kim, In Kyoung; Yoon, Hyoung Kyu; Kwon, Soon Suk

    2017-01-01

    Purpose Asthma is a chronic airway disease characterized by airway remodeling, leading to a progressive decline in lung function. Therapeutic agents that attenuate airway remodeling can complement the limited effects of traditional glucocorticoids. In this study, we investigated the effect of resveratrol on allergic airway inflammation and remodeling in a murine model of chronic bronchial asthma. Methods Peribronchial smooth muscle thickening that developed in mice challenged with a 3-month repeated exposure to ovalbumin (OVA) was used to study airway remodeling. Oral resveratrol was administered daily during the OVA challenge. The expression of TGF-β1/Smad signaling proteins and downstream mesenchymal markers in the presence or absence of resveratrol was examined in bronchial epithelial cells. Results OVA sensitization and chronic challenge increased airway hyperresponsiveness, inflammation, goblet cell hyperplasia, α-smooth muscle actin (SMA), and collagen deposition. Resveratrol effectively suppressed OVA-induced airway inflammation and remodeling. The expression of TGF-β1/phosphorylated Smad2/3 was increased in the lung tissues of OVA-challenged mice but effectively inhibited by resveratrol. In bronchial epithelial cells, the TGF-β1-induced expression of the mesenchymal markers snail, slug, vimentin, and α-SMA was suppressed by resveratrol treatment. Conclusions Resveratrol effectively ameliorated both airway inflammation and airway structural changes in a mouse model of bronchial asthma. These effects were mediated by decreased TGF-β1 expression, in turn suppressing TGF-β1/Smad signaling and the epithelial-mesenchymal transition process. Our results demonstrate the potential benefits of resveratrol for the treatment of airway remodeling associated with bronchial asthma. PMID:27826959

  5. A locus regulating bronchial hyperresponsiveness maps to chromosome 5q

    SciTech Connect

    Levitt, R.C.; Meyers, D.A.; Bleecker, E.R.

    1994-09-01

    Bronchial hyperresponsiveness (BHR) is one of the hallmarks of asthma. BHR correlates well with asthmatic symptoms and the response to treatment. Moreover, BHR appears to be closely related to airways inflammation. Numerous studies have demonstrated a familial aggregation; however, this phenotype is not likely inherited as a simple Mendelian trait. BHR is also closely associated with total serum IgE levels, as are allergy and asthma. We studied 92 families from Northern Holland ascertained through a parent with asthma who were originally studied between 1962-1970. Since there are a number of candidate genes on chromosome 5q potentially important in producing BHR, families were genotyped for markers in this region. These genes regulate IgE production and the cellular elements that are likely involved in inflammation associated with BHR, allergy and asthma. They include IL-4, IL-3, IL-5, IL-9, IL-12, IL-13 and GM-CSF. Linkage of BHR with markers on 5q was tested using a model free sib-pair method. The data suggest a locus for BHR maps near the cytokine gene cluster on 5q. This region appears critical in producing susceptibility to BHR and possibly to asthma.

  6. Decreasing SMPD1 activity in BEAS-2B bronchial airway epithelial cells results in increased NRF2 activity, cytokine synthesis and neutrophil recruitment.

    PubMed

    MacFadden-Murphy, Elyse; Roussel, Lucie; Martel, Guy; Bérubé, Julie; Rousseau, Simon

    2017-01-22

    Niemann-Pick disease (NPD) type B is a rare autosomal recessive disease characterized by variable levels of impairment in sphingomyelin phosphodiesterase 1 (SMPD1) activity. Lung involvement is the most important prognostic factor in NPD-B, with recurrent respiratory infections starting in infancy being the major cause of morbidity and mortality. We hypothesized that decreased SMPD1 activity impaired airway epithelium host defense response. SMPD1 activity was reduced using inducible shRNA. Surprisingly, decreasing SMPD1 activity by 50%, resulted in increased neutrophil recruitment, both at baseline and in response to bacterial stimulation. This correlated with elevated levels of cytokine mRNA shown to contribute to neutrophil recruitment in unstimulated (e.g. IL-8 and GRO-α) and infected cells (e.g. IL-8, GRO-α, GM-CSF and CCL20). Instead of preventing the host defence responses, decreased SMPD1 activity results in an inflammatory response even in the absence of infection. Moreover, decreasing SMPD1 activity resulted in a pro-oxidative shift. Accordingly, expression of an inactive mutant, SMPD1[L225P] but not the WT enzyme increased activation of the antioxidant transcription factor NRF2. Therefore, decreasing SMPD1 activity by 50% in airway epithelial cells, the equivalent of the loss of one allele, results in the accumulation of oxidants that activates NRF2 and a concomitant increased cytokine production as well as neutrophil recruitment. This can result in a chronic inflammatory state that impairs host defence similar to scenarios observe in other chronic inflammatory lung disease such as Chronic Obstructive Pulmonary Disease or Cystic Fibrosis.

  7. [Bronchial hyperresponsiveness to methacholine in children under 4 years with recurrent bronchitis].

    PubMed

    de Mir Messa, Inés; Moreno Galdó, Antonio; Cobos Barroso, Nicolás; Gartner, Sílvia; Martín de Vicente, Carlos; Rovira Amigo, Sandra; Torrent Vernetta, Alba; Liñán Cortés, Santos

    2010-12-01

    To evaluate bronchial hyperresponsiveness in children under 4 years of age with recurrent wheezing bronchitis, and to determine if its presence or absence can predict the subsequent progression to a transient or persistent wheezing bronchitis phenotype. A bronchial challenge test was performed with methacholine using a modified tidal volume method, without sedation in a group of patients from 8 to 47 months of age with recurrent wheezing bronchitis and a control group of healthy children. A decrease in oxygen saturation of ≥ 5% or an increase in respiration rate of >50% [PCwheeze (PCw)] was considered a positive response. The patients were subsequently clinically followed up to assess their progress. A total of 63 patients and 16 controls were studied (mean age 23.9 vs. 25.2 months). The PCw was lower than the control group (≤ 4 mg/ml) in 43 (68%) children from the bronchitis group (P<0.001). No significant adverse effects were observed on performing the test. After a mean follow up of 28.5 months, completed in 49 of the patients, no differences were seen between the presence of bronchial hyperresponsiveness at the beginning of the study and the subsequent progression to transient, infrequent and frequent wheezing (P=0.63). A high percentage of children under 4 years of age affected by wheezing bronchitis had a bronchial hyperresponse. The subsequent progression to transient or persistent wheezing bronchitis phenotype is not associated with bronchial hyperresponsiveness. Copyright © 2010 SEPAR. Published by Elsevier Espana. All rights reserved.

  8. Construction of a Der p2-transgenic plant for the alleviation of airway inflammation

    PubMed Central

    Lee, CC; Ho, H; Lee, KT; Jeng, ST; Chiang, BL

    2011-01-01

    In clinical therapy, the amount of antigen administered to achieve oral tolerance for allergic diseases is large, and the cost is a major consideration. In this study, we used tobacco plants to develop a large-scale protein production system for allergen-specific immunotherapy, and we investigated the mechanisms of oral tolerance induced by a transgenic plant-derived antigen. We used plants (tobacco leaves) transgenic for the Dermatophagoides pteronyssinus 2 (Der p2) antigen to produce Der p2. Mice received total protein extract from Der p2 orally once per day over 6 days (days 0–2 and days 6–8). Mice were also sensitized and challenged with yeast-derived recombinant Der p2 (rDer p2), after which the mice were examined for airway hyper-responsiveness and airway inflammation. After sensitization and challenge with rDer p2, mice that were fed with total protein extracted from transgenic plants showed decreases in serum Der p2-specific IgE and IgG1 titers, decreased IL-5 and eotaxin levels in bronchial alveolar lavage fluid, and eosinophil infiltration in the airway. In addition, hyper-responsiveness was also decreased in mice that were fed with total protein extracted from transgenic plants, and CD4+CD25+Foxp3+ regulatory T cells were significantly increased in mediastinal and mesenteric lymph nodes. Furthermore, splenocytes isolated from transgenic plant protein-fed mice exhibited decreased proliferation and increased IL-10 secretion after stimulation with rDer p2. The data here suggest that allergen-expressing transgenic plants could be used for therapeutic purposes for allergic diseases. PMID:21602845

  9. Airway Inflammation and Hypersensitivity Induced by Chronic Smoking

    PubMed Central

    Kou, Yu Ru; Kwong, Kevin; Lee, Lu-Yuan

    2011-01-01

    Airway hypersensitivity, characterized by enhanced excitability of airway sensory nerves, is a prominent pathophysiological feature in patients with airway inflammatory diseases. Although the underlying pathogenic mechanism is not fully understood, chronic airway inflammation is believed to be primarily responsible. Cigarette smoking is known to cause chronic airway inflammation, accompanied by airway hyperresponsiveness. Experimental evidence indicates that enhanced excitability of vagal bronchopulmonary sensory nerves and increased tachykinin synthesis in these nerves resulting from chronic inflammation are important contributing factors to the airway hyperresponsiveness. Multiple inflammatory mediators released from various types of structural and inflammatory cells are involved in the smoking-induced airway inflammation, which is mainly regulated by redox-sensitive signaling pathways and transcription factors. Furthermore, recent studies have reported potent sensitizing and stimulatory effects of these inflammatory mediators such as prostanoids and reactive oxygen species on these sensory nerves. In summary, these studies using cigarette smoking as an experimental approach have identified certain potentially important cell signaling pathways and underlying mechanisms of the airway hypersensitivity induced by chronic airway inflammation. PMID:21397052

  10. Theophylline and cAMP inhibit lysophosphatidic acid-induced hyperresponsiveness of bovine tracheal smooth muscle cells

    PubMed Central

    Sakai, Jiro; Oike, Masahiro; Hirakawa, Masakazu; Ito, Yushi

    2003-01-01

    We have established an in vitro model of airway hyperresponsiveness, using a bovine tracheal smooth muscle cell (BTSMC)-embedded collagen gel lattice. When the gel was pretreated with lysophosphatidic acid (LPA), which activates the small G protein RhoA, ATP- and high K+ solution-induced gel contraction was significantly augmented. This was not due to the modulation of Ca2+ mobilizing properties, since ATP- and high K+-induced Ca2+ transients were not significantly different between control and LPA-treated BTSMC. Y-27632, an inhibitor of Rho-kinase, suppressed the LPA-induced augmentation of gel contraction, whereas it did not inhibit the contraction of control gels. Theophylline (> 1 μm) reversed the LPA-induced augmentation of gel contraction, whereas it inhibited control gel contraction only with a very high concentration (100 μm). We confirmed that theophylline increased the intracellular concentration of cAMP ([cAMP]i) in BTSMC. Elevation of [cAMP]i with dibutyryl cAMP or forskolin also reversed the LPA-induced augmentation of gel contraction. Furthermore, theophylline, as well as dibutyryl cAMP and forskolin, suppressed the LPA-induced membrane translocation of RhoA, indicating that they prevented airway hyperresponsiveness by inhibiting RhoA. We conclude from these results that theophylline inhibits LPA-induced, RhoA/Rho-kinase-mediated hyperresponsiveness of tracheal smooth muscle cells due to the accumulation of cAMP. PMID:12679373

  11. Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation.

    PubMed

    Helyes, Z; Kemény, Á; Csekő, K; Szőke, É; Elekes, K; Mester, M; Sándor, K; Perkecz, A; Kereskai, L; Márk, L; Bona, Á; Benkő, A; Pintér, E; Szolcsányi, J; Ledent, C; Sperlágh, B; Molnár, T F

    2017-08-01

    Sporadic clinical reports suggested that marijuana smoking induces spontaneous pneumothorax, but no animal models were available to validate these observations and to study the underlying mechanisms. Therefore, we performed a systematic study in CD1 mice as a predictive animal model and assessed the pathophysiological alterations in response to 4-mo-long whole body marijuana smoke with integrative methodologies in comparison with tobacco smoke. Bronchial responsiveness was measured with unrestrained whole body plethysmography, cell profile in the bronchoalveolar lavage fluid with flow cytometry, myeloperoxidase activity with spectrophotometry, inflammatory cytokines with ELISA, and histopathological alterations with light microscopy. Daily marijuana inhalation evoked severe bronchial hyperreactivity after a week. Characteristic perivascular/peribronchial edema, atelectasis, apical emphysema, and neutrophil and macrophage infiltration developed after 1 mo of marijuana smoking; lymphocyte accumulation after 2 mo; macrophage-like giant cells, irregular or destroyed bronchial mucosa, goblet cell hyperplasia after 3 mo; and severe atelectasis, emphysema, obstructed or damaged bronchioles, and endothelial proliferation at 4 mo. Myeloperoxidase activity, inflammatory cell, and cytokine profile correlated with these changes. Airway hyperresponsiveness and inflammation were not altered in mice lacking the CB1 cannabinoid receptor. In comparison, tobacco smoke induced hyperresponsiveness after 2 mo and significantly later caused inflammatory cell infiltration/activation with only mild emphysema. We provide the first systematic and comparative experimental evidence that marijuana causes severe airway hyperresponsiveness, inflammation, tissue destruction, and emphysema, which are not mediated by the CB1 receptor. Copyright © 2017 the American Physiological Society.

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

    PubMed

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

    2016-11-01

    Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and TH2 and TH17 pulmonary profiles. Notably, nonsensitized obese mice already exhibited increased lung ILC counts and tissue eosinophil infiltration compared with values in lean mice in the absence of AHR. The numbers of total and cytokine-expressing lung ILC2s and ILC3s further increased in HDM-challenged obese mice compared with those in HDM-challenged lean mice, and this was accompanied by high IL-33 and IL-1β levels and decreased ILC markers in visceral adipose tissue. Furthermore, depletion of ILCs with an anti-CD90 antibody, followed by T-cell reconstitution, led to a profound decrease in allergic airway inflammatory features in obese mice, including TH2 and TH17 infiltration. These results indicate that HFD-induced obesity might exacerbate allergic airway inflammation through mechanisms involving ILC2s and ILC3s. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  13. Behavioral Inhibition in Rhesus Monkeys (Macaca mulatta) Is Related to the Airways Response, but Not Immune Measures, Commonly Associated with Asthma

    PubMed Central

    Chun, Katie; Miller, Lisa A.; Schelegle, Edward S.; Hyde, Dallas M.; Capitanio, John P.

    2013-01-01

    Behavioral inhibition reflects a disposition to react warily to novel situations, and has been associated with atopic diseases such as asthma. Retrospective work established the relationship between behavioral inhibition in rhesus monkeys (Macaca mulatta) and airway hyperresponsiveness, but not atopy, and the suggestion was made that behavioral inhibition might index components of asthma that are not immune-related. In the present study, we prospectively examined the relationship between behavioral inhibition and airway hyperresponsiveness, and whether hormonal and immune measures often associated with asthma were associated with behavioral inhibition and/or airway hyperresponsiveness. In a sample of 49 yearling rhesus monkeys (mean = 1.25 years, n = 24 behaviorally inhibited animals), we measured in vitro cytokine levels (IL-4, IL-10, IL-12, IFN-γ) in response to stimulation, as well as peripheral blood cell percentages, cortisol levels, and percentage of regulatory T-cells (CD3+CD4+CD25+FOXP3+). Airway reactivity was assessed using an inhaled methacholine challenge. Bronchoalveolar lavage was performed and the proportion of immune cells was determined. Behaviorally inhibited monkeys had airway hyperresponsiveness as indicated by the methacholine challenge (p = 0.031), confirming our earlier retrospective result. Airway hyperresponsiveness was also associated with lower lymphocyte percentages in lavage fluid and marginally lower plasma cortisol concentrations. However, none of the tested measures was significantly related to both behavioral inhibition and airway hyperresponsiveness, and so could not mediate their relationship. Airway hyperresponsiveness is common to atopic and non-atopic asthma and behavioral inhibition has been related to altered autonomic activity in other studies. Our results suggest that behavioral inhibition might index an autonomically mediated reactive airway phenotype, and that a variety of stimuli (including inflammation

  14. Reduced levels of maternal progesterone during pregnancy increase the risk for allergic airway diseases in females only.

    PubMed

    Hartwig, Isabel R V; Bruenahl, Christian A; Ramisch, Katherina; Keil, Thomas; Inman, Mark; Arck, Petra C; Pincus, Maike

    2014-10-01

    Observational as well as experimental studies support that prenatal challenges seemed to be associated with an increased risk for allergic airway diseases in the offspring. However, insights into biomarkers involved in mediating this risk are largely elusive. We here aimed to test the association between endogenous and exogenous factors documented in pregnant women, including psychosocial, endocrine, and life style parameters, and the risk for allergic airway diseases in the children later in life. We further pursued to functionally test identified factors in a mouse model of an allergic airway response. In a prospectively designed pregnancy cohort (n = 409 families), women were recruited between the 4th and 12th week of pregnancy. To investigate an association between exposures during pregnancy and the incidence of allergic airway disease in children between 3 and 5 years of age, multiple logistic regression analyses were applied. Further, in prenatally stressed adult offspring of BALB/c-mated BALB/c female mice, asthma was experimentally induced by ovalbumin (OVA) sensitization. In addition to the prenatal stress challenge, some pregnant females were treated with the progesterone derivative dihydrodydrogesterone (DHD). In humans, we observed that high levels of maternal progesterone in early human pregnancies were associated with a decreased risk for an allergic airway disease (asthma or allergic rhinitis) in daughters (adjusted OR 0.92; 95% confidence interval [CI] 0.84 to 1.00) but not sons (aOR 1.02, 95% CI 0.94-1.10). In mice, prenatal DHD supplementation of stress-challenged dams attenuated prenatal stress-induced airway hyperresponsiveness exclusively in female offspring. Reduced levels of maternal progesterone during pregnancy-which can result from high stress perception-increase the risk for allergic airway diseases in females but not in males. Key messages: Lower maternal progesterone during pregnancy increases the risk for allergic airway disease

  15. Immunostimulatory DNA mediates inhibition of eosinophilic inflammation and airway hyperreactivity independent of natural killer cells in vivo.

    PubMed

    Broide, D H; Stachnick, G; Castaneda, D; Nayar, J; Miller, M; Cho, J; Rodriquez, M; Roman, M; Raz, E

    2001-11-01

    Immunostimulatory DNA sequences (ISS) inhibit eosinophilic inflammation and airway hyperreactivity in mouse models of asthma. In vitro ISS activate natural killer (NK) cells to secrete IFN-gamma, and this cytokine is hypothesized to contribute to the antiallergic effect of ISS in vivo. We investigated whether ISS activation of NK cells is important in mediating the reduction in airway hyperreactivity and the antieosinophilic effect of ISS in vivo. We assessed whether ISS modulated the development of eosinophilic airway inflammation and airway hyperreactivity to methacholine in ovalbumin (OVA)-sensitized and OVA allergen-challenged mice pretreated with an antibody to deplete NK cells. Mice sensitized and challenged with OVA had significant bronchoalveolar lavage and lung eosinophilia, as well as airway hyperresponsiveness. ISS induced significant inhibition of bronchoalveolar lavage and lung eosinophilia, as well as airway hyperresponsiveness, in OVA-sensitized mice pretreated before OVA challenge with an NK cell-depleting antibody (NK(-) mice), as well as in mice pretreated with a control non-NK cell-depleting antibody (NK(+) mice). The NK cell-depleting antibody inhibited ISS-induced IFN-gamma production by spleen cells. These studies demonstrate that depletion of NK cells has no significant effect on ISS-mediated inhibition of airway eosinophilia and airway hyperresponsiveness in vivo, suggesting that non-NK cells and cytokines other than IFN-gamma derived from NK cells mediate the majority of the ISS-inhibitory effect on eosinophilic inflammation and airway hyperresponsiveness in vivo.

  16. Airway Surface Dehydration by Transforming Growth Factor β (TGF-β) in Cystic Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel and Can Be Rescued by the Drug Pirfenidone*

    PubMed Central

    Manzanares, Dahis; Krick, Stefanie; Baumlin, Nathalie; Dennis, John S.; Tyrrell, Jean; Tarran, Robert; Salathe, Matthias

    2015-01-01

    Transforming growth factor β1 (TGF-β1) is not only elevated in airways of cystic fibrosis (CF) patients, whose airways are characterized by abnormal ion transport and mucociliary clearance, but TGF-β1 is also associated with worse clinical outcomes. Effective mucociliary clearance depends on adequate airway hydration, governed by ion transport. Apically expressed, large-conductance, Ca2+- and voltage-dependent K+ (BK) channels play an important role in this process. In this study, TGF-β1 decreased airway surface liquid volume, ciliary beat frequency, and BK activity in fully differentiated CF bronchial epithelial cells by reducing mRNA expression of the BK γ subunit leucine-rich repeat-containing protein 26 (LRRC26) and its function. Although LRRC26 knockdown itself reduced BK activity, LRRC26 overexpression partially reversed TGF-β1-induced BK dysfunction. TGF-β1-induced airway surface liquid volume hyper-absorption was reversed by the BK opener mallotoxin and the clinically useful TGF-β signaling inhibitor pirfenidone. The latter increased BK activity via rescue of LRRC26. Therefore, we propose that TGF-β1-induced mucociliary dysfunction in CF airways is associated with BK inactivation related to a LRRC26 decrease and is amenable to treatment with clinically useful TGF-β1 inhibitors. PMID:26338706

  17. Anti-oxidant N-acetylcysteine diminishes diesel exhaust-induced increased airway responsiveness in person with airway hyper-reactivity.

    PubMed

    Carlsten, Chris; MacNutt, Meaghan J; Zhang, Zhihong; Sava, Francesco; Pui, Mandy M

    2014-06-01

    Inhalation of diesel exhaust (DE) at moderate concentrations causes increased airway responsiveness in asthmatics and increased airway resistance in both healthy and asthmatic subjects, but the effect of baseline airway responsiveness and anti-oxidant supplementation on this dynamic is unknown. We aimed to determine if changes in airway responsiveness due to DE are attenuated by thiol anti-oxidant supplementation, particularly in those with underlying airway hyper-responsiveness. Participants took N-acetylcysteine (600 mg) or placebo capsules three times daily for 6 days. On the last of these 6 days, participants were exposed for 2 h to either filtered air (FA) or DE (300 μg/m(3) of particulate matter smaller than 2.5 microns). Twenty-six non-smokers were studied under each of three experimental conditions (filtered air with placebo, diesel exhaust with placebo, and diesel exhaust with N-acetylcysteine) using a randomized, double-blind, crossover design, with a 2-week washout between conditions. Methacholine challenge was performed pre-exposure (baseline airway responsiveness) and post-exposure (effect of exposure). Anti-oxidant supplementation reduced baseline airway responsiveness in hyper-responsive individuals by 20% (p = 0.001). In hyper-responsive individuals, airway responsiveness increased 42% following DE compared with FA (p = 0.03) and this increase was abrogated with anti-oxidant supplementation (diesel exhaust with N-acetylcysteine vs. filtered air with placebo, p = 0.85). Anti-oxidant (N-acetylcysteine) supplementation protects against increased airway responsiveness associated with DE inhalation and reduces need for supplement bronchodilators in those with baseline airway hyper-responsiveness. Individuals with variants in genes of oxidative stress metabolism when exposed to DE are protected from increases in airway responsiveness if taking anti-oxidant supplementation.

  18. Potentiation by viral respiratory infection of ovalbumin-induced guinea-pig tracheal hyperresponsiveness: role for tachykinins.

    PubMed Central

    Ladenius, A. R.; Folkerts, G.; van der Linde, H. J.; Nijkamp, F. P.

    1995-01-01

    1. We investigated whether virus-induced airway hyperresponsiveness in guinea-pigs could be modulated by pretreatment with capsaicin and whether viral respiratory infections could potentiate ovalbumin-aerosol-induced tracheal hyperresponsiveness. 2. Animals were inoculated intratracheally with bovine parainfluenza-3 virus or control medium 7 days after treatment with capsaicin (50 mg kg-1, s.c.). Four days after inoculation, tracheal contractions were measured to increasing concentrations of substance P, histamine and the cholinoceptor agonist, arecoline. 3. In tracheae from virus-infected guinea-pigs, contractions in response to substance P, histamine and arecoline were significantly enhanced (P < 0.01) by 144%, 46% and 77%, respectively. Capsaicin pretreatment inhibited the hyperresponsiveness to substance P partly (62%) and to histamine and arecoline completely. 4. In another series of experiments animals were first sensitized with ovalbumin (20 mg kg-1, i.p.). After 14 days animals were exposed to either saline or ovalbumin aerosols for 8 days. After 4 aerosol exposures (4 days) animals were inoculated with either parainfluenza-3 virus or control medium. One day after the last ovalbumin aerosol, tracheal contraction in response to increasing concentrations of substance P, histamine and arecoline was measured. 5. Tracheae from ovalbumin-aerosol-exposed control inoculated animals showed a similar degree of airway hyperresponsiveness to saline-aerosol-exposed virus-treated guinea-pigs. Virus inoculation of ovalbumin-treated animals significantly potentiated the tracheal contractions to substance P compared to either of the treatments alone. The contractions in response to histamine and arecoline were only slightly enhanced.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582502

  19. Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration.

    PubMed

    Liu, Wenrui; Kong, Hui; Zeng, Xiaoning; Wang, Jingjing; Wang, Zailiang; Yan, Xiaopei; Wang, Yanli; Xie, Weiping; Wang, Hong

    2015-08-15

    Chronic airway diseases are characterized by airway remodeling which is attributed partly to the proliferation and migration of airway smooth muscle cells (ASMCs). ATP-sensitive potassium (KATP) channels have been identified in ASMCs. Mount evidence has suggested that KATP channel openers can reduce airway hyperresponsiveness and alleviate airway remodeling. Opening K(+) channels triggers K(+) efflux, which leading to membrane hyperpolarization, preventing Ca(2+)entry through closing voltage-operated Ca(2+) channels. Intracellular Ca(2+) is the most important regulator of muscle contraction, cell proliferation and migration. K(+) efflux decreases Ca(2+) influx, which consequently influences ASMCs proliferation and migration. As a KATP channel opener, iptakalim (Ipt) has been reported to restrain the proliferation of pulmonary arterial smooth muscle cells (PASMCs) involved in vascular remodeling, while little is known about its impact on ASMCs. The present study was designed to investigate the effects of Ipt on human ASMCs and the mechanisms underlying. Results obtained from cell counting kit-8 (CCK-8), flow cytometry and 5-ethynyl-2'-deoxyuridine (EdU) incorporation showed that Ipt significantly inhibited platelet-derived growth factor (PDGF)-BB-induced ASMCs proliferation. ASMCs migration induced by PDGF-BB was also suppressed by Ipt in transwell migration and scratch assay. Besides, the phosphorylation of Ca(2+)/calmodulin-dependent kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), protein kinase B (Akt), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were as well alleviated by Ipt administration. Furthermore, we found that the inhibition of Ipt on the PDGF-BB-induced proliferation and migration in human ASMCs was blocked by glibenclamide (Gli), a selective KATP channel antagonist. These findings provide a strong evidence to support that Ipt antagonize the proliferating and migrating effects of PDGF-BB on

  20. NK cells contribute to persistent airway inflammation and AHR during the later stage of RSV infection in mice.

    PubMed

    Long, Xiaoru; Xie, Jun; Zhao, Keting; Li, Wei; Tang, Wei; Chen, Sisi; Zang, Na; Ren, Luo; Deng, Yu; Xie, Xiaohong; Wang, Lijia; Fu, Zhou; Liu, Enmei

    2016-10-01

    RSV can lead to persistent airway inflammation and AHR and is intimately associated with childhood recurrent wheezing and asthma, but the underlying mechanisms remain unclear. There are high numbers of NK cells in the lung, which not only play important roles in the acute stage of RSV infection, but also are pivotal in regulating the pathogenesis of asthma. Therefore, in this study, we assumed that NK cells might contribute to persistent airway disease during the later stage of RSV infection. Mice were killed at serial time points after RSV infection to collect samples. Leukocytes in bronchoalveolar lavage fluid (BALF) were counted, lung histopathology was examined, and airway hyperresponsiveness (AHR) was measured by whole-body plethysmography. Cytokines were detected by ELISA, and NK cells were determined by flow cytometry. Rabbit anti-mouse asialo-GM-1 antibodies and resveratrol were used to deplete or suppress NK cells. Inflammatory cells in BALF, lung tissue damage and AHR were persistent for 60 days post-RSV infection. Type 2 cytokines and NK cells were significantly increased during the later stage of infection. When NK cells were decreased by the antibodies or resveratrol, type 2 cytokines, the persistent airway inflammation and AHR were all markedly reduced. NK cells can contribute to the RSV-associated persistent airway inflammation and AHR at least partially by promoting type 2 cytokines. Therefore, therapeutic targeting of NK cells may provide a novel approach to alleviating the recurrent wheezing subsequent to RSV infection.

  1. Neuronal eotaxin and the effects of ccr3 antagonist on airway hyperreactivity and M2 receptor dysfunction

    PubMed Central

    Fryer, Allison D.; Stein, Louis H.; Nie, Zhenying; Curtis, Damian E.; Evans, Christopher M.; Hodgson, Simon T.; Jose, Peter J.; Belmonte, Kristen E.; Fitch, Erin; Jacoby, David B.

    2006-01-01

    Eosinophils cluster around airway nerves in patients with fatal asthma and in antigen-challenged animals. Activated eosinophils release major basic protein, which blocks inhibitory M2 muscarinic receptors (M2Rs) on nerves, increasing acetylcholine release and potentiating vagally mediated bronchoconstriction. We tested whether GW701897B, an antagonist of CCR3 (the receptor for eotaxin as well as a group of eosinophil active chemokines), affected vagal reactivity and M2R function in ovalbumin-challenged guinea pigs. Sensitized animals were treated with the CCR3 antagonist before inhaling ovalbumin. Antigen-challenged animals were hyperresponsive to vagal stimulation, but those that received the CCR3 antagonist were not. M2R function was lost in antigen-challenged animals, but not in those that received the CCR3 antagonist. Although the CCR3 antagonist did not decrease the number of eosinophils in lung tissues as assessed histologically, CCR3 antagonist prevented antigen-induced clustering of eosinophils along the nerves. Immunostaining revealed eotaxin in airway nerves and in cultured airway parasympathetic neurons from both guinea pigs and humans. Both IL-4 and IL-13 increased expression of eotaxin in cultured airway parasympathetic neurons as well as in human neuroblastoma cells. Thus, signaling via CCR3 mediates eosinophil recruitment to airway nerves and may be a prerequisite to blockade of inhibitory M2Rs by eosinophil major basic protein. PMID:16374515

  2. Deguelin Attenuates Allergic Airway Inflammation via Inhibition of NF-κb Pathway in Mice

    PubMed Central

    Bao, Zhang; Zhang, Pei; Yao, Yinan; Lu, Guohua; Tong, Zhongkai; Yan, Bing; Tu, Lingfang; Yang, Guangdie; Zhou, Jianying

    2017-01-01

    Asthma is a chronic respiratory disease characterized by airway inflammation and remodeling, resulting in a substantial economic burden on both patients and society. Deguelin, a constituent of the Leguminosae family, exhibits anti-proliferative and anti-inflammatory activities in cancer mice models via inhibiting phosphatidylinositol 3-kinases and the NF-κB pathway. We demonstrated that deguelin effectively reduced OVA-induced inflammatory cell recruitment, decreased lung tissue inflammation and mucus production, suppressed airway hyperresponsiveness, and inhibited serum immunoglobulin and Th2 cytokine levels in a dose-dependent manner in asthmatic mice. In addition, we found that deguelin reduced inflammatory gene expressions both in vivo and in vitro, which were closely associated with activation of the NF-κB signaling pathway. Thus, we further explored the underlying mechanisms of deguelin in normal human bronchial epithelial cells (BEAS-2B). Our results suggested that deguelin inhibited NF-κB binding activity by enhancing the ability of IκBα to maintain NF-κB in an inactive form in the cytoplasm and preventing the TNF-α induced translocation of p65 to the nucleus. In conclusion, our research indicates that deguelin attenuates allergic airway inflammation via inhibition of NF-κB pathway in mice model and may act as a potential therapeutic agent for patients with allergic airway inflammation. PMID:28529457

  3. Targeted HAS2 Expression Lessens Airway Responsiveness in Chronic Murine Allergic Airway Disease.

    PubMed

    Walker, Julia K L; Theriot, Barbara S; Ghio, Michael; Trempus, Carol S; Wong, Jordan E; McQuade, Victoria L; Liang, Jiurong; Jiang, Dianhua; Noble, Paul W; Garantziotis, Stavros; Kraft, Monica; Ingram, Jennifer L

    2017-08-08

    Hyaluronan (HA), a major component of extracellular matrix, is secreted by airway structural cells. For example, airway fibroblasts in allergic asthma secrete elevated levels of HA in association with increased hyaluronan synthase 2 (HAS2) expression. Thus, we hypothesized that HA accumulation in the airway wall may contribute to airway remodeling and hyperresponsiveness in allergic airways disease. Transgenic mice were generated in which the smooth muscle α-actin (αSMA) promoter drives HAS2 expression. Mixed male and female αSMA-HAS2 mice (HAS2+ mice, n=16; HAS2- mice, n=13) were sensitized via intraperitoneal injection, and then chronically challenged with aerosolized ovalbumin (OVA) for 6 weeks. To test airway responsiveness, increasing doses of methacholine were delivered intravenously, and airway resistance was measured using the forced oscillation technique. HA, cytokines, and cell types were analyzed in bronchoalveolar lavage fluid, serum and whole lung homogenates. Lung sections were stained using antibodies specific for hyaluronan binding protein (HABP) and αSMA, as well as Masson's trichrome stain. Staining of lung tissue demonstrated significantly increased peribronchial HA, αSMA, and collagen deposition in OVA-challenged αSMA-HAS2+ mice compared to αSMA-HAS2- mice. Unexpectedly, OVA-challenged αSMA-HAS2+ displayed significantly reduced airway responsiveness to methacholine compared to similarly-treated αSMA-HAS2- mice. Total numbers of inflammatory cell types in the bronchoalveolar lavage fluid of OVA-challenged αSMA-HAS2+ mice were not significantly different from that of OVA-challenged αSMA-HAS2- mice. Allergen-challenged mice that overexpress HAS2 in myofibroblasts and smooth muscle cells develop increased airway fibrosis, which lessens airway hyperresponsiveness to bronchoconstrictors.

  4. Peptidoglycan recognition protein 1 promotes house dust mite-induced airway inflammation in mice.

    PubMed

    Yao, Xianglan; Gao, Meixia; Dai, Cuilian; Meyer, Katharine S; Chen, Jichun; Keeran, Karen J; Nugent, Gayle Z; Qu, Xuan; Yu, Zu-Xi; Dagur, Pradeep K; McCoy, J Philip; Levine, Stewart J

    2013-12-01

    Peptidoglycan recognition protein (Pglyrp) 1 is a pattern-recognition protein that mediates antibacterial host defense. Because we had previously shown that Pglyrp1 expression is increased in the lungs of house dust mite (HDM)-challenged mice, we hypothesized that it might modulate the pathogenesis of asthma. Wild-type and Pglyrp1(-/-) mice on a BALB/c background received intranasal HDM or saline, 5 days/week for 3 weeks. HDM-challenged Pglyrp1(-/-) mice showed decreases in bronchoalveolar lavage fluid eosinophils and lymphocytes, serum IgE, and mucous cell metaplasia, whereas airway hyperresponsiveness was not changed when compared with wild-type mice. T helper type 2 (Th2) cytokines were reduced in the lungs of HDM-challenged Pglyrp1(-/-) mice, which reflected a decreased number of CD4(+) Th2 cells. There was also a reduction in C-C chemokines in bronchoalveolar lavage fluid and lung homogenates from HDM-challenged Pglyrp1(-/-) mice. Furthermore, secretion of CCL17, CCL22, and CCL24 by alveolar macrophages from HDM-challenged Pglyrp1(-/-) mice was markedly reduced. As both inflammatory cells and airway epithelial cells express Pglyrp1, bone marrow transplantation was performed to generate chimeric mice and assess which cell type promotes HDM-induced airway inflammation. Chimeric mice lacking Pglyrp1 on hematopoietic cells, not structural cells, showed a reduction in HDM-induced eosinophilic and lymphocytic airway inflammation. We conclude that Pglyrp1 expressed by hematopoietic cells, such as alveolar macrophages, mediates HDM-induced airway inflammation by up-regulating the production of C-C chemokines that recruit eosinophils and Th2 cells to the lung. This identifies a new family of innate immune response proteins that promotes HDM-induced airway inflammation in asthma.

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

    PubMed

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

    2017-01-01

    Although the prominent role of TH2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. We sought to investigate the relative contribution of ILC2 and adaptive TH2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Wild-type, Gata-3(+/nlslacZ) (Gata-3-haploinsufficient), RAR-related orphan receptor α (RORα)(fl/fl)IL7R(Cre) (ILC2-deficient), and recombination-activating gene (Rag) 2(-/-) mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and TH2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and TH2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and TH2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2(-/-) mice. These data indicate that dysregulation of ILC2s and TH2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure. Copyright © 2016 American Academy of

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

    PubMed

    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.

  7. Involvement of RhoA-mediated Ca2+ sensitization in antigen-induced bronchial smooth muscle hyperresponsiveness in mice

    PubMed Central

    Chiba, Yoshihiko; Ueno, Ayako; Shinozaki, Koji; Takeyama, Hisao; Nakazawa, Shuji; Sakai, Hiroyasu; Misawa, Miwa

    2005-01-01

    Background It has recently been suggested that RhoA plays an important role in the enhancement of the Ca2+ sensitization of smooth muscle contraction. In the present study, a participation of RhoA-mediated Ca2+ sensitization in the augmented bronchial smooth muscle (BSM) contraction in a murine model of allergic asthma was examined. Methods Ovalbumin (OA)-sensitized BALB/c mice were repeatedly challenged with aerosolized OA and sacrificed 24 hours after the last antigen challenge. The contractility and RhoA protein expression of BSMs were measured by organ-bath technique and immunoblotting, respectively. Results Repeated OA challenge to sensitized mice caused a BSM hyperresponsiveness to acetylcholine (ACh), but not to high K+-depolarization. In α-toxin-permeabilized BSMs, ACh induced a Ca2+ sensitization of contraction, which is sensitive to Clostridium botulinum C3 exoenzyme, indicating that RhoA is implicated in this Ca2+ sensitization. Interestingly, the ACh-induced, RhoA-mediated Ca2+ sensitization was significantly augmented in permeabilized BSMs of OA-challenged mice. Moreover, protein expression of RhoA was significantly increased in the hyperresponsive BSMs. Conclusion These findings suggest that the augmentation of Ca2+ sensitizing effect, probably via an up-regulation of RhoA protein, might be involved in the enhanced BSM contraction in antigen-induced airway hyperresponsiveness. PMID:15638941

  8. Diagnostic tools assessing airway remodelling in asthma.

    PubMed

    Manso, L; Reche, M; Padial, M A; Valbuena, T; Pascual, C

    2012-01-01

    Asthma is an inflammatory disease of the lower airways characterised by the presence of airway inflammation, reversible airflow obstruction and airway hyperresponsiveness and alterations on the normal structure of the airways, known as remodelling. Remodelling is characterised by the presence of metaplasia of mucous glands, thickening of the lamina reticularis, increased angiogenesis, subepithelial fibrosis and smooth muscle hypertrophy/hyperplasia. Several techniques are being optimised at present to achieve a suitable diagnosis for remodelling. Diagnostic tools could be divided into two groups, namely invasive and non-invasive methods. Invasive techniques bring us information about bronchial structural alterations, obtaining this information directly from pathological tissue, and permit measure histological modification placed in bronchi layers as well as inflammatory and fibrotic cell infiltration. Non-invasive techniques were developed to reduce invasive methods disadvantages and measure airway remodelling-related markers such as cytokines, inflammatory mediators and others. An exhaustive review of diagnostic tools used to analyse airway remodelling in asthma, including the most useful and usually employed methods, as well as the principal advantages and disadvantages of each of them, bring us concrete and summarised information about all techniques used to evaluate alterations on the structure of the airways. A deep knowledge of these diagnostic tools will make an early diagnosis of airway remodelling possible and, probably, early diagnosis will play an important role in the near future of asthma. Copyright © 2011 SEICAP. Published by Elsevier Espana. All rights reserved.

  9. Airway and Extracellular Matrix Mechanics in COPD

    PubMed Central

    Bidan, Cécile M.; Veldsink, Annemiek C.; Meurs, Herman; Gosens, Reinoud

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases worldwide, and is characterized by airflow obstruction that is not fully reversible with treatment. Even though airflow obstruction is caused by airway smooth muscle contraction, the extent of airway narrowing depends on a range of other structural and functional determinants that impact on active and passive tissue mechanics. Cells and extracellular matrix in the airway and parenchymal compartments respond both passively and actively to the mechanical stimulation induced by smooth muscle contraction. In this review, we summarize the factors that regulate airway narrowing and provide insight into the relative contributions of different constituents of the extracellular matrix and their biomechanical impact on airway obstruction. We then review the changes in extracellular matrix composition in the airway and parenchymal compartments at different stages of COPD, and finally discuss how these changes impact airway narrowing and the development of airway hyperresponsiveness. Finally, we position these data in the context of therapeutic research focused on defective tissue repair. As a conclusion, we propose that future works should primarily target mild or early COPD, prior to the widespread structural changes in the alveolar compartment that are more characteristic of severe COPD. PMID:26696894

  10. Alcohol Decreases Organic Dust-Stimulated Airway Epithelial TNF-Alpha Through a Nitric Oxide and Protein Kinase-Mediated Inhibition of TACE.

    PubMed

    Gerald, Carresse L; Romberger, Debra J; DeVasure, Jane M; Khazanchi, Rohan; Nordgren, Tara M; Heires, Art J; Sisson, Joseph H; Wyatt, Todd A

    2016-02-01

    Farm workers in rural areas consume more alcohol than those who reside in urban areas. Occupational exposures such as agricultural work can pose hazards on the respiratory system. It is established that hog barn dust induces inflammation in the airway, including the release of cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-8. We have shown that alcohol alters airway epithelial innate defense through changes in both nitric oxide (NO) and cAMP-dependent protein kinase A (PKA). Simultaneous exposure to hog barn dust and alcohol decreases inflammatory mediators, TNF-α, IL-6, and IL-8, in mice. Previously, mice exposed to both alcohol and hog barn dust showed a depleted amount of lymphocytes compared to mice exposed only to hog barn dust. Weakening of the innate immune response could lead to enhanced susceptibility to disease. In addition, mice that were co-exposed to hog barn dust and alcohol also experienced increased mortality. Because we recently demonstrated that PKA activation inhibits the TNF-α sheddase, TNF-α-converting enzyme (TACE), we hypothesized that an alcohol-mediated PKA pathway blocks TACE activity and prevents the normative inflammatory response to hog barn dust exposure. To delineate these effects, we used PKA pathway inhibitors (adenylyl cyclase [AC], cAMP, and PKA) to modulate the effects of alcohol on dust-stimulated TNF-α release in the bronchial epithelial cell line, BEAS-2B. Alcohol pretreatment blocked TACE activity and TNF-α release in hog barn dust-treated cells. Alcohol continued to block hog barn dust-mediated TNF-α release in the presence of the particulate AC inhibitor, SQ22,536. The soluble adenylyl cyclase inhibitor, KH7, however, significantly increased the inflammatory response to hog barn dust. phosphodiesterase 4 inhibitors significantly elevated cAMP and enhanced alcohol-mediated inhibition of dust-stimulated TNF-α release. In addition, the NO synthase inhibitor, l-NMMA, also reversed

  11. Regulation of eosinophilia and allergic airway inflammation by the glycan-binding protein galectin-1

    PubMed Central

    Ge, Xiao Na; Ha, Sung Gil; Greenberg, Yana G.; Rao, Amrita; Bastan, Idil; Blidner, Ada G.; Rao, Savita P.; Rabinovich, Gabriel A.; Sriramarao, P.

    2016-01-01

    Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflammatory activities, functions as a proresolving mediator in autoimmune and chronic inflammatory disorders. However, its role in allergic airway inflammation has not yet been elucidated. We evaluated the effects of Gal-1 on eosinophil function and its role in a mouse model of allergic asthma. Allergen exposure resulted in airway recruitment of Gal-1–expressing inflammatory cells, including eosinophils, as well as increased Gal-1 in extracellular spaces in the lungs. In vitro, extracellular Gal-1 exerted divergent effects on eosinophils that were N-glycan– and dose-dependent. At concentrations ≤0.25 µM, Gal-1 increased eosinophil adhesion to vascular cell adhesion molecule-1, caused redistribution of integrin CD49d to the periphery and cell clustering, but inhibited ERK(1/2) activation and eotaxin-1–induced migration. Exposure to concentrations ≥1 µM resulted in ERK(1/2)-dependent apoptosis and disruption of the F-actin cytoskeleton. At lower concentrations, Gal-1 did not alter expression of adhesion molecules (CD49d, CD18, CD11a, CD11b, L-selectin) or of the chemokine receptor CCR3, but decreased CD49d and CCR3 was observed in eosinophils treated with higher concentrations of this lectin. In vivo, allergen-challenged Gal-1–deficient mice exhibited increased recruitment of eosinophils and CD3+ T lymphocytes in the airways as well as elevated peripheral blood and bone marrow eosinophils relative to corresponding WT mice. Further, these mice had an increased propensity to develop airway hyperresponsiveness and displayed significantly elevated levels of TNF-α in lung tissue. This study suggests that Gal-1 can limit eosinophil recruitment to allergic airways and suppresses airway inflammation by inhibiting cell migration and promoting eosinophil apoptosis. PMID:27457925

  12. Regulation of eosinophilia and allergic airway inflammation by the glycan-binding protein galectin-1.

    PubMed

    Ge, Xiao Na; Ha, Sung Gil; Greenberg, Yana G; Rao, Amrita; Bastan, Idil; Blidner, Ada G; Rao, Savita P; Rabinovich, Gabriel A; Sriramarao, P

    2016-08-16

    Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflammatory activities, functions as a proresolving mediator in autoimmune and chronic inflammatory disorders. However, its role in allergic airway inflammation has not yet been elucidated. We evaluated the effects of Gal-1 on eosinophil function and its role in a mouse model of allergic asthma. Allergen exposure resulted in airway recruitment of Gal-1-expressing inflammatory cells, including eosinophils, as well as increased Gal-1 in extracellular spaces in the lungs. In vitro, extracellular Gal-1 exerted divergent effects on eosinophils that were N-glycan- and dose-dependent. At concentrations ≤0.25 µM, Gal-1 increased eosinophil adhesion to vascular cell adhesion molecule-1, caused redistribution of integrin CD49d to the periphery and cell clustering, but inhibited ERK(1/2) activation and eotaxin-1-induced migration. Exposure to concentrations ≥1 µM resulted in ERK(1/2)-dependent apoptosis and disruption of the F-actin cytoskeleton. At lower concentrations, Gal-1 did not alter expression of adhesion molecules (CD49d, CD18, CD11a, CD11b, L-selectin) or of the chemokine receptor CCR3, but decreased CD49d and CCR3 was observed in eosinophils treated with higher concentrations of this lectin. In vivo, allergen-challenged Gal-1-deficient mice exhibited increased recruitment of eosinophils and CD3(+) T lymphocytes in the airways as well as elevated peripheral blood and bone marrow eosinophils relative to corresponding WT mice. Further, these mice had an increased propensity to develop airway hyperresponsiveness and displayed significantly elevated levels of TNF-α in lung tissue. This study suggests that Gal-1 can limit eosinophil recruitment to allergic airways and suppresses airway inflammation by inhibiting cell migration and promoting eosinophil apoptosis.

  13. Liver reperfusion-induced decrease in dynamic compliance and increase in airway resistance are ameliorated by preischemic treatment with melatonin through scavenging hydroxyl radicals in rat lungs.

    PubMed

    Yeh, J-H; Su, C-L; Chen, C F; Wang, D; Wang, J-J

    2012-05-01

    Acute lung injury is frequently observed in patients subsequent to liver ischemia and reperfusion (I/R) injury. However, the changes in pulmonary function, eg, lung dynamic compliance (C(dyn)) and airway resistance (RI), are not well understood. We sought to study the alternations in pulmonary function during liver I/R and the protective effects of preischemic treatment with melatonin. Animals were divided into 3 groups: sham-operated, liver I/R, and intraperitoneal (i.p.) pretreatment with melatonin (15 mg/kg). Liver I/R was performed by clamping the hepatic artery and portal vein for 30 minutes followed by releasing for 2 hours. The C(dyn) and RI were studied at baseline and at 2 hours of reperfusion. We assessed the level of pulmonary hydroxyl radicals by methylguanidine (MG) content in the bronchoalveolar lavage fluid (BALF) as well as the liver damage using plasma levels of lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT). After 2 hours of liver reperfusion, C(dyn) was reduced by ∼25%, while RI increased by ∼16% (P < .05). The decreased C(dyn) and increased RI were markedly attenuated by melatonin pretreatment (P < .05). Melatonin pretreatment also protected the liver against I/R injury (P < .05), as seen by reduced LDH, GOT and GPT along with markedly reduced hydroxyl radicals (P < .05). Preischemic treatment with melatonin protected lung function against damage by liver I/R. The improvement in lung function was strongly associated with decreased hydroxyl radicals in the lungs. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Rosiglitazone reverses salbutamol-induced β2-adrenoceptor tolerance in airway smooth muscle

    PubMed Central

    Fogli, Stefano; Pellegrini, Silvia; Adinolfi, Barbara; Mariotti, Veronica; Melissari, Erika; Betti, Laura; Fabbrini, Laura; Giannaccini, Gino; Lucacchini, Antonio; Bardelli, Claudio; Stefanelli, Fabio; Brunelleschi, Sandra; Breschi, Maria Cristina

    2011-01-01

    BACKGROUND AND PURPOSE β2-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)γ agonist rosiglitazone modulated salbutamol-induced β2-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACH An in vivo model of homologous β2-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent β2-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study. KEY RESULTS In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of β2-adrenoceptor gene and a marked decrease in β-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored β2-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPARγ agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitroβ2-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and β2-adrenoceptor expression. Rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONS These data suggest a potential pharmacodynamic interaction between PPARγ agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic

  15. World Trade Center fine particulate matter causes respiratory tract hyperresponsiveness in mice.

    PubMed Central

    Gavett, Stephen H; Haykal-Coates, Najwa; Highfill, Jerry W; Ledbetter, Allen D; Chen, Lung Chi; Cohen, Mitchell D; Harkema, Jack R; Wagner, James G; Costa, Daniel L

    2003-01-01

    Pollutants originating from the destruction of the World Trade Center (WTC) in New York City on 11 September 2001 have been reported to cause adverse respiratory responses in rescue workers and nearby residents. We examined whether WTC-derived fine particulate matter [particulate matter with a mass median aerodynamic diameter < 2.5 microm (PM2.5)] has detrimental respiratory effects in mice to contribute to the risk assessment of WTC-derived pollutants. Samples of WTC PM2.5 were derived from settled dust collected at several locations around Ground Zero on 12 and 13 September 2001. Aspirated samples of WTC PM2.5 induced mild to moderate degrees of pulmonary inflammation 1 day after exposure but only at a relatively high dose (100 microg). This response was not as great as that caused by 100 microg PM2.5 derived from residual oil fly ash (ROFA) or Washington, DC, ambient air PM [National Institute of Standards and Technology, Standard Reference Material (SRM) 1649a]. However, this same dose of WTC PM2.5 caused airway hyperresponsiveness to methacholine aerosol comparable to that from SRM 1649a and to a greater degree than that from ROFA. Mice exposed to lower doses by aspiration or inhalation exposure did not develop significant inflammation or hyperresponsiveness. These results show that exposure to high levels of WTC PM2.5 can promote mechanisms of airflow obstruction in mice. Airborne concentrations of WTC PM2.5 that would cause comparable doses in people are high (approximately 425 microg/m3 for 8 hr) but conceivable in the aftermath of the collapse of the towers when rescue and salvage efforts were in effect. We conclude that a high-level exposure to WTC PM2.5 could cause pulmonary inflammation and airway hyperresponsiveness in people. The effects of chronic exposures to lower levels of WTC PM2.5, the persistence of any respiratory effects, and the effects of coarser WTC PM are unknown and were not examined in these studies. Degree of exposure and respiratory

  16. World Trade Center fine particulate matter causes respiratory tract hyperresponsiveness in mice.

    PubMed

    Gavett, Stephen H; Haykal-Coates, Najwa; Highfill, Jerry W; Ledbetter, Allen D; Chen, Lung Chi; Cohen, Mitchell D; Harkema, Jack R; Wagner, James G; Costa, Daniel L

    2003-06-01

    Pollutants originating from the destruction of the World Trade Center (WTC) in New York City on 11 September 2001 have been reported to cause adverse respiratory responses in rescue workers and nearby residents. We examined whether WTC-derived fine particulate matter [particulate matter with a mass median aerodynamic diameter < 2.5 microm (PM2.5)] has detrimental respiratory effects in mice to contribute to the risk assessment of WTC-derived pollutants. Samples of WTC PM2.5 were derived from settled dust collected at several locations around Ground Zero on 12 and 13 September 2001. Aspirated samples of WTC PM2.5 induced mild to moderate degrees of pulmonary inflammation 1 day after exposure but only at a relatively high dose (100 microg). This response was not as great as that caused by 100 microg PM2.5 derived from residual oil fly ash (ROFA) or Washington, DC, ambient air PM [National Institute of Standards and Technology, Standard Reference Material (SRM) 1649a]. However, this same dose of WTC PM2.5 caused airway hyperresponsiveness to methacholine aerosol comparable to that from SRM 1649a and to a greater degree than that from ROFA. Mice exposed to lower doses by aspiration or inhalation exposure did not develop significant inflammation or hyperresponsiveness. These results show that exposure to high levels of WTC PM2.5 can promote mechanisms of airflow obstruction in mice. Airborne concentrations of WTC PM2.5 that would cause comparable doses in people are high (approximately 425 microg/m3 for 8 hr) but conceivable in the aftermath of the collapse of the towers when rescue and salvage efforts were in effect. We conclude that a high-level exposure to WTC PM2.5 could cause pulmonary inflammation and airway hyperresponsiveness in people. The effects of chronic exposures to lower levels of WTC PM2.5, the persistence of any respiratory effects, and the effects of coarser WTC PM are unknown and were not examined in these studies. Degree of exposure and respiratory

  17. Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease.

    PubMed

    Foong, Rachel E; Bosco, Anthony; Troy, Niamh M; Gorman, Shelley; Hart, Prue H; Kicic, Anthony; Zosky, Graeme R

    2016-09-01

    Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function. A BALB/c mouse model of vitamin D deficiency was established by dietary manipulation. Responsiveness to methacholine, airway smooth muscle (ASM) mass, mucus cell metaplasia, lung and airway inflammation, and cytokines in bronchoalveolar lavage (BAL) fluid were assessed. Gene expression patterns in mouse lung samples were profiled by RNA-Seq. HDM exposure increased inflammation and inflammatory cytokines in BAL, baseline airway resistance, tissue elastance, and ASM mass. Vitamin D deficiency enhanced the HDM-induced influx of lymphocytes into BAL, ameliorated the HDM-induced increase in ASM mass, and protected against the HDM-induced increase in baseline airway resistance. RNA-Seq identified nine genes that were differentially regulated by vitamin D deficiency in the lungs of HDM-treated mice. Immunohistochemical staining confirmed that protein expression of midline 1 (MID1) and adrenomedullin was differentially regulated such that they promoted inflammation, while hypoxia-inducible lipid droplet-associated, which is associated with ASM remodeling, was downregulated. Protein expression studies in human bronchial epithelial cells also showed that addition of vitamin D decreased MID1 expression. Differential regulation of these genes by vitamin D deficiency could determine lung inflammation and pathophysiology and suggest that the effect of vitamin D deficiency on HDM-induced allergic airways disease is complex.

  18. Protective effect of antiasthma drugs on late asthmatic reactions and increased airway responsiveness induced by toluene diisocyanate in sensitized subjects.

    PubMed

    Mapp, C; Boschetto, P; dal Vecchio, L; Crescioli, S; de Marzo, N; Paleari, D; Fabbri, L M

    1987-12-01

    To determine whether 4 drugs used in the treatment of asthma inhibit the late asthmatic reaction and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied 24 sensitized subjects divided into 4 groups. Beclomethasone aerosol (1 mg bid), slow-release theophylline (6.5 mg/kg bid), slow-release verapamil (120 mg bid), and cromolyn (20 mg qid via spinhaler), were administered for 7 days, respectively, to 1 of the 4 groups, according to a double-blind, crossover, placebo-controlled study design. When the subjects were treated with placebo, verapamil, or cromolyn, FEV1 markedly decreased and airway responsiveness increased after exposure to TDI. By contrast, beclomethasone prevented the late asthmatic reaction and the associated increase in airway responsiveness to methacholine induced by TDI. Slow-release theophylline partially inhibited both the immediate and the late asthmatic reactions but had no effect on airway hyperresponsiveness to methacholine. These results suggest that only high-dose inhaled steroids can completely block TDI-induced late asthmatic reactions.

  19. Bystander immunotherapy as a strategy to control allergen-driven airway inflammation.

    PubMed

    Navarro, S; Lazzari, A; Kanda, A; Fleury, S; Dombrowicz, D; Glaichenhaus, N; Julia, V

    2015-07-01

    Allergic asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), lung infiltration of Th2 cells, and high levels of IgE. To date, allergen-specific immunotherapy (SIT) is the only treatment that effectively alleviates clinical symptoms and has a long-term effect after termination. Unfortunately, SIT is unsuitable for plurisensitized patients, and highly immunogenic allergens cannot be used. To overcome these hurdles, we sought to induce regulatory CD4(+) T cells (Treg) specific to an exogenous antigen that could be later activated as needed in vivo to control allergic responses. We have established an experimental approach in which mice tolerized to ovalbumin (OVA) were sensitized to the Leishmania homolog of receptors for activated c kinase (LACK) antigen, and subsequently challenged with aerosols of LACK alone or LACK and OVA together. Upon OVA administration, AHR and allergic airway responses were strongly reduced. OVA-induced suppression was mediated by CD25(+) Treg, required CTLA-4 and ICOS signaling and resulted in decreased numbers of migrating airway dendritic cells leading to a strong impairment in the proliferation of allergen-specific Th2 cells. Therefore, inducing Treg specific to a therapeutic antigen that could be further activated in vivo may represent a safe and novel curative approach for allergic asthma.

  20. Hesperidin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model.

    PubMed

    Wei, Dajun; Ci, Xinxin; Chu, Xiao; Wei, Miaomiao; Hua, Shucheng; Deng, Xuming

    2012-02-01

    Hesperidin, a flavanone glycoside comprised of the flavanone hesperetin and the disaccharide rutinose, is a plentiful and inexpensive by-product of citrus cultivation. It has been reported to exert a wide range of pharmacological effects that include antioxidant, anti-inflammatory, and anticarcinogenic properties. In this study, we attempt to determine whether hesperidin inhibits inflammatory mediators in the mouse allergic asthma model. Mice were sensitized and challenged by ovalbumin (OVA) to induce chronic airway inflammation and airway remodeling. The administration of hesperidin significantly decreased the number of infiltrating inflammatory cells and Th2 cytokines in bronchoalveolar lavage (BAL) fluid compared with the OVA-induced group of mice. In addition, hesperidin reduced OVA-specific IgE levels in serum. Hesperidin markedly alleviated the OVA-induced airway hyperresponsiveness (AHR) to inhaled methacholine. Based on lung histopathological studies using hematoxylin and eosin and alcian blue-periodic acid-Schiff staining, hesperidin inhibited inflammatory cell infiltration and mucus hypersecretion compared with the OVA-induced group of mice. These findings provide new insight into the immunopharmacological role of hesperidin in terms of its effects in a murine model of asthma.

  1. Effect of once daily and twice daily sustained release theophylline formulations on daytime variation of bronchial hyperresponsiveness in asthmatic patients

    PubMed Central

    Ferrari, M.; Olivieri, M.; Lampronti, G.; Bonazza, L.; Biasin, C.; Nacci, P.; Talamini, G.; Lo, C

    1997-01-01

    BACKGROUND: Previous studies evaluating spirometric values and symptoms have shown that once daily theophylline administered in the evening produces greater stabilisation of the airway function in asthmatic patients than the prototype theophylline given twice a day. The aim of this study was to compare the effects on bronchial responsiveness to methacholine of an ultrasustained release theophylline formulation (Diffumal-24, Malesci, Florence, Italy) administered once a day, a sustained release theophylline formulation (Theo-Dur, Recordati, Milan, Italy) administered twice a day, and placebo. METHODS: The study was performed in 12 adult patients with asthma using a randomised, double blind, three phase, cross-over design. Each phase lasted seven days and was followed or preceded by at least three days of theophylline washout. Diffumal-24 was administered once a day at 20.00 hours whereas Theo-Dur was given twice a day at 08.00 hours and 20.00 hours. In each patient the total daily dose of theophylline was the same during both phases. The dose of the two active preparations was titrated to individual needs before the beginning of the study and then given in divided or once daily doses. At 08.00, 14.00, and 20.00 hours on day 7 of each phase serum theophylline concentrations were measured and spirometric tests (FEV1) and bronchial challenge with methacholine were also performed. RESULTS: When the administration of Diffumal-24 was compared with that of Theo-Dur, a higher serum theophylline concentration of the former was seen in the morning whereas at 20.00 hours the reverse was true. Compared with placebo, at 08.00 hours Diffumal-24 improved FEV1 whereas Theo-Dur did not (difference between treatments 0.29 1, 95% CI 0.12 to 0.45). At 08.00 hours Diffumal-24 decreased bronchial sensitivity to methacholine, expressed as a natural logarithm of PD20, to a greater extent than Theo-Dur (difference between treatments 0.54 log units, 95% CI 0.016 to 1.08). The morning

  2. Airway smooth muscle in airway reactivity and remodeling: what have we learned?

    PubMed Central

    2013-01-01

    It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca2+]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro- vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM “activity” result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. PMID:24142517

  3. Ion channel regulation of intracellular calcium and airway smooth muscle function.

    PubMed

    Perez-Zoghbi, Jose F; Karner, Charlotta; Ito, Satoru; Shepherd, Malcolm; Alrashdan, Yazan; Sanderson, Michael J

    2009-10-01

    Airway hyper-responsiveness associated with asthma is mediated by airway smooth muscle cells (SMCs) and has a complicated etiology involving increases in cell contraction and proliferation and the secretion of inflammatory mediators. Although these pathological changes are diverse, a common feature associated with their regulation is a change in intracellular Ca(2+) concentration ([Ca(2+)](i)). Because the [Ca(2+)](i) itself is a function of the activity and expression of a variety of ion channels, in both the plasma membrane and sarcoplasmic reticulum of the SMC, the modification of this ion channel activity may predispose airway SMCs to hyper-responsiveness. Our objective is to review how ion channels determine the [Ca(2+)](i) and influence the function of airway SMCs and emphasize the potential of ion channels as sites for therapeutic approaches to asthma.

  4. Mechanisms of acute increases in airway responsiveness caused by environmental chemicals

    SciTech Connect

    Sheppard, D.

    1988-01-01

    Inhalation of inhaled environmental chemicals has long been recognized as a cause of acute increases in airway responsiveness. Extensive studies of the mechanisms of action of two of these chemicals, ozone and toluene diisocyanate, have been conducted during the past decade. The results of these studies suggest that acute airway inflammation plays an important role in the effect of inhaled chemicals but that the specific aspects of the inflammatory response that lead to the development of airway hyperresponsiveness are different for different stimuli and among different mammalian species. These observations suggest that in vivo airway hyperresponsiveness can arise via several different mechanisms and is thus not likely to reflect a single underlying defect. 24 references.

  5. Wogonin Induces Eosinophil Apoptosis and Attenuates Allergic Airway Inflammation

    PubMed Central

    Dorward, David A.; Sharma, Sidharth; Rennie, Jillian; Felton, Jennifer M.; Alessandri, Ana L.; Duffin, Rodger; Schwarze, Jurgen; Haslett, Christopher; Rossi, Adriano G.

    2015-01-01

    Rationale: Eosinophils are key effector cells in allergic diseases, including allergic rhinitis, eczema, and asthma. Their tissue presence is regulated by both recruitment and increased longevity at inflamed sites. Objectives: To investigate the ability of the flavone wogonin to induce eosinophil apoptosis in vitro and attenuate eosinophil-dominant allergic inflammation in vivo in mice. Methods: Human and mouse eosinophil apoptosis in response to wogonin was investigated by cellular morphology, flow cytometry, mitochondrial membrane permeability, and pharmacological caspase inhibition. Allergic lung inflammation was modeled in mice sensitized and challenged with ovalbumin. Bronchoalveolar lavage (BAL) and lung tissue were examined for inflammation, mucus production, and inflammatory mediator production. Airway hyperresponsiveness to aerosolized methacholine was measured. Measurements and Main Results: Wogonin induced time- and concentration-dependent human and mouse eosinophil apoptosis in vitro. Wogonin-induced eosinophil apoptosis occurred with activation of caspase-3 and was inhibited by pharmacological caspase inhibition. Wogonin administration attenuated allergic airway inflammation in vivo with reductions in BAL and interstitial eosinophil numbers, increased eosinophil apoptosis, reduced airway mucus production, and attenuated airway hyperresponsiveness. This wogonin-induced reduction in allergic airway inflammation was prevented by concurrent caspase inhibition in vivo. Conclusions: Wogonin induces eosinophil apoptosis and attenuates allergic airway inflammation, suggesting that it has therapeutic potential for the treatment of allergic inflammation in humans. PMID:25629436

  6. The effects of current therapies on airway remodeling in asthma and new possibilities for treatment and prevention.

    PubMed

    Royce, S G; Tang, M L K

    2009-06-01

    Airway inflammation, airway remodeling and airway hyperresponsiveness are the fundamental components of pathogenesis that lead to symptoms and lung function changes in asthma. Airway remodeling describes the structural changes to the airways in asthma. The remodeling process involves diverse pathological changes including epithelial metaplasia, subepithelial fibrosis, angiogenesis and smooth muscle thickening. Airway remodeling contributes to irreversible loss of lung function and airway hyperresponsiveness. Remodeling is associated with severe and persistent disease but can also occur early in the course of disease pathogenesis and does not resolve spontaneously. Current asthma therapies, for example corticosteroids, are successful in treating allergic inflammation, an important factor contributing to remodeling, but do not specifically target the remodeling process, and remodeling changes progress despite optimal control of inflammation. Moreover, airway remodeling is not eradicated or prevented despite widespread use of anti-inflammatory treatments. There is limited evidence for the effectiveness of leukotriene inhibitors, phosphodiesterase inhibitors, mast cell tryptase inhibitors, and peroxisome proliferator-activated receptor gamma agonists in the treatment or prevention of remodeling changes. The search for novel therapies that can specifically reverse or prevent airway remodeling is an active area of research. Treatments that may be useful in preventing airway remodeling include those that directly or indirectly target single or multiple components of the airway remodeling process. Identification of novel asthma genes may also allow disease targeting. A better understanding of airway remodeling in asthma will facilitate the development of new treatments for asthma beyond control of symptoms and inflammation.

  7. Surgical Airway

    PubMed Central

    Patel, Sapna A; Meyer, Tanya K

    2014-01-01

    Close to 3% of all intubation attempts are considered difficult airways, for which a plan for a surgical airway should be considered. Our article provides an overview of the different types of surgical airways. This article provides a comprehensive review of the main types of surgical airways, relevant anatomy, necessary equipment, indications and contraindications, preparation and positioning, technique, complications, and tips for management. It is important to remember that the placement of a surgical airway is a lifesaving procedure and should be considered in any setting when one “cannot intubate, cannot ventilate”. PMID:24741501

  8. Serelaxin improves the therapeutic efficacy of RXFP1-expressing human amnion epithelial cells in experimental allergic airway disease.

    PubMed

    Royce, Simon G; Tominaga, Anna M; Shen, Matthew; Patel, Krupesh P; Huuskes, Brooke M; Lim, Rebecca; Ricardo, Sharon D; Samuel, Chrishan S

    2016-12-01

    Current asthma therapies primarily target airway inflammation (AI) and suppress episodes of airway hyperresponsiveness (AHR) but fail to treat airway remodelling (AWR), which can develop independently of AI and contribute to irreversible airway obstruction. The present study compared the anti-remodelling and therapeutic efficacy of human bone marrow-derived mesenchymal stem cells (MSCs) to that of human amnion epithelial stem cells (AECs) in the setting of chronic allergic airways disease (AAD), in the absence or presence of an anti-fibrotic (serelaxin; RLX). Female Balb/c mice subjected to the 9-week model of ovalbumin (OVA)-induced chronic AAD, were either vehicle-treated (OVA alone) or treated with MSCs or AECs alone [intranasally (i.n.)-administered with 1×10(6) cells once weekly], RLX alone (i.n.-administered with 0.8 mg/ml daily) or a combination of MSCs or AECs and RLX from weeks 9-11 (n=6/group). Measures of AI, AWR and AHR were then assessed. OVA alone exacerbated AI, epithelial damage/thickness, sub-epithelial extracellular matrix (ECM) and total collagen deposition, markers of collagen turnover and AHR compared with that in saline-treated counterparts (all P<0.01 compared with saline-treated controls). RLX or AECs (but not MSCs) alone normalized epithelial thickness and partially diminished the OVA-induced fibrosis and AHR by ∼40-50% (all P<0.05 compared with OVA alone). Furthermore, the combination treatments normalized epithelial thickness, measures of fibrosis and AHR to that in normal mice, and significantly decreased AI. Although AECs alone demonstrated greater protection against the AAD-induced AI, AWR and AHR, compared with that of MSCs alone, combining RLX with MSCs or AECs reversed airway fibrosis and AHR to an even greater extent. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  9. NF-kB Induction in Airway Epithelium Increases Lung Inflammation in Allergen Challenged Mice

    PubMed Central

    Sheller, James R.; Polosukhin, Vasiliy V.; Mitchell, Daphne; Cheng, D-S.; Peebles, R. Stokes; Blackwell, Timothy S.

    2012-01-01

    NF-kB is a critical transcription factor for the production of many inflammatory cytokines. It is activated in the airway epithelium of human asthmatics and in mice after allergic stimulation. To examine the role of NF-kB activation in allergic inflammation we generated transgenic mouse lines that allowed for the inducible stimulation of NF-kB in airway epithelial cells. After allergic sensitization with ovalbumin and alum, mice were challenged daily with ovalbumin aerosols and NF-kB was activated in airway epithelium by administration of doxycycline. Enhancement of airway epithelial NF-kB expression alone did not lead to increased airway responsiveness to methacholine. However induction of epithelial NF-kB during allergic inflammation caused airway hyperresponsiveness, increased airway neutrophilic and lymphocytic inflammation and goblet cell hyperplasia. Accompanying the exaggerated inflammation was an increase in the cytokines, G-CSF, IL-15, and KC. Interestingly, the counter regulatory interleukin, IL-10, was suppressed by NF-kB activation. The epithelial NF-kB dependent modulation of these cytokines provides a plausible explanation for the increased inflammation seen with overexpression of NF-kB. Modulation of airway epithelial NF-kB activation enhances the airway hyperresponsiveness and mucus secretion found in the mouse lung during allergic inflammation. NF-kB represents a potential target for pharmacologic intervention in human asthma. PMID:19995280

  10. C5 Modulates Airway Hyperreactivity and Pulmonary Eosinophilia during Enhanced Respiratory Syncytial Virus Disease by Decreasing C3a Receptor Expression▿

    PubMed Central

    Melendi, Guillermina A.; Hoffman, Scott J.; Karron, Ruth A.; Irusta, Pablo M.; Laham, Federico R.; Humbles, Alison; Schofield, Brian; Pan, Chien-Hsiung; Rabold, Richard; Thumar, Bhagvanji; Thumar, Adeep; Gerard, Norma P.; Mitzner, Wayne; Barnum, Scott R.; Gerard, Craig; Kleeberger, Steven R.; Polack, Fernando P.

    2007-01-01

    Enhanced respiratory syncytial virus disease, a serious pulmonary disorder that affected recipients of an inactivated vaccine against respiratory syncytial virus in the 1960s, has delayed the development of vaccines against the virus. The enhanced disease was characterized by immune complex-mediated airway hyperreactivity and a severe pneumonia associated with pulmonary eosinophilia. In this paper, we show that complement factors contribute to enhanced-disease phenotypes. Mice with a targeted disruption of complement component C5 affected by the enhanced disease displayed enhanced airway reactivity, lung eosinophilia, and mucus production compared to wild-type mice and C5-deficient mice reconstituted with C5. C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents. Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production. These results indicate that C5 plays a crucial role in modulating the enhanced-disease phenotype, by affecting expression of C3aR in the lungs. These findings reveal a novel autoregulatory mechanism for the complement cascade that affects the innate and adaptive immune responses. PMID:17079327

  11. PULMONARY HYPERRESPONSIVENESS FOLLOWING DERMAL EXPOSURE TO SELECTED DIISOCYANATES

    EPA Science Inventory

    PULMONARY HYPERRESPONSIVENESS FOLLOWING DERMAL EXPOSURE TO SELECTED DIISOCYANATES

    M.J.K. Selgrade, E.H. Boykin, N.H. Coates, D.L. Doerfler, S.H. Gavett
    Experimental Toxicology Div., National Health and Environmental Research Laboratory, Office of Research and Developmen...

  12. PULMONARY HYPERRESPONSIVENESS FOLLOWING DERMAL EXPOSURE TO SELECTED DIISOCYANATES

    EPA Science Inventory

    PULMONARY HYPERRESPONSIVENESS FOLLOWING DERMAL EXPOSURE TO SELECTED DIISOCYANATES

    M.J.K. Selgrade, E.H. Boykin, N.H. Coates, D.L. Doerfler, S.H. Gavett
    Experimental Toxicology Div., National Health and Environmental Research Laboratory, Office of Research and Developmen...

  13. Leukocytic cell sources of airway tissue kallikrein

    PubMed Central

    Lauredo, Isabel T.; Forteza, Rosanna M.; Botvinnikova, Yelena; Abraham, William M.

    2008-01-01

    Lung tissue kallikrein (TK) is a serine proteinase that putatively plays a role in the pathophysiology of asthma by generating kallidin and bradykinin, mediators that contribute to airway hyperresponsiveness. In previous studies we observed biphasic increases in TK activity in bronchoalveolar lavage fluid following airway allergen challenge in allergic sheep. Although glandular TK is likely a major source of the initial increase in TK, the sources of the late increases in TK that are associated with the development of airway hyperresponsiveness may be dependent on activated resident and recruited inflammatory cells including alveolar macrophages (AMs) and neutrophils (PMNs). These cells increase concomitantly with the late increases in TK activity. To test this hypothesis, we obtained AMs from bronchoalveolar lavage fluid and PMNs and monocytes (precursors of AMs) from sheep blood and determined whether these cells contained TK and whether these same cells could release TK upon activation. Using confocal microscopy, immunocytochemical techniques, and enzyme activity assays, we found that all three cell types contained and secreted TK. All three cell types demonstrated basal release of TK, which could be increased after stimulation with zymosan. In addition, PMNs also released TK in the presence of phorbol ester, suggesting multiple secretory pathways in these cells. Further-more, we showed that human monocytes also contain and secrete TK. We conclude that in the airways, monocytes, PMNs, and AMs may contribute to increased TK activity. Knowing the sources of TK in the airways could be important in understanding the mechanisms of inflammation that contribute to the pathophysiology of asthma and may help in the development of new therapies to control the disease. PMID:14660481

  14. Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration

    SciTech Connect

    Liu, Wenrui; Kong, Hui; Zeng, Xiaoning; Wang, Jingjing; Wang, Zailiang; Yan, Xiaopei; Wang, Yanli; Xie, Weiping Wang, Hong

    2015-08-15

    Chronic airway diseases are characterized by airway remodeling which is attributed partly to the proliferation and migration of airway smooth muscle cells (ASMCs). ATP-sensitive potassium (K{sub ATP}) channels have been identified in ASMCs. Mount evidence has suggested that K{sub ATP} channel openers can reduce airway hyperresponsiveness and alleviate airway remodeling. Opening K{sup +} channels triggers K{sup +} efflux, which leading to membrane hyperpolarization, preventing Ca{sup 2+}entry through closing voltage-operated Ca{sup 2+} channels. Intracellular Ca{sup 2+} is the most important regulator of muscle contraction, cell proliferation and migration. K{sup +} efflux decreases Ca{sup 2+} influx, which consequently influences ASMCs proliferation and migration. As a K{sub ATP} channel opener, iptakalim (Ipt) has been reported to restrain the proliferation of pulmonary arterial smooth muscle cells (PASMCs) involved in vascular remodeling, while little is known about its impact on ASMCs. The present study was designed to investigate the effects of Ipt on human ASMCs and the mechanisms underlying. Results obtained from cell counting kit-8 (CCK-8), flow cytometry and 5-ethynyl-2′-deoxyuridine (EdU) incorporation showed that Ipt significantly inhibited platelet-derived growth factor (PDGF)-BB-induced ASMCs proliferation. ASMCs migration induced by PDGF-BB was also suppressed by Ipt in transwell migration and scratch assay. Besides, the phosphorylation of Ca{sup 2+}/calmodulin-dependent kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), protein kinase B (Akt), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were as well alleviated by Ipt administration. Furthermore, we found that the inhibition of Ipt on the PDGF-BB-induced proliferation and migration in human ASMCs was blocked by glibenclamide (Gli), a selective K{sub ATP} channel antagonist. These findings provide a strong evidence to support that Ipt

  15. Asthma, airway inflammation and treatment in elite athletes.

    PubMed

    Helenius, Ilkka; Lumme, Aki; Haahtela, Tari

    2005-01-01

    Highly trained athletes are repeatedly and strongly exposed to cold air during winter training and to many inhalant irritants and allergens all year round. Asthma occurs most commonly in athletes engaging in endurance events such as cross-country skiing, swimming, or long-distance running. As well as the type of training, a major risk factor is atopic disposition. A mixed type of eosinophilic and neutrophilic airway inflammation has been shown to affect elite swimmers, ice-hockey players, and cross-country skiers. The inflammation may represent a form of repeated thermal, mechanical, or osmotic airway trauma resulting in a healing or remodelling process. Elite athletes commonly use antiasthma drugs to treat exercise-induced bronchial symptoms. Only a few controlled studies have been conducted on the effects of antiasthma drugs on asthma symptoms, bronchial hyperresponsiveness and airway inflammation in elite athletes. Inhaled beta(2)-adrenoceptor agonists are effective against exercise-induced bronchospasm. In contrast, airway inflammation, bronchial hyperresponsiveness and symptoms have responded poorly to inhaled corticosteroids and leukotriene antagonists. As discontinuing high-level exercise has proved effective in reducing eosinophilic airway inflammation, exercise or training should be restricted in athletes having troublesome symptoms and sputum eosinophilia. Switching training to less irritating environments should be considered whenever possible. It appears to be difficult to change the 'natural course' of asthma in athletes by anti-inflammatory treatment.

  16. Role of capsaicin-sensitive afferents and sensory neuropeptides in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity in the mouse.

    PubMed

    Elekes, Krisztián; Helyes, Zsuzsanna; Németh, József; Sándor, Katalin; Pozsgai, Gábor; Kereskai, László; Börzsei, Rita; Pintér, Erika; Szabó, Arpád; Szolcsányi, János

    2007-06-07

    Substance P (SP) and calcitonin gene-related peptide (CGRP) released from capsaicin-sensitive afferents induce neurogenic inflammation via NK(1), NK(2) and CGRP1 receptor activation. This study examines the role of capsaicin-sensitive fibres and sensory neuropeptides in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity with functional, morphological and biochemical techniques in mice. Carbachol-induced bronchoconstriction was measured with whole body plethysmography 24 h after intranasal lipopolysaccharide administration. SP and CGRP were determined with radioimmunoassay, myeloperoxidase activity with spectrophotometry, interleukin-1beta with ELISA and histopathological changes with semiquantitative scoring from lung samples. Treatments with resiniferatoxin for selective destruction of capsaicin-sensitive afferents, NK(1) antagonist SR 140333, NK(2) antagonist SR 48968, their combination, or CGRP1 receptor antagonist CGRP(8-37) were performed. Lipopolysaccharide significantly increased lung SP and CGRP concentrations, which was prevented by resiniferatoxin pretreatment. Resiniferatoxin-desensitization markedly enhanced inflammation, but decreased bronchoconstriction. CGRP(8-37) or combination of SR 140333 and SR 48968 diminished neutrophil accumulation, MPO levels and IL-1beta production, airway hyperresponsiveness was inhibited only by SR 48968. This is the first evidence that capsaicin-sensitive afferents exert a protective role in endotoxin-induced airway inflammation, but contribute to increased bronchoconstriction. Activation of CGRP1 receptors or NK(1)+NK(2) receptors participate in granulocyte accumulation, but NK(2) receptors play predominant role in enhanced airway resistance.

  17. KyoT2 downregulates airway remodeling in asthma.

    PubMed

    Hu, Mei; Ou-Yang, Hai-Feng; Han, Xing-Peng; Ti, Xin-Yu; Wu, Chang-Gui

    2015-01-01

    The typical pathological features of asthma are airway remodeling and airway hyperresponsiveness (AHR). KyoT2, a negative modulator of Notch signaling, has been linked to asthma in several previous studies. However, whether KyoT2 is involved in the regulation of airway remodeling or the modulation of airway resistance in asthma is unclear. In this study, we aimed to evaluate the therapeutic potential of KyoT2 in preventing asthma-associated airway remodeling and AHR. BALB/c mice were used to generate a mouse model of asthma. Additionally, the expression of Hes1 and Notch1 in airway was analyzed using Immunofluorescence examination. The asthmatic mice were intranasally administered adenovirus expressing KyoT2 and were compared to control groups. Furthermore, subepithelial fibrosis and other airway remodeling features were analyzed using hematoxylin and eosin staining, Van Gieson's staining and Masson's trichrome staining. AHR was also evaluated. This study revealed that KyoT2 downregulated the expression of Hes1, repressed airway remodeling, and alleviated AHR in asthmatic mice. It is reasonable to assume that KyoT2 downregulates airway remodeling and resistance in asthmatic mice through a Hes1-dependent mechanism. Therefore, KyoT2 is a potential clinical treatment strategy for asthma.

  18. Airway mucus hypersecretion in asthma: an undervalued pathology?

    PubMed

    Rogers, Duncan F

    2004-06-01

    Airway mucus hypersecretion is a feature of many patients with asthma. It is indicative of poor asthma control and contributes to morbidity and mortality. Excess mucus not only obstructs airways but also contributes to airway hyperresponsiveness. Furthermore, asthma might have a specific mucus hypersecretory phenotype. Goblet cell hyperplasia and submucosal gland hypertrophy are shared with other hypersecretory diseases, such as chronic obstructive pulmonary disease; however, some features are different, including mucus plugging, mucus "tethering" to goblet cells, plasma exudation, and increased amounts of a low charge glycoform of mucin (MUC)5B and the presence of MUC2 in secretions. Experimentally, most of the inflammatory mediators and neural mechanisms implicated in the pathophysiology of asthma impact upon the mucus hypersecretory phenotype. There is currently huge research interest in identifying targets involved in inducing mucus abnormalities, which should lead to the rational design of anti-hypersecretory drugs for treatment of airway mucus hypersecretion in asthma.

  19. Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity.

    PubMed Central

    DiCosmo, B F; Geba, G P; Picarella, D; Elias, J A; Rankin, J A; Stripp, B R; Whitsett, J A; Flavell, R A

    1994-01-01

    We produced transgenic mice which overexpress human IL-6 in the airway epithelial cells. Transgenic mice develop a mononuclear cell infiltrate adjacent to large and mid-sized airways. Immunohistochemistry reveals these cells to be predominantly CD4+ cells, MHC class II+ cells, and B220+ cells. Transgenic mice and nontransgenic mice had similar baseline respiratory system resistance (0.47 +/- 0.06 vs 0.43 +/- 0.04 cmH2O/ml per s at 9 wk of age, P = NS and 0.45 +/- 0.07 vs 0.43 +/- 0.09 cmH2O/ml per s at 17 wk of age, P = NS). Transgenic mice, however, required a significantly higher log dose of methacholine to produce a 100% increase in respiratory system resistance as compared with non-transgenic littermates (1.34 +/- 0.24 vs 0.34 +/- 0.05 mg/ml, P < or = 0.01). We conclude that the expression of human IL-6 in the airways of transgenic mice results in a CD4+, MHC class II+, B220+ lymphocytic infiltrate surrounding large and mid-sized airways that does not alter basal respiratory resistance, but does diminish airway reactivity to methacholine. These findings demonstrate an uncoupling of IL-6-induced airway lymphocytic inflammation and airway hyperresponsiveness and suggest that some forms of airway inflammation may serve to restore altered airway physiology. Images PMID:7962549

  20. The effect of 15-HPETE on airway responsiveness and pulmonary cell recruitment in rabbits

    PubMed Central

    Riccio, M M; Matsumoto, T; Adcock, J J; Douglas, G J; Spina, D; Page, C P

    1997-01-01

    In the present study we have investigated the effect of 15-hydroperoxyeicosatetraenoic acid (15-HPETE) and 15-hydroxyeicosatetraenoic acid (15-HETE) on airway responsiveness to inhaled histamine in rabbits in vivo. 15-HPETE increased airway responsiveness to histamine 24 h after tracheal instillation and this was associated with a cellular infiltration consisting mainly of neutrophils, as measured by bronchoalveolar lavage. The airway hyperresponsiveness induced by 15-HPETE was still present 72 h after tracheal instillation of 15-HPETE, but had returned to baseline values one week post challenge. The number of neutrophils in bronchoalveolar lavage remained significantly elevated compared to pre-challenge levels. In contrast to 15-HPETE, the major metabolite 15-HETE, failed to alter airway hyperresponsiveness to histamine despite the recruitment of neutrophils into the lung, suggesting that the effect of 15-HPETE was not secondary to the generation of this metabolite nor dependent on the influx of neutrophils. Both capsaicin and atropine but not the peripherally acting μ-opioid receptor agonist, BW443C (H-Tyr-D-Arg-Gly-Phe(4-NO2)-Pro-NH4), attenuated 15-HPETE-induced hyperresponsiveness. The increased cellular infiltration induced by 15-HPETE was only attenuated by capsaicin. The results of the present study suggest that the release of 15-HPETE into the airways could contribute to sensitization of afferent nerve endings analogous to the hyperalgesia induced by this mediator in skin. PMID:9313932

  1. Increased oxidative DNA damage and decreased expression of base excision repair proteins in airway epithelial cells of women who cook with biomass fuels.

    PubMed

    Mukherjee, Bidisha; Bindhani, Banani; Saha, Hirak; Ray, Manas Ranjan

    2014-09-01

    To investigate whether biomass burning causes oxidative DNA damage and alters the expression of DNA base excision repair (BER) proteins in airway cells, sputum samples were collected from 80 premenopausal rural biomass-users and 70 age-matched control women who cooked with liquefied petroleum gas. Compared with control the airway cells of biomass-users showed increased DNA damage in alkaline comet assay. Biomass-users showed higher percentage of cells expressing oxidative DNA damage marker 8-oxoguanine and lower percentages of BER proteins OGG1 and APE1 by immunocytochemical staining. Reactive oxygen species (ROS) generation was doubled and level of superoxide dismutase was depleted significantly among biomass-users. The concentrations of particulate matters were higher in biomass-using households which positively correlated with ROS generation and negatively with BER proteins expressions. ROS generation was positively correlated with 8-oxoguanine and negatively with BER proteins suggesting cooking with biomass is a risk for genotoxicity among rural women in their child-bearing age. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Central Role of Cellular Senescence in TSLP-Induced Airway Remodeling in Asthma

    PubMed Central

    Wu, Jinxiang; Dong, Fangzheng; Wang, Rui-An; Wang, Junfei; Zhao, Jiping; Yang, Mengmeng; Gong, Wenbin; Cui, Rutao; Dong, Liang

    2013-01-01

    Background Airway remodeling is a repair process that occurs after injury resulting in increased airway hyper-responsiveness in asthma. Thymic stromal lymphopoietin (TSLP), a vital cytokine, plays a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. TSLP is also a critical factor in airway remodeling in asthma. Objectives To examine the role of TSLP-induced cellular senescence in airway remodeling of asthma in vitro and in vivo. Methods Cellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis. Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Senescence-Associated β-galactosidase (SA-β-Gal) staining, and BrdU assays were used to detect cellular senescence. In addition, the Stat3-targeted inhibitor, WP1066, was evaluated in an asthma mouse model to determine if inhibiting cellular senescence influences airway remodeling in asthma. Results Activation of cellular senescence as evidenced by checkpoint activation and cell cycle arrest was detected in airway epithelia samples from patients with asthma. Furthermore, TSLP-induced cellular senescence was required for airway remodeling in vitro. In addition, a mouse asthma model indicates that inhibiting cellular senescence blocks airway remodeling and relieves airway resistance. Conclusion TSLP stimulation can induce cellular senescence during airway remodeling in asthma. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling. PMID:24167583

  3. Silencing nociceptor neurons reduces allergic airway inflammation

    PubMed Central

    Talbot, Sébastien; Abdulnour, Raja-Elie E.; Burkett, Patrick R.; Lee, Seungkyu; Cronin, Shane J.F.; Pascal, Maud A.; Laedermann, Cedric; Foster, Simmie L.; Tran, Johnathan V.; Lai, Nicole; Chiu, Isaac M.; Ghasemlou, Nader; DiBiase, Matthew; Roberson, David; Von Hehn, Christian; Agac, Busranour; Haworth, Oliver; Seki, Hiroyuki; Penninger, Josef M.; Kuchroo, Vijay K.; Bean, Bruce P.; Levy, Bruce D.; Woolf, Clifford J.

    2015-01-01

    Summary Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8+ sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large pore ion channels to specifically block nociceptors, substantially reduced ovalbumin or house dust mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4+ and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma. PMID:26119026

  4. Caveolin-1 knockout mice exhibit airway hyperreactivity

    PubMed Central

    Aravamudan, Bharathi; VanOosten, Sarah K.; Meuchel, Lucas W.; Vohra, Pawan; Thompson, Michael; Sieck, Gary C.; Prakash, Y. S.

    2012-01-01

    Caveolae are flask-shaped plasma membrane invaginations expressing the scaffolding caveolin proteins. Although caveolins have been found in endothelium and epithelium (where they regulate nitric oxide synthase activity), their role in smooth muscle is still under investigation. We and others have previously shown that caveolae of human airway smooth muscle (ASM), which express caveolin-1, contain Ca2+ and force regulatory proteins and are involved in mediating the effects of inflammatory cytokines such as TNF-α on intracellular Ca2+ concentration responses to agonist. Accordingly, we tested the hypothesis that in vivo, absence of caveolin-1 leads to reduced airway hyperresponsiveness, using a knockout (KO) (Cav1 KO) mouse and an ovalbumin-sensitized/challenged (OVA) model of allergic airway hyperresponsiveness. Surprisingly, airway responsiveness to methacholine, tested by use of a FlexiVent system, was increased in Cav1 KO control (CTL) as well as KO OVA mice, which could not be explained by a blunted immune response to OVA. In ASM of wild-type (WT) OVA mice, expression of caveolin-1, the caveolar adapter proteins cavins 1–3, and caveolae-associated Ca2+ and force regulatory proteins such as Orai1 and RhoA were all increased, effects absent in Cav1 KO CTL and OVA mice. However, as with WT OVA, both CTL and OVA Cav1 KO airways showed signs of enhanced remodeling, with high expression of proliferation markers and increased collagen. Separately, epithelial cells from airways of all three groups displayed lower endothelial but higher inducible nitric oxide synthase and arginase expression. Arginase activity was also increased in these three groups, and the inhibitor nor-NOHA (N-omega-nor-l-arginine) enhanced sensitivity of isolated tracheal rings to ACh, especially in Cav1 KO mice. On the basis of these data disproving our original hypothesis, we conclude that caveolin-1 has complex effects on ASM vs. epithelium, resulting in airway hyperreactivity in vivo mediated

  5. The Impact of Vitamin D on Asthmatic Human Airway Smooth Muscle

    PubMed Central

    Hall, Sannette C.; Fischer, Kimberly D.; Agrawal, Devendra K.

    2016-01-01

    Asthma is a chronic heterogeneous disorder, which involves airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. The airway smooth muscle (ASM) bundle regulates the broncho-motor tone and plays a critical role in AHR as well as orchestrating inflammation. Vitamin D deficiency has been linked to increased severity and exacerbations of symptoms in asthmatic patients. It has been shown to modulate both immune and structural cells, including ASM cells, in inflammatory diseases. Given that current asthma therapies have not been successful in reversing airway remodeling, vitamin D supplementation as a potential therapeutic option has gained a great deal of attention. Here, we highlight the potential immunomodulatory properties of vitamin D in regulating ASM function and airway inflammation in bronchial asthma. PMID:26634624

  6. Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility

    PubMed Central

    Cook, Daniel P.; Rector, Michael V.; Bouzek, Drake C.; Michalski, Andrew S.; Gansemer, Nicholas D.; Reznikov, Leah R.; Li, Xiaopeng; Stroik, Mallory R.; Ostedgaard, Lynda S.; Abou Alaiwa, Mahmoud H.; Thompson, Michael A.; Prakash, Y. S.; Krishnan, Ramaswamy; Meyerholz, David K.; Seow, Chun Y.

    2016-01-01

    Rationale: An asthma-like airway phenotype has been described in people with cystic fibrosis (CF). Whether these findings are directly caused by loss of CF transmembrane conductance regulator (CFTR) function or secondary to chronic airway infection and/or inflammation has been difficult to determine. Objectives: Airway contractility is primarily determined by airway smooth muscle. We tested the hypothesis that CFTR is expressed in airway smooth muscle and directly affects airway smooth muscle contractility. Methods: Newborn pigs, both wild type and with CF (before the onset of airway infection and inflammation), were used in this study. High-resolution immunofluorescence was used to identify the subcellular localization of CFTR in airway smooth muscle. Airway smooth muscle function was determined with tissue myography, intracellular calcium measurements, and regulatory myosin light chain phosphorylation status. Precision-cut lung slices were used to investigate the therapeutic potential of CFTR modulation on airway reactivity. Measurements and Main Results: We found that CFTR localizes to the sarcoplasmic reticulum compartment of airway smooth muscle and regulates airway smooth muscle tone. Loss of CFTR function led to delayed calcium reuptake following cholinergic stimulation and increased myosin light chain phosphorylation. CFTR potentiation with ivacaftor decreased airway reactivity in precision-cut lung slices following cholinergic stimulation. Conclusions: Loss of CFTR alters porcine airway smooth muscle function and may contribute to the airflow obstruction phenotype observed in human CF. Airway smooth muscle CFTR may represent a therapeutic target in CF and other diseases of airway narrowing. PMID:26488271

  7. FSTL1 PROMOTES ASTHMATIC AIRWAY REMODELING BY INDUCING ONCOSTATIN M

    PubMed Central

    Miller, Marina; Beppu, Andrew; Rosenthal, Peter; Pham, Alexa; Das, Sudipta; Karta, Maya; Song, Dae Jin; Vuong, Christine; Doherty, Taylor; Croft, Michael; Zuraw, Bruce; Zhang, Xu; Gao, Xiang; Aceves, Seema; Chouiali, Fazila; Hamid, Qutayba; Broide, David H.

    2016-01-01

    Chronic asthma is associated with airway remodeling and decline in lung function. Here we show that follistatin like 1 (Fstl1), a mediator not previously associated with asthma is highly expressed by macrophages in the lungs of severe human asthmatics. Chronic allergen challenged Lys-Cretg/Fstl1Δ/Δ mice in whom Fstl1 is inactivated in macrophages/myeloid cells had significantly reduced airway remodeling and reduced levels of oncostatin M (OSM) a cytokine previously not known to be regulated by Fstl1. The importance of the Fstl1 induction of OSM to airway remodeling was demonstrated in murine studies in which administration of Fstl1 induced airway remodeling and increased OSM, while administration of an anti-OSM antibody blocked the effect of Fstl1 on inducing airway remodeling, eosinophilic airway inflammation, and airway hyperresponsiveness all cardinal features of asthma. Overall, these studies demonstrate that the Fstl1/oncostatin M pathway may be a novel pathway to inhibit airway remodeling in severe human asthma. PMID:26355153

  8. Cyclic nitroxide radicals attenuate inflammation and Hyper-responsiveness in a mouse model of allergic asthma.

    PubMed

    Assayag, Miri; Goldstein, Sara; Samuni, Amram; Berkman, Neville

    2015-10-01

    The effects of stable cyclic nitroxide radicals have been extensively investigated both in vivo and in vitro demonstrating anti-inflammatory, radioprotective, anti-mutagenic, age-retardant, hypotensive, anti-cancer and anti-teratogenic activities. Yet, these stable radicals have not been evaluated in asthma and other airway inflammatory disorders. The present study investigated the effect of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (TPL) and 3-carbamoyl-proxyl (3-CP) in a mouse model of ovalbumin (OVA)-induced allergic asthma. Both 3-CP and TPL were non-toxic when administered either orally (1% w/w nitroxide-containing chow) or via intraperitoneal (IP) injection (∼300 mg/kg). Feeding the mice orally demonstrated that 3-CP was more effective than TPL in reducing inflammatory cell recruitment into the airway and in suppressing airway hyper-responsiveness (AHR) in OVA-challenged mice. To characterize the optimal time-window of intervention and mode of drug administration, 3-CP was given orally during allergen sensitization, during allergen challenge or during both sensitization and challenge stages, and via IP injection or intranasal instillation for 3 days during the challenge period. 3-CP given via all modes of delivery markedly inhibited OVA-induced airway inflammation, expression of cytokines, AHR and protein nitration of the lung tissue. Oral administration during the entire experiment was the most efficient delivery of 3-CP and was more effective than dexamethasone a potent corticosteroid used for asthma treatment. Under a similar administration regimen (IP injection before the OVA challenge), the effect of 3-CP was similar to that of dexamethasone and even greater on AHR and protein nitration. The protective effect of the nitroxides, which preferentially react with free radicals, in suppressing the increase of main asthmatic inflammatory markers substantiate the key role played by reactive oxygen and nitrogen species in the molecular mechanism of

  9. The Effect of Omega-3 Fatty Acids on Bronchial Hyperresponsiveness, Sputum Eosinophilia, and Mast Cell Mediators in Asthma

    PubMed Central

    Bood, Johan; Alkhabaz, Ahmad; Balgoma, David; Otis, Joceline; Delin, Ingrid; Dahlén, Barbro; Wheelock, Craig E.; Nair, Parameswaran; Dahlén, Sven-Erik; O’Byrne, Paul M.

    2015-01-01

    BACKGROUND: Omega-3 fatty acid supplements have been reported to inhibit exercise-induced bronchoconstriction (EIB). It has not been determined whether omega-3 supplements inhibit airway sensitivity to inhaled mannitol, a test for bronchial hyperresponsiveness (BHR) and model for EIB in people with mild to moderate asthma. METHODS: In a double-blind, crossover trial, subjects with asthma who had BHR to inhaled mannitol (n = 23; 14 men; mean age, 28 years; one-half taking regular inhaled corticosteroids) were randomized to omega-3 supplements (4.0 g/d eicosapentaenoic acid and 2.0 g/d docosahexaenoic acid) or matching placebo for 3 weeks separated by a 3-week washout. The primary outcome was the provoking dose of mannitol (mg) to cause a 15% fall in FEV1 (PD15). Secondary outcomes were sputum eosinophil count, spirometry, Asthma Control Questionnaire (ACQ) score, serum triacylglyceride level, and lipid mediator profile in urine and serum. RESULTS: PD15 (geometric mean, 95% CI) to mannitol following supplementation with omega-3s (78 mg, 51-119 mg) was not different from placebo (88 mg, 56-139 mg, P = .5). There were no changes in sputum eosinophils (mean ± SD) in a subgroup of 11 subjects (omega-3, 8.4% ± 8.2%; placebo, 7.8% ± 11.8%; P = .9). At the end of each treatment period, there were no differences in FEV1 % predicted (omega-3, 85% ± 13%; placebo, 84% ± 11%; P = .9) or ACQ score (omega-3, 1.1% ± 0.5%; placebo, 1.1% ± 0.5%; P = .9) (n = 23). Omega-3s caused significant lowering of blood triglyceride levels and expected shifts in serum fatty acids and eicosanoid metabolites, confirming adherence to the supplements; however, no changes were observed in urinary mast cell mediators. CONCLUSIONS: Three weeks of omega-3 supplements does not improve BHR to mannitol, decrease sputum eosinophil counts, or inhibit urinary excretion of mast cell mediators in people with mild to moderate asthma, indicating that dietary omega-3 supplementation is not useful in the

  10. The effect of omega-3 fatty acids on bronchial hyperresponsiveness, sputum eosinophilia, and mast cell mediators in asthma.

    PubMed

    Brannan, John D; Bood, Johan; Alkhabaz, Ahmad; Balgoma, David; Otis, Joceline; Delin, Ingrid; Dahlén, Barbro; Wheelock, Craig E; Nair, Parameswaran; Dahlén, Sven-Erik; O'Byrne, Paul M

    2015-02-01

    Omega-3 fatty acid supplements have been reported to inhibit exercise-induced bronchoconstriction (EIB). It has not been determined whether omega-3 supplements inhibit airway sensitivity to inhaled mannitol, a test for bronchial hyperresponsiveness (BHR) and model for EIB in people with mild to moderate asthma. In a double-blind, crossover trial, subjects with asthma who had BHR to inhaled mannitol (n = 23; 14 men; mean age, 28 years; one-half taking regular inhaled corticosteroids) were randomized to omega-3 supplements (4.0 g/d eicosapentaenoic acid and 2.0 g/d docosahexaenoic acid) or matching placebo for 3 weeks separated by a 3-week washout. The primary outcome was the provoking dose of mannitol (mg) to cause a 15% fall in FEV1 (PD15). Secondary outcomes were sputum eosinophil count, spirometry, Asthma Control Questionnaire (ACQ) score, serum triacylglyceride level, and lipid mediator profile in urine and serum. PD15 (geometric mean, 95% CI) to mannitol following supplementation with omega-3s (78 mg, 51-119 mg) was not different from placebo (88 mg, 56-139 mg, P = .5). There were no changes in sputum eosinophils (mean ± SD) in a subgroup of 11 subjects (omega-3, 8.4% ± 8.2%; placebo, 7.8% ± 11.8%; P = .9). At the end of each treatment period, there were no differences in FEV1 % predicted (omega-3, 85% ± 13%; placebo, 84% ± 11%; P = .9) or ACQ score (omega-3, 1.1% ± 0.5%; placebo, 1.1% ± 0.5%; P = .9) (n = 23). Omega-3s caused significant lowering of blood triglyceride levels and expected shifts in serum fatty acids and eicosanoid metabolites, confirming adherence to the supplements; however, no changes were observed in urinary mast cell mediators. Three weeks of omega-3 supplements does not improve BHR to mannitol, decrease sputum eosinophil counts, or inhibit urinary excretion of mast cell mediators in people with mild to moderate asthma, indicating that dietary omega-3 supplementation is not useful in the short-term treatment of asthma. Clinical

  11. Preventive Intra Oral Treatment of Sea Cucumber Ameliorate OVA-Induced Allergic Airway Inflammation.

    PubMed

    Lee, Da-In; Park, Mi-Kyung; Kang, Shin Ae; Choi, Jun-Ho; Kang, Seok-Jung; Lee, Jeong-Yeol; Yu, Hak Sun

    2016-01-01

    Sea cucumber extracts have potent biological effects, including anti-viral, anti-cancer, antibacterial, anti-oxidant, and anti-inflammation effects. To understand their anti-asthma effects, we induced allergic airway inflammation in mice after 7 oral administrations of the extract. The hyper-responsiveness value in mice with ovalbumin (OVA)-alum-induced asthma after oral injection of sea cucumber extracts was significantly lower than that in the OVA-alum-induced asthma group. In addition, the number of eosinophils in the lungs of asthma-induced mice pre-treated with sea cucumber extract was significantly decreased compared to that of PBS pre-treated mice. Additionally, CD4[Formula: see text]CD25[Formula: see text]Foxp3[Formula: see text]T (regulatory T; Treg) cells significantly increased in mesenteric lymph nodes after 7 administrations of the extract. These results suggest that sea cucumber extract can ameliorate allergic airway inflammation via Treg cell activation and recruitment to the lung.

  12. Matrix Metalloproteinase-1 Activation Contributes to Airway Smooth Muscle Growth and Asthma Severity.

    PubMed

    Naveed, Shams-Un-Nisa; Clements, Debbie; Jackson, David J; Philp, Christopher; Billington, Charlotte K; Soomro, Irshad; Reynolds, Catherine; Harrison, Timothy W; Johnston, Sebastian L; Shaw, Dominick E; Johnson, Simon R

    2017-04-15

    Matrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of people with asthma. To investigate whether MMP-1 could be activated by mast cells and increase asthma severity. Patients with stable asthma and healthy control subjects underwent spirometry, methacholine challenge, and bronchoscopy, and their airway smooth muscle cells were grown in culture. A second asthma group and control subjects had symptom scores, spirometry, and bronchoalveolar lavage before and after rhinovirus-induced asthma exacerbations. Extracellular matrix was prepared from decellularized airway smooth muscle cultures. MMP-1 protein and activity were assessed. Airway smooth muscle cells generated pro-MMP-1, which was proteolytically activated by mast cell tryptase. Airway smooth muscle treated with activated mast cell supernatants produced extracellular matrix, which enhanced subsequent airway smooth muscle growth by 1.5-fold (P < 0.05), which was dependent on MMP-1 activation. In asthma, airway pro-MMP-1 was 5.4-fold higher than control subjects (P = 0.002). Mast cell numbers were associated with airway smooth muscle proliferation and MMP-1 protein associated with bronchial hyperresponsiveness. During exacerbations, MMP-1 activity increased and was associated with fall in FEV1 and worsening asthma symptoms. MMP-1 is activated by mast cell tryptase resulting in a proproliferative extracellular matrix. In asthma, mast cells are associated with airway smooth muscle growth, MMP-1 levels are associated with bronchial hyperresponsiveness, and MMP-1 activation are associated with exacerbation severity. Our findings suggest that airway smooth muscle/mast cell interactions contribute to asthma severity by transiently increasing MMP activation, airway smooth muscle growth, and airway responsiveness.

  13. Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodeling, and airways obstruction.

    PubMed Central

    Tang, W; Geba, G P; Zheng, T; Ray, P; Homer, R J; Kuhn, C; Flavell, R A; Elias, J A

    1996-01-01

    Interleukin-11 is a pleotropic cytokine produced by lung stromal cells in response to respiratory viruses, cytokines, and histamine. To further define its potential effector functions, the Clara cell 10-kD protein promoter was used to express IL-11 and the airways of the resulting transgene mice were characterized. In contrast to transgene (-) littermates, the airways of IL-11 transgene (+) animals manifest nodular peribronchiolar mononuclear cell infiltrates and impressive airways remodeling with subepithelial fibrosis. The inflammatory foci contained large numbers of B220(+) and MHC Class II(+) cells and lesser numbers of CD3(+), CD4(+), and CD8(+) cells. The fibrotic response contained increased amounts of types III and I collagen, increased numbers of alpha smooth muscle actin and desmin-containing cells and a spectrum of stromal elements including fibroblasts, myofibroblasts, and smooth muscle cells. Physiologic evaluation also demonstrated that 2-mo-old transgene (+) mice had increased airways resistance and non-specific airways hyperresponsiveness to methacholine when compared with their transgene (-) littermates. These studies demonstrate that the targeted expression of IL-11 in the mouse airway causes a B and T cell-predominant inflammatory response, airway remodeling with increased types III and I collagen, the local accumulation of fibroblasts, myofibroblasts, and myocytes, and obstructive physiologic dysregulation. IL-11 may play an important role in the inflammatory and fibrotic responses in viral and/or nonviral human airway disorders. PMID:8981933

  14. Increase in exhaled nitric oxide is associated with bronchial hyperresponsiveness among apprentices.

    PubMed

    Tossa, Paul; Paris, Christophe; Zmirou-Navier, Denis; Demange, Valérie; Acouetey, Dovi-Stéphanie; Michaely, Jean-Pierre; Bohadana, Abraham

    2010-09-15

    Airway inflammation is a hallmark of asthma. Several studies have validated the use of the fractional concentration of exhaled nitric oxide (Fe(NO)) as a surrogate marker of airway inflammation in asthma. We examined how the change in Fe(NO) levels, since the beginning of occupational exposure, could be associated with the incidence of bronchial hyperresponsiveness (BHR) among baker, pastry maker, and hairdresser apprentices during their 2-year training. A standardized questionnaire was administered; skin prick tests for common and specific occupational allergens were done; methacholine challenge and measurement of Fe(NO) were performed 6, 12, and 15 months after the first examination. Of 441 apprentices initially included, 351 completed the study. The increase in Fe(NO), since the beginning of exposure, was associated with the incidence of BHR (odds ratio, 2.00 [95% confidence interval, 1.21-3.32] per unit increase in log parts per billion) both in atopic and nonatopic subjects. The average increase in Fe(NO) was similar in atopic and nonatopic subjects and was unrelated to past or current smoking habits, sex, or training track. Atopy in bakers/pastry makers and sensitization to alkaline persulfates in hairdressers were also independently associated with the incidence of BHR. BHR occurred sooner among bakers/pastry makers than among hairdressers, but its incidence leveled off later. Our results suggest that measurement of Fe(NO), a simple and reproducible test, could be useful in the screening of BHR in workers newly exposed to agents known to cause occupational asthma.

  15. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness.

    PubMed Central

    Casale, T B; Wood, D; Richerson, H B; Trapp, S; Metzger, W J; Zavala, D; Hunninghake, G W

    1987-01-01

    Using a sensitive single isotope enzymatic assay we measured bronchoalveolar lavage (BAL) fluid histamine in asymptomatic normal (nonallergic), allergic rhinitic, and allergic asthmatic subjects. Normal subjects were found to have little or no detectable amounts of histamine in BAL fluid (11 +/- 11 pg/ml), and few BAL fluid mast cells. In comparison, the allergic rhinitics and allergic asthmatics had much higher amounts of BAL fluid histamine (113 +/- 53 and 188 +/- 42 pg/ml, respectively), and a significantly greater number of BAL fluid mast cells. Furthermore, despite having equivalent baseline pulmonary function values, allergic asthmatics with BAL fluid histamine levels greater than 100 pg/ml required only 7 +/- 2 breath units of methacholine to induce a 20% drop in forced expiratory volume in 1 s (FEV1) (PD20FEV1) while asthmatics with BAL fluid histamine levels less than 100 pg/ml required 49 +/- 19 breath units (P less than 0.05). These data suggest that allergic asthmatics have ongoing lung mast cell degranulation that might contribute to the etiology of airway hyperresponsiveness. Images PMID:3549781

  16. Relationship between exhaled NO, respiratory symptoms, lung function, bronchial hyperresponsiveness, and blood eosinophilia in school children

    PubMed Central

    Steerenberg, P; Janssen, N; de Meer, G; Fischer, P; Nierkens, S; van Loveren, H; Opperhuizen, A; Brunekreef, B; van Amsterdam, J G C

    2003-01-01

    Methods: Levels of eNO in a sample of 450 children aged 7–12 years out of a total sample of 2504 school children living in different urban areas near motorways were determined. The aim of this cross-sectional study was to explore the relationship between eNO, impairment of lung function (PEF, FVC, FEV1 and MMEF), bronchial hyperresponsiveness (BHR), and blood eosinophilia in children with and without atopy as assessed by skin prick testing. Results: Regression analysis showed that wheezing and nasal discharge and conjunctivitis that had occurred during the previous 12 months were positively associated with eNO levels in atopic children (relative increase of 1.48 and 1.41, respectively; p<0.05) but not in non-atopic children. Similarly, BHR and the number of blood eosinophils per ml were positively associated with eNO levels in atopic children (relative increase of 1.55 and 2.29, respectively; p<0.05) but not in non-atopic children. The lung function indices PEF, FVC, FEV1 and MMEF were not associated with eNO levels. Conclusions: In addition to conventional lung function tests and symptom questionnaires, eNO is a suitable measure of airway inflammation and its application may reinforce the power of epidemiological surveys on respiratory health. PMID:12612304

  17. Chinese herbal medicine formula Gu-Ben-Fang-Xiao-Tang attenuates airway inflammation by modulating Th17/Treg balance in an ovalbumin-induced murine asthma model

    PubMed Central

    Ruan, Guiying; Tao, Baohong; Wang, Dongguo; Li, Yong; Wu, Jingyi; Yin, Genquan

    2016-01-01

    Gu-Ben-Fang-Xiao-Tang (GBFXT) is a traditional Chinese medicine formula consisting of 11 medicinal plants, which has been used in the treatment of asthma. The present study aimed to determine the protective effects and the underlying mechanisms of GBFXT on ovalbumin (OVA)-induced allergic inflammation in a mouse model of allergic asthma. A total of 50 mice were randomly assigned to the following five experimental groups: Normal, model, montelukast (2.6 mg/kg), 12 g/kg GBFXT and 36 g/kg GBFXT groups. Airway responsiveness was measured using the forced oscillation technique, while differential cell count in the bronchoalveolar lavage fluid (BALF) was measured by Wright-Giemsa staining. Histological assessment was performed by hematoxylin and eosin staining, while BALF levels of Th17/Treg cytokines were measured by enzyme-linked immunosorbent assay, and the proportions of Th17 and Treg cells were evaluated by flow cytometry. The results showed that GBFXT suppressed airway hyperresponsiveness during methacholine-induced constriction, reduced the percentage of leukocytes and eosinophils, and resulted in decreased absolute neutrophil infiltration in lung tissue. In addition, GBFXT treatment significantly decreased the IL-17A cytokine level and increased the IL-10 cytokine level in the BALF. Furthermore, GBFXT significantly suppressed Th17 cells and increased Treg cells in asthmatic mice. In conclusion, the current results demonstrated that GBFXT may effectively inhibit the progression of airway inflammation in allergic asthma, partially by modulating the Th17/Treg cell balance. PMID:27588063

  18. The effect of serine protease inhibitors on airway inflammation in a chronic allergen-induced asthma mouse model.

    PubMed

    Lin, Chih-Che; Lin, Li-Jen; Wang, Shulhn-Der; Chiang, Chung-Jen; Chao, Yun-Peng; Lin, Joseph; Kao, Shung-Te

    2014-01-01

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

  19. Structural and functional localization of airway effects from episodic exposure of infant monkeys to allergen and/or ozone

    SciTech Connect

    Joad, Jesse P. . E-mail: jesse.joad@ucdmc.ucdavis.edu; Kott, Kayleen S.; Bric, John M.; Peake, Janice L.; Plopper, Charles G.; Schelegle, Edward S.; Gershwin, Laurel J.; Pinkerton, Kent E.

    2006-08-01

    Both allergen and ozone exposure increase asthma symptoms and airway responsiveness in children. Little is known about how these inhalants may differentially modify airway responsiveness in large proximal as compared to small distal airways. We evaluated whether bronchi and respiratory bronchioles from infant monkeys exposed episodically to allergen and/or ozone differentially develop intrinsic hyperresponsiveness to methacholine and whether eosinophils and/or pulmonary neuroendocrine cells play a role. Infant monkeys were exposed episodically for 5 months to: (1) filtered air, (2) aerosolized house dust mite allergen, (3) ozone 0.5 ppm, or (4) house dust mite allergen + ozone. Studying the function/structure relationship of the same lung slices, we evaluated methacholine airway responsiveness and histology of bronchi and respiratory bronchioles. In bronchi, intrinsic responsiveness was increased by allergen exposure, an effect reduced by bombesin antagonist. In respiratory bronchioles, intrinsic airway responsiveness was increased by allergen + ozone exposure. Eosinophils were increased by allergen and allergen + ozone exposure in bronchi and by allergen exposure in respiratory bronchioles. In both airways, exposure to allergen + ozone resulted in fewer tissue eosinophils than did allergen exposure alone. In bronchi, but not in respiratory bronchioles, the number of eosinophils and neuroendocrine cells correlated with airway responsiveness. We conclude that episodically exposing infant monkeys to house dust mite allergen with or without ozone increased intrinsic airway responsiveness to methacholine in bronchi differently than in respiratory bronchioles. In bronchi, eosinophils and neuroendocrine cells may play a role in the development of airway hyperresponsiveness.

  20. Treatment with 8-OH-modified adenine (TLR7 ligand)-allergen conjugates decreases T helper type 2-oriented murine airway inflammation.

    PubMed

    Nencini, Francesca; Pratesi, Sara; Petroni, Giulia; Filì, Lucia; Cardilicchia, Elisa; Casini, Andrea; Occhiato, Ernesto Giovanni; Calosi, Laura; Bani, Daniele; Romagnani, Sergio; Maggi, Enrico; Parronchi, Paola; Vultaggio, Alessandra

    2015-08-01

    A strategy to improve allergen-specific immunotherapy is to employ new adjuvants stably linked to allergens. The study is addressed to evaluate the in vivo and in vitro effects of allergens [natural Dermatophagoides pteronyssinus 2 (nDer p 2) and ovalbumin (OVA)] chemically bound to an 8-OH-modified adenine. Humoral and cellular responses were analysed in allergen-sensitized and challenged mice by using conjugates (Conj) in a therapeutic setting. The in vitro activity of the conjugates on cytokine production induced by bone marrow dendritic cells and the co-culture system was also investigated. The nDer p 2-Conj treatment in nDer p 2-primed and challenged BALB/c mice reduced the numbers of eosinophils in bronchoalveolar lavage fluid and lung, airway allergen-driven interleukin-13 (IL-13) production in lung mononuclear cells and IgE, in comparison with nDer p 2-treated mice. The increase of IgG2a paralleled that of interferon-γ (IFN-γ) and IL-10 in allergen-stimulated spleen cells. Similar effects were elicited by treatment with OVA-Conj in an OVA-driven BALB/c model. The nDer p 2-Conj or OVA-Conj redirected memory T helper type 2 cells towards the production of IL-10 and IFN-γ also in C57BL/6 mice and when subcutaneously administered. Interleukin-10, IL-12 and IL-27 were produced in vitro by Conj-stimulated bone marrow dendritic cells, whereas IL-10 and IFN-γ were up-regulated in co-cultures of CD11c(+) and CD4(+) T cells from Conj-treated mice stimulated with allergen. Cytofluorometric analysis indicated that the Conj expanded IFN-γ- and IL-10- producing memory T cells. The Conj effects on IL-10(-/-) and IL-12(-/-) mice confirmed the role of IL-10 and IFN-γ in inducing a protective and balanced redirection the T helper type 2-mediated airway inflammation.

  1. Programmed Death Ligand 1 Promotes Early-Life Chlamydia Respiratory Infection-Induced Severe Allergic Airway Disease.

    PubMed

    Starkey, Malcolm R; Nguyen, Duc H; Brown, Alexandra C; Essilfie, Ama-Tawiah; Kim, Richard Y; Yagita, Hideo; Horvat, Jay C; Hansbro, Philip M

    2016-04-01

    Chlamydia infections are frequent causes of respiratory illness, particularly pneumonia in infants, and are linked to permanent reductions in lung function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. In the current study, we investigated the role of programmed death (PD)-1 and its ligands PD-L1 and PD-L2 in promoting early-life Chlamydia respiratory infection, and infection-induced airway hyperresponsiveness (AHR) and severe allergic airway disease in later life. Infection increased PD-1 and PD-L1, but not PD-L2, mRNA expression in the lung. Flow cytometric analysis of whole lung homogenates identified monocytes, dendritic cells, CD4(+), and CD8(+) T cells as major sources of PD-1 and PD-L1. Inhibition of PD-1 and PD-L1, but not PD-L2, during infection ablated infection-induced AHR in later life. Given that PD-L1 was the most highly up-regulated and its targeting prevented infection-induced AHR, subsequent analyses focused on this ligand. Inhibition of PD-L1 had no effect on Chlamydia load but suppressed infection-induced pulmonary inflammation. Infection decreased the levels of the IL-13 decoy receptor in the lung, which were restored to baseline levels by inhibition of PD-L1. Finally, inhibition of PD-L1 during infection prevented subsequent infection-induced severe allergic airways disease in later life by decreasing IL-13 levels, Gob-5 expression, mucus production, and AHR. Thus, early-life Chlamydia respiratory infection-induced PD-L1 promotes severe inflammation during infection, permanent reductions in lung function, and the development of more severe allergic airway disease in later life.

  2. High-fat diet promotes lung fibrosis and attenuates airway eosinophilia after exposure to cockroach allergen in mice.

    PubMed

    Ge, Xiao Na; Greenberg, Yana; Hosseinkhani, M Reza; Long, Eric K; Bahaie, Nooshin S; Rao, Amrita; Ha, Sung Gil; Rao, Savita P; Bernlohr, David A; Sriramarao, P

    2013-11-01

    Obesity is an important risk factor for asthma but the mechanistic basis for this association is not well understood. In the current study, the impact of obesity on lung inflammatory responses after allergen exposure was investigated. C57BL/6 mice maintained on a high-fat diet (HFD) or a normal diet (ND) after weaning were sensitized and challenged with cockroach allergen (CRA). Airway inflammation was assessed based on inflammatory cell recruitment, measurement of lung Th1-Th2 cytokines, chemokines, eicosanoids, and other proinflammatory mediators as well as airway hyperresponsiveness (AHR). CRA-challenged mice fed a HFD exhibited significantly decreased allergen-induced airway eosinophilia along with reduced lung IL-5, IL-13, LTC4, CCL11, and CCL2 levels as well as reduced mucus secretion and smooth muscle mass compared to ND fed mice. However, allergen-challenged HFD fed mice demonstrated significantly increased PAI-1 and reduced PGE2 levels in the lung relative to corresponding ND fed mice. Interestingly, saline-exposed HFD fed mice demonstrated elevated baseline levels of TGF-β1, arginase-1, hypoxia-inducible factor-1α, and lung collagen expression associated with decreased lung function compared to corresponding ND fed mice. These studies indicate that a HFD inhibits airway eosinophilia while altering levels of PAI-1 and PGE2 in response to CRA in mice. Further, a HFD can lead to the development of lung fibrosis even in the absence of allergen exposure which could be due to innate elevated levels of specific profibrotic factors, potentially affecting lung function during asthma.

  3. D-tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease.

    PubMed

    Kepert, Inge; Fonseca, Juliano; Müller, Constanze; Milger, Katrin; Hochwind, Kerstin; Kostric, Matea; Fedoseeva, Maria; Ohnmacht, Caspar; Dehmel, Stefan; Nathan, Petra; Bartel, Sabine; Eickelberg, Oliver; Schloter, Michael; Hartmann, Anton; Schmitt-Kopplin, Philippe; Krauss-Etschmann, Susanne

    2017-05-01

    Chronic immune diseases, such as asthma, are highly prevalent. Currently available pharmaceuticals improve symptoms but cannot cure the disease. This prompted demands for alternatives to pharmaceuticals, such as probiotics, for the prevention of allergic disease. However, clinical trials have produced inconsistent results. This is at least partly explained by the highly complex crosstalk among probiotic bacteria, the host's microbiota, and immune cells. The identification of a bioactive substance from probiotic bacteria could circumvent this difficulty. We sought to identify and characterize a bioactive probiotic metabolite for potential prevention of allergic airway disease. Probiotic supernatants were screened for their ability to concordantly decrease the constitutive CCL17 secretion of a human Hodgkin lymphoma cell line and prevent upregulation of costimulatory molecules of LPS-stimulated human dendritic cells. Supernatants from 13 of 37 tested probiotic strains showed immunoactivity. Bioassay-guided chromatographic fractionation of 2 supernatants according to polarity, followed by total ion chromatography and mass spectrometry, yielded C11H12N2O2 as the molecular formula of a bioactive substance. Proton nuclear magnetic resonance and enantiomeric separation identified D-tryptophan. In contrast, L-tryptophan and 11 other D-amino acids were inactive. Feeding D-tryptophan to mice before experimental asthma induction increased numbers of lung and gut regulatory T cells, decreased lung TH2 responses, and ameliorated allergic airway inflammation and hyperresponsiveness. Allergic airway inflammation reduced gut microbial diversity, which was increased by D-tryptophan. D-tryptophan is a newly identified product from probiotic bacteria. Our findings support the concept that defined bacterial products can be exploited in novel preventative strategies for chronic immune diseases. Copyright © 2016. Published by Elsevier Inc.

  4. Single-Cell Analysis of Mast Cell Degranulation Induced by Airway Smooth Muscle-Secreted Chemokines

    PubMed Central

    Manning, Benjamin M.; Meyer, Audrey F.; Gruba, Sarah M.; Haynes, Christy L.

    2015-01-01

    Background Asthma is a chronic inflammatory disease characterized by narrowed airways, bronchial hyper-responsiveness, mucus hyper-secretion, and airway remodeling. Mast cell (MC) infiltration into airway smooth muscle (ASM) is a defining feature of asthma, and ASM regulates the inflammatory response by secreting chemokines, including CXCL10 and CCL5. Single cell analysis offers a unique approach to study specific cellular signaling interactions within large and complex signaling networks such as the inflammatory microenvironment in asthma. Methods Carbon fiber microelectrode amperometry was used to study the effects of ASM–secreted chemokines on mouse peritoneal MC degranulation. Results MC degranulation in response to CXCL10 and CCL5 was monitored at the single cell level. Relative to IgE-mediated degranulation, CXCL10- and CCL5-stimulated MCs released a decreased amount of serotonin per granule with fewer release events per cell. Decreased serotonin released per granule was correlated with increased spike half-width and rise-time values. Conclusions MCs are directly activated with ASM-associated chemokines. CXCL10 and CCL5 induce less robust MC degranulation compared to IgE- and A23187-stimulation. The kinetics of MC degranulation are signaling pathway-dependent, suggesting a biophysical mechanism of regulated degranulation that incorporates control over granule trafficking, transport, and docking machinery. General Significance The biophysical mechanisms, including variations in number of exocytotic release events, serotonin released per granule, and the membrane kinetics of exocytosis that underlie MC degranulation in response to CXCL10 and CCL5 were characterized at the single cell level. These findings clarify the function of ASM-derived chemokines as instigators of MC degranulation relative to classical mechanisms of MC stimulation. PMID:25986989

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

    PubMed Central

    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

  6. Quercetin Blocks Airway Epithelial Cell Chemokine Expression

    PubMed Central

    Nanua, Suparna; Zick, Suzanna M.; Andrade, Juan E.; Sajjan, Umadevi S.; Burgess, John R.; Lukacs, Nicholas W.; Hershenson, Marc B.

    2006-01-01

    Quercetin (3,3′,4′,5,7-pentahydroxyflavone), a dietary flavonoid, is an inhibitor of phosphatidylinositol (PI) 3-kinase and potent antioxidant. We hypothesized that quercetin blocks airway epithelial cell chemokine expression via PI 3-kinase–dependent mechanisms. Pretreatment with quercetin and the PI 3–kinase inhibitor LY294002 each reduced TNF-α–induced IL-8 and monocyte chemoattractant protein (MCP)-1 (also called CCL2) expression in cultured human airway epithelial cells. Quercetin also inhibited TNF-α–induced PI 3-kinase activity, Akt phosphorylation, intracellular H2O2 production, NF-κB transactivation, IL-8 promoter activity, and steady-state mRNA levels, consistent with the notion that quercetin inhibits chemokine expression by attenuating NF-κB transactivation via a PI 3-kinase/Akt-dependent pathway. Quercetin also reduced TNF-α–induced chemokine secretion in the presence of the transcriptional inhibitor actinomycin D, while inducing phosphorylation of eukaryotic translation initiation factor (eIF)-2α, suggesting that quercetin attenuates chemokine expression by post-transcriptional as well as transcriptional mechanisms. Finally, we tested the effects of quercetin in cockroach antigen–sensitized and –challenged mice. These mice show MCP-1–dependent airways hyperresponsiveness and inflammation. Quercetin significantly reduced lung MCP-1 and methacholine responsiveness. We conclude that quercetin blocks airway cell chemokine expression via transcriptional and post-transcriptional pathways. PMID:16794257

  7. IMD-4690, a Novel Specific Inhibitor for Plasminogen Activator Inhibitor-1, Reduces Allergic Airway Remodeling in a Mouse Model of Chronic Asthma via Regulating Angiogenesis and Remodeling-Related Mediators

    PubMed Central

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

    2015-01-01

    Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling. PMID:25785861

  8. HSP70/CD80 DNA vaccine inhibits airway remodeling by regulating the transcription factors T-bet and GATA-3 in a murine model of chronic asthma

    PubMed Central

    Yan, Li; Xiao-Ling, Shi; Zheng-Yan, Cheng; Guo-Ping, Li; Sen, Zhong

    2013-01-01

    Introduction Airway remodeling is an important pathologic feature of chronic asthma. T-bet and GATA-3, the key transcription factors for differentiation toward Th1 and Th2 cells, play an important role in the pathogenesis of airway inflammation, airway hyperresponsiveness and airway remodeling. Previous studies showed that HSP70/CD80 DNA vaccine can reduce airway hyperresponsiveness and airway inflammation in acute asthmatic mice. The present study was designed to determine the effect of HSP70/CD80 DNA vaccine on airway remodeling through regulating the development of Th1/Th2. Material and methods Before being sensitized and challenged by ovalbumin, the BALB/c mice were immunized with DNA vaccine. Lung tissues were assessed by histological examinations. Interferon-γ (IFN-γ)/interleukin-4 (IL-4) levels in bronchoalveolar lavage fluid were determined by ELISA and expressions of IFN-γ, IL-4, T-bet and GATA-3 in spleen were evaluated by real-time polymerase chain reaction. Results Chronic asthmatic mice had higher airway hyperresponsiveness, a thicker airway wall, more PAS-positive goblet cells, more subepithelial extracellular matrix deposition and more proliferating airway smooth muscle (ASM)-like cells than control mice (p < 0.05). Compared with the chronic asthmatic mice, the treatment with HSP70/CD80 DNA vaccine could reduce airway hyperreactivity, mucus secretion, subepithelial collagen deposition, and smooth muscle cell proliferation (p < 0.05). DNA vaccination also increased levels of IFN-γ/IL-4 in BAL fluid (p < 0.05), and expression of T-bet/GATA-3 in the spleen (p < 0.05). Conclusions HSP70/CD80 DNA vaccine can inhibit airway remodeling through regulating the development of Th1/Th2 subsets in asthmatic mice. PMID:24273578

  9. Bronchospasm and its biophysical basis in airway smooth muscle

    PubMed Central

    Fredberg, Jeffrey J

    2004-01-01

    Airways hyperresponsiveness is a cardinal feature of asthma but remains unexplained. In asthma, the airway smooth muscle cell is the key end-effector of bronchospasm and acute airway narrowing, but in just the past five years our understanding of the relationship of responsiveness to muscle biophysics has dramatically changed. It has become well established, for example, that muscle length is equilibrated dynamically rather than statically, and that non-classical features of muscle biophysics come to the forefront, including unanticipated interactions between the muscle and its time-varying load, as well as the ability of the muscle cell to adapt rapidly to changes in its dynamic microenvironment. These newly discovered phenomena have been described empirically, but a mechanistic basis to explain them is only beginning to emerge. PMID:15084229

  10. Correlation of Airway Hyper-responsiveness with Obstructive with Spirometric Indices and FEV1 90% Predicted

    DTIC Science & Technology

    2012-04-01

    Evans et al described pulmonary function in 20 patients with acromegaly , noting increased vital capacity (120% of predicted) in 8 males with a normal...muscle function and control of breathing in patients with acromegaly . Eur Respir J 1997;10(5):977-982. 19. Armour J, Donnelly PM, Bye PTP. The large

  11. [Therapeutic effects of histone deacetylase inhibitor givinostat on air inflammation and high airway resistance in a murine asthma model].

    PubMed

    Su, X M; Ren, Y; Kong, L F; Kang, J

    2017-02-01

    Objective: To investigate the therapeutic effects of givinostat, a histone deacetylase inhibitor (HDACI), on the development of chronic asthma with airway inflammation, airway remodeling and airway hyperresponsiveness (AHR). Methods: BALB/C mice were randomly divided into control group, asthma group, dexamethasone group and givinostat group (n=12 per group). AHR was assessed. Total cell numbers and differential counts, interleukin-4(IL-4), interleukin-5(IL-5) and interferon-γ (IFNγ) levels in the bronchoalveolar lavage fluid (BALF) were measured in the above 4 groups. The pathology of lung tissue was evaluated. Immunohistochemical (IHC) staining and Western blot were used to detect α smooth muscle actin(α-SMA) and transforming growth factor-β1(TGFβ1). Results: Compared with the asthma only group, givinostat treatment relieved airway resistance (2.96±1.01 vs 6.50±0.79, P<0.05). Total inflammatory cells [(33.04±5.62)×10(4)/ml vs (98.04±9.27)×10(4)/ml, P<0.01], eosinophil cells [(9.17±2.33)×10(4)/ml vs(37.64±6.98)×10(4)/ml, P<0.01], IL-4 [(10.12±2.98)ng/ml vs (16.88±2.78)ng/ml, P<0.05] and IL-5 [(27.09±3.62)ng/ml vs (37.86±7.34)ng/ml, P<0.05] levels were all reduced in givinostat group, while IFNγ [(91.86±23.73)pg/ml vs (60.49±11.88)pg/ml, P>0.05] was enhanced in BALF. Inflammatory cell infiltration around the airway was reduced, with decreased inflammatory cell score[(1.60±0.69)points vs (3.40±0.68) points, P<0.01] and inflammatory cell number (111.65±31.41 vs 601.25±186.85, P<0.01). The goblet cell metaplasia [(26.36±2.33)% vs (57.21±11.56)%] and collagen deposition area [(52.77±7.58)μm(2)/μm vs (111.81±12.40)μm(2)/μm] were obviously reduced (P<0.01). The expressions of α-SMA and TGFβ1 in the lung tissue were both significantly decreased (P<0.01). Conclusion: Givinostat treatment can reduce airway inflammation, airway remodeling and airway hyperresponsiveness in chronic asthma. Its effect is comparable to that of glucocorticoid

  12. Glucagon-Like Peptide 1 Receptor: A Novel Pharmacological Target for Treating Human Bronchial Hyperresponsiveness.

    PubMed

    Rogliani, Paola; Calzetta, Luigino; Capuani, Barbara; Facciolo, Francesco; Cazzola, Mario; Lauro, Davide; Matera, Maria Gabriella

    2016-12-01

    Asthma is associated with several comorbidities, such as type 2 diabetes mellitus, which may lead to bronchial hyperresponsiveness (BHR). Because glucagon-like peptide (GLP) 1 regulates glucose homeostasis, we pharmacologically investigated the influence of the GLP1 receptor (GLP1-R) agonist, exendin-4, on BHR induced in human isolated airways. The effect of exendin-4 was assessed in human isolated airways undergoing overnight passive sensitization and high-glucose stimulation, two conditions mimicking ex vivo the BHR typical of patients with asthma and diabetes, respectively. GLP1-R activation modulated the bronchial contractile tone induced by transmural stimulation (maximum effect -56.7 ± 3.6%; onset of action, 28.2 ± 4.4 min). Exendin-4 prevented BHR induced by both high-glucose stimulation and passive sensitization (-37.8 ± 7.5% and -74.9 ± 3.9%, P < 0.05 versus control, respectively) through selective activation of GLP1-R and in an epithelium-independent manner. The cAMP-dependent protein kinase A inhibitor, KT5720, reduced the protective role of exendin-4 (P > 0.05 versus passively sensitized tissues). The GLP1-R stimulation by overnight incubation with exendin-4 induced the overexpression of adenylyl cyclase isoform V (+48.4 ± 1.3%, P < 0.05 versus passively sensitized tissues) and restored the cAMP levels depleted by this procedure (+330.8 ± 63.3%, P < 0.05 versus passively sensitized tissues). In conclusion, GLP1-R may represent a novel target for treating BHR by activating the cAMP-dependent protein kinase A pathway in human airways, and GLP1-R agonists could be used as a "new" class to treat patients with asthma and patients with type 2 diabetes mellitus with BHR.

  13. Sports in extreme conditions: the impact of exercise in cold temperatures on asthma and bronchial hyper-responsiveness in athletes.

    PubMed

    Carlsen, Kai-Håkon

    2012-09-01

    Exercise-induced asthma (EIA) and bronchial hyper-responsiveness (BHR) are frequently reported among elite athletes of outdoor endurance winter sports, particularly in cross-country and biathlon skiers. The pathogenesis of EIA is related to water loss and heat-loss through the increased respiration during exercise, leading to mediator release, airways inflammation and increased parasympathetic nervous activity in the airways, causing bronchial constriction and BHR. In the competing elite athlete this is presently considered to be due to the frequently repeated increased ventilation during training and competitions in combination with the repeated environmental exposure to cold air in outdoor winter sports. It is important that athletes at risk of asthma and BHR are monitored through regular medical control with assessment of lung function and BHR, and when BHR or asthma is diagnosed, optimal controlling treatment through anti-inflammatory treatment by inhaled steroids should be started and relieving treatment (inhaled ipratropium bromide and inhaled β2-agonists) should be used to relieve bronchial constriction if present.

  14. Effect of heparin and a low-molecular weight heparinoid on PAF-induced airway responses in neonatally immunized rabbits.

    PubMed Central

    Sasaki, M.; Herd, C. M.; Page, C. P.

    1993-01-01

    1. We have investigated the effect of an unfractionated heparin preparation, a low-molecular weight heparinoid (Org 10172) and the polyanionic molecule polyglutamic acid against PAF-induced airway hyperresponsiveness and pulmonary cell infiltration in neonatally immunized rabbits in vivo. 2. Exposure of neonatally immunized rabbits to aerosolized platelet activating factor (PAF) (80 micrograms ml-1 for 60 min) elicited an increase in airway responsiveness to inhaled histamine 24 h and 72 h following challenge which was associated with an infiltration of inflammatory cells into the airways, as assessed by bronchoalveolar lavage (BAL). 3. A significant increase in the total numbers of cells recovered from BAL fluid was associated with significantly increased cell numbers of neutrophils, eosinophils and mononuclear cells 24 h following PAF exposure. The numbers of eosinophils and neutrophils in the airways remained elevated 72 h after challenge. 4. The intravenous administration of an unfractionated preparation of heparin (100 units kg-1) or Org 10172 (100 micrograms kg-1) 30 min prior to PAF exposure significantly inhibited the airway hyperresponsiveness induced by PAF, 24 h and 72 h following challenge. PAF-induced hyperresponsiveness was not significantly affected by prior intravenous administration of polyglutamic acid (100 micrograms kg-1). 5. The intravenous administration of unfractionated heparin (100 units kg-1), Org 10172 (100 micrograms kg-1) or polyglutamic acid (100 micrograms kg-1) 30 min prior to PAF exposure significantly inhibited the expected increase in total cell infiltration. 6. This study shows that unfractionated heparin and a low-molecular weight heparinoid, Org 10172, are capable of inhibiting both the airway hyperresponsiveness and pulmonary cell infiltration induced by PAF in the rabbit. PMID:7693273

  15. Role of ROCK2 in CD4(+) cells in allergic airways responses in mice.

    PubMed

    Kasahara, D I; Mathews, J A; Ninin, F M C; Wurmbrand, A P; Liao, J K; Shore, S A

    2017-02-01

    Rho kinases (ROCKs) contribute to allergic airways disease. ROCKs also play a role in lymphocyte proliferation and migration. To determine the role of ROCK2 acting within CD4(+) cells in allergic airways responses. ROCK2-haploinsufficient (ROCK2(+/-) ) and wild-type mice were sensitized with ovalbumin (OVA). ROCK2(+/-) mice then received either CD4(+) cells from ROCK2-sufficient OVA TCR transgenic (OT-II) mice or saline i.v. 48 h before challenge with aerosolized OVA. Wild-type mice received saline before challenge. Allergic airways responses were measured 48 h after the last challenge. Allergic airways responses were also assessed in mice lacking ROCK2 only in CD4(+) cells (ROCK2(CD)(4Cre) mice) vs. control (CD4-Cre and ROCK2(flox/flox) ) mice. OVA-induced increases in bronchoalveolar lavage lymphocytes, eosinophils, IL-13, IL-5, and eotaxin were reduced in ROCK2(+/-) vs. wild-type mice, as were airway hyperresponsiveness and mucous hypersecretion. In ROCK2(+/-) mice, adoptive transfer with CD4(+) cells from OT-II mice restored effects of OVA on lymphocytes, eosinophils, IL-13, IL-5, and mucous hypersecretion to wild-type levels, whereas eotaxin and airway hyperresponsiveness were not affected. ROCK2 inhibitors reduced IL-13-induced release of eotaxin from airway smooth muscle (ASM), similar to effects of these inhibitors on ASM contractility. Despite the ability of adoptive transfer to restore allergic airways inflammation in ROCK2-insufficient mice, allergic inflammation was not different in ROCK2(CD)(4Cre) vs. control mice. ROCK2 contributes to allergic airways responses likely via effects within ASM cells and within non-lymphocyte cells involved in lymphocyte activation and migration into the airways. © 2016 John Wiley & Sons Ltd.

  16. Airway responsiveness to psychological processes in asthma and health

    PubMed Central

    Ritz, Thomas

    2012-01-01

    Psychosocial factors have been found to impact airway pathophysiology in respiratory disease with considerable consistency. Influences on airway mechanics have been studied particularly well. The goal of this article is to review the literature on airway responses to psychological stimulation, discuss potential pathways of influence, and present a well-established emotion-induction paradigm to study airway obstruction elicited by unpleasant stimuli. Observational studies have found systematic associations between lung function and daily mood changes. The laboratory-based paradigm of bronchoconstrictive suggestion has been used successfully to elicit airway obstruction in a substantial proportion of asthmatic individuals. Other studies have demonstrated modulation of airway responses to standard airway challenges with exercise, allergens, or pharmacological agents by psychological factors. Standardized emotion-induction techniques have consistently shown airway constriction during unpleasant stimulation, with surgery, blood, and injury stimuli being particularly powerful. Findings with various forms of stress induction have been more mixed. A number of methodological factors may account for variability across studies, such as choice of measurement technique, temporal association between stimulation and measurement, and the specific quality and intensity of the stimulus material, in particular the extent of implied action-orientation. Research has also begun to elucidate physiological processes associated with psychologically induced airway responses, with vagal excitation and ventilatory influences being the most likely candidate pathways, whereas the role of specific central nervous system pathways and inflammatory processes has been less studied. The technique of emotion-induction using films has the potential to become a standardized challenge paradigm for the further exploration of airway hyperresponsiveness mediated by central nervous system processes. PMID

  17. Nonlinear Compliance Modulates Dynamic Bronchoconstriction in a Multiscale Airway Model

    PubMed Central

    Hiorns, Jonathan E.; Jensen, Oliver E.; Brook, Bindi S.

    2014-01-01

    The role of breathing and deep inspirations (DI) in modulating airway hyperresponsiveness remains poorly understood. In particular, DIs are potent bronchodilators of constricted airways in nonasthmatic subjects but not in asthmatic subjects. Additionally, length fluctuations (mimicking DIs) have been shown to reduce mean contractile force when applied to airway smooth muscle (ASM) cells and tissue strips. However, these observations are not recapitulated on application of transmural pressure (PTM) oscillations (that mimic tidal breathing and DIs) in isolated intact airways. To shed light on this paradox, we have developed a biomechanical model of the intact airway, accounting for strain-stiffening due to collagen recruitment (a large component of the extracellular matrix (ECM)), and dynamic actomyosin-driven force generation by ASM cells. In agreement with intact airway studies, our model shows that PTM fluctuations at particular mean transmural pressures can lead to only limited bronchodilation. However, our model predicts that moving the airway to a more compliant point on the static pressure-radius relationship (which may involve reducing mean PTM), before applying pressure fluctuations, can generate greater bronchodilation. This difference arises from competition between passive strain-stiffening of ECM and force generation by ASM yielding a highly nonlinear relationship between effective airway stiffness and PTM, which is modified by the presence of contractile agonist. Effectively, the airway at its most compliant may allow for greater strain to be transmitted to subcellular contractile machinery. The model predictions lead us to hypothesize that the maximum possible bronchodilation of an airway depends on its static compliance at the PTM about which the fluctuations are applied. We suggest the design of additional experimental protocols to test this hypothesis. PMID:25517167

  18. Self-Assembling Nanoparticles Containing Dexamethasone as a Novel Therapy in Allergic Airways Inflammation

    PubMed Central

    Kenyon, Nicholas J.; Bratt, Jennifer M.; Lee, Joyce; Luo, Juntao; Franzi, Lisa M.; Zeki, Amir A.; Lam, Kit S.

    2013-01-01

    Nanocarriers can deliver a wide variety of drugs, target them to sites of interest, and protect them from degradation and inactivation by the body. They have the capacity to improve drug action and decrease undesirable systemic effects. We have previously developed a well-defined non-toxic PEG-dendritic block telodendrimer for successful delivery of chemotherapeutics agents and, in these studies, we apply this technology for therapeutic development in asthma. In these proof-of-concept experiments, we hypothesized that dexamethasone contained in self-assembling nanoparticles (Dex-NP) and delivered systemically would target the lung and decrease allergic lung inflammation and airways hyper-responsiveness to a greater degree than equivalent doses of dexamethasone (Dex) alone. We found that ovalbumin (Ova)-exposed mice treated with Dex-NP had significantly fewer total cells (2.78±0.44×105 (n = 18) vs. 5.98±1.3×105 (n = 13), P<0.05) and eosinophils (1.09±0.28×105 (n = 18) vs. 2.94±0.6×105 (n = 12), p<0.05) in the lung lavage than Ova-exposed mice alone. Also, lower levels of the inflammatory cytokines IL-4 (3.43±1.2 (n = 11) vs. 8.56±2.1 (n = 8) pg/ml, p<0.05) and MCP-1 (13.1±3.6 (n = 8) vs. 28.8±8.7 (n = 10) pg/ml, p<0.05) were found in lungs of the Dex-NP compared to control, and they were not lower in the Dex alone group. In addition, respiratory system resistance was lower in the Dex-NP compared to the other Ova-exposed groups suggesting a better therapeutic effect on airways hyperresponsiveness. Taken together, these findings from early-stage drug development studies suggest that the encapsulation and protection of anti-inflammatory agents such as corticosteroids in nanoparticle formulations can improve efficacy. Further development of novel drugs in nanoparticles is warranted to explore potential treatments for chronic inflammatory diseases such as asthma. PMID:24204939

  19. Low molecular weight fucoidan ameliorates streptozotocin-induced hyper-responsiveness of aortic smooth muscles in type 1 diabetes rats.

    PubMed

    Liang, Zhengyang; Zheng, Yuanyuan; Wang, Jing; Zhang, Quanbin; Ren, Shuang; Liu, Tiantian; Wang, Zhiqiang; Luo, Dali

    2016-09-15

    Low molecular weight fucoidan (LMWF) was prepared from Laminaria japonica Areschoug, a popular seafood and medicinal plant consumed in Asia. Chinese have long been using it as a traditional medicine for curing hypertension and edema. This study was intent to investigate the possible beneficial effect of LMWF on hyper-responsiveness of aortic smooth muscles instreptozotocin (STZ)-induced type 1 diabetic rats. Sprague-Dawley rats were made diabetic by injection of STZ, followed by the administration of LMWF (50 or 100mg/kg/day) or probucol (100mg/kg/day) for 12 weeks. Body weight, blood glucose level, basal blood pressure, serum lipid profiles, oxidative stress, prostanoids production, and vasoconstriction response of endothelium-denuded aorta rings to phenylephrine were measured by Real time-PCR, Western blots, ELISA assay, and force myograph, respectively. LMWF (100mg/kg/day)-treated group showed robust improvements on STZ-induced body weight-loss, hypertension, and hyperlipidaemia as indicated by decreased serum level of total cholesterol, triglyceride, and low density lipoprotein cholesterol; while probucol, a lipid-modifying drug with antioxidant properties, displayed mild effects. In addition, LMWF appreciably ameliorated STZ-elicited hyper-responsiveness and oxidative stress in aortic smooth muscles as indicated by decreased superoxide level, increased glutathione content and higher superoxide dismutase activity. Furthermore, administration with LMWF dramatically prevented cyclooxygenase-2 stimulation and restored the up-regulation of thromboxane synthase and down-regulation of 6-keto-PGF1α (a stable metabolic product of prostaglandin I2) in the STZ-administered rats. This study demonstrates for the first time that LMWF can protect against hyperlipidaemia, hypertension, and hyper-responsiveness of aortic smooth muscles in type 1 diabetic rat via, at least in part, amelioration of oxidative stress and restoration of prostanoids levels in aortic smooth muscles

  20. IL-17 producing T cells correlate with polysensitization but not with bronchial hyperresponsiveness in patients with allergic rhinitis

    PubMed Central

    2014-01-01

    Background Th2-type T cell response has a considerable role in atopic diseases. The involvement of Th17 and IL-17 in atopy process provided new understanding of allergic diseases. Bronchial hyperresponsiveness is quite common in allergic rhinitis. We aimed to explore the expression of IL-17 producing CD3+ CD4+ T cells in peripheral blood of rhinitic patients, with/without bronchial hyperresponsiveness and sensitized to common allergens, as this relationship has not been examined. Methods Sixty one patients with allergic rhinitis and thirty controls were examined. IL-17 producing T cells were detected by flow cytometry, IL-17, IL-4 and IL-13 levels in peripheral blood were evaluated by ELISA. Bronchial hyperresponsiveness was investigated with methacholine challenge test. Atopy was evaluated by skin prick tests with common allergens. Results IL-17 producing T cell percentage of AR group was significantly higher: 2.59 ± 1.32 than in controls 1.24 ± 0.22, (p = 0.001). Significant sex related difference in CD3+ CD4+ IL-17 T cells was observed: respectively in male patients versus female 3.15 ± 1.8% and 2.31 ± 0.9%, (p = 0.02). Rhinitics had greater bronchodilator responses compared to controls (p = 0.001), however the percentages of T cells in both groups appeared equal. Serum IL-17 levels in AR group were significantly higher (5.10 ± 4.40) pg/ml than in controls (3.46 ±1.28) pg/ml, (p = 0.04). IL-4 levels (0.88 ± 1.27) and IL-13 levels (3.14 ± 5.85) in patients were significantly higher than in control’s (0.54 ± 0.10) pg/ml, (p = 0.001) and (1.19 ± 0.64) pg/ml; (p = 0.001) respectively. The percentages of T cells in patients sensitized to 5 allergens (group I) were significantly lower (1.91 ± 0.62) than those sensitized to more than 5 allergens (group II) (2.91 ± 1.5) (p = 0.004). Conclusions The observed higher levels of IL-17 producing T cells in polysensitized males suggest a role of IL-17 in pathogenesis of AR. The higher airway responsiveness in AR

  1. Airway responses to salbutamol after exposure to chemical warfare.

    PubMed

    Boskabady, Mohammad H; Attaran, Dawood; Shaffei, Mohammad N

    2008-03-01

    Increased airway responsiveness to beta-agonists is noted in asthmatics and smokers. The lung may be exposed to chemical warfare agents such as mustard gas and pulmonary complications of exposure range from no effect to severe bronchial stenosis. There is little understanding of airway hyperresponsiveness to beta-agonist drugs in chemical war victims and this study examined airway responsiveness to salbutamol in victims of chemical warfare. The threshold concentrations of inhaled salbutamol required for a 20% change in FEV(1) as PC(20), or a 35% change in specific airway conductance (sGaw) as PC(35) were measured in 22 persons exposed to chemical warfare and 15 normal control subjects. In 11 of the 22 subjects PC(20) salbutamol could be measured and in 15 of the 22 subjects PC(35) salbutamol could be measured. This group of patients was the responder group (PC(20) = 10.79 and PC(35) = 8.55 mg/L) and in them the concentration of salbutamol needed for a response was significantly lower than that required in normal controls (PC(20) = 237.68 and PC(35) = 88.72 mg/L, P < 0.001). There was a significant correlation between FEV(1) and PC(20) salbutamol (r = 0.815, P < 0.001). These results showed increased airway responsiveness to salbutamol in most subjects exposed to chemical warfare; this was correlated with airway calibre.

  2. Baicalein Reduces Airway Injury in Allergen and IL-13 Induced Airway Inflammation

    PubMed Central

    Mabalirajan, Ulaganathan; Ahmad, Tanveer; Rehman, Rakhshinda; Leishangthem, Geeta Devi; Dinda, Amit Kumar; Agrawal, Anurag; Ghosh, Balaram; Sharma, Surendra Kumar

    2013-01-01

    Background Baicalein, a bioflavone present in the dry roots of Scutellaria baicalensis Georgi, is known to reduce eotaxin production in human fibroblasts. However, there are no reports of its anti-asthma activity or its effect on airway injury. Methodology/Principal Findings In a standard experimental asthma model, male Balb/c mice that were sensitized with ovalbumin (OVA), treated with baicalein (10 mg/kg, ip) or a vehicle control, either during (preventive use) or after OVA challenge (therapeutic use). In an alternate model, baicalein was administered to male Balb/c mice which were given either IL-4 or IL-13 intranasally. Features of asthma were determined by estimating airway hyperresponsiveness (AHR), histopathological changes and biochemical assays of key inflammatory molecules. Airway injury was determined with apoptotic assays, transmission electron microscopy and assessing key mitochondrial functions. Baicalein treatment reduced AHR and inflammation in both experimental models. TGF-β1, sub-epithelial fibrosis and goblet cell metaplasia, were also reduced. Furthermore, baicalein treatment significantly reduced 12/15-LOX activity, features of mitochondrial dysfunctions, and apoptosis of bronchial epithelia. Conclusion/Significance Our findings demonstrate that baicalein can attenuate important features of asthma, possibly through the reduction of airway injury and restoration of mitochondrial function. PMID:23646158

  3. Exposure of airway epithelial cells to Pseudomonas aeruginosa biofilm-derived quorum sensing molecules decrease the activity of the anti-oxidant response element bound by NRF2.

    PubMed

    Roussel, Lucie; Rousseau, Simon

    2017-02-05

    Chronic bacterial infections in cystic fibrosis lung disease are often characterized by Pseudomonas aeruginosa biofilms that are regulated by bacterial intercellular signals termed quorum sensing (QS), such as N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL). This study reports that biofilm-derived exoproducts decrease the transcriptional activity of the anti-oxidant response element in bronchial epithelial cells. In a live co-culture assay of BEAS-2B cells and P. aeruginosa biofilm, the QS molecule 3OC12-HSL was an important but not sole contributor to the inhibition of basal NRF2 luciferase reporter activity. Moreover, biofilm-derived exoproducts and 3OC12-HSL decrease the expression of endogenous antioxidant response element-regulated genes hemeoxygenase-1 (HO-1) and NAD(P)H Quinone Dehydrogenase-1 (NQO-1) while they increase IL-8 expression. As previously reported, IL-8 expression is partially dependent on p38 MAPK activity, but the inhibitory effect of biofilm QS molecules on HO-1 and NQO-1 expression occurs independently of this protein kinase. Finally, the transfection of CFTRdelF508 but not its wild type counterpart decreases basal, planktonic PsaDM and sulforaphane-driven NRF2 luciferase reporter activity in BEAS-2B cells. Therefore, the presence of quorum sensing molecules derived from bacterial biofilms lowers the transcriptional activity of the anti-oxidant response element, which may contribute to the establishment of chronic bacterial infections, especially in the presence of mutated CFTR. Increasing NRF2 activity may thus be a promising strategy to potentiate anti-biofilm activity in cystic fibrosis lung disease.

  4. Bronchial hyperresponsiveness in women with chronic obstructive pulmonary disease related to wood smoke

    PubMed Central

    González-García, Mauricio; Torres-Duque, Carlos A; Bustos, Adriana; Jaramillo, Claudia; Maldonado, Darío

    2012-01-01

    Purpose Chronic obstructive pulmonary disease (COPD) related to wood smoke exposure is characterized by important inflammation of the central and peripheral airways without significant emphysema. The objective of this study is to describe the bronchial hyperresponsiveness (BHR) level in women with COPD related to wood smoke exposure and to compare it with the BHR in women with COPD related to tobacco smoking. Materials and methods Two groups of women with stable COPD were studied: (1) wood smoke exposed (WS-COPD); and (2) tobacco smoke exposed (TS-COPD). A methacholine challenge test (MCT) was performed in all patients according to American Thoracic Society criteria. BHR levels were compared using the methacholine concentration, which caused a 20% fall in the FEV1 (PC20). Results Thirty-one patients, 19 with WS-COPD and 12 with TS-COPD, were included. There were no significant differences between the groups in baseline FVC, FEV1, IC, FEF25–75, and FEF25–75/FVC. All 31 patients had a positive MCT (PC20 < 16 mg/mL) and the fall in the FEV1 and IC was similar in both groups. The severity of BHR was significantly higher in the WS-COPD patients (PC20: 0.39 mg/mL) than in the TS-COPD patients (PC20: 1.24 mg/mL) (P = 0.028). The presence of cough, phlegm, and dyspnea during the test were similar in both groups. Conclusion We found moderate to severe BHR in women with WS-COPD, which was more severe than in the TS-COPD women with similar age and airflow obstruction. This paper suggests that the structural and inflammatory changes induced by the chronic exposure to wood smoke, described in other studies, can explain the differences with TS-COPD patients. Future studies may clarify our understanding of the impact of BHR on COPD physiopathology, phenotypes, and treatment strategies. PMID:22791990

  5. Resting calcium influx in airway smooth muscle.

    PubMed

    Montaño, Luis M; Bazán-Perkins, Blanca

    2005-01-01

    Plasma membrane Ca2+ leak remains the most uncertain of the cellular Ca2+ regulation pathways. During passive Ca2+ influx in non-stimulated smooth muscle cells, basal activity of constitutive Ca2+ channels seems to be involved. In vascular smooth muscle, the 3 following Ca2+ entry pathways contribute to this phenomenon: (i) via voltage-dependent Ca2+ channels, (ii) receptor gated Ca2+ channels, and (iii) store operated Ca2+ channels, although, in airway smooth muscle it seems only 2 passive Ca2+ influx pathways are implicated, one sensitive to SKF 96365 (receptor gated Ca2+ channels) and the other to Ni2+ (store operated Ca2+ channels). Resting Ca2+ entry could provide a sufficient amount of Ca2+ and contribute to resting intracellular Ca2+ concentration ([Ca2+]i), maintenance of the resting membrane potential, myogenic tone, and sarcoplasmic reticulum-Ca2+ refilling. However, further research, especially in airway smooth muscle, is required to better explore the physiological role of this passive Ca2+ influx pathway as it could be involved in airway hyperresponsiveness.

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

    PubMed

    Ma, Yuan; Ge, Ai; Zhu, Wen; Liu, Ya-Nan; Ji, Ning-Fei; Zha, Wang-Jian; Zhang, Jia-Xiang; Zeng, Xiao-Ning; Huang, Mao

    2016-01-01

    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 abolished by morin

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

    PubMed Central

    Ma, Yuan; Ge, Ai; Zhu, Wen; Liu, Ya-Nan; Ji, Ning-Fei; Zha, Wang-Jian; Zhang, Jia-Xiang; Zeng, Xiao-Ning

    2016-01-01

    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 abolished by

  8. Effect of inhaled magnesium sulfate on bronchial hyperresponsiveness.

    PubMed

    Wang, Hui; Xiong, Yi; Gong, Caihui; Yin, Lijuan; Yan, Li; Yuan, Xiaoping; Liu, Sha; Shi, Tiantian; Dai, Jihong

    2015-04-01

    To determine the response of nebulized magnesium sulfate on the lung function of children with bronchial hyperresponsiveness. Eighty-four children with asthma were divided into three groups randomly: magnesium sulfate (M), albuterol (A), and a combination of magnesium sulfate and albuterol (M + A). All patients were nebulized with acetylcholine, and then treated as designed. Lung function was compared between the three groups. Forced expiratory volume in first second (FEV1) significantly improved in all the three groups but it was better in (A) and (M + A) compared to (M) at 10 min and 20 min [10 min: 1.26 L ± 0.53 (A) vs. 1.10 L ± 0.27 (M), 1.35 L ± 0.59 (M + A) vs. 1.10 L ± 0.27 (M), p < 0.05; 20 min: 1.32 L ± 0.61 (A) vs. 1.17 L ± 0.30 (M), 1.42 L ± 0.59 (M + A) vs. 1.17 L ± 0.30 (M), p < 0.05]. Variation of FEV1, as absolute value at 10 min or 20 min over post-Ach FEV1 was significantly different in (A) or (M + A) compared to (M). Nebulized albuterol and magnesium sulfate + albuterol can more effectively improve FEV1 in children with bronchial hyperresponsiveness than nebulized magnesium sulfate at 10 min and 20 min after inhalation. It is further suggested that addition of magnesium sulfate to albuterol does not result in additional benefit.

  9. Effect of heparin on antigen-induced airway responses and pulmonary leukocyte accumulation in neonatally immunized rabbits

    PubMed Central

    Preuss, Janet M H; Page, Clive P

    2000-01-01

    The effect of single administrations of aerosolized heparin, low molecular weight heparin (LMWH) and the linear polyanionic molecule, polyglutamic acid (PGA) were examined on antigen-induced airway hyperresponsiveness and leukocyte accumulation in neonatally immunized rabbits.Adult litter-matched NZW rabbits immunized within 24 h of birth with Alternaria tenuis antigen were treated with heparin, LMWH or PGA prior to or following antigen challenge (Alternaria tenuis). For each drug-treated group, a parallel group of rabbits were treated with the appropriate vehicle. In all groups, airway responsiveness to inhaled histamine and bronchoalveolar lavage (BAL) was performed 24 h prior to and following antigen challenge.Basal lung function in terms of resistance (RL) and dynamic compliance (Cdyn) and acute bronchoconstriction was unaltered by pre-treatment with heparin, LMWH or PGA compared to their respective vehicles 24 h prior to or following antigen challenge.In vehicle-treated animals, airway hyperresponsiveness to inhaled histamine was indicated by an increase in the maximal responses of the cumulative concentration-effect curves to histamine and reductions in RLPC50 and CdynPC35 values 24 h following antigen challenge.Heparin and LMWH given prior to antigen challenge significantly inhibited the development of airway hyperresponsiveness, whereas PGA did not. When given following antigen challenge, all three drugs failed to inhibit the development of airway hyperresponsiveness.Eosinophil and neutrophil cell numbers in BAL fluid increased significantly 24 h following antigen challenge. Heparin, LMWH and PGA failed to inhibit the increase in cell numbers following antigen challenge whether given prior to or following antigen challenge. PMID:10780962

  10. Selaginella uncinata flavonoids ameliorated ovalbumin-induced airway inflammation in a rat model of asthma.

    PubMed

    Yu, Bing; Cai, Wei; Zhang, Huan-Huan; Zhong, Yu-Sen; Fang, Jie; Zhang, Wen-You; Mo, Li; Wang, Lu-Chen; Yu, Chen-Huan

    2017-01-04

    Selaginella uncinata (Desv.) Spring, known as "Cuiyuncao", is a perennial herb widely distributed in the Southeast Asian countries. In the folk medicine, the local minority commonly use it to treat cough and asthma for centuries. This study was carried out to investigate the protective mechanisms of total flavonoids from S. uncinata (SUF) on airway hyperresponsiveness, cytokine release and bitter taste receptors (T2Rs) signaling with emphasis on inflammatory responses in a rat model of ovalbumin (OVA)-induced asthma. Rats were sensitized and challenged with OVA to induce typical asthmatic reactions. Pathological changes of lung tissue were examined by HE staining. The serum levels of T cell-associated cytokines (IFN-γ, IL-4, IL-5 and IL-13), total IgE and OVA-specific IgE were determined by enzyme-linked immunosorbent assay (ELISA). Gene expressions of T2R10, IP3R1 and Orai1 in lung tissue were assayed by fluorescence quantitative real-time polymerase chain reaction (FQ-PCR) while protein expressions of NFAT1 and c-Myc were assayed by western blot analysis. The activation of SUF was investigated on tansgentic T2R10-GFP HEK293 cells. SUF treatment attenuated airway hyperresponsiveness and goblet cell hyperplasia compared with OVA-challenged asthmatic rats. The serum levels of IL-4, IL-5 and IL-13 as well as total and OVA-specific IgE were decreased while serum IFN-γ was increased in SUF-treated rats. SUF treatment significantly up-regulated T2R10 gene expression, down-regulated IP3R1 and Orai1 gene expression. SUF further suppressed eotaxin, NFAT1 and c-Myc protein expression in lung tissues of OVA-challenged rats. These results imply that SUF exerts anti-inflammatory function through the T2R10/IP3R1/NFAT1 dependent signaling pathway, and may warrant further evaluation as a possible agent for the treatment of asthma. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Respiratory symptoms and airway responsiveness in apparently healthy workers exposed to flour dust.

    PubMed

    Bohadana, A B; Massin, N; Wild, P; Kolopp, M N; Toamain, J P

    1994-06-01

    Our aim was to measure the levels of exposure to wheat flour dust in a modern industrial bakery, and to assess the relationship between respiratory symptoms, sensitization to wheat flour antigens and airway responsiveness in the workforce. Forty four flour-exposed male workers and 164 unexposed controls were examined. Inspirable dust concentrations were measured using personal samplers. Respiratory symptoms were assessed by questionnaire, sensitization to wheat flour antigens by skin-prick tests, and methacholine airway challenge (MAC) test using an abbreviated method. Subjects were labelled MAC+ if forced expiratory volume in one second (FEV1) fell by 20% or more. The linear dose-response slope (DRS) was calculated as the percentage fall in FEV1 at last dose divided by the total dose administered. Inspirable dust concentrations were within acceptable limits in all working areas but one. The proportion of subjects with one or more symptoms and with airway hyperresponsiveness was significantly greater among flour-exposed workers than among controls. Using logistic or linear regression analysis, airway responsiveness was found to be strongly related to working at the bakery and to the baseline level of lung function. A positive skin-prick test was found in only 11% of flour-exposed workers and 6% of controls. In conclusion, our data show that despite exposure to relatively low concentration levels of inspirable flour dust, subjects working in the baking industry are at risk of developing both respiratory symptoms and airway hyperresponsiveness.

  12. The Phillips airway.

    PubMed

    Haridas, R P; Wilkinson, D J

    2012-07-01

    The Phillips airway was developed by George Ramsay Phillips. There is no known original description of the airway and the earliest known reference to it is from 1919. The airway and its modifications are described.

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

    PubMed

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

    2008-10-01

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

  14. Downregulation of Orai1 expression in the airway alleviates murine allergic rhinitis

    PubMed Central

    Wang, Yi; Lin, Lin

    2012-01-01

    Orai1 is the key subunit of the Ca2+-release-activated Ca2+ channel. Our previous report has demonstrated that Orai1 expression in the airway was upregulated in the ovalbumin (OVA)-induced allergic rhinitis (AR) mouse models. To observe whether inhibition of Orai1 expression in the airway could suppress symptoms in a murine model of AR and to assess the impacts of this inhibition on the responses of local and systemic immunocytes, we administered recombinant lentivirus vectors that encoded shRNA against ORAI1 (lenti-ORAI1) into the nostrils of OVA-sensitized mice before the challenges, and analyzed its effect on allergic responses, as compared with the unsensitized mice and untreated AR mice. Administration of lenti-ORAI1 into the nasal cavity successfully infected cells in the epithelial layer of the nasal mucosa, and significantly decreased the frequencies of sneezing and nasal rubbing of the mice. Protein levels of leukotriene C4, OVA-specific IgE, and IL-4 in the nasal lavage fluid and serum and eosinophil cation protein in the serum were also significantly reduced by lenti-ORAI1, as were the mRNA levels of these factors in the nasal mucosa and spleen. These data suggested that administration of lenti-ORAI1 into the nasal cavity effectively decreased Orai1 expression in the nasal mucosa, alleviated AR symptoms, and partially inhibited the hyperresponsiveness of the local and systemic immune cells including T cells, B cells, mast cells and eosinophils that are involved in the pathogenesis of AR. PMID:22170034

  15. Blockage of upper airway

    MedlinePlus

    ... Airway obstruction - acute upper Images Throat anatomy Choking Respiratory system References Cukor J, Manno M. Pediatric respiratory emergencies: upper airway obstruction and infections. In: Marx ...

  16. NKG2D mediates NK cell hyperresponsiveness and influenza-induced pathologies in a mouse model of chronic obstructive pulmonary disease.

    PubMed

    Wortham, Brian W; Eppert, Bryan L; Motz, Greg T; Flury, Jennifer L; Orozco-Levi, Mauricio; Hoebe, Kasper; Panos, Ralph J; Maxfield, Melissa; Glasser, Stephan W; Senft, Albert P; Raulet, David H; Borchers, Michael T

    2012-05-01

    Chronic obstructive pulmonary disease (COPD) is characterized by peribronchial and perivascular inflammation and largely irreversible airflow obstruction. Acute disease exacerbations, due frequently to viral infections, lead to enhanced disease symptoms and contribute to long-term progression of COPD pathology. Previously, we demonstrated that NK cells from cigarette smoke (CS)-exposed mice exhibit enhanced effector functions in response to stimulating cytokines or TLR ligands. In this article, we show that the activating receptor NKG2D is a key mediator for CS-stimulated NK cell hyperresponsiveness, because CS-exposed NKG2D-deficient mice (Klrk1(-/-)) did not exhibit enhanced effector functions as assessed by cytokine responsiveness. NK cell cytotoxicity against MHC class I-deficient targets was not affected in a COPD model. However, NK cells from CS-exposed mice exhibit greater cytotoxic activity toward cells that express the NKG2D ligand RAET1ε. We also demonstrate that NKG2D-deficient mice exhibit diminished airway damage and reduced inflammation in a model of viral COPD exacerbation, which do not affect viral clearance. Furthermore, adoptive transfer of NKG2D(+) NK cells into CS-exposed, influenza-infected NKG2D-deficient mice recapitulated the phenotypes observed in CS-exposed, influenza-infected wild-type mice. Our findings indicate that NKG2D stimulation during long-term CS exposure is a central pathway in the development of NK cell hyperresponsiveness and influenza-mediated exacerbations of COPD.

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

    PubMed

    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.

  18. Role of Rho kinase isoforms in murine allergic airway responses.

    PubMed

    Zhu, M; Liu, P-Y; Kasahara, D I; Williams, A S; Verbout, N G; Halayko, A J; Fedulov, A; Shoji, T; Williams, E S; Noma, K; Shore, S A; Liao, J K

    2011-10-01

    Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses. Wildtype (WT) mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1(+/-) and ROCK2(+/-), respectively) were sensitised and challenged with ovalbumin. ROCK expression and activation were assessed by western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment. Compared with WT mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1(+/-) and ROCK2(+/-) mice, respectively, without changes in the other isoform. In WT lungs, ROCK activation increased after ovalbumin challenge and was sustained for several hours. This activation was reduced in ROCK1(+/-) and ROCK2(+/-) lungs. Airway responsiveness was comparable in WT, ROCK1(+/-), and ROCK2(+/-) mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in WT, but not ROCK1(+/-) or ROCK2(+/-) mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1(+/-) and ROCK2(+/-) versus WT mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1(+/-) mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses.

  19. The p110δ subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice.

    PubMed

    Kang, Bit Na; Ha, Sung Gil; Ge, Xiao Na; Reza Hosseinkhani, M; Bahaie, Nooshin S; Greenberg, Yana; Blumenthal, Malcolm N; Puri, Kamal D; Rao, Savita P; Sriramarao, P

    2012-06-01

    Trafficking and recruitment of eosinophils during allergic airway inflammation is mediated by the phosphatidylinositol 3-kinase (PI3K) family of signaling molecules. The role played by the p110δ subunit of PI3K (PI3K p110δ) in regulating eosinophil trafficking and recruitment was investigated using a selective pharmacological inhibitor (IC87114). Treatment with the PI3K p110δ inhibitor significantly reduced murine bone marrow-derived eosinophil (BM-Eos) adhesion to VCAM-1 as well as ICAM-1 and inhibited activation-induced changes in cell morphology associated with reduced Mac-1 expression and aberrant cell surface localization/distribution of Mac-1 and α4. Infused BM-Eos demonstrated significantly decreased rolling and adhesion in inflamed cremaster muscle microvessels of mice treated with IC87114 compared with vehicle-treated mice. Furthermore, inhibition of PI3K p110δ significantly attenuated eotaxin-1-induced BM-Eos migration and prevented eotaxin-1-induced changes in the cytoskeleton and cell morphology. Knockdown of PI3K p110δ with siRNA in BM-Eos resulted in reduced rolling, adhesion, and migration, as well as inhibition of activation-induced changes in cell morphology, validating its role in regulating trafficking and migration. Finally, in a mouse model of cockroach antigen-induced allergic airway inflammation, oral administration of the PI3K p110δ inhibitor significantly inhibited airway eosinophil recruitment, resulting in attenuation of airway hyperresponsiveness in response to methacholine, reduced mucus secretion, and expression of proinflammatory molecules (found in inflammatory zone-1 and intelectin-1). Overall, these findings indicate the important role played by PI3K p110δ in mediating BM-Eos trafficking and migration by regulating adhesion molecule expression and localization/distribution as well as promoting changes in cell morphology that favor recruitment during inflammation.

  20. The p110δ subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice

    PubMed Central

    Kang, Bit Na; Ha, Sung Gil; Ge, Xiao Na; Reza Hosseinkhani, M.; Bahaie, Nooshin S.; Greenberg, Yana; Blumenthal, Malcolm N.; Puri, Kamal D.; Rao, Savita P.

    2012-01-01

    Trafficking and recruitment of eosinophils during allergic airway inflammation is mediated by the phosphatidylinositol 3-kinase (PI3K) family of signaling molecules. The role played by the p110δ subunit of PI3K (PI3K p110δ) in regulating eosinophil trafficking and recruitment was investigated using a selective pharmacological inhibitor (IC87114). Treatment with the PI3K p110δ inhibitor significantly reduced murine bone marrow-derived eosinophil (BM-Eos) adhesion to VCAM-1 as well as ICAM-1 and inhibited activation-induced changes in cell morphology associated with reduced Mac-1 expression and aberrant cell surface localization/distribution of Mac-1 and α4. Infused BM-Eos demonstrated significantly decreased rolling and adhesion in inflamed cremaster muscle microvessels of mice treated with IC87114 compared with vehicle-treated mice. Furthermore, inhibition of PI3K p110δ significantly attenuated eotaxin-1-induced BM-Eos migration and prevented eotaxin-1-induced changes in the cytoskeleton and cell morphology. Knockdown of PI3K p110δ with siRNA in BM-Eos resulted in reduced rolling, adhesion, and migration, as well as inhibition of activation-induced changes in cell morphology, validating its role in regulating trafficking and migration. Finally, in a mouse model of cockroach antigen-induced allergic airway inflammation, oral administration of the PI3K p110δ inhibitor significantly inhibited airway eosinophil recruitment, resulting in attenuation of airway hyperresponsiveness in response to methacholine, reduced mucus secretion, and expression of proinflammatory molecules (found in inflammatory zone-1 and intelectin-1). Overall, these findings indicate the important role played by PI3K p110δ in mediating BM-Eos trafficking and migration by regulating adhesion molecule expression and localization/distribution as well as promoting changes in cell morphology that favor recruitment during inflammation. PMID:22427531

  1. Serine protease inhibitors nafamostat mesilate and gabexate mesilate attenuate allergen-induced airway inflammation and eosinophilia in a murine model of asthma.

    PubMed

    Chen, Chih-Lung; Wang, Shulhn-Der; Zeng, Zhao-Ying; Lin, Kuo-Juei; Kao, Shung-Te; Tani, Thoru; Yu, Chun-Keung; Wang, Jiu-Yao

    2006-07-01

    Serine proteases such as mast cell tryptase and certain allergens are important in the pathogenesis of allergic inflammation of asthma. We sought to investigate the effects of serine protease inhibitors nafamostat mesilate (FUT), gabexate mesilate (FOY), and ulinastatin (UTI) on airway inflammation in a mouse model of allergic asthma. BALB/c mice were sensitized to Dermatophagoides pteronyssinus (Der p) and intratracheally challenged with Der p (0.5 mg/mL). Therapeutic doses of FUT (0.0625 mg/kg), FOY (20 mg/kg), and UTI (10,000 U/kg) were intra-peritoneally injected into 3 corresponding sensitized mice during the sensitization phase (protocol 1) or 24 hours after allergen challenge (protocol 2). Both FUT-treated and FOY-treated sensitized mice had reduced mast cells activation, airway hyperresponsiveness, attenuated eosinophils infiltrations, and decreased Der p-induced IL-4 and TNF-alpha, but increased IL-12 cytokine production in bronchoalveolar lavage fluid compared with nontreated mice. Furthermore, FUT treatment downregulated the expression of IL-1beta, TNF-alpha, IL-6, eotaxin, inducible NO synthase, CD86, and nuclear factor-kappaB activation, but enhanced the expression of IL-12 and IL-10 in Der p-stimulated alveolar macrophages. UTI-treated mice have no significant change of the aforementioned measurements compared with nontreated sensitized mice. Nafamostat mesilate and FOY exerting the therapeutic effect in allergen-induced airway inflammation was a result not only of their inhibitory action in the early phase of mast cells activation but also of immunoregulatory function in the late phase of allergic inflammation. Such properties of FUT and FOY might be a potential therapeutic approach for asthma. The clinical used of serine protease inhibitors FUT and FOY may also have implications for treating airway inflammation of asthma.

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

    PubMed

    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

    2015-09-01

    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. 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. 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. 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. Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents

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

    PubMed

    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.

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

    PubMed Central

    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

  5. Protein tyrosine phosphatase SHP2 regulates TGF-β1 production in airway epithelia and asthmatic airway remodeling in mice

    PubMed Central

    Qin, X.-J.; Zhang, G.-S.; Zhang, X.; Qiu, Z.-W.; Wang, P.-L.; Li, Y.-W.; Li, W.; Xie, Q.-M.; Ke, Y.-H.; Lee, J. J.; Shen, H.-H.

    2014-01-01

    Background Transforming growth factor (TGF)-β1 produced in airway epithelia has been suggested as a contributor to the airway remodeling observed in asthma patients. The protein tyrosine phosphatase SHP2 is a demonstrable modulator of TGF-β1 production and thus a potential regulator of airway remodeling. Objectives To define the signal event by which SHP2 regulates asthmatic responses in airway epithelial cells by using a mouse model of experimental OVA-induced airway remodeling. Methods The airways of Shp2flox/flox mice were infected with recombinant adenovirus vectors expressing a Cre recombinase–green fluorescence protein (GFP) fusion protein as part of allergen provocation studies using mice sensitized with ovalbumin (OVA) and repeatedly challenged with OVA. Several endpoint pathologies were assessed, including airway hyper-responsiveness (AHR), lung inflammatory score, peribronchial collagen deposition, and α-smooth muscle actin (SMA) hyperplasia. In vitro studies using airway epithelial cells (BEAS-2B) were used to investigate the role of SHP2 in the regulation of pulmonary remodeling events, including the expression of collagen, α-SMA, and TGF-β1. Results Chronic OVA challenges in wild-type mice resulted in airway remodeling and lung dysfunction (e.g., increased inflammatory scores, collagen deposition (fibrosis), smooth muscle hyperplasia, and a significant increase in AHR). These endpoint pathology metrics were each significantly attenuated by conditional shp2 gene knockdown in airway epithelia. In vitro studies using BEAS-2B cells also demonstrated that the level of TGF-β1 production by these cells correlated with the extent of shp2 gene expression. Conclusions SHP2 activities in airway epithelial cells appear to modulate TGF-β1 production and, in turn, regulate allergic airway remodeling following allergen provocation. Clinical Implications Our findings identify SHP2 as a previously underappreciated contributor to the airway remodeling and lung

  6. Cordycepin alleviates airway hyperreactivity in a murine model of asthma by attenuating the inflammatory process.

    PubMed

    Yang, Xiaofeng; Li, Yanxiang; He, Yanhao; Li, Tingting; Wang, Weirong; Zhang, Jiye; Wei, Jingyuan; Deng, Yanhong; Lin, Rong

    2015-06-01

    Cordycepin (Cor), which is a naturally occurring nucleoside derivative isolated from Cordyceps militaris, has been shown to exert excellent antiinflammatory activity in a murine model of acute lung injury. Thus, this study aimed to evaluate the antiasthmatic activity of Cor (10, 20, and 40 mg/kg) and to investigate the possible underlying molecular mechanisms. We found that Cor attenuated airway hyperresponsiveness, mucus hypersecretion, and ovalbumin (Ova)-specific immunoglobulin (Ig) E, and alleviated lung inflammation with decreased eosinophils and macrophages in the bronchoalveolar lavage (BAL) fluid. Notably, Cor reduced the upregulation of eotaxin, intercellular cell adhesion molecule-1 (ICAM-1), IL-4, IL-5, and IL-13 in the BAL fluid. Furthermore, Cor markedly blocked p38-MAPK and nuclear factor-kappaB (NF-κB) signalling pathway activation in the Ova-driven asthmatic mice. In conclusion, this study demonstrated that some of the antiasthmatic benefits of Cor attributable to diets and/or tonics may result from reductions in inflammatory processes and that these antiasthmatic properties involve the inhibition of Th2-type responses through the suppression of the p38-MAPK and NF-κB signalling pathways. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Toll-like Receptors, Triggering Receptor Expressed on Myeloid Cells Family Members and Receptor for Advanced Glycation End-products in Allergic Airway Inflammation

    PubMed Central

    Hall, Sannette C.; Agrawal, Devendra K.

    2016-01-01

    Asthma is a chronic disorder of the airways characterized by cellular infiltration, airway hyper-responsive and airway inflammation. Innate immune cells are the first line of defense against endogenous and exogenous signals in the airways and as such possess a diverse array of pattern recognition receptors. Toll-like receptors are crucial sentinels which when activated, can either promote or ameliorate the inflammatory response in predisposed individuals. The recently discovered triggering receptor expressed on myeloid cells family members are emerging mediators of inflammation. These receptors are believed to modulate inflammatory responses by collaborating with classic PRRs. Endogenous signals like HMGB-1, signaling through the receptor for advanced glycation end products, also promotes inflammation, however, its contribution to inflammation in the airways is not well known. Here, we discuss the role of each receptor in airway inflammation and highlight potential synergistic mechanisms, which contribute to disease pathogenesis in allergic asthma. PMID:26678062

  8. Static and dynamic stress heterogeneity in a multiscale model of the asthmatic airway wall.

    PubMed

    Hiorns, J E; Jensen, O E; Brook, B S

    2016-07-01

    Airway hyperresponsiveness (AHR) is a key characteristic of asthma that remains poorly understood. Tidal breathing and deep inspiration ordinarily cause rapid relaxation of airway smooth muscle (ASM) (as demonstrated via application of length fluctuations to tissue strips) and are therefore implicated in modulation of AHR, but in some cases (such as application of transmural pressure oscillations to isolated intact airways) this mechanism fails. Here we use a multiscale biomechanical model for intact airways that incorporates strain stiffening due to collagen recruitment and dynamic force generation by ASM cells to show that the geometry of the airway, together with interplay between dynamic active and passive forces, gives rise to large stress and compliance heterogeneities across the airway wall that are absent in tissue strips. We show further that these stress heterogeneities result in auxotonic loading conditions that are currently not replicated in tissue-strip experiments; stresses in the strip are similar to hoop stress only at the outer airway wall and are under- or overestimates of stresses at the lumen. Taken together these results suggest that a previously underappreciated factor, stress heterogeneities within the airway wall and consequent ASM cellular response to this micromechanical environment, could contribute to AHR and should be explored further both theoretically and experimentally. Copyright © 2016 the American Physiological Society.

  9. Blood eosinophil counts during bronchiolitis are related to bronchial hyper-responsiveness and lung function in early adolescence.

    PubMed

    Mikalsen, Ingvild Bruun; Halvorsen, Thomas; Øymar, Knut

    2014-01-01

    To assess whether inflammatory markers measured in urine and blood during acute bronchiolitis in infancy were associated with asthma, lung function, bronchial hyper-responsiveness (BHR) and atopy at 11 years of age. We included 105 children hospitalised for bronchiolitis during their first year of life. At hospitalisation, urinary (U-) eosinophil protein X, U-leukotriene E4 , U-prostaglandin 9α, 11β-PGF2 and blood eosinophil counts were measured. Ninety-five children (90%) were available for follow-up at 11 years of age. At follow-up, higher blood eosinophil counts obtained during bronchiolitis were observed in the group with asthma than in the group without asthma (median 0.27 versus 0.09 × 10(9) /L, respectively, p = 0.048). By regression analyses, blood eosinophil counts during the acute bronchiolitis were positively associated with BHR (p = 0.006) and negatively associated with forced expiratory volume in first second (p = 0.025) at 11 years of age. None of the other inflammatory markers were associated with asthma, lung function, BHR or atopy at 11 years of age. Eosinophil inflammation during bronchiolitis may have a long-term impact on lung function and airway responsiveness. The associations could be related to virus-host interactions during bronchiolitis or to predisposed children. ©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  10. Short-term roxithromycin treatment attenuates airway inflammation via MAPK/NF-κB activation in a mouse model of allergic asthma.

    PubMed

    Ci, Xinxin; Chu, Xiao; Xu, Xue; Li, Hongyu; Deng, Xuming

    2012-07-01

    We investigated whether roxithromycin reduces ovalbumin-specific allergic asthma symptoms in mice, and we further investigated the inhibitory mechanism of roxithromycin in ovalbumin-specific allergic asthma. Mice were divided into five groups (n = 10 for each): control group, roxithromycin-treated groups (5, 20 and 40 mg/kg) and ovalbumin-challenged group. We measured the recruitment of inflammatory cells into the bronchoalveolar lavage fluid (BALF) or the lung tissues by Kwik-Diff and hematoxylin and eosin (H&E) staining, goblet cell hyperplasia by alcian blue-periodic acid-Schiff (AB-PAS) staining, airway hyperresponsiveness (AHR) by whole-body plethysmograph chamber, cytokine and immunoglobulin E (IgE) levels by ELISA, and the activation of mitogen-activated protein (MAP) kinases and nuclear factor-kappa B (NF-κB) in the lung tissues by Western blotting. Treatment with roxithromycin resulted in fewer inflammatory cells in the BALF and peribronchial areas, and decreased AHR, goblet cell hyperplasia, IgE levels and inflammatory cytokines, as well as MAP kinases and NF-κB activation, which are increased in lung tissues of mice with ovalbumin-induced allergic asthma. Our data suggest that oral administration of roxithromycin suppresses ovalbumin-induced airway inflammation and AHR by regulating the inflammatory cytokines via MAP kinases/NF-κB pathway in inflammatory cells. Based on these results, we suggest that roxithromycin may be used as a therapeutic agent for allergy-induced asthma.

  11. Notch ligand delta-like 4 regulates development and pathogenesis of allergic airway responses by modulating IL-2 production and Th2 immunity.

    PubMed

    Jang, Sihyug; Schaller, Matthew; Berlin, Aaron A; Lukacs, Nicholas W

    2010-11-15

    Activation of the canonical Notch pathways has been implicated in Th cell differentiation, but the role of specific Notch ligands in Th2-mediated allergic airway responses has not been completely elucidated. In this study, we show that delta-like ligand 4 (Dll4) was upregulated on dendritic cells in response to cockroach allergen. Blocking Dll4 in vivo during either the primary or secondary response enhanced allergen-induced pathogenic consequences including airway hyperresponsiveness and mucus production via increased Th2 cytokines. In vitro assays demonstrated that Dll4 regulates IL-2 in T cells from established Th2 responses as well as during primary stimulation. Notably, Dll4 blockade during the primary, but not the secondary, response increased IL-2 levels in lung and lymph node of allergic mice. The in vivo neutralization of Dll4 was associated with increased expansion and decreased apoptosis during the primary allergen sensitization. Moreover, Dll4-mediated Notch activation of T cells during primary stimulation in vitro increased apoptosis during the contraction/resting phase of the response, which could be rescued by exogenous IL-2. Consistent with the role for Dll4-mediated IL-2 regulation in overall T cell function, the frequency of IL-4-producing cells was also significantly altered by Dll4 both in vivo and in vitro. These data demonstrate a regulatory role of Dll4 both in initial Th2 differentiation and in Th2 cytokine production in established allergic responses.

  12. Prevention of airway inflammation with topical cream containing imiquimod and small interfering RNA for natriuretic peptide receptor

    PubMed Central

    Wang, Xiaoqin; Xu, Weidong; Mohapatra, Subhra; Kong, Xiaoyuan; Li, Xu; Lockey, Richard F; Mohapatra, Shyam S

    2008-01-01

    Background Asthma is a complex disease, characterized by reversible airway obstruction, hyperresponsiveness and chronic inflammation. Principle pharmacologic treatments for asthma include bronchodilating beta2-agonists and anti-inflammatory glucocorticosteroids; but these agents do not target the main cause of the disease, the generation of pathogenic Th2 cells. We previously reported reduction in allergic inflammation in mice deficient in the ANP receptor NPRA. Here we determined whether siRNA for natriuretic peptide receptor A (siNPRA) protected against asthma when administered transdermally. Methods Imiquimod cream mixed with chitosan nanoparticles containing either siRNA green indicator (siGLO) or siNPRA was applied to the skin of mice. Delivery of siGLO was confirmed by fluorescence microscopy. The anti-inflammatory activity of transdermal siNPRA was tested in OVA-sensitized mice by measuring airway hyperresponsiveness, eosinophilia, lung histopathology and pro-inflammatory cytokines. Results SiGLO appearing in the lung proved the feasibility of transdermal delivery. In a mouse asthma model, BALB/c mice treated with imiquimod cream containing siNPRA chitosan nanoparticles showed significantly reduced airway hyperresponsiveness, eosinophilia, lung histopathology and pro-inflammatory cytokines IL-4 and IL-5 in lung homogenates compared to controls. Conclusion These results demonstrate that topical cream containing imiquimod and siNPRA nanoparticles exerts an anti-inflammatory effect and may provide a new and simple therapy for asthma. PMID:18279512

  13. Resolution of cell-mediated airways diseases

    PubMed Central

    2010-01-01

    "Inflammation resolution" has of late become a topical research area. Activation of resolution phase mechanisms, involving select post-transcriptional regulons, transcription factors, 'autacoids', and cell phenotypes, is now considered to resolve inflammatory diseases. Critical to this discourse on resolution is the elimination of inflammatory cells through apoptosis and phagocytosis. For major inflammatory diseases such as asthma and COPD we propose an alternative path to apoptosis for cell elimination. We argue that transepithelial migration of airway wall leukocytes, followed by mucociliary clearance, efficiently and non-injuriously eliminates pro-inflammatory cells from diseased airway tissues. First, it seems clear that numerous infiltrated granulocytes and lymphocytes can be speedily transmitted into the airway lumen without harming the epithelial barrier. Then there are a wide range of 'unexpected' findings demonstrating that clinical improvement of asthma and COPD is not only associated with decreasing numbers of airway wall inflammatory cells but also with increasing numbers of these cells in the airway lumen. Finally, effects of inhibition of transepithelial migration support the present hypothesis. Airway inflammatory processes have thus been much aggravated when transepithelial exit of leukocytes has been inhibited. In conclusion, the present hypothesis highlights risks involved in drug-induced inhibition of transepithelial migration of airway wall leukocytes. It helps interpretation of common airway lumen data, and suggests approaches to treat cell-mediated airway inflammation. PMID:20540713

  14. Feasibility and acceptability of using bronchial hyperresponsiveness to manage asthma in primary care: a pilot study.

    PubMed

    Turton, James A; Glasgow, Nicholas J; Brannan, John D

    2012-03-01

    To determine if indirect testing for bronchial hyperresponsiveness (BHR) to monitor inhaled corticosteroid (ICS) treatment in asthma is feasible and acceptable in primary care. Fourteen adult patients with asthma aged 22-70 years (4M:10F, forced expiratory volume in 1 s >70% predicted) taking ICS performed a test for BHR using mannitol on three visits 6 weeks apart. ICS dose adjustments were made based on the presence of BHR. The Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire were used at each visit. A semi structured interview at study exit assessed subject acceptability. BHR did not return in those with no BHR at study entry (n=9) with decreasing ICS dose. Improvements in BHR with increasing ICS dose (n=5) were observed with clinically significant improvements in AQLQ (mean score increase >0.5, p=0.02). Feasibility and acceptability of BHR testing was demonstrated. It is feasible and acceptable to perform BHR testing using mannitol to help identify patients with asthma who would benefit from ICS dose increases and those with no BHR who could have a dose reduction. Australia New Zealand Clinical Trial Registry ACTRN12610000807055.

  15. Myeloid cell HIF-1α regulates asthma airway resistance and eosinophil function

    PubMed Central

    Akong-Moore, Kathryn; Feldstein, Stephanie; Johansson, Per; Nyugen, Anh; McEachern, Elisa K.; Nicatia, Shari; Cowburn, Andrew S.; Olson, Joshua; Cho, Jae Youn; Isaacs, Hart; Johnson, Randall S.; Broide, David H.; Nizet, Victor

    2013-01-01

    Hypoxia-inducible factor (HIF)-1α is a master regulator of inflammatory activities of myeloid cells, including neutrophils and macrophages. These studies examine the role of myeloid cell HIF-1α in regulating asthma induction and pathogenesis, and for the first time, evaluate the roles of HIF-1α and HIF-2α in the chemotactic properties of eosinophils, the myeloid cells most associated with asthma. Wild-type (WT) and myeloid cell-specific HIF-1α knockout (KO) C57BL/6 mice were studied in an ovalbumin (OVA) model of asthma. Administration of the pharmacological HIF-1α antagonist YC-1 was used to corroborate findings from the genetic model. WT, HIF-1α, and HIF-2α KO eosinophils underwent in vitro chemotaxis assays. We found that deletion of HIF-1α in myeloid cells and systemic treatment with YC-1 during asthma induction decreased airway hyperresponsiveness (AHR). Deletion of HIF-1α in myeloid cells in OVA-induced asthma also reduced eosinophil infiltration, goblet cell hyperplasia, and levels 34 of cytokines IL-4, IL-5, and IL-13 in the lung. HIF-1α inhibition with YC-1 during asthma induction decreased eosinophilia in bronchoalveolar lavage, lung parenchyma, and blood, as well as decreased total lung inflammation, IL-5, and serum OVA-specific IgE levels. Deletion of HIF-1α in eosinophils decreased their chemotaxis, while deletion of the isoform HIF-2α led to increased chemotaxis. This work demonstrates that HIF-1α in myeloid cells plays a role in asthma pathogenesis, particularly in AHR development. Additionally, treatment with HIF-1α inhibitors during asthma induction decreases AHR and eosinophilia. Finally, we show that HIF- 1α and HIF-2α regulate eosinophil migration in opposing ways. PMID:23250618

  16. Low-dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice.

    PubMed

    Chandler, Joshua D; Wongtrakool, Cherry; Banton, Sophia A; Li, Shuzhao; Orr, Michael L; Barr, Dana Boyd; Neujahr, David C; Sutliff, Roy L; Go, Young-Mi; Jones, Dean P

    2016-07-01

    Inhalation of cadmium (Cd) is associated with lung diseases, but less is known concerning pulmonary effects of Cd found in the diet. Cd has a decades-long half-life in humans and significant bioaccumulation occurs with chronic dietary intake. We exposed mice to low-dose CdCl2 (10 mg/L in drinking water) for 20 weeks, which increased lung Cd to a level similar to that of nonoccupationally exposed adult humans. Cd-treated mice had increased airway hyperresponsiveness to methacholine challenge, and gene expression array showed that Cd altered the abundance of 443 mRNA transcripts in mouse lung. In contrast to higher doses, low-dose Cd did not elicit increased metallothionein transcripts in lung. To identify pathways most affected by Cd, gene set enrichment of transcripts was analyzed. Results showed that major inducible targets of low-dose Cd were neuronal receptors represented by enriched olfactory, glutamatergic, cholinergic, and serotonergic gene sets. Olfactory receptors regulate chemosensory function and airway hypersensitivity, and these gene sets were the most enriched. Targeted metabolomics analysis showed that Cd treatment also increased metabolites in pathways of glutamatergic (glutamate), serotonergic (tryptophan), cholinergic (choline), and catecholaminergic (tyrosine) receptors in the lung tissue. Protein abundance measurements showed that the glutamate receptor GRIN2A was increased in mouse lung tissue. Together, these results show that in mice, oral low-dose Cd increased lung Cd to levels comparable to humans, increased airway hyperresponsiveness and disrupted neuronal pathways regulating bronchial tone. Therefore, dietary Cd may promote or worsen airway hyperresponsiveness in multiple lung diseases including asthma. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  17. The Airway Microbiome at Birth

    PubMed Central

    Lal, Charitharth Vivek; Travers, Colm; Aghai, Zubair H.; Eipers, Peter; Jilling, Tamas; Halloran, Brian; Carlo, Waldemar A.; Keeley, Jordan; Rezonzew, Gabriel; Kumar, Ranjit; Morrow, Casey; Bhandari, Vineet; Ambalavanan, Namasivayam

    2016-01-01

    Alterations of pulmonary microbiome have been recognized in multiple respiratory disorders. It is critically important to ascertain if an airway microbiome exists at birth and if so, whether it is associated with subsequent lung disease. We found an established diverse and similar airway microbiome at birth in both preterm and term infants, which was more diverse and different from that of older preterm infants with established chronic lung disease (bronchopulmonary dysplasia). Consistent temporal dysbiotic changes in the airway microbiome were seen from birth to the development of bronchopulmonary dysplasia in extremely preterm infants. Genus Lactobacillus was decreased at birth in infants with chorioamnionitis and in preterm infants who subsequently went on to develop lung disease. Our results, taken together with previous literature indicating a placental and amniotic fluid microbiome, suggest fetal acquisition of an airway microbiome. We speculate that the early airway microbiome may prime the developing pulmonary immune system, and dysbiosis in its development may set the stage for subsequent lung disease. PMID:27488092

  18. Modulation of Allergic Airway Inflammation by the Oral Pathogen Porphyromonas gingivalis▿

    PubMed Central

    Card, Jeffrey W.; Carey, Michelle A.; Voltz, James W.; Bradbury, J. Alyce; Ferguson, Catherine D.; Cohen, Eric A.; Schwartz, Samuel; Flake, Gordon P.; Morgan, Daniel L.; Arbes, Samuel J.; Barrow, David A.; Barros, Silvana P.; Offenbacher, Steven; Zeldin, Darryl C.

    2010-01-01

    Accumulating evidence suggests that bacteria associated with periodontal disease may exert systemic immunomodulatory effects. Although the improvement in oral hygiene practices in recent decades correlates with the increased incidence of asthma in developed nations, it is not known whether diseases of the respiratory system might be influenced by the presence of oral pathogens. The present study sought to determine whether subcutaneous infection with the anaerobic oral pathogen Porphyromonas gingivalis exerts a regulatory effect on allergic airway inflammation. BALB/c mice sensitized and subsequently challenged with ovalbumin exhibited airway hyperresponsiveness to methacholine aerosol and increased airway inflammatory cell influx and Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13) content relative to those in nonallergic controls. Airway inflammatory cell and cytokine contents were significantly reduced by establishment of a subcutaneous infection with P. gingivalis prior to allergen sensitization, whereas serum levels of ovalbumin-specific IgE and airway responsiveness were not altered. Conversely, subcutaneous infection initiated after allergen sensitization did not alter inflammatory end points but did reduce airway responsiveness in spite of increased serum IgE levels. These data provide the first direct evidence of a regulatory effect of an oral pathogen on allergic airway inflammation and responsiveness. Furthermore, a temporal importance of the establishment of infection relative to allergen sensitization is demonstrated for allergic outcomes. PMID:20308298

  19. Airway remodeling and inflammation in competitive swimmers training in indoor chlorinated swimming pools.

    PubMed

    Bougault, Valérie; Loubaki, Lionel; Joubert, Philippe; Turmel, Julie; Couture, Christian; Laviolette, Michel; Chakir, Jamila; Boulet, Louis-Philippe

    2012-02-01

    Airway disorders are common in regular chlorinated swimming pool attendees, particularly competitive athletes, but the impact of intense swimming training on airway function and structure remains unclear. This study aimed to evaluate airway inflammation and remodeling in elite swimmers. Twenty-three elite swimmers were tested during off-training season. All had exhaled nitric oxide measurement, methacholine test, eucapnic voluntary hyperpnea challenge, allergy skin prick tests, and bronchoscopy with bronchial biopsies. Clinical data and tissues from 10 age-matched mild-asthmatic and 10 healthy nonallergic subjects were used for comparison. Swimmers had increased airway mucosa eosinophil and mast cell counts than did controls (P < .05). They had more goblet cell hyperplasia and higher mucin expression than did healthy or asthmatic subjects (P < .05). A greater submucosal type I and III collagen expression and tenascin deposition was also observed in swimmers than in controls (P < .05). Neither exhaled nitric oxide nor airway responsiveness to methacholine or eucapnic voluntary hyperpnea challenge correlated with these inflammatory and remodeling changes. Intense, long-term swimming training in indoor chlorinated swimming pools is associated with airway changes similar to those seen in mild asthma, but with higher mucin expression. These changes were independent from airway hyperresponsiveness. The long-term physiological and clinical consequences of these changes remain to be clarified. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  20. Cutting edge: STAT6 signaling in eosinophils is necessary for development of allergic airway inflammation.

    PubMed

    Stokes, Kindra; LaMarche, Nelson M; Islam, Nasif; Wood, Amie; Huang, Weishan; August, Avery

    2015-03-15

    Eosinophils are critical cellular mediators in allergic asthma and inflammation; however, the signals that regulate their functions are unclear. The transcription factor STAT6 regulates Th2 cytokine responses, acting downstream of IL-4 and IL-13. We showed previously that eosinophil-derived IL-13 plays an important role in the recruitment of T cells to the lung and the subsequent development of allergic asthma. However, whether eosinophils respond to Th2 signals to control allergic airway inflammation is unclear. In this report, we show that STAT6(-/-) eosinophils are unable to induce the development of allergic lung inflammation, including recruitment of CD4(+) T cells, mucus production, and development of airways hyperresponsiveness. This is likely due to the reduced migration of STAT6(-/-) eosinophils to the lung and in response to eotaxin. These data indicate that, like Th cells, eosinophils need to respond to Th2 cytokines via STAT6 during the development of allergic airway inflammation.

  1. Airway-parenchymal interdependence

    PubMed Central

    Paré, Peter D; Mitzner, Wayne

    2015-01-01

    In this manuscript we discuss the interaction of the lung parenchyma and the airways as well as the physiological and pathophysiological significance of this interaction. These two components of the respiratory organ can be thought of as two independent elastic structures but in fact the mechanical properties of one influence the behavior of the other. Traditionally the interaction has focused on the effects of the lung on the airways but there is good evidence that the opposite is also true, i.e., that the mechanical properties of the airways influence the elastic properties of the parenchyma. The interplay between components of the respiratory system including the airways, parenchyma and vasculature is often referred to as “interdependence.” This interdependence transmits the elastic recoil of the lung to create an effective pressure that dilates the airways as transpulmonary pressure and lung volume increase. By using a continuum mechanics analysis of the lung parenchyma, it is possible to predict the effective pressure between the airways and parenchyma, and these predictions can be empirically evaluated. Normal airway caliber is maintained by this pressure in the adventitial interstitium of the airway, and it counteracts airway compression during forced expiration as well as the ability of airway smooth muscle to narrow airways. Interdependence has physiological and pathophysiological significance. Weakening of the forces of interdependence contributes to airway dysfunction and gas exchange impairment in acute and chronic airway diseases including asthma and emphysema. PMID:23723029

  2. Airway pressure release ventilation: theory and practice.

    PubMed

    Frawley, P M; Habashi, N M

    2001-05-01

    Airway pressure release ventilation (APRV) is a relatively new mode of ventilation, that only became commercially available in the United States in the mid-1990s. Airway pressure release ventilation produces tidal ventilation using a method that differs from any other mode. It uses a release of airway pressure from an elevated baseline to simulate expiration. The elevated baseline facilitates oxygenation, and the timed releases aid in carbon dioxide removal. Advantages of APRV include lower airway pressures, lower minute ventilation, minimal adverse effects on cardio-circulatory function, ability to spontan