Science.gov

Sample records for airway symptoms induced

  1. Piperazine-induced airway symptoms: exposure-response relationships and selection in an occupational setting

    SciTech Connect

    Hagmar, L.; Bellander, T.; Ranstam, J.; Skerfving, S.

    1984-01-01

    The heterocyclic secondary amine piperazine is known to cause asthma. In a cohort of 602 workers, employed during the period 1942-1979, at a chemical industry where piperazine is handled, a study conducted by means of a mailed questionnaire showed a strong exposure-response relationship as to frequency of work-related airway symptoms indicating asthma. In the most exposed group about a third of the workers had experienced such symptoms. Age, length of employment, smoking habits, and previous work-related asthmatic symptoms, but not atopy, modified the response. Further, there was an association between piperazine exposure and chronic bronchitis. In the most exposed group every fourth subject had chronic bronchitis. The frequency was modified by smoking habits; atopy was a confounder. Although many subjects, especially high-exposed ones, left work because of airway symptoms, there was no difference in occurrence of airway symptoms between former and present employees.

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

    PubMed Central

    Brant, Tereza C S; Yoshida, Carolina T; de S. Carvalho, Tomas; Nicola, Marina L; Martins, Jocimar A; Braga, Lays M; de Oliveira, Regiani C; Leyton, Vilma; de André, Carmen S; Saldiva, Paulo H N; Rubin, Bruce K; Nakagawa, Naomi K

    2014-01-01

    OBJECTIVES: There is evidence that outdoor workers exposed to high levels of air pollution exhibit airway inflammation and increased airway symptoms. We hypothesized that these workers would experience increased airway symptoms and decreased nasal mucociliary clearance associated with their exposure to air pollution. METHODS: In total, 25 non-smoking commercial motorcyclists, aged 18-44 years, were included in this study. These drivers work 8-12 hours per day, 5 days per week, driving on urban streets. Nasal mucociliary clearance was measured by the saccharine transit test; airway acidification was measured by assessing the pH of exhaled breath condensate; and airway symptoms were measured by the Sino-nasal Outcome Test-20 questionnaire. To assess personal air pollution exposure, the subjects used a passive-diffusion nitrogen dioxide (NO2) concentration-monitoring system during the 14 days before each assessment. The associations between NO2 and the airway outcomes were analyzed using the Mann-Whitney test and the Chi-Square test. Clinicaltrials.gov: NCT01976039. RESULTS: Compared with clearance in healthy adult males, mucociliary clearance was decreased in 32% of the motorcyclists. Additionally, 64% of the motorcyclists had airway acidification and 92% experienced airway symptoms. The median personal NO2 exposure level was 75 mg/m3 for these subjects and a significant association was observed between NO2 and impaired mucociliary clearance (p = 0.036). CONCLUSION: Non-smoking commercial motorcyclists exhibit increased airway symptoms and airway acidification as well as decreased nasal mucociliary clearance, all of which are significantly associated with the amount of exposure to air pollution. PMID:25628001

  3. Allergen-induced airway responses.

    PubMed

    Gauvreau, Gail M; El-Gammal, Amani I; O'Byrne, Paul M

    2015-09-01

    Environmental allergens are an important cause of asthma and can contribute to loss of asthma control and exacerbations. Allergen inhalation challenge has been a useful clinical model to examine the mechanisms of allergen-induced airway responses and inflammation. Allergen bronchoconstrictor responses are the early response, which reaches a maximum within 30 min and resolves by 1-3 h, and late responses, when bronchoconstriction recurs after 3-4 h and reaches a maximum over 6-12 h. Late responses are followed by an increase in airway hyperresponsiveness. These responses occur when IgE on mast cells is cross-linked by an allergen, causing degranulation and the release of histamine, neutral proteases and chemotactic factors, and the production of newly formed mediators, such as cysteinyl leukotrienes and prostaglandin D2. Allergen-induced airway inflammation consists of an increase in airway eosinophils, basophils and, less consistently, neutrophils. These responses are mediated by the trafficking and activation of myeloid dendritic cells into the airways, probably as a result of the release of epithelial cell-derived thymic stromal lymphopoietin, and the release of pro-inflammatory cytokines from type 2 helper T-cells. Allergen inhalation challenge has also been a widely used model to study potential new therapies for asthma and has an excellent negative predictive value for this purpose. PMID:26206871

  4. Review of the upper airway, including olfaction, as mediator of symptoms.

    PubMed Central

    Shusterman, Dennis

    2002-01-01

    The upper airway serves as air conditioner, filter, and warning device. Two neurological modalities, olfaction and trigeminal chemoreception, inform us of the chemical qualities of the air we breathe. A number of poorly understood conditions, including nonallergic rhinitis, irritant-induced rhinitis, odor-triggered asthma, odor-triggered panic attacks, chemical-induced olfactory dysfunction, and irritant-associated vocal cord dysfunction, involve induction of symptoms by odorant and/or irritant chemicals in the upper airway. This article is a summary of the knowledge and theories about these various conditions, and highlights those aspects of nasal anatomy, physiology, and pathophysiology relevant to their understanding. PMID:12194901

  5. Irritant-induced airway disorders.

    PubMed

    Brooks, Stuart M; Bernstein, I Leonard

    2011-11-01

    Thousands of persons experience accidental high-level irritant exposures each year but most recover and few die. Irritants function differently than allergens because their actions proceed nonspecifically and by nonimmunologic mechanisms. For some individuals, the consequence of a single massive exposure to an irritant, gas, vapor or fume is persistent airway hyperresponsiveness and the clinical picture of asthma, referred to as reactive airways dysfunction syndrome (RADS). Repeated irritant exposures may lead to chronic cough and continual airway hyperresponsiveness. Cases of asthma attributed to repeated irritant-exposures may be the result of genetic and/or host factors. PMID:21978855

  6. Exercise-induced airways constriction 1

    PubMed Central

    Simonsson, Bo G.; Skoogh, B-E.; Ekström-Jodal, B.

    1972-01-01

    Airway conductance was measured in a body plethysmograph at different lung volumes before and after graded exercise. In 14 out of 19 patients, mostly asthmatics, airway conductance fell significantly after exercise. These subjects also showed other signs of an increased bronchial reactivity to different stimuli, including forced breathing, hyperventilation, and cold air, but they had no exogenous allergy. The exercise-induced bronchoconstriction could be blocked by atropine in six of the nine patients tested. Exercise-induced bronchoconstriction in patients with clinical and physiological evidence of increased airway reactivity thus seems to be primarily mediated via a vagal reflex, probably from hyperresponsive airway mechanoreceptors reacting to increased ventilatory flow or lung distension. No relation was found between PaCO2 or pH and the severity of airways constriction. Cromoglycic acid failed to block the exercise reaction in five of the six hyperreactive patients tested. In addition to or following the vagal reflex a disturbed relation between beta and alpha receptors in bronchial muscles or a release of humoral spasmogens may contribute to the progression of post-exercise airways constriction. PMID:4624586

  7. Permanent respiratory impairment and upper airway symptoms despite clinical improvement in patients with reactive airways dysfunction syndrome.

    PubMed

    Demeter, S L; Cordasco, E M; Guidotti, T L

    2001-04-10

    We previously reported clinical findings for 19 patients who developed symptomatic airways hyperactivity following an acute exposure to an inhaled irritant and who were given the diagnosis of reactive airways dysfunction syndrome (RADS). We now report on nine of these patients who have been followed for a mean of 9 years, allowing assessment of function, symptoms, and comorbidity beyond the early phase of acute airway injury and inflammation. None of the patients have resolved their airway hyper-responsiveness and symptoms completely, although only in one subject, who had a premorbid history of asthma, has the condition progressed. A common feature has been sinusitis and other upper-airway symptoms. We conclude that in this group of patients, RADS presented in a consistent pattern regardless of the cause of airway injury, resolved only partially, even in subjects without a premorbid history of respiratory disease, and was associated with significant secondary morbidity, especially affecting the upper airway. This pattern was evident regardless of smoking status or age at time of exposure. We conclude that for these subjects, RADS was a distinct entity with a consistent natural history that conferred permanent impairment, but did generally improve somewhat over time. PMID:11327398

  8. Airway-Related Symptoms and Surgeries in Patients With Mucopolysaccharidosis I

    PubMed Central

    Bruce, Iain A.; Wraith, James E.; Travers, Helen; Fallet, Shari

    2015-01-01

    Objective: Mucopolysaccharidosis I (MPS I) is a progressive, debilitating, and life-threatening genetic disease, which, owing to the nonspecific nature of the early symptoms, is often unrecognized and associated with significant diagnostic delays. To improve early recognition leading to early diagnosis and initiation of treatment, we characterized the extent of airway-related symptoms and surgeries among patients with MPS I. Methods: Analysis of the frequency of airway-related symptoms and surgeries from 1041 patients enrolled in the MPS I Registry and correlation with other systemic manifestations of MPS I. Results: Airway-related symptoms (macroglossia, enlarged tonsils, reactive airway disease/asthma, or sleep disturbances) were reported for as many as 85% of Hurler, 83% of Hurler-Scheie, and 65% of Scheie patients—very often before the diagnosis of MPS I was established. Surgeries for an airway indication were reported in 39% of patients and many had at least 1 airway-related surgery before the diagnosis of MPS I was confirmed. The mean percentage of patients with airway-related symptoms for whom hernias and/or dysostosis multiplex were also reported was 84% and 54%, respectively. Conclusion: Airway-related symptoms and surgeries are common and often the earliest presenting feature in MPS I. Improved recognition of early MPS I disease manifestations may lead to earlier diagnosis and treatment. PMID:25214650

  9. Importance of airway inflammation for hyperresponsiveness induced by ozone. [Dogs

    SciTech Connect

    Holtzman, M.J.; Fabbri, L.M.; O'Byrne, P.M.; Gold, B.D.; Aizawa, H.; Walters, E.H.; Alpert, S.E.; Nadel, J.A.

    1983-06-01

    We studied whether ozone-induced airway hyperresponsiveness correlates with the development of airway inflammation in dogs. To assess airway responsiveness, we determined increases in pulmonary resistance produced by delivering acetylcholine aerosol to the airways. To assess airway inflammation, we biopsied the airway mucosa and counted the number of neutrophils present in the epithelium. Airway responsiveness and inflammation were assessed in anesthetized dogs before ozone exposure and then 1 h and 1 wk after ozone (2.1 ppm, 2 h). Airway responsiveness increased markedly at 1 h after ozone and returned to control levels 1 wk later in each of 6 dogs, but it did not change after ozone in another 4 dogs. Furthermore, dogs that became hyperresponsive also developed a marked and reversible increase in the number of neutrophils in the epithelium, whereas dogs that did not become hyperresponsive had no change in the number of neutrophils. For the group of dogs, the level of airway responsiveness before and after ozone exposure correlated closely with the number of epithelial neutrophils. The results suggest that ozone-induced airway hyperresponsiveness may depend on the development of an acute inflammatory response in the airways.

  10. Airway Symptoms and Biological Markers in Nasal Lavage Fluid in Subjects Exposed to Metalworking Fluids

    PubMed Central

    Fornander, Louise; Graff, Pål; Wåhlén, Karin; Ydreborg, Kjell; Flodin, Ulf; Leanderson, Per; Lindahl, Mats; Ghafouri, Bijar

    2013-01-01

    Backgrounds Occurrence of airway irritation among industrial metal workers was investigated. The aims were to study the association between exposures from water-based metal working fluids (MWF) and the health outcome among the personnel, to assess potential effects on the proteome in nasal mucous membranes, and evaluate preventive actions. Methods The prevalence of airway symptoms related to work were examined among 271 metalworkers exposed to MWF and 24 metal workers not exposed to MWF at the same factory. At the same time, air levels of potentially harmful substances (oil mist, morpholine, monoethanolamine, formaldehyde) generated from MWF was measured. Nasal lavage fluid was collected from 13 workers and 15 controls and protein profiles were determined by a proteomic approach. Results Airway symptoms were reported in 39% of the workers exposed to MWF although the measured levels of MWF substances in the work place air were low. Highest prevalence was found among workers handling the MWF machines but also those working in the same hall were affected. Improvement of the ventilation to reduce MWF exposure lowered the prevalence of airway problems. Protein profiling showed significantly higher levels of S100-A9 and lower levels of SPLUNC1, cystatin SN, Ig J and β2-microglobulin among workers with airway symptoms. Conclusions This study confirms that upper airway symptoms among metal workers are a common problem and despite low levels of MWF-generated substances, effects on airway immune proteins are found. Further studies to clarify the role of specific MWF components in connection to airway inflammation and the identified biological markers are warranted. PMID:24391738

  11. 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. PMID:26916919

  12. 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

  13. Inflammation-induced plasticity of the afferent innervation of the airways.

    PubMed Central

    Carr, M J; Undem, B J

    2001-01-01

    The activation of primary afferent neurons that innervate the airways leads to homeostatic and defensive reflexes. The anatomic and physiologic characteristics of these afferent fibers do not appear to be static properties but rather appear to change rapidly in response to inflammation. The threshold for activation of airway afferent neurons to various stimuli, for example, is not fixed; these fibers can be become sensitized during inflammation. A subset of nociceptive-like (C-fibers) airway afferent neurons not only participates in centrally mediated reflexes but is also thought to release neuropeptides at their peripheral terminals, leading to neurogenic inflammation. An increase in the content of tachykinins is commonly seen in inflamed tissues, and there is accumulating evidence that irritation and inflammation of the airways is associated with the induction of tachykinin synthesis in non-nociceptive airway afferent fibers that under normal conditions do not contain neuropeptides. The release of neurokinins from the peripheral terminals in the airways and their central terminals in the brain stem may contribute to the symptoms of inflammatory airway diseases. Elevated release of neurokinins from peripheral terminals may promote local inflammatory responses, and the release of neurokinins in the brainstem, together with inflammation-induced increases in the excitability of afferent fibers, may culminate in altered visceral autonomic reflex activity, changes in breathing pattern, and cough. PMID:11544165

  14. [Exercise-induced airway obstruction in asthmatic children and adolescents].

    PubMed

    Zapletal, A; Zbojan, J; Pohanka, V

    1992-03-01

    In 115 asymptomatic asthmatic children and adolescents (age 6-18 years) there was studied the magnitude of airway obstruction, induced by various physical efforts and assessed from the recording of maximum expiratory flow-volume curves and in some patients by "specific" airway conductance measurement in a body plethysmograph. The effects of 5 minutes free running outdoors, 5 minutes of exercise on a bicycle ergometer (2 watts/kg of body weight), routine swimming training in swimming pool and of forced expiration maneuver on the magnitude of airway obstruction were assessed. The most frequent and largest degree of airway obstruction was observed after 5 min. free running outdoors (heart rate after running 160-200/min). The obstruction was revealed in 80-100% asthmatics in various groups. The chosen lung function parameters showed exercise-induced airway obstruction in the same patients in various proportions as well as the magnitude of the obstruction. Following free running outdoors the values of maximum expiratory flow at 25% of vital capacity and "specific" airway conductance were most reduced. Spontaneous retreat of obstruction was observed in the course of 2 hours. The physical exercise on a bicycle ergometer was a small stimulus in inducing of airway obstruction. The swimming in a pool did not provoke any obstruction. In 10% of our asthmatics airway obstruction was observed following forced expiration maneuver. Airway obstruction induced by 5 minutes free running outdoors and assessed best by flow-volume curves appeared as a suitable test in the assessment of airway hyperresponsiveness. PMID:1591810

  15. Fstl1 Promotes Asthmatic Airway Remodeling by Inducing Oncostatin M.

    PubMed

    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

    2015-10-15

    Chronic asthma is associated with airway remodeling and decline in lung function. In this article, we show that follistatin-like 1 (Fstl1), a mediator not previously associated with asthma, is highly expressed by macrophages in the lungs of humans with severe asthma. Chronic allergen-challenged Lys-Cre(tg) /Fstl1(Δ/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, whereas administration of an anti-OSM Ab 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/OSM pathway may be a novel pathway to inhibit airway remodeling in severe human asthma. PMID:26355153

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

    EPA Science Inventory

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

  17. Flat trachea syndrome: a rare condition with symptoms similar to obstructive airway disease.

    PubMed

    Gani, Mohammed Akil D; Rogers, Vanessa J C; Sachak, Khalid H; Marzouk, Joseph F K

    2015-01-01

    Flat trachea syndrome, commonly known as 'tracheobronchomalacia', is a central airway disease characterised by excessive expiratory collapse of the tracheobronchial posterior membrane due to weakness in the airway walls. Patients present with symptoms such as chronic cough, dyspnoea and recurrent respiratory tract infections, which are often attributed to more common conditions such as asthma and chronic obstructive pulmonary disease (COPD). The term 'Flat Trachea Syndrome' was first proposed by Niranjan and Marzouk in 2010 following a retrospective study of 28 patients with the condition who underwent surgery for it. The authors advocated the term due to the primary abnormality being collapse of the posterior membranous wall of the central airways as opposed to softening of the tracheal cartilage (tracheobronchomalacia), which they proposed is a misnomer. We present a rare case of a patient with flat trachea syndrome on a history of COPD who initially presented with recurrent respiratory tract infections. PMID:25721828

  18. Chlorine-induced injury to the airways in mice.

    PubMed

    Martin, James G; Campbell, Holly R; Iijima, Hiroaki; Gautrin, Denyse; Malo, Jean-Luc; Eidelman, David H; Hamid, Qutayba; Maghni, Karim

    2003-09-01

    Exposure to chlorine gas (Cl2) causes occupational asthma that we hypothesized occurs through the induction of airway inflammation and airway hyperresponsiveness by oxidative damage. Respiratory mechanics and airway responsiveness to methacholine were assessed in A/J mice 24 hours after a 5-minute exposure to 100, 200, 400, or 800 ppm Cl2 and 2 and 7 days after inhalation of 400 ppm Cl2. Airway responsiveness was higher 24 hours after 400 and 800 ppm Cl2. Responsiveness after inhalation of 400 ppm Cl2 returned to normal by 2 days but was again elevated at 7 days. Airway epithelial loss, patchy alveolar damage, proteinaceous exudates, and inflammatory cells within alveolar walls were observed in animals exposed to 800 ppm Cl2. Macrophages, granulocytes, epithelial cells, and nitrate/nitrite levels increased in lung lavage fluid. Increased inducible nitric oxide synthase expression and oxidation of lung proteins were observed. Epithelial cells and alveolar macrophages from mice exposed to 800 ppm Cl2 stained for 3-nitrotyrosine residues. Inhibition of inducible nitric oxide synthase with 1400W (1 mg/kg) abrogated the Cl2-induced changes in responsiveness. We conclude that chlorine exposure causes functional and pathological changes in the airways associated with oxidative stress. Inducible nitric oxide synthase is involved in the induction of changes in responsiveness to methacholine. PMID:12724121

  19. Ozone exposure increases eosinophilic airway response induced by previous allergen challenge.

    PubMed

    Vagaggini, Barbara; Taccola, Mauro; Cianchetti, Silvana; Carnevali, Stefano; Bartoli, Maria Laura; Bacci, Elena; Dente, Federico L; Di Franco, Antonella; Giannini, Daniele; Paggiaro, Pier Luigi

    2002-10-15

    We investigated whether exposure to ozone (O(3)) 24 hours after an allergen challenge test would increase airway eosinophilia induced by allergen in subjects with mild asthma with late airway response. Twelve subjects with mild atopic asthma participated in a randomized, single-blind study. Subjects underwent allergen challenge 24 hours before a 2 hour exposure to O(3) (0.27 ppm) or filtered air. Pulmonary function was monitored during the allergen challenge and after the exposure to O(3) or air. Six hours later, induced sputum was collected. After 4 weeks, the experiment was repeated with the same subjects. Allergen induced a comparable late airway response in both challenges. O(3) exposure induced a significant decrease in FVC, FEV(1), and vital capacity, and was associated with a significant increase in total symptom score compared with air exposure. The percentage of eosinophils, but not the percentage of neutrophils, in induced sputum was significantly higher after exposure to O(3) than after exposure to air (p = 0.04). These results indicate that O(3) exposure after a late airway response elicited by allergen challenge can potentiate the eosinophilic inflammatory response induced by the allergen challenge itself in subjects with mild atopic asthma. This observation may help explain the synergistic effect of air pollution and allergen exposure in the exacerbation of asthma. PMID:12379550

  20. 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

  1. 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. PMID:26276827

  2. Neuro-immune interactions in chemical-induced airway hyperreactivity.

    PubMed

    Devos, Fien C; Boonen, Brett; Alpizar, Yeranddy A; Maes, Tania; Hox, Valérie; Seys, Sven; Pollaris, Lore; Liston, Adrian; Nemery, Benoit; Talavera, Karel; Hoet, Peter H M; Vanoirbeek, Jeroen A J

    2016-08-01

    Asthma may be induced by chemical sensitisers, via mechanisms that are still poorly understood. This type of asthma is characterised by airway hyperreactivity (AHR) and little airway inflammation. Since potent chemical sensitisers, such as toluene-2,4-diisocyanate (TDI), are also sensory irritants, it is suggested that chemical-induced asthma relies on neuro-immune mechanisms.We investigated the involvement of transient receptor potential channels (TRP) A1 and V1, major chemosensors in the airways, and mast cells, known for their ability to communicate with sensory nerves, in chemical-induced AHR.In vitro intracellular calcium imaging and patch-clamp recordings in TRPA1- and TRPV1-expressing Chinese hamster ovarian cells showed that TDI activates murine TRPA1, but not TRPV1. Using an in vivo model, in which an airway challenge with TDI induces AHR in TDI-sensitised C57Bl/6 mice, we demonstrated that AHR does not develop, despite successful sensitisation, in Trpa1 and Trpv1 knockout mice, and wild-type mice pretreated with a TRPA1 blocker or a substance P receptor antagonist. TDI-induced AHR was also abolished in mast cell deficient Kit(Wsh) (/Wsh) mice, and in wild-type mice pretreated with the mast cell stabiliser ketotifen, without changes in immunological parameters.These data demonstrate that TRPA1, TRPV1 and mast cells play an indispensable role in the development of TDI-elicited AHR. PMID:27126687

  3. NITROTYROSINE ATTENUATES RSV-INDUCED INFLAMMATION IN AIRWAY EPITHELIAL CELLS

    EPA Science Inventory

    Nitrotyrosine attenuates RSV-induced inflammation in airway epithelial cells. Joleen Soukup, Zuowei Li, Susanne Becker and Yuh-Chin Huang. NHEERL, ORD, USEPA, RTP, North Carolina, CEMALB, University of North Carolina, Chapel Hill, North Carolina

    Nitrotyrosine (NO2Tyr) is a...

  4. Angiogenesis is induced by airway smooth muscle strain.

    PubMed

    Hasaneen, Nadia A; Zucker, Stanley; Lin, Richard Z; Vaday, Gayle G; Panettieri, Reynold A; Foda, Hussein D

    2007-10-01

    Angiogenesis is an important feature of airway remodeling in both chronic asthma and chronic obstructive pulmonary disease (COPD). Airways in those conditions are exposed to excessive mechanical strain during periods of acute exacerbations. We recently reported that mechanical strain of human airway smooth muscle (HASM) led to an increase in their proliferation and migration. Sustained growth in airway smooth muscle in vivo requires an increase in the nutritional supply to these muscles, hence angiogenesis. In this study, we examined the hypothesis that cyclic mechanical strain of HASM produces factors promoting angiogenic events in the surrounding vascular endothelial cells. Our results show: 1) a significant increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, migration, and tube formation following incubation in conditioned media (CM) from HASM cells exposed to mechanical strain; 2) mechanical strain of HASM cells induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited the proliferation, migration, and tube formations of HMVEC-L induced by the strained airway smooth muscle CM; 4) mechanical strain of HASM induced a significant increase in hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein, a transcription factor required for VEGF gene transcription; and 5) mechanical strain of HASM induced HIF-1alpha/VEGF through dual phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces signal transduction pathway through PI3K/Akt/mTOR and ERK pathways that lead to an increase in HIF-1alpha, a transcription factor required for VEGF expression. VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen with repeated exacerbation of asthma and COPD. PMID:17693481

  5. Continuous positive airway pressure therapy is associated with improvement in overactive bladder symptoms in women with obstructive sleep apnea syndrome

    PubMed Central

    Ipekci, Tumay; Cetintas, Gulgun; Celik, Orcun; Sarac, Sema; Tunckiran, Ahmet; Ilbey, Yusuf Ozlem

    2016-01-01

    Introduction To evaluate the impact of continuous positive airway pressure (CPAP) therapy on overactive bladder (OAB) symptoms in women with obstructive sleep apnea syndrome (OSAS). Material and methods One-hundred and fifty women underwent an overnight polysomnography study between May 2014 and September 2014. Their voiding symptoms were evaluated using the OAB symptom score (OABSS) and International Consultation on Incontinence Questionnaire Short-Form at OSAS diagnosis and approximately 3-months after CPAP therapy. OSAS severity was assessed according to the apnea-hypopnea-index. Results We evaluated 140 women and 111 of them (79.3%) reported symptoms consistent with OAB. There were no statistically significant differences between OSAS severity with a prevalence of OAB (p = 0.92). The prevalence of urinary incontinence (UI) was 35.7% (n = 50) and 39.6% (n = 44) in all patients and patients with OAB, respectively. There were no statistically significant differences between UI with OAB (p = 0.58). Baseline OABSS is comparable between OSAS severity (p = 0.143). After 3-months CPAP therapy, OABSS and ICIQ-SF sum scores were significantly decreased in patients with severe and moderate OSAS (p <0.01), however, change of OABSS sum score was insignificant in patients with mild OSAS (p = 0.44). Conclusions CPAP therapy improves the OAB, OABSS and ICIQ-SF scores in women with severe and moderate OSAS. OSAS-induced OAB may be alleviated following CPAP therapy. PMID:27123331

  6. 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

  7. [Acute airway obstruction during chemotherapy-induced agranulocytosis with fever].

    PubMed

    Vandenbos, F; Deswardt, Ph; Hyvernat, H; Burel-Vandenbos, F; Bernardin, G

    2006-02-01

    Acute airway obstruction caused by mucoid impaction can cause sometimes life-threatening respiratory distress. Bronchial plugging is usually observed in subjects with chronic diseases such as asthma, allergic bronchopulmonary aspergillosis, or cystic fibrosis. In children, it can be related to heart failure. Acute airway obstruction in a patient without a chronic respiratory disease is exceptional. We report the case of a patient who developed bronchial plugs obstructing the bronchi during a period of agranulocytosis induced by chemotherapy. The patient experienced acute respiratory distress with asphyxia. The plugs were composed of fibrin and required several fibroscopic procedures for clearance. To our knowledge, this is the first case report of acute airway obstruction by plugging during a period of agranulocytosis. PMID:16604039

  8. Endothelial leukocyte adhesion molecule-1 mediates antigen-induced acute airway inflammation and late-phase airway obstruction in monkeys.

    PubMed Central

    Gundel, R H; Wegner, C D; Torcellini, C A; Clarke, C C; Haynes, N; Rothlein, R; Smith, C W; Letts, L G

    1991-01-01

    This study examines the role of endothelial leukocyte adhesion molecule-1 (ELAM-1) in the development of the acute airway inflammation (cell influx) and late-phase airway obstruction in a primate model of extrinsic asthma. In animals sensitive to antigen, a single inhalation exposure induced the rapid expression of ELAM-1 (6 h) exclusively on vascular endothelium that correlated with the influx of neutrophils into the lungs and the onset of late-phase airway obstruction. In contrast, basal levels of ICAM-1 was constitutively expressed on vascular endothelium and airway epithelium before antigen challenge. After the single antigen exposure, changes in ICAM-1 expression did not correlate with neutrophil influx or the change in airway caliber. This was confirmed by showing that pretreatment with a monoclonal antibody to ICAM-1 did not inhibit the acute influx of neutrophils associated with late-phase airway obstruction, whereas a monoclonal antibody to ELAM-1 blocked both the influx of neutrophils and the late-phase airway obstruction. This study demonstrates a functional role for ELAM-1 in the development of acute airway inflammation in vivo. We conclude that, in primates, the late-phase response is the result of an ELAM-1 dependent influx of neutrophils. Therefore, the regulation of ELAM-1 expression may provide a novel approach to controlling the acute inflammatory response, and thereby, affecting airway function associated with inflammatory disorders, including asthma. Images PMID:1717514

  9. INDUCED SPUTUM DERIVES FROM THE CENTRAL AIRWAYS: CONFIRMATION USING A RADIOLABELED AEROSOL BOLUS DELIVERY TECHNIQUE

    EPA Science Inventory

    Indirect evidence suggests that induced sputum derives from the surfaces of the bronchial airways. To confirm this experimentally, we employed a radiolabeled aerosol bolus delivery technique that preferentially deposits aerosol in the central airways in humans. We hypothesized th...

  10. Secondhand smoke exposure induces acutely airway acidification and oxidative stress.

    PubMed

    Kostikas, Konstantinos; Minas, Markos; Nikolaou, Eftychia; Papaioannou, Andriana I; Liakos, Panagiotis; Gougoura, Sofia; Gourgoulianis, Konstantinos I; Dinas, Petros C; Metsios, Giorgos S; Jamurtas, Athanasios Z; Flouris, Andreas D; Koutedakis, Yiannis

    2013-02-01

    Previous studies have shown that secondhand smoke induces lung function impairment and increases proinflammatory cytokines. The aim of the present study was to evaluate the acute effects of secondhand smoke on airway acidification and airway oxidative stress in never-smokers. In a randomized controlled cross-over trial, 18 young healthy never-smokers were assessed at baseline and 0, 30, 60, 120, 180 and 240 min after one-hour secondhand smoke exposure at bar/restaurant levels. Exhaled NO and CO measurements, exhaled breath condensate collection (for pH, H(2)O(2) and NO(2)(-)/NO(3)(-) measurements) and spirometry were performed at all time-points. Secondhand smoke exposure induced increases in serum cotinine and exhaled CO that persisted until 240 min. Exhaled breath condensate pH decreased immediately after exposure (p < 0.001) and returned to baseline by 180 min, whereas H(2)O(2) increased at 120 min and remained increased at 240 min (p = 0.001). No changes in exhaled NO and NO(2)/NO(3) were observed, while decreases in FEV(1) (p < 0.001) and FEV(1)/FVC (p < 0.001) were observed after exposure and returned to baseline by 180 min. A 1-h exposure to secondhand smoke induced airway acidification and increased airway oxidative stress, accompanied by significant impairment of lung function. Despite the reversal in EBC pH and lung function, airway oxidative stress remained increased 4 h after the exposure. Clinical trial registration number (EudraCT): 2009-013545-28. PMID:23218453

  11. The effect of selective antagonist of H4 receptor JNJ7777120 on nasal symptoms, cough, airway reactivity and inflammation in guinea pigs.

    PubMed

    Kovacova-Hanuskova, E; Gavliakova, S; Buday, T; Kosutova, P; Mokra, D; Urbanova-Fulmekova, A; Mokry, J; Plevkova, J

    2015-09-15

    The efficacy of H4R antagonist JNJ7777120 on nasal symptoms, cough, airway resistance (Raw), inflammatory cell count in bronchoalveolar lavage (BAL) and blood in ovalbumin (OVA) induced allergic rhinitis (AR) was studied in guinea pigs. Animals (n=8) were sensitized by i.p. OVA and were repeatedly challenged with nasal OVA to induce rhinitis, seven animals were not sensitized. Animals were pre-treated with JNJ7777120 2.5 and 5mg/kg i.p. 30 min prior OVA. Cough was induced by inhalation of citric acid, Raw was measured in vivo by Pennock's method as baseline, during AR and after JNJ7777120 treatment. Leucocyte count in BAL and blood was analyzed. JNJ7777120 (5mg/kg) significantly suppressed nasal symptoms and the number of coughs. This compound significantly inhibited airway reactivity to histamine, but not methacholine. Pre-treatment with JNJ7777120 5mg/kg did not influence significantly the leucocyte count in BAL and blood except for a significant decrease in monocyte count in blood compared to the control group (p<0.05). We conclude that the antitussive action of JNJ7777120 is peripheral. The primary effect of the compound is anti-inflammatory, and the suppression of cough is a consequence of reduced airway inflammation. PMID:26003849

  12. Analysis of airway secretions in a model of sulfur dioxide induced chronic obstructive pulmonary disease (COPD)

    PubMed Central

    Wagner, Ulrich; Staats, Petra; Fehmann, Hans-Christoph; Fischer, Axel; Welte, Tobias; Groneberg, David A

    2006-01-01

    Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20–25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion. In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD. PMID:16759388

  13. Early interleukin 4-dependent response can induce airway hyperreactivity before development of airway inflammation in a mouse model of asthma.

    PubMed

    To, Y; Dohi, M; Tanaka, R; Sato, A; Nakagome, K; Yamamoto, K

    2001-10-01

    In experimental models of bronchial asthma with mice, airway inflammation and increase in airway hyperreactivity (AHR) are induced by a combination of systemic sensitization and airway challenge with allergens. In this report, we present another possibility: that systemic antigen-specific sensitization alone can induce AHR before the development of inflammation in the airway. Male BALB/c mice were sensitized with ovalbumin (OVA) by a combination of intraperitoneal injection and aerosol inhalation, and various parameters for airway inflammation and hyperreactivity were sequentially analyzed. Bronchial response measured by a noninvasive method (enhanced pause) and the eosinophil count and interleukin (IL)-5 concentration in bronchoalveolar lavage fluid (BALF) gradually increased following the sensitization, and significant increase was achieved after repeated OVA aerosol inhalation along with development of histologic changes of the airway. In contrast, AHR was already significantly increased by systemic sensitization alone, although airway inflammation hardly developed at that time point. BALF IL-4 concentration and the expression of IL-4 mRNA in the lung reached maximal values after the systemic sensitization, then subsequently decreased. Treatment of mice with anti-IL-4 neutralizing antibody during systemic sensitization significantly suppressed this early increase in AHR. In addition, IL-4 gene-targeted mice did not reveal this early increase in AHR by systemic sensitization. These results suggest that an immune response in the lung in an early stage of sensitization can induce airway hyperreactivity before development of an eosinophilic airway inflammation in BALB/c mice and that IL-4 plays an essential role in this process. If this early increase in AHR does occur in sensitized human infants, it could be another therapeutic target for early prevention of the future onset of asthma. PMID:11598151

  14. Mechanisms to Suppress ILC2-induced Airway Inflammation.

    PubMed

    Kabata, Hiroki; Moro, Kazuyo; Koyasu, Shigeo; Fukunaga, Koichi; Asano, Koichiro; Betsuyaku, Tomoko

    2016-03-01

    Epithelial cell-derived cytokines such as IL-33 and IL-25 activate group 2 innate lymphoid cells (ILC2s), which are known to be important sources of type 2 cytokines such as IL-5 and IL-13 in a variety of asthma mouse models. Recently, human studies have also reported the involvement of ILC2s in asthma, as ILC2s are increased in peripheral blood and bronchoalveolar lavage fluid in patients with asthma. Compared with positive regulators such as IL-25 and IL-33, the mechanisms to suppress the ILC2s-induced inflammation remain unclear. Because ILC2s express various cytokine receptors, the function of ILC2s would likely be influenced by cytokines present around ILC2s in the lungs. We reported that IL-2, IL-7, and thymic stromal lymphopoietin (TSLP) induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) and promoted the proliferation of ILC2s and type 2 cytokine production when combined with IL-33. TSLP enhanced the expression of Bcl-xL, an antiapoptotic molecule, and caused corticosteroid-resistant airway inflammation via ILC2s in mice. Furthermore, pimozide, a STAT5 inhibitor, counteracted the TSLP-induced corticosteroid resistance and suppressed airway inflammation. As a negative regulator, we have found that IFN-γ and IL-27 suppressed the proliferation and type 2 cytokine production of ILC2s in vitro and in vivo. Interestingly, ILC2s-induced eosinophilic inflammation was more severe in IFN-γ receptor-deficient mice than in control mice. These findings suggest the importance of environmental cytokines for the regulation of ILC2s, and this would lead to a new approach to control airway inflammation in asthma. PMID:27027961

  15. Acid aspiration-induced airways hyperresponsiveness in mice.

    PubMed

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

    2009-12-01

    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 microl 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 (R(N)), and tissue damping (G) were derived from Zrs. Aspirate pH of 1.8 led to a significant overall increase in peak R(N), 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

  16. 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

  17. Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation.

    PubMed

    Feng, Qiuqin; Su, Zhonglan; Song, Shiyu; Χu, Hui; Zhang, Bin; Yi, Long; Tian, Man; Wang, Hongwei

    2016-09-01

    Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS‑2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-κB (NF-κB), cyclo-oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-α (IFN-α) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-κB, COX-2, MAPK and Stat3, which orchestrate pro‑inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of

  18. Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation

    PubMed Central

    Feng, Qiuqin; Su, Zhonglan; Song, Shiyu; Xu, Hui; Zhang, Bin; Yi, Long; Tian, Man; Wang, Hongwei

    2016-01-01

    Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS-2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-κB (NF-κB), cyclo-oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-α (IFN-α) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-κB, COX-2, MAPK and Stat3, which orchestrate pro-inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of RSV infection

  19. Effects of ozone and endotoxin coexposure on rat airway epithelium: potentiation of toxicant-induced alterations.

    PubMed

    Wagner, J G; Hotchkiss, J A; Harkema, J R

    2001-08-01

    Tropospheric ozone is the major oxidizing component in photochemical smog and is one of the most pervasive problems to human health of the criteria air pollutants for which the National Ambient Air Quality Standards have been designated by the Clean Air Act. Although many adverse health effects of ozone exposure have been documented in both humans and laboratory animals, controversy surrounds the establishment and implementation of ozone standards set forth by the U.S. Environmental Protection Agency. Because people are commonly exposed to more than one air pollutant at a time, studies that examine coexposures to airborne materials may be more relevant for assessing their risks to human health. Airborne biogenic substances such as pollens, spores, and bacterial products are ubiquitous in the environment, and when inhaled can cause adverse respiratory symptoms. One such biogenic agent, bacterial endotoxin, is a potent stimulus of airway inflammation and is a ubiquitous airborne contaminant commonly found in domestic, agricultural, and industrial settings. Little is known about the interaction of exposures to biogenic substances and criteria air pollutants such as ozone. In the last few years we have performed a series of studies in rodents that examined the biologic responses of the respiratory epithelium after airway exposures to both endotoxin and ozone. When exposed to ozone (0.5 ppm 8 hr/day for 3 days), Fischer rats develop lesions in the nasal transitional epithelium, whereas intranasal instillation of endotoxin (20 microg) elicits epithelial lesions in the respiratory epithelium of the nose and conducting airways. Our studies were designed to examine how exposure to one toxicant may affect the airway epithelial lesions induced by the other toxicant. We investigated the potential role of acute inflammation in the enhancement of airway epithelial lesions after exposure of these two toxicants in neutrophil-sufficient and neutrophil-deficient rodents. A summary

  20. Effects of ozone and endotoxin coexposure on rat airway epithelium: potentiation of toxicant-induced alterations.

    PubMed Central

    Wagner, J G; Hotchkiss, J A; Harkema, J R

    2001-01-01

    Tropospheric ozone is the major oxidizing component in photochemical smog and is one of the most pervasive problems to human health of the criteria air pollutants for which the National Ambient Air Quality Standards have been designated by the Clean Air Act. Although many adverse health effects of ozone exposure have been documented in both humans and laboratory animals, controversy surrounds the establishment and implementation of ozone standards set forth by the U.S. Environmental Protection Agency. Because people are commonly exposed to more than one air pollutant at a time, studies that examine coexposures to airborne materials may be more relevant for assessing their risks to human health. Airborne biogenic substances such as pollens, spores, and bacterial products are ubiquitous in the environment, and when inhaled can cause adverse respiratory symptoms. One such biogenic agent, bacterial endotoxin, is a potent stimulus of airway inflammation and is a ubiquitous airborne contaminant commonly found in domestic, agricultural, and industrial settings. Little is known about the interaction of exposures to biogenic substances and criteria air pollutants such as ozone. In the last few years we have performed a series of studies in rodents that examined the biologic responses of the respiratory epithelium after airway exposures to both endotoxin and ozone. When exposed to ozone (0.5 ppm 8 hr/day for 3 days), Fischer rats develop lesions in the nasal transitional epithelium, whereas intranasal instillation of endotoxin (20 microg) elicits epithelial lesions in the respiratory epithelium of the nose and conducting airways. Our studies were designed to examine how exposure to one toxicant may affect the airway epithelial lesions induced by the other toxicant. We investigated the potential role of acute inflammation in the enhancement of airway epithelial lesions after exposure of these two toxicants in neutrophil-sufficient and neutrophil-deficient rodents. A summary

  1. Immunolocalization of NLRP3 Inflammasome in Normal Murine Airway Epithelium and Changes following Induction of Ovalbumin-Induced Airway Inflammation.

    PubMed

    Tran, Hai B; Lewis, Martin D; Tan, Lor Wai; Lester, Susan E; Baker, Leonie M; Ng, Jia; Hamilton-Bruce, Monica A; Hill, Catherine L; Koblar, Simon A; Rischmueller, Maureen; Ruffin, Richard E; Wormald, Peter J; Zalewski, Peter D; Lang, Carol J

    2012-01-01

    Little is known about innate immunity and components of inflammasomes in airway epithelium. This study evaluated immunohistological evidence for NLRP3 inflammasomes in normal and inflamed murine (Balb/c) airway epithelium in a model of ovalbumin (OVA) induced allergic airway inflammation. The airway epithelium of control mice exhibited strong cytoplasmic staining for total caspase-1, ASC, and NLRP3, whereas the OVA mice exhibited strong staining for active caspase-1, with redistribution of caspase-1, IL-1β and IL-18, indicating possible activation of the NLRP3 inflammasome. Active caspase-1, NLRP3, and other inflammasome components were also detected in tissue eosinophils from OVA mice, and may potentially contribute to IL-1β and IL-18 production. In whole lung, inRNA expression of NAIP and procaspase-1 was increased in OVA mice, whereas NLRP3, IL-1β and IL-18 decreased. Some OVA-treated mice also had significantly elevated and tightly correlated serum levels of IL-1β and TNFα. In cultured normal human bronchial epithelial cells, LPS priming resulted in a significant increase in NLRP3 and II-lp protein expression. This study is the first to demonstrate NLRP3 inflammasome components in normal airway epithelium and changes with inflammation. We propose activation and/or luminal release of the inflammasome is a feature of allergic airway inflammation which may contribute to disease pathogenesis. PMID:22523501

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

    PubMed

    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; Anathy, Vikas

    2016-06-01

    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

  3. Effect of an anti-Mo1 MAb on ozone-induced airway inflammation and airway hyperresponsiveness in dogs

    SciTech Connect

    Li, Z.; Daniel, E.E.; Lane, C.G.; Arnaout, M.A.; O'Byrne, P.M. )

    1992-12-01

    Ozone inhalation causes neutrophil migration into the airway and airway hyperresponsiveness in dogs. The leukocyte adhesion molecule Mo1 (CD11b/CD18) is a heterodimeric glycoprotein the expression of which is necessary for neutrophil adhesion to endothelium. To evaluate the contribution of Mo1 to ozone-induced neutrophil influx and airway hyperresponsiveness, six dogs were treated intravenously with an Anti-Mo1 monoclonal antibody (3.75 mg/kg in normal saline) that binds to both human and canine Mo1, or the diluent alone, 1.5 h before inhaling ozone (3 ppm for 30 min), or dry air. Airway responses to doubling doses of inhaled acetylcholine (ACh) were measured before and after inhalation of ozone. Neutrophil influx was assessed by bronchoalveolar lavage (BAL) performed after the second ACh inhalation. Treatment with anti-Mo1 prevented the ozone-induced influx of neutrophils into BAL. After diluent and inhaled dry air, the neutrophil count in BAL was 1.49 +/- 1.26 (SE) x 10(4) (5.0% of total cells). After diluent and inhaled ozone, the neutrophil count increased to 7.27 +/- 3.22 (SE) x 10(4) (22.6% of total cells) (P < 0.05). After anti-Mo1 and inhaled ozone, the neutrophil count was 1.48 +/- 0.62 (SE) x 10(4) (8.5% of total cells). Treatment with anti-Mo1 also significantly reduced the number of eosinophils in BAL after ozone. Ozone-induced ACh airway hyperresponsiveness was not prevented by treatment with anti-Mo1. These results indicate that expression of Mo1 is necessary for ozone-induced neutrophil migration into the airway lumen.

  4. Airway dysfunction in swimmers.

    PubMed

    Bougault, Valérie; Boulet, Louis-Philippe

    2012-05-01

    Elite competitive swimmers are particularly affected by airway disorders that are probably related to regular and intense training sessions in a chlorinated environment. Upper and lower airway respiratory symptoms, rhinitis, airway hyper-responsiveness, and exercise-induced bronchoconstriction are highly prevalent in these athletes, but their influence on athletic performance is still unclear. The authors reviewed the main upper and lower respiratory ailments observed in competitive swimmers who train in indoor swimming pools, their pathophysiology, clinical significance and possible effects on performance. Issues regarding the screening of these disorders, their management and preventive measures are addressed. PMID:22247299

  5. Pristimerin attenuates ovalbumin-induced allergic airway inflammation in mice.

    PubMed

    Jin, Yingli; Wang, Yujia; Zhao, Danning; Ma, Sitong; Lu, Jing; Shuang, Guan

    2016-06-01

    Pristimerin has been shown to possess antiinflammatory activity. However, its potential use for asthma induced by airway inflammation has not yet been studied. First, we established a ovalbumin (OVA)-induced allergic asthma mice model. BALB/c mice were immunized and challenged by OVA. Treatment with pristimerin caused a marked reduction in the levels of OVA-specific IgE, immune cells, and IL-4, IL-5, IL-13 secretion. Histological studies using H&E staining were used to study the alterations in lung tissue. These results were similar to those obtained with dexamethasone treatment. We then investigated which signal transduction mechanisms could be implicated in pristimerin activity by Western blot. The data showed that pristimerin could inhibit MAPKs and NF-κB inflammatory pathways. PMID:27098091

  6. Dendritic cells and alveolar macrophages mediate IL-13–induced airway inflammation and chemokine production

    PubMed Central

    Crapster-Pregont, Margaret; Yeo, Janice; Sanchez, Raquel L.; Kuperman, Douglas A.

    2013-01-01

    Background IL-13 in the airway induces pathologies that are highly characteristic of asthma, including mucus metaplasia, airway hyperreactivity (AHR), and airway inflammation. As such, it is important to identify the IL-13–responding cell types that mediate each of the above pathologies. For example, IL-13’s effects on epithelium contribute to mucus metaplasia and AHR. IL-13’s effects on smooth muscle also contribute to AHR. However, it has been difficult to identify the cell types that mediate IL-13–induced airway inflammation. Objective We sought to determine which cell types mediate IL-13–induced airway inflammation. Methods We treated the airways of mice with IL-13 alone or in combination with IFN-γ. We associated the inhibitory effect of IFN-γ on IL-13–induced airway inflammation and chemokine production with cell types in the lung that coexpress IL-13 and IFN-γ receptors. We then evaluated IL-13–induced responses in CD11c promoter–directed diphtheria toxin receptor–expressing mice that were depleted of both dendritic cells and alveolar macrophages and in CD11b promoter–directed diphtheria toxin receptor– expressing mice that were depleted of dendritic cells. Results Dendritic cell and alveolar macrophage depletion protected mice from IL-13–induced airway inflammation and CCL11, CCL24, CCL22, and CCL17 chemokine production. Preferential depletion of dendritic cells protected mice from IL-13–induced airway inflammation and CCL22 and CCL17 chemokine production but not from IL-13–induced CCL11 and CCL24 chemokine production. In either case mice were not protected from IL-13–induced AHR and mucus metaplasia. Conclusions Pulmonary dendritic cells and alveolar macrophages mediate IL-13–induced airway inflammation and chemokine production. (J Allergy Clin Immunol 2012;129:1621-7.) PMID:22365581

  7. Snoring-Induced Nerve Lesions in the Upper Airway

    PubMed Central

    Poothrikovil, Rajesh P; Al Abri, Mohammed A

    2012-01-01

    The prevalence of habitual snoring is extremely high in the general population, and is reported to be roughly 40% in men and 20% in women. The low-frequency vibrations of snoring may cause physical trauma and, more specifically, peripheral nerve injuries, just as jobs which require workers to use vibrating tools over the course of many years result in local nerve lesions in the hands. Histopathological analysis of upper airway (UA) muscles have shown strong evidence of a varying severity of neurological lesions in groups of snoring patients. Neurophysiological assessment shows evidence of active and chronic denervation and re-innervation in the palatopharyngeal muscles of obstructive sleep apnoea (OSA) patients. Neurogenic lesions of UA muscles induced by vibration trauma impair the reflex dilation abilities of the UA, leading to an increase in the possibility of UA collapse. The neurological factors which are partly responsible for the progressive nature of OSAS warrant the necessity of early assessment in habitual snorers. PMID:22548134

  8. Interrelationships between diagnosed asthma, asthma-like symptoms, and abnormal airway behaviour in adolescence: the Odense Schoolchild Study.

    PubMed Central

    Siersted, H. C.; Mostgaard, G.; Hyldebrandt, N.; Hansen, H. S.; Boldsen, J.; Oxhøj, H.

    1996-01-01

    BACKGROUND: The diagnosis of asthma is based on several characteristics including symptoms and suitable tests of airway lability. However, it is neither clear to what degree various tests and symptoms identify the same subjects, nor how these characteristics are best combined to diagnose asthma. The interrelationships between physician-diagnosed asthma, asthma-like symptoms, and abnormal airway function, as defined by four commonly used tests, have therefore been assessed. METHODS: A population based sample of 495 Danish schoolchildren aged 12-15 years, comprising 292 randomly selected subjects and 203 subjects considered at risk of having or developing asthma, was examined. Symptoms and background information were recorded by questionnaire. The test panel consisted of baseline forced expiratory volume in one second (FEV1%), provocation with treadmill exercise (EXE) and with inhaled methacholine (PD15), and monitoring of peak expiratory flow (PEF) twice daily for two weeks. RESULTS: The sensitivity for diagnosed asthma was highest for PD15 followed by PEF monitoring, whereas specificity for asthma or asthma-like symptoms was marginally higher with the other two tests. Most symptomatic subjects with any positive test were identified by PD15 alone (75%) or in combination with PEF monitoring (89%). PEF variability was more susceptible to treatment with inhaled steroids than the PD15 index. Although inter-test agreement was weak (kappa < 0.40 for all pairs), significant associations were found between PD15 and EXE, PEF and EXE, and FEV1% and PD15. CONCLUSIONS: The agreement between the four tests was weak. In particular, PEF variability and methacholine responsiveness seem to identify different varieties of airway pathophysiology. The combined use of methacholine provocation testing and PEF monitoring may be helpful as an epidemiological screening tool for asthma. PMID:8711678

  9. Airway Surface Dehydration Aggravates Cigarette Smoke-Induced Hallmarks of COPD in Mice

    PubMed Central

    Seys, Leen J. M.; Verhamme, Fien M.; Dupont, Lisa L.; Desauter, Elke; Duerr, Julia; Seyhan Agircan, Ayca; Conickx, Griet; Joos, Guy F.; Brusselle, Guy G.

    2015-01-01

    Introduction Airway surface dehydration, caused by an imbalance between secretion and absorption of ions and fluid across the epithelium and/or increased epithelial mucin secretion, impairs mucociliary clearance. Recent evidence suggests that this mechanism may be implicated in chronic obstructive pulmonary disease (COPD). However, the role of airway surface dehydration in the pathogenesis of cigarette smoke (CS)-induced COPD remains unknown. Objective We aimed to investigate in vivo the effect of airway surface dehydration on several CS-induced hallmarks of COPD in mice with airway-specific overexpression of the β-subunit of the epithelial Na+ channel (βENaC). Methods βENaC-Tg mice and wild-type (WT) littermates were exposed to air or CS for 4 or 8 weeks. Pathological hallmarks of COPD, including goblet cell metaplasia, mucin expression, pulmonary inflammation, lymphoid follicles, emphysema and airway wall remodelling were determined and lung function was measured. Results Airway surface dehydration in βENaC-Tg mice aggravated CS-induced airway inflammation, mucin expression and destruction of alveolar walls and accelerated the formation of pulmonary lymphoid follicles. Moreover, lung function measurements demonstrated an increased compliance and total lung capacity and a lower resistance and hysteresis in βENaC-Tg mice, compared to WT mice. CS exposure further altered lung function measurements. Conclusions We conclude that airway surface dehydration is a risk factor that aggravates CS-induced hallmarks of COPD. PMID:26066648

  10. High glucose induces dysfunction of airway epithelial barrier through down-regulation of connexin 43.

    PubMed

    Yu, Hongmei; Yang, Juan; Zhou, Xiangdong; Xiao, Qian; Lü, Yang; Xia, Li

    2016-03-01

    The airway epithelium is a barrier to the inhaled antigens and pathogens. Connexin 43 (Cx43) has been found to play critical role in maintaining the function of airway epithelial barrier and be involved in the pathogenesis of the diabetic retinal vasculature, diabetes nephropathy and diabetes skin. Hyperglycemia has been shown to be an independent risk factor for respiratory infections. We hypothesize that the down-regulation of Cx43 induced by HG alters the expression of tight junctions (zonula occludens-1 (ZO-1) and occludin) and contributes to dysfunction of airway epithelial barrier, and Cx43 plays a critical role in the process in human airway epithelial cells (16 HBE). We show that high glucose (HG) decreased the expression of ZO-1 and occludin, disassociated interaction between Cx43 and tight junctions, and then increased airway epithelial transepithelial electrical resistance (TER) and permeability by down-regulation of Cx43 in human airway epithelial cells. These observations demonstrate an important role for Cx43 in regulating HG-induced dysfunction of airway epithelial barrier. These findings may bring new insights into the molecular pathogenesis of pulmonary infection related to diabetes mellitus and lead to novel therapeutic intervention for the dysfunction of airway epithelial barrier in chronic inflammatory airway diseases. PMID:26902399

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

    PubMed

    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; Morrisey, Edward E

    2016-05-01

    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

  12. Cigarette Smoke Modulates Expression of Human Rhinovirus-Induced Airway Epithelial Host Defense Genes

    PubMed Central

    Proud, David; Hudy, Magdalena H.; Wiehler, Shahina; Zaheer, Raza S.; Amin, Minaa A.; Pelikan, Jonathan B.; Tacon, Claire E.; Tonsaker, Tabitha O.; Walker, Brandie L.; Kooi, Cora; Traves, Suzanne L.; Leigh, Richard

    2012-01-01

    Human rhinovirus (HRV) infections trigger acute exacerbations of chronic obstructive pulmonary disease (COPD) and asthma. The human airway epithelial cell is the primary site of HRV infection and responds to infection with altered expression of multiple genes, the products of which could regulate the outcome to infection. Cigarette smoking aggravates asthma symptoms, and is also the predominant risk factor for the development and progression of COPD. We, therefore, examined whether cigarette smoke extract (CSE) modulates viral responses by altering HRV-induced epithelial gene expression. Primary cultures of human bronchial epithelial cells were exposed to medium alone, CSE alone, purified HRV-16 alone or to HRV-16+ CSE. After 24 h, supernatants were collected and total cellular RNA was isolated. Gene array analysis was performed to examine mRNA expression. Additional experiments, using real-time RT-PCR, ELISA and/or western blotting, validated altered expression of selected gene products. CSE and HRV-16 each induced groups of genes that were largely independent of each other. When compared to gene expression in response to CSE alone, cells treated with HRV+CSE showed no obvious differences in CSE-induced gene expression. By contrast, compared to gene induction in response to HRV-16 alone, cells exposed to HRV+CSE showed marked suppression of expression of a number of HRV-induced genes associated with various functions, including antiviral defenses, inflammation, viral signaling and airway remodeling. These changes were not associated with altered expression of type I or type III interferons. Thus, CSE alters epithelial responses to HRV infection in a manner that may negatively impact antiviral and host defense outcomes. PMID:22808255

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

    PubMed

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

    2014-01-01

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

  14. Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs

    PubMed Central

    Bruun, Donald A.; Jacoby, David B.; van Rooijen, Nico; Lein, Pamela J.; Fryer, Allison D.

    2013-01-01

    Organophosphorus pesticides (OPs) are implicated in human asthma. We previously demonstrated that, at concentrations that do not inhibit acetylcholinesterase activity, the OP parathion causes airway hyperreactivity in guinea pigs as a result of functional loss of inhibitory M2 muscarinic receptors on parasympathetic nerves. Because macrophages are associated with asthma, we investigated whether macrophages mediate parathion-induced M2 receptor dysfunction and airway hyperreactivity. Airway physiology was measured in guinea pigs 24 h after a subcutaneous injection of parathion. Pretreatment with liposome-encapsulated clodronate induced alveolar macrophage apoptosis and prevented parathion-induced airway hyperreactivity in response to electrical stimulation of the vagus nerves. As determined by qPCR, TNF-α and IL-1β mRNA levels were increased in alveolar macrophages isolated from parathion-treated guinea pigs. Parathion treatment of alveolar macrophages ex vivo did not significantly increase IL-1β and TNF-α mRNA but did significantly increase TNF-α protein release. Consistent with these data, pretreatment with the TNF-α inhibitor etanercept but not the IL-1β receptor inhibitor anakinra prevented parathion-induced airway hyperreactivity and protected M2 receptor function. These data suggest a novel mechanism of OP-induced airway hyperreactivity in which low-level parathion activates macrophages to release TNF-α-causing M2 receptor dysfunction and airway hyperreactivity. These observations have important implications regarding therapeutic approaches for treating respiratory disease associated with OP exposures. PMID:23377347

  15. Facilitation of Allergic Sensitization and Allergic Airway Inflammation by Pollen-Induced Innate Neutrophil Recruitment.

    PubMed

    Hosoki, Koa; Aguilera-Aguirre, Leopoldo; Brasier, Allan R; Kurosky, Alexander; Boldogh, Istvan; Sur, Sanjiv

    2016-01-01

    Neutrophil recruitment is a hallmark of rapid innate immune responses. Exposure of airways of naive mice to pollens rapidly induces neutrophil recruitment. The innate mechanisms that regulate pollen-induced neutrophil recruitment and the contribution of this neutrophilic response to subsequent induction of allergic sensitization and inflammation need to be elucidated. Here we show that ragweed pollen extract (RWPE) challenge in naive mice induces C-X-C motif ligand (CXCL) chemokine synthesis, which stimulates chemokine (C-X-C motif) receptor 2 (CXCR2)-dependent recruitment of neutrophils into the airways. Deletion of Toll-like receptor 4 (TLR4) abolishes CXCL chemokine secretion and neutrophil recruitment induced by a single RWPE challenge and inhibits induction of allergic sensitization and airway inflammation after repeated exposures to RWPE. Forced induction of CXCL chemokine secretion and neutrophil recruitment in mice lacking TLR4 also reconstitutes the ability of multiple challenges of RWPE to induce allergic airway inflammation. Blocking RWPE-induced neutrophil recruitment in wild-type mice by administration of a CXCR2 inhibitor inhibits the ability of repeated exposures to RWPE to stimulate allergic sensitization and airway inflammation. Administration of neutrophils derived from naive donor mice into the airways of Tlr4 knockout recipient mice after each repeated RWPE challenge reconstitutes allergic sensitization and inflammation in these mice. Together these observations indicate that pollen-induced recruitment of neutrophils is TLR4 and CXCR2 dependent and that recruitment of neutrophils is a critical rate-limiting event that stimulates induction of allergic sensitization and airway inflammation. Inhibiting pollen-induced recruitment of neutrophils, such as by administration of CXCR2 antagonists, may be a novel strategy to prevent initiation of pollen-induced allergic airway inflammation. PMID:26086549

  16. The effect of antioxidants on ozone-induced airway hyperresponsiveness in dogs

    SciTech Connect

    Matsui, S.; Jones, G.L.; Woolley, M.J.; Lane, C.G.; Gontovnick, L.S.; O'Byrne, P.M. )

    1991-12-01

    The role of oxygen radicals in causing ozone-induced airway hyperresponsiveness in dogs was examined by pretreating dogs with allopurinol and/or deferoxamine mesylate (desferal), which are inhibitors of oxygen radical generation, before ozone inhalation. Acetylcholine airway responsiveness was measured before and after either air or ozone inhalation (3 ppm for 20 min) on 5 experimental days separated by at least 2 wk. On each day, the dogs were pretreated intravenously with allopurinol (50 mg/kg) followed by inhaled desferal (1,000 mg inhalation) or with allopurinol followed by the diluent for desferal or with the diluent for allopurinol and desferal or with both diluents. The effect of ozone on acetylcholine airway responsiveness was expressed as the differences in the log-transformed preozone-postozone acetylcholine provocative concentrations. When dogs received both diluents or either treatment alone, ozone inhalation caused airway hyperresponsiveness. The mean log differences for the preozone-postozone acetylcholine provocative concentration were 0.804 (SEM, 0.17) for both diluents, 0.524 (SEM, 0.16) for allopurinol alone, and 0.407 (SEM, 0.22) for desferal alone. However, the combination of allopurinol and desferal significantly inhibited the development of ozone-induced airway hyperresponsiveness, the log difference being 0.195 (SEM, 0.11) (p less than 0.05), without inhibiting ozone-induced neutrophil influx into the airways. The results suggest that the production of oxygen radicals is important in the pathogenesis of ozone-induced airway hyperresponsiveness.

  17. Inhalation of chlorine causes long-standing lung inflammation and airway hyperresponsiveness in a murine model of chemical-induced lung injury.

    PubMed

    Jonasson, Sofia; Koch, Bo; Bucht, Anders

    2013-01-01

    Chlorine is highly irritating when inhaled, and is a common toxic industrial gas causing tissue damage in the airways followed by an acute inflammatory response. In this study, we investigated mechanisms by which chlorine exposure may cause reactive airways dysfunction syndrome (RADS) and we examined the dose-dependency of the development of symptoms. Mice were exposed to 50 or 200 ppm Cl(2) during a single 15 min exposure in a nose-only container. The experiment terminated 2, 6, 12, 24, 48, 72 h and 7, 14, 28 and 90 days post exposure. Inflammatory cell counts in bronchoalveolar lavage (BAL), secretion of inflammatory mediators in BAL, occurrence of lung edema and histopathological changes in lung tissue was analyzed at each time-point. Airway hyperresponsiveness (AHR) was studied after 24 and 48 h and 7, 14, 28 and 90 days. The results showed a marked acute response at 6h (50 ppm) and 12h (200 ppm) post exposure as indicated by induced lung edema, increased airway reactivity in both central and peripheral airways, and an airway inflammation dominated by macrophages and neutrophils. The inflammatory response declined rapidly in airways, being normalized after 48 h, but inflammatory cells were sustained in lung tissue for at least seven days. In addition, a sustained AHR was observed for at least 28 days. In summary, this mouse model of chlorine exposure shows delayed symptoms of hyperreactive airways similar to human RADS. We conclude that the model can be used for studies aimed at improved understanding of adverse long-term responses following inhalation of chlorine. PMID:23146759

  18. Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells

    PubMed Central

    Knox, Alan J.

    2015-01-01

    Human airway smooth muscle cells (HASMC) contribute to asthma pathophysiology through an increased smooth muscle mass and elevated cytokine/chemokine output. Little is known about how HASMC and the airway epithelium interact to regulate chronic airway inflammation and remodeling. Amphiregulin is a member of the family of epidermal growth factor receptor (EGFR) agonists with cell growth and proinflammatory roles and increased expression in the lungs of asthma patients. Here we show that bradykinin (BK) stimulation of HASMC increases amphiregulin secretion in a mechanism dependent on BK-induced COX-2 expression, increased PGE2 output, and the stimulation of HASMC EP2 and EP4 receptors. Conditioned medium from BK treated HASMC induced CXCL8, VEGF, and COX-2 mRNA and protein accumulation in airway epithelial cells, which were blocked by anti-amphiregulin antibodies and amphiregulin siRNA, suggesting a paracrine effect of HASMC-derived amphiregulin on airway epithelial cells. Consistent with this, recombinant amphiregulin induced CXCL8, VEGF, and COX-2 in airway epithelial cells. Finally, we found that conditioned media from amphiregulin-stimulated airway epithelial cells induced amphiregulin expression in HASMC and that this was dependent on airway epithelial cell COX-2 activity. Our study provides evidence of a dynamic axis of interaction between HASMC and epithelial cells that amplifies CXCL8, VEGF, COX-2, and amphiregulin production. PMID:26047642

  19. 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. PMID:22792275

  20. Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems.

    PubMed

    Huh, Dongeun; Fujioka, Hideki; Tung, Yi-Chung; Futai, Nobuyuki; Paine, Robert; Grotberg, James B; Takayama, Shuichi

    2007-11-27

    We describe a microfabricated airway system integrated with computerized air-liquid two-phase microfluidics that enables on-chip engineering of human airway epithelia and precise reproduction of physiologic or pathologic liquid plug flows found in the respiratory system. Using this device, we demonstrate cellular-level lung injury under flow conditions that cause symptoms characteristic of a wide range of pulmonary diseases. Specifically, propagation and rupture of liquid plugs that simulate surfactant-deficient reopening of closed airways lead to significant injury of small airway epithelial cells by generating deleterious fluid mechanical stresses. We also show that the explosive pressure waves produced by plug rupture enable detection of the mechanical cellular injury as crackling sounds. PMID:18006663

  1. Allergen-induced traffic of bone marrow eosinophils, neutrophils and lymphocytes to airways.

    PubMed

    Johansson, Anna-Karin; Sergejeva, Svetlana; Sjöstrand, Margareta; Lee, James J; Lötvall, Jan

    2004-11-01

    We evaluated whether bone marrow (BM) inflammatory cells have capacity to traffic into the airways following allergen exposure in a mouse model of allergen-induced airway inflammation. We also evaluated the effect of IL-5 overexpression on (i) the production of eosinophils in BM, (ii) the accumulation of eosinophils, neutrophils and lymphocytes in blood and airways and (iii) the changes in CD34+ cell numbers in BM, blood and airways. Bromodeoxyuridine (BrdU) was used to label cells produced during the exposure period. Furthermore, CD3 splenocytes were adoptively transferred to investigate the BM inflammatory response. Allergen exposure induced traffic of BM eosinophils, neutrophils and lymphocytes to the airways and increased the number of BrdU+ eosinophils, neutrophils, lymphocytes and CD34+ cells in BALf. IL-5 overexpression enhanced the eosinophilopoiesis and increased the presence of BrdU+ eosinophils and CD34+ cells in airways and enhanced the number of CD34+ cells in BM and blood after allergen exposure. Adoptive transfer of CD3 lymphocytes overexpressing IL-5 caused increased BM eosinophilia. In conclusion, allergen exposure induces traffic of not only newly produced eosinophils but also newly produced neutrophils and lymphocytes into the airways. PMID:15384047

  2. Smad molecules expression pattern in human bronchial airway induced by sulfur mustard.

    PubMed

    Adelipour, Maryam; Imani Fooladi, Abbas Ali; Yazdani, Samaneh; Vahedi, Ensieh; Ghanei, Mostafa; Nourani, Mohammad Reza

    2011-09-01

    Airway remodelling is characterized by the thickening and reorganization of the airways seen in mustard lung patients. Mustard lung is the general description for the chronic obstructive pulmonary disease induced by sulfur mustard(SM). Pulmonary disease was diagnosed as the most important disorder in individuals that had been exposed to sulfur mustard. Sulfur mustard is a chemical warfare agent developed during Wars. Iraqi forces frequently used it against Iranian during Iran -Iraq in the 1980-1988. Peribronchial fibrosis result from airway remodeling that include excess of collagen of extracellular matrix deposition in the airway wall. Some of Smads families in association with TGF-β are involved in airway remodeling due to lung fibrosis. In the present study we compared the mRNA expression of Smad2, Smad3, and Smad4 and Smad7 genes in airway wall biopsies of chemical-injured patients with non-injured patients as control. We used airway wall biopsies of ten unexposed patients and fifteen SM-induced patients. Smads expression was evaluated by RT-PCR followed by bands densitometry. Expression levels of Smad3 and Smad4 in SM exposed patients were upregulated but Smad2 and Smad7 was not significantly altered. Our results revealed that Smad3, and 4 may be involved in airway remodeling process in SM induced patients by activation of TGF-β. Smad pathway is the most represented signaling mechanism for airway remodeling and peribronchial fibrosis. The complex of Smads in the nucleus affects a series of genes that results in peribronchial fibrosis in SM-induced patients. PMID:21891820

  3. Alternaria extract activates autophagy that induces IL-18 release from airway epithelial cells.

    PubMed

    Murai, Hiroki; Okazaki, Shintaro; Hayashi, Hisako; Kawakita, Akiko; Hosoki, Koa; Yasutomi, Motoko; Sur, Sanjiv; Ohshima, Yusei

    2015-09-01

    Alternaria alternata is a major outdoor allergen that causes allergic airway diseases. Alternaria extract (ALT-E) has been shown to induce airway epithelial cells to release IL-18 and thereby initiate Th2-type responses. We investigated the underlying mechanisms involved in IL-18 release from ALT-E-stimulated airway epithelial cells. Normal human bronchial epithelial cells and A549 human lung adenocarcinoma cells were stimulated with ALT-E in the presence of different inhibitors of autophagy or caspases. IL-18 levels in culture supernatants were measured by ELISA. The numbers of autophagosomes, an LC3-I to LC3-II conversion, and p62 degradation were determined by immunofluorescence staining and immunoblotting. 3-methyladenine and bafilomycin, which inhibit the formation of preautophagosomal structures and autolysosomes, respectively, suppressed ALT-E-induced IL-18 release by cells, whereas caspase 1 and 8 inhibitors did not. ALT-E-stimulation increased autophagosome formation, LC-3 conversion, and p62 degradation in airway epithelial cells. LPS-stimulation induced the LC3 conversion in A549 cells, but did not induce IL-18 release or p62 degradation. Unlike LPS, ALT-E induced airway epithelial cells to release IL-18 via an autophagy dependent, caspase 1 and 8 independent pathway. Although autophagy has been shown to negatively regulate canonical inflammasome activity in TLR-stimulated macrophages, our data indicates that this process is an unconventional mechanism of IL-18 secretion by airway epithelial cells. PMID:26032499

  4. Roflumilast Ameliorates Airway Hyperresponsiveness Caused by Diet-Induced Obesity in a Murine Model.

    PubMed

    Park, Hye Jung; Lee, Jae-Hyun; Park, Yoon Hee; Han, Heejae; Sim, Da Woon; Park, Kyung Hee; Park, Jung-Won

    2016-07-01

    Obese patients with asthma respond poorly to conventional asthma medications, resulting in severe symptoms and poor prognosis. Roflumilast, a phosphodiesterase-4 inhibitor that lowers the levels of various substances that are implicated in obese subjects with asthma, may be effective in the treatment of those subjects. We evaluated the potential of roflumilast as a novel therapeutic agent for obese subjects with asthma. We designed three models: diet-induced obesity (DIO); DIO with ovalbumin (OVA); and OVA. We fed C57BL/6J mice a high-fat diet for 3 months with or without OVA sensitization and challenge. Roflumilast or dexamethasone was administered orally three times at 2-day intervals in the last experimental week. Airway hyperresponsiveness resulting from DIO significantly improved in the roflumilast-treated group compared with the dexamethasone-treated groups. Although DIO did not affect the cell proliferation in bronchoalveolar lavage fluid, increased fibrosis was seen in the DIO group, which significantly improved from treatment with roflumilast. DIO-induced changes in adiponectin and leptin levels were improved by roflumilast, whereas dexamethasone aggravated them. mRNA levels and proteins of TNF-α, transforming growth factor-β, IL-1β, and IFN-γ increased in the DIO group and decreased with roflumilast. The reactive oxygen species levels were also increased in the DIO group and decreased by roflumilast. In the DIO plus OVA and OVA models, roflumilast improved Th1 and Th2 cell activation to a greater extent than dexamethasone. Roflumilast is significantly more effective than dexamethasone against airway hyperresponsiveness caused by DIO in the murine model. Roflumilast may represent a promising therapeutic agent for the treatment of obese patients with asthma. PMID:26756251

  5. Inhalation of honey reduces airway inflammation and histopathological changes in a rabbit model of ovalbumin-induced chronic asthma

    PubMed Central

    2014-01-01

    Background Honey is widely used in folk medicine to treat cough, fever, and inflammation. In this study, the effect of aerosolised honey on airway tissues in a rabbit model of ovalbumin (OVA)-induced asthma was investigated. The ability of honey to act either as a rescuing agent in alleviating asthma-related symptoms or as a preventive agent to preclude the occurrence of asthma was also assessed. Methods Forty New Zealand white rabbits were sensitized twice with mixture of OVA and aluminium hydroxide on days 1 and 14. Honey treatments were given from day 23 to day 25 at two different doses (25% (v/v) and 50% (v/v) of honey diluted in sterile phosphate buffer saline. In the aerosolised honey as a rescue agent group, animals were euthanized on day 28; for the preventive group, animals were further exposed to aerosolised OVA for 3 days starting from day 28 and euthanized on day 31. The effects of honey on inflammatory cell response, airway inflammation, and goblet cell hyperplasia were assessed for each animal. Results Histopathological analyses revealed that aerosolised honey resulted in structural changes of the epithelium, mucosa, and submucosal regions of the airway that caused by the induction with OVA. Treatment with aerosolised honey has reduced the number of airway inflammatory cells present in bronchoalveolar lavage fluid and inhibited the goblet cell hyperplasia. Conclusion In this study, aerosolised honey was used to effectively treat and manage asthma in rabbits, and it could prove to be a promising treatment for asthma in humans. Future studies with a larger sample size and studies at the gene expression level are needed to better understand the mechanisms by which aerosolised honey reduces asthma symptoms. PMID:24886260

  6. Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness.

    PubMed

    McGovern, Toby K; Chen, Michael; Allard, Benoit; Larsson, Kjell; Martin, James G; Adner, Mikael

    2016-01-15

    Airway exposure to organic dust (OD) from swine confinement facilities induces airway inflammation dominated by neutrophils and airway hyperresponsiveness (AHR). One important neutrophilic innate defense mechanism is the induction of oxidative stress. Therefore, we hypothesized that neutrophils exacerbate airway dysfunction following OD exposure by increasing oxidant burden. BALB/C mice were given intranasal challenges with OD or PBS (1/day for 3 days). Mice were untreated or treated with a neutrophil-depleting antibody, anti-Ly6G, or the antioxidant dimethylthiourea (DMTU) prior to OD exposure. Twenty-four hours after the final exposure, we measured airway responsiveness in response to methacholine (MCh) and collected bronchoalveolar lavage fluid to assess pulmonary inflammation and total antioxidant capacity. Lung tissue was harvested to examine the effect of OD-induced antioxidant gene expression and the effect of anti-Ly6G or DMTU. OD exposure induced a dose-dependent increase of airway responsiveness, a neutrophilic pulmonary inflammation, and secretion of keratinocyte cytokine. Depletion of neutrophils reduced OD-induced AHR. DMTU prevented pulmonary inflammation involving macrophages and neutrophils. Neutrophil depletion and DMTU were highly effective in preventing OD-induced AHR affecting large, conducting airways and tissue elastance. OD induced an increase in total antioxidant capacity and mRNA levels of NRF-2-dependent antioxidant genes, effects that are prevented by administration of DMTU and neutrophil depletion. We conclude that an increase in oxidative stress and neutrophilia is critical in the induction of OD-induced AHR. Prevention of oxidative stress diminishes neutrophil influx and AHR, suggesting that mechanisms driving OD-induced AHR may be dependent on neutrophil-mediated oxidant pathways. PMID:26545900

  7. 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 ...

  8. Generation of airway epithelial cells with native characteristics from mouse induced pluripotent stem cells.

    PubMed

    Yoshie, Susumu; Imaizumi, Mitsuyoshi; Nakamura, Ryosuke; Otsuki, Koshi; Ikeda, Masakazu; Nomoto, Yukio; Wada, Ikuo; Omori, Koichi

    2016-05-01

    Airway epithelial cells derived from induced pluripotent stem (iPS) cells are expected to be a useful source for the regeneration of airway epithelium. Our preliminary study of embryoid body (EB) formation and the air-liquid interface (ALI) method suggested that mouse iPS cells can differentiate into airway epithelial cells. However, whether the cells generated from mouse iPS cells had the character and phenotype of native airway epithelial cells remained uninvestigated. In this study, we generated airway epithelial cells from EBs by culturing them under serum-free conditions supplemented with Activin and bFGF and by the ALI method and characterized the iPS cell-derived airway epithelial cells in terms of their gene expression, immunoreactivity, morphology, and function. Analysis by quantitative real-time reverse transcription-polymerase chain reaction(RT-PCR) revealed that the expression of the undifferentiated cell marker Nanog decreased time-dependently after the induction of differentiation, whereas definitive endoderm markers Foxa2 and Cxcr4 were transiently up-regulated. Thereafter, the expression of airway epithelium markers such as Tubb4a, Muc5ac, and Krt5 was detected by RT-PCR and immunostaining. The formation of tight junctions was also confirmed by immunostaining and permeability assay. Analysis by hematoxylin and eosin staining and scanning electron microscopy indicated that the cells generated from mouse iPS cells formed airway-epithelium-like tissue and had cilia, the movement of which was visualized and observed to be synchronized. These results demonstrate that the airway epithelial cells generated by our method have native characteristics and open new perspectives for the regeneration of injured airway epithelium. PMID:26590823

  9. Immunomodulation of airway epithelium cell activation by mesenchymal stromal cells ameliorates house dust mite-induced airway inflammation in mice.

    PubMed

    Duong, Khang M; Arikkatt, Jaisy; Ullah, M Ashik; Lynch, Jason P; Zhang, Vivian; Atkinson, Kerry; Sly, Peter D; Phipps, Simon

    2015-11-01

    Allergic asthma is underpinned by T helper 2 (Th2) inflammation. Redundancy in Th2 cytokine function and production by innate and adaptive immune cells suggests that strategies aimed at immunomodulation may prove more beneficial. Hence, we sought to determine whether administration of mesenchymal stromal cells (MSCs) to house dust mite (HDM) (Dermatophagoides pteronyssinus)-sensitized mice would suppress the development of Th2 inflammation and airway hyperresponsiveness (AHR) after HDM challenge. We report that the intravenous administration of allogeneic donor MSCs 1 hour before allergen challenge significantly attenuated the features of allergic asthma, including tissue eosinophilia, Th2 cytokine (IL-5 and IL-13) levels in bronchoalveolar lavage fluid, and AHR. The number of infiltrating type 2 innate lymphoid cells was not affected by MSC transfer, suggesting that MSCs may modulate the adaptive arm of Th2 immunity. The effect of MSC administration was long lasting; all features of allergic airway disease were significantly suppressed in response to a second round of HDM challenge 4 weeks after MSC administration. Further, we observed that MSCs decreased the release of epithelial cell-derived alarmins IL-1α and high mobility group box-1 in an IL-1 receptor antagonist-dependent manner. This significantly decreased the expression of the pro-Th2 cytokine IL-25 and reduced the number of activated and antigen-acquiring CD11c(+)CD11b(+) dendritic cells in the lung and mediastinal lymph nodes. Our findings suggest that MSC administration can ameliorate allergic airway inflammation by blunting the amplification of epithelial-derived inflammatory cytokines induced by HDM exposure and may offer long-term protection against Th2-mediated allergic airway inflammation and AHR. PMID:25789608

  10. Airway symptoms and lung function in the local population after the oil tank explosion in Gulen, Norway

    PubMed Central

    2012-01-01

    Background Oil tanks containing a mixture of hydrocarbons, including sulphuric compounds, exploded and caught fire in an industrial harbour. This study assesses airway symptoms and lung function in the nearby population 1½ years after the explosion. Methods A cross-sectional study included individuals ≥18 years old. Individuals living <6 km (sub-groups <3km and 3–6 km) from the accident site formed the exposed group, individuals living >20 km away formed a control group. A questionnaire and spirometry tests were completed by 223 exposed individuals (response rate men 70%, women 75%) and 179 control individuals (response rate men 51%, women 65%). Regression analyses included adjustment for smoking, occupational exposure, atopy, infection in the preceding month and age. Analyses of symptoms were also adjusted for stress reactions related to the accident. Results Exposed individuals experienced significantly more blocked nose (odds ratio 1.7 [95% confidence interval 1.0, 2.8]), rhinorrhoea (1.6 [1.1, 3.3]), nose irritation (3.4 [2.0, 5.9]), sore throat (3.1 [1.8, 5.5]), morning cough (3.5 [2.0, 5.5]), daily cough (2.2 [1.4, 3.7]), cough >3 months a year (2.9 [1.5, 5.3]) and cough with phlegm (1.9 [1.2, 3.1]) than control individuals. A significantly increasing trend was found for nose symptoms and cough, depending on the proximity of home address to explosion site (daily cough, 3-6km 1.8 [1.0, 3.1], <3km 3.0 [1.7, 6.4]). Lung function measurements were significantly lower in the exposed group than in the control group, FEV1 adjusted mean difference −123 mL [95% confidence interval −232, -14]), FEV1% predicted −2.5 [−5.5, 0.5], FVC −173 mL [− 297, -50], FVC% predicted −3.1 [− 5.9, -0.4], and airway obstruction (GOLD II/III). Conclusions Based on cross sectional analyses, individuals living in an area with air pollution from an oil tank explosion had more airway symptoms and lower lung function than a control group 1½ years after the incident. PMID

  11. Influence of treatment on peak expiratory flow and its relation to airway hyperresponsiveness and symptoms. The Dutch CNSLD Study Group.

    PubMed Central

    Kerstjens, H. A.; Brand, P. L.; de Jong, P. M.; Koëter, G. H.; Postma, D. S.

    1994-01-01

    BACKGROUND--Despite effective treatments, the morbidity and mortality of obstructive airways disease (asthma and COPD) remains high. Home monitoring of peak expiratory flow (PEF) is increasingly being advocated as an aid to better management of obstructive airways disease. The few available studies describing effects of treatment on the level and variation of PEF have involved relatively small numbers of subjects and did not use control groups. METHODS--Patients aged 18-60 years were selected with PC20 < or = 8 mg/ml and FEV1 < 95% confidence interval of predicted normal. They were randomised to receive, in addition to a beta 2 agonist, either an inhaled corticosteroid (BA+CS), an anticholinergic (BA+AC), or a placebo (BA+PL). One hundred and forty one of these subjects with moderately severe obstructive airways disease completed seven periods of two weeks of morning and afternoon PEF measurements at home during 18 months of blind follow up. RESULTS--Improvements in PEF occurred within the first three months of treatment with BA+CS and was subsequently maintained: the mean (SE) increase in morning PEF was 51 (8) l/min in the BA+CS group compared with no change in the other two groups. Similarly, afternoon PEF increased by 22 (7) l/min. Diurnal variation in PEF (amplitude %mean) decreased from 18.0% to 10.2% in the first three months of treatment with BA+CS. Within-subject relations between changes in diurnal variation in PEF and changes in PC20 were found to be predominantly negative (median rho-0.40) but with a large scatter. Relations between diurnal variation in PEF and changes in symptom scores, FEV1, and bronchodilator response were even weaker. CONCLUSIONS--In patients with moderately severe obstructive airways disease, PEF rates and variation are greatly improved by inhaled corticosteroids. Since the relation of diurnal PEF variation with PC20, symptoms, FEV1, and bronchodilator response were all weak, these markers of disease severity may all provide

  12. O/sub 3/-induced change in bronchial reactivity to methacholine and airway inflammation in humans

    SciTech Connect

    Seltzer, J.; Bigby, B.G.; Stulbarg, M.; Holtzman, M.J.; Nadel, J.A.; Ueki, I.F.; Leikauf, G.D.; Goetzl, E.J.; Boushey, H.A.

    1986-04-01

    The increase in airway responsiveness induced by O/sub 3/ exposure in dogs is associated with airway epithelial inflammation, as evidenced by an increase in the number of neutrophils (polymorphonuclear leukocytes) found in epithelial biopsies and in bronchoalveolar lavage fluid. We investigated in 10 healthy, human subjects whether O/sub 3/-induced hyperresponsiveness was similarly associated with airway inflammation by examining changes in the types of cells recovered in bronchoalveolar lavage fluid obtained after exposure to air or to O/sub 3/ (0.4 or 0.6 ppm). We also measured the concentrations of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in lavage fluid. We measured airway responsiveness to inhaled methacholine aerosol before and after each exposure and performed bronchoalveolar lavage 3 h later. We found more neutrophils in the lavage fluid from O/sub 3/-exposed subjects, especially in those in whom O/sub 3/ exposure produced an increase in airway responsiveness. We also found significant increases in the concentrations of prostaglandins E2, F2 alpha, and thromboxane B2 in lavage fluid from O/sub 3/-exposed subjects. These results show that in human subjects O/sub 3/-induced hyperresponsiveness to methacholine is associated with an influx of neutrophils into the airways and with changes in the levels of some cyclooxygenase metabolites of arachidonic acid.

  13. Effects of salbutamol and enantiomers on allergen-induced asthmatic reactions and airway hyperreactivity.

    PubMed

    Westerhof, F J; Zuidhof, A B; Kok, L; Meurs, H; Zaagsma, J

    2005-05-01

    Salbutamol consists of a racemic mixture of R- and S-salbutamol. R-salbutamol (levalbuterol) is the active bronchodilating enantiomer, whereas S-salbutamol is thought to be pharmacologically inactive or to exert adverse effects. This study evaluated the bronchoprotective effects of inhalation of therapeutically relevant doses of the racemate and individual enantiomers in guinea pigs. It was found that basal airway reactivity to histamine was similarly reduced 30 min after inhalation of equivalent doses of RS- and R-salbutamol; this protective effect disappeared within 3 h. Inhalation of RS- and R-salbutamol 30 min before and 5.5 h after allergen challenge suppressed allergen-induced airway hyperreactivity to histamine after the early and late asthmatic reaction, completely inhibiting the early asthmatic reaction and tending to reduce the development of the late asthmatic reaction. At 5 h after allergen challenge, the inhibition of airway hyperreactivity was more pronounced in animals treated with R-salbutamol compared to racemate-treated animals. Both basal airway reactivity and allergen-induced hyperreactivity were not affected by S-salbutamol. Inflammatory cell infiltration was not affected by the racemate or the individual enantiomers. In conclusion, inhalation of therapeutically relevant doses of R- and RS-salbutamol effectively suppress allergen-induced airway reactivity after the early and late asthmatic reactions, the R-enantiomer being slightly more potent with respect to early airway reactivity than the racemate. No adverse effects were observed for the S-enantiomer. PMID:15863644

  14. 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.

  15. Effect of dexamethasone and ACC on bacteria-induced mucin expression in human airway mucosa.

    PubMed

    Hauber, Hans-Peter; Goldmann, Torsten; Vollmer, Ekkehard; Wollenberg, Barbara; Zabel, Peter

    2007-11-01

    Gram-negative bacteria can stimulate mucin production, but excessive mucus supports bacterial infection and consequently leads to airway obstruction. Therefore, the effect of dexamethasone (DEX) and the antioxidant acetyl-cysteine (ACC) on bacteria-induced mucus expression was investigated. Explanted human airway mucosa and mucoepidermoid cells (Calu-3) were stimulated with lipopolysaccharide (LPS) or PAM3 (a synthetic lipoprotein). DEX or ACC were added to either LPS- or PAM3-stimulated airway mucosa or Calu-3 cells. Mucin mRNA expression (MUC5AC) and total mucus glycoconjugates (mucin protein) were quantified using real-time PCR and periodic acid Schiff staining. LPS and PAM3 significantly increased mucin expression in airway mucosa and Calu-3 cells (P < 0.05). DEX alone had no significant effect on mucin expression in airway mucosa or Calu-3 cells (P > 0.05). In contrast, DEX significantly reduced LPS- and PAM3-induced mucin expression in explanted mucosal tissue and mucin expression in Calu-3 cells (P < 0.05). In explanted human airway mucosa ACC alone significantly increased mucin expression (P < 0.05). In contrast, ACC significantly decreased LPS- and PAM3-induced mucin expression (P < 0.05). In Calu-3 cells ACC alone had no significant effect on mucin expression (P > 0.05). ACC decreased LPS- and PAM3-induced mucin expression, but this effect was not significant (P > 0.05). These data suggest that DEX can effectively reduce bacteria-induced mucin expression in the airways. ACC alone may increase mucin expression in noninfected mucosa, but it decreased bacteria-induced mucin expression. Further studies are warranted to evaluate whether the effect of DEX or ACC is clinically relevant. PMID:17600317

  16. The role of mast cells in citric acid-induced airway constriction and cough.

    PubMed

    Lai, Yih-Loong; Wu, Li-Ling; Lin, Tai-Yin; Lin, Chien-He

    2009-11-30

    Inhalation of citric acid (CA) causes airway constriction and coughing. To investigate the role of mast cells in CA-induced airway constriction and cough, three experiments using guinea pigs were carried out. In the first experiment, we used compound 48/80 to deplete mast cells, cromolyn sodium to stabilize mast cells, MK-886 to inhibit synthesis of leukotrienes, pyrilamine to antagonize histamine H1 receptor, methysergide to antagonize serotonin receptor, and indomethacin to inhibit cyclooxygenase. In the second experiment, compound 48/80-pretreated animals were divided into 2 parts; the first one was used to test the role of exogenous leukotriene (LT) C4, while the second one to test the role of exogenous histamine. Decreases in respiratory compliance (Crs) and forced expiratory volume in 0.1 sec (FEV0.1) were used as indicators for airway constriction in anesthetized guinea pigs. CA-induced cough was recorded for 12 min using a barometric body plethysmograph in conscious animals. In the third experiment, the activation of mast cells upon CA inhalation was investigated by determining lung tissue or arterial plasma histamine concentration in animals. Exposure to CA induced marked airway constriction and increase in cough number. Compound 48/80, cromolyn sodium, MK-886 and pyrilamine, but not indomethacin or methysergide, significantly attenuated CA-induced airway constriction and cough. Injection of LTC4 or histamine caused a significant increase in CA-induced airway constriction and cough in compound 48/80-pretreated animals. In addition, CA inhalation caused significant increase in lung tissue and plasma histamine concentrations, which were blocked by compound 48/80 pretreatment. These results suggest that mast cells play an important role in CA aerosol inhalation-induced airway constriction and cough via perhaps mediators including LTs and histamine. PMID:20359123

  17. Histamine-induced airway mucosal exudation of bulk plasma and plasma-derived mediators is not inhibited by intravenous bronchodilators.

    PubMed

    Svensson, C; Alkner, U; Pipkorn, U; Persson, C G

    1994-01-01

    Experimental data suggest the possibility that common bronchodilators, such as the xanthines and beta 2-adrenoceptor agonists, may produce microvascular anti-permeability effects in the subepithelial microcirculation of the airways. In this study, we have examined the effect of bronchodilators given intravenously on exudation of different-sized plasma proteins (albumin and fibrinogen) and the generation of plasma-derived peptides (bradykinins) in human nasal airways challenged with histamine. In a double-blind, crossover, placebo-controlled and randomised trial, 12 normal volunteers were given i.v.infusions of terbutaline sulphate, theophylline and enprofylline to produce therapeutic drug levels. The effect of topical nasal provocation with histamine was closely followed by frequently nasal lavage with saline. The lavage fluid levels of albumin, fibrinogen and bradykinins increased significantly after each histamine provocation. The ratio of albumin-to-fibrinogen in plasma and the lavage fluid was 24 and 56, respectively, indicating that topical histamine provocation induced a largely non-sieved flux of macromolecules across the endothelial-epithelial barriers. The systemically administered drugs did not affect the nasal symptoms (sneezing, secretion and blockage), nor did they significantly reduce the levels of plasma proteins and plasma-derived mediators in the nasal lavage fluids. The present data suggest that systemic xanthines and beta 2-adrenoceptor agonists, at clinically employed plasma levels, may not affect the microvascular (and epithelial) exudative permeability and the bradykinin forming capacity of human airways. PMID:8005188

  18. Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms

    SciTech Connect

    Broström, Julia M.; Ye, Zhi-wei; Axmon, Anna; Littorin, Margareta; Tinnerberg, Håkan; Lindh, Christian H.; Zheng, Huiyuan; Ghalali, Aram; Stenius, Ulla; Jönsson, Bo A.G.; Högberg, Johan

    2015-09-15

    Diisocyanates are industrial chemicals which have a wide range of applications in developed and developing countries. They are notorious lung toxicants and respiratory sensitizers. However, the mechanisms behind their adverse effects are not adequately characterized. Autotaxin (ATX) is an enzyme producing lysophosphatidic acid (LPA), and the ATX-LPA axis has been implicated in lung related inflammatory conditions and diseases, including allergic asthma, but not to toxicity of environmental low-molecular-weight chemicals. We investigated effects of toluene diisocyanate (TDI) on ATX induction in human lung epithelial cell models, and we correlated LPA-levels in plasma to biomarkers of TDI exposure in urine collected from workers exposed to < 5 ppb (parts per billion). Information on workers' symptoms was collected through interviews. One nanomolar TDI robustly induced ATX release within 10 min in vitro. A P2X7- and P2X4-dependent microvesicle formation was implicated in a rapid ATX release and a subsequent protein synthesis. Co-localization between purinergic receptors and ATX was documented by immunofluorescence and confocal microscopy. The release was modulated by monocyte chemoattractant protein-1 (MCP-1) and by extracellular ATP. In workers, we found a dose–response relationship between TDI exposure biomarkers in urine and LPA levels in plasma. Among symptomatic workers reporting “sneezing”, the LPA levels were higher than among non-symptomatic workers. This is the first report indicating induction of the ATX-LPA axis by an environmental low-molecular-weight chemical, and our data suggest a role for the ATX-LPA axis in TDI toxicity. - Highlights: • Human epithelial cells release autotaxin in response to 1 nM toluene diisocyanate (TDI). • The release involves P2X4 and P2X7 receptors and is modulated by ATP and MCP-1. • Lysophosphatidic acid (LPA) was measured in workers exposed to < 5 ppb TDI. • LPA in plasma correlated to TDI exposure biomarkers in

  19. Airway smooth muscle changes in the nitrofen-induced congenital diaphragmatic hernia rat model.

    PubMed

    Belik, Jaques; Davidge, Sandra T; Zhang, Wei; Pan, Jingyi; Greer, John J

    2003-05-01

    In the fetal rat, nitrofen induces congenital diaphragmatic hernia (CDH) and pulmonary vascular remodeling similar to what is observed in the human condition. Airway hyperactivity is common in infants with CDH and attributed to the ventilator-induced airway damage. The purpose of this study was to test the hypothesis that airway smooth muscle mechanical properties are altered in the nitrofen-induced CDH rat model. Lungs from nitrofen-exposed fetuses with hernias (CDH) or intact diaphragm (nitrofen) and untreated fetuses (control) were studied on gestation d 21. The left intrapulmonary artery and bronchi were removed and mounted on a wire myograph, and lung expression, content, and immunolocalization of cyclooxygenases COX-1 and COX-2 were evaluated. Pulmonary artery muscle in the CDH group had significantly (p < 0.01) lower force generation compared with control and nitrofen groups. In contrast, the same generation bronchial smooth muscle of the CDH and nitrofen groups developed higher force compared with control. Whereas no differences were found in endothelium-dependent pulmonary vascular muscle tone, the epithelium-dependent airway muscle relaxation was significantly decreased (p < 0.01) in the CDH and nitrofen groups. The lung mRNA levels of COX-1 and COX-2 were increased in the CDH and nitrofen groups. COX-1 vascular and airway immunostaining, as well as COX-1 and COX-2 lung protein content, were increased in the CDH group. This is the first report of airway smooth muscle abnormalities in the nitrofen-induced fetal rat model of CDH. We speculate that congenital airway muscle changes may be present in the human form of this disease. PMID:12612200

  20. Mast cell mediators in citric acid-induced airway constriction of guinea pigs

    SciTech Connect

    Lin, C.-H.; Lai, Y.-L. . E-mail: tiger@ha.mc.ntu.edu.tw

    2005-08-15

    We demonstrated previously that mast cells play an important role in citric acid (CA)-induced airway constriction. In this study, we further investigated the underlying mediator(s) for this type of airway constriction. At first, to examine effects caused by blocking agents, 67 young Hartley guinea pigs were divided into 7 groups: saline + CA; methysergide (serotonin receptor antagonist) + CA; MK-886 (leukotriene synthesis inhibitor) + CA; mepyramine (histamine H{sub 1} receptor antagonist) + CA; indomethacin (cyclooxygenase inhibitor) + CA; cromolyn sodium (mast cell stabilizer) + CA; and compound 48/80 (mast cell degranulating agent) + CA. Then, we tested whether leukotriene C{sub 4} (LTC{sub 4}) or histamine enhances CA-induced airway constriction in compound 48/80-pretreated guinea pigs. We measured dynamic respiratory compliance (Crs) and forced expiratory volume in 0.1 s (FEV{sub 0.1}) during either baseline or recovery period. In addition, we detected histamine level, an index of pulmonary mast cell degranulation, in bronchoalveolar lavage (BAL) samples. Citric acid aerosol inhalation caused decreases in Crs and FEV{sub 0.1}, indicating airway constriction in the control group. This airway constriction was significantly attenuated by MK-886, mepyramine, cromolyn sodium, and compound 48/80, but not by either methysergide or indomethacin. Both LTC{sub 4} and histamine infusion significantly increased the magnitude of CA-induced airway constriction in compound 48/80-pretreated guinea pigs. Citric acid inhalation caused significant increase in histamine level in the BAL sample, which was significantly suppressed by compound 48/80. These results suggest that leukotrienes and histamine originating from mast cells play an important role in CA inhalation-induced noncholinergic airway constriction.

  1. 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.

  2. Intracellular insulin-like growth factor-1 induces Bcl-2 expression in airway epithelial cells.

    PubMed

    Chand, Hitendra S; Harris, Jennifer Foster; Mebratu, Yohannes; Chen, Yangde; Wright, Paul S; Randell, Scott H; Tesfaigzi, Yohannes

    2012-05-01

    Bcl-2, a prosurvival protein, regulates programmed cell death during development and repair processes, and it can be oncogenic when cell proliferation is deregulated. The present study investigated what factors modulate Bcl-2 expression in airway epithelial cells and identified the pathways involved. Microarray analysis of mRNA from airway epithelial cells captured by laser microdissection showed that increased expression of IL-1β and insulin-like growth factor-1 (IGF-1) coincided with induced Bcl-2 expression compared with controls. Treatment of cultured airway epithelial cells with IL-1β and IGF-1 induced Bcl-2 expression by increasing Bcl-2 mRNA stability with no discernible changes in promoter activity. Silencing the IGF-1 expression using short hairpin RNA showed that intracellular IGF-1 (IC-IGF-1) was increasing Bcl-2 expression. Blocking epidermal growth factor receptor or IGF-1R activation also suppressed IC-IGF-1 and abolished the Bcl-2 induction. Induced expression and colocalization of IC-IGF-1 and Bcl-2 were observed in airway epithelial cells of mice exposed to LPS or cigarette smoke and of patients with cystic fibrosis and chronic bronchitis but not in the respective controls. These studies demonstrate that IC-IGF-1 induces Bcl-2 expression in epithelial cells via IGF-1R and epidermal growth factor receptor pathways, and targeting IC-IGF-1 could be beneficial to treat chronic airway diseases. PMID:22461702

  3. Protective Effects of the Polyphenol Sesamin on Allergen-Induced TH2 Responses and Airway Inflammation in Mice

    PubMed Central

    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. PMID:24755955

  4. Computed nasal resistance compared with patient-reported symptoms in surgically treated nasal airway passages: A preliminary report

    PubMed Central

    Garcia, Guilherme J. M.; Frank, Dennis O.; Cannon, Daniel E.; Pawar, Sachin S.; Rhee, John S.

    2012-01-01

    Background: Nasal airway obstruction (NAO) is a common health condition impacting mood, energy, recreation, sleep, and overall quality of life. Nasal surgery often addresses NAO but the results are sometimes unsatisfactory. Evaluating surgical treatment efficacy could be improved if objective tests were available that correlated with patient-reported measures of symptoms. The goal of this study was to develop methods for comparing nasal resistance computed by computational fluid dynamics (CFD) models with patient-reported symptoms of NAO using early data from a 4-year prospective study. Methods: Computed tomography (CT) scans and patient-reported scores from the Nasal Obstruction Symptom Evaluation (NOSE) scale and a visual analog scale (VAS) measuring unilateral airflow sensation were obtained pre- and postoperatively in two NAO patients showing no significant mucosal asymmetry who were successfully treated with functional nasal surgery, including septoplasty. Pre- and postsurgery CFD models were created from the CT scans. Numerical simulation of steady-state inspiratory airflow was used to calculate bilateral and unilateral CFD-derived nasal resistance (CFD-NR). Results: In both subjects, NOSE and VAS scores improved after surgery, bilateral CFD-NR decreased, and unilateral CFD-NR decreased on the affected side. In addition, NOSE and VAS scores tracked with unilateral CFD-NR on the affected side. Conclusion: These preliminary results suggest a possible correlation between unilateral NR and patient-reported symptoms and imply that analysis of unilateral obstruction should focus on the affected side. A formal investigation of unilateral CFD-NR and patient-reported symptoms in a series of NAO patients is needed to determine if these variables are correlated. PMID:22643935

  5. Bronchoconstriction and airway biology: potential impact and therapeutic opportunities.

    PubMed

    Gosens, Reinoud; Grainge, Chris

    2015-03-01

    Recent work has demonstrated that mechanical forces occurring in the airway as a consequence of bronchoconstriction are sufficient to not only induce symptoms but also influence airway biology. Animal and human in vitro and in vivo work demonstrates that the airways are structurally and functionally altered by mechanical stress induced by bronchoconstriction. Compression of the airway epithelium and mechanosensing by the airway smooth muscle trigger the activation and release of growth factors, causing cell proliferation, extracellular matrix protein accumulation, and goblet cell differentiation. These effects of bronchoconstriction are of major importance to asthma pathophysiology and appear sufficient to induce remodeling independent of the inflammatory response. We review these findings in detail and discuss previous studies in light of this new evidence regarding the influence of mechanical forces in the airways. Furthermore, we highlight potential impacts of therapies influencing mechanical forces on airway structure and function in asthma. PMID:25732446

  6. Reproducibility of the airway response to an exercise protocol standardized for intensity, duration, and inspired air conditions, in subjects with symptoms suggestive of asthma

    PubMed Central

    2010-01-01

    Background Exercise testing to aid diagnosis of exercise-induced bronchoconstriction (EIB) is commonly performed. Reproducibility of the airway response to a standardized exercise protocol has not been reported in subjects being evaluated with mild symptoms suggestive of asthma but without a definite diagnosis. This study examined reproducibility of % fall in FEV1 and area under the FEV1 time curve for 30 minutes in response to two exercise tests performed with the same intensity and duration of exercise, and inspired air conditions. Methods Subjects with mild symptoms of asthma exercised twice within approximately 4 days by running for 8 minutes on a motorized treadmill breathing dry air at an intensity to induce a heart rate between 80-90% predicted maximum; reproducibility of the airway response was expressed as the 95% probability interval. Results Of 373 subjects challenged twice 161 were positive (≥10% fall FEV1 on at least one challenge). The EIB was mild and 77% of subjects had <15% fall on both challenges. Agreement between results was 76.1% with 56.8% (212) negative (< 10% fall FEV1) and 19.3% (72) positive on both challenges. The remaining 23.9% of subjects had only one positive test. The 95% probability interval for reproducibility of the % fall in FEV1 and AUC0-30 min was ± 9.7% and ± 251% for all 278 adults and ± 13.4% and ± 279% for all 95 children. The 95% probability interval for reproducibility of % fall in FEV1 and AUC0-30 min for the 72 subjects with two tests ≥10% fall FEV1 was ± 14.6% and ± 373% and for the 34 subjects with two tests ≥15% fall FEV1 it was ± 12.2% and ± 411%. Heart rate and estimated ventilation achieved were not significantly different either on the two test days or when one test result was positive and one was negative. Conclusions Under standardized, well controlled conditions for exercise challenge, the majority of subjects with mild symptoms of asthma demonstrated agreement in test results. Performing two

  7. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration.

    PubMed

    Clunes, Lucy A; Davies, Catrin M; Coakley, Raymond D; Aleksandrov, Andrei A; Henderson, Ashley G; Zeman, Kirby L; Worthington, Erin N; Gentzsch, Martina; Kreda, Silvia M; Cholon, Deborah; Bennett, William D; Riordan, John R; Boucher, Richard C; Tarran, Robert

    2012-02-01

    Cigarette smoke (CS) exposure induces mucus obstruction and the development of chronic bronchitis (CB). While many of these responses are determined genetically, little is known about the effects CS can exert on pulmonary epithelia at the protein level. We, therefore, tested the hypothesis that CS exerts direct effects on the CFTR protein, which could impair airway hydration, leading to the mucus stasis characteristic of both cystic fibrosis and CB. In vivo and in vitro studies demonstrated that CS rapidly decreased CFTR activity, leading to airway surface liquid (ASL) volume depletion (i.e., dehydration). Further studies revealed that CS induced internalization of CFTR. Surprisingly, CS-internalized CFTR did not colocalize with lysosomal proteins. Instead, the bulk of CFTR shifted to a detergent-resistant fraction within the cell and colocalized with the intermediate filament vimentin, suggesting that CS induced CFTR movement into an aggresome-like, perinuclear compartment. To test whether airway dehydration could be reversed, we used hypertonic saline (HS) as an osmolyte to rehydrate ASL. HS restored ASL height in CS-exposed, dehydrated airway cultures. Similarly, inhaled HS restored mucus transport and increased clearance in patients with CB. Thus, we propose that CS exposure rapidly impairs CFTR function by internalizing CFTR, leading to ASL dehydration, which promotes mucus stasis and a failure of mucus clearance, leaving smokers at risk for developing CB. Furthermore, our data suggest that strategies to rehydrate airway surfaces may provide a novel form of therapy for patients with CB. PMID:21990373

  8. 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.

  9. [Allergens-induced sensitization alters airway epithelial adhesion molecules expression in mice].

    PubMed

    Zeng, Dan; Tan, Mei-Ling; Xiang, Yang; Qin, Xiao-Qun; Zhu, Li-Ming; Dai, Ai-Guo

    2015-12-25

    To explore the relationship between the epithelial adhesion molecules and immune responses of airway epithelium, we observed the expression of integrin β4 and intercellular adhesion molecule-1 (ICAM-1) in the mice airway epithelium after sensitization with allergens. BALB/c mice were sensitized with intraperitoneal injection of ovalbumin (OVA) or house dust mite (HDM) and then developed airway hyper-responsiveness as determined by barometric whole-body plethysmography. Both OVA and HDM sensitization led to increases of the number of peripheral leukocytes as well as inflammatory cells infiltration in lungs. OVA sensitized mice showed more severe inflammatory cells infiltration than HDM sensitized mice. Immunohistochemistry analysis of mice lung tissues revealed that sensitization with both allergens also led to a decrease of integrin β4 expression and an increase of ICAM-1 expression in airway epithelia. OVA sensitized mice showed a more significant increase of ICAM-1 expression compared with HDM sensitized mice. siRNA mediated silencing of integrin β4 gene in 16HBE cells resulted in an up-regulation of ICAM-1 expression. Our results indicate a possible role of airway epithelial adhesion molecules in allergen-induced airway immune responses. PMID:26701635

  10. Zinc oxide nanoparticles induce eosinophilic airway inflammation in mice.

    PubMed

    Huang, Kuo-Liang; Lee, Yi-Hsin; Chen, Hau-Inh; Liao, Huang-Shen; Chiang, Bor-Luen; Cheng, Tsun-Jen

    2015-10-30

    Zinc oxide nanoparticles (ZnO NPs) have been widely used in industry. The metal composition of PM2.5 might contribute to the higher prevalence of asthma. To investigate the effects of ZnO NPs on allergic airway inflammation, mice were first exposed to different concentrations of ZnO NPs (0.1 mg/kg, 0.5 mg/kg) or to a combination of ZnO NPs and chicken egg ovalbumin (OVA) by oropharyngeal aspiration on day 0 and day 7 and then were sacrificed 5 days later. The subsequent time course of airway inflammation in the mice after ZnO NPs exposure was evaluated on days 1, 7, and 14. To further determine the role of zinc ions, ZnCl2 was also administered. The inflammatory cell count, cytokine levels in the bronchoalveolar lavage fluid (BALF), and lung histopathology were examined. We found significant neutrophilia after exposure to high-dose ZnO NPs on day 1 and significant eosinophilia in the BALF at 7 days. However, the expression levels of the T helper 2 (Th2) cytokines IL-4, IL-5, and IL-13 increased significantly after 24h of exposure to only ZnO NPs and then decreased gradually. These results suggested that ZnO NPs could cause eosinophilic airway inflammation in the absence of allergens. PMID:26010476

  11. Interleukin-22 exacerbates airway inflammation induced by short-term exposure to cigarette smoke in mice

    PubMed Central

    Li, Jiu-rong; Zhou, Wei-xun; Huang, Ke-wu; Jin, Yang; Gao, Jin-ming

    2014-01-01

    Aim: Interleukin-22 (IL-22) exhibits both proinflammatory and anti-inflammatory properties in various biological processes. In this study we explored the effects of exogenous recombinant IL-22 (rIL-22) on cigarette smoke (CS)-induced airway inflammation in mice. Methods: Male C57BL/6 mice were divided into groups: (1) CS group exposed to tobacco smoke for 3 consecutive days, (2) rIL-22 group received rIL-22 (100 mg/kg, ip), and (3) CS plus rIL-22 group, received rIL-22 (100 mg/kg, ip) before the CS exposure. The airway resistance (Rn), lung morphology, inflammatory cells in the airways, and inflammatory cytokines and CXCR3 ligands in both bronchoalveolar lavage (BAL) fluids and lung tissues were analyzed. Results: CS alone significantly elevated IL-22 level in the BAL fluid. Both CS and rIL-22 significantly augmented airway resistance, an influx of inflammatory cells into the airways and lung parenchyma, and significantly elevated levels of pro-inflammatory cytokines (TGFβ1 and IL-17A) and CXCR3 chemokines (particularly CXCL10) at the mRNA and/or protein levels. Furthermore, the effects of rIL-22 on airway resistance and inflammation were synergistic with those of CS, as demonstrated by a further increased Rn value, infiltration of greater numbers of inflammatory cells into the lung, higher levels of inflammatory cytokines and chemokines, and more severe pathological changes in CS plus rIL-22 group as compared to those in CS group. Conclusion: Exogenous rIL-22 exacerbates the airway inflammatory responses to CS exposure in part by inducing expression of several proinflammatory cytokines and CXCR3 ligands. PMID:25345745

  12. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration

    PubMed Central

    Clunes, Lucy A.; Davies, Catrin M.; Coakley, Raymond D.; Aleksandrov, Andrei A.; Henderson, Ashley G.; Zeman, Kirby L.; Worthington, Erin N.; Gentzsch, Martina; Kreda, Silvia M.; Cholon, Deborah; Bennett, William D.; Riordan, John R.; Boucher, Richard C.; Tarran, Robert

    2012-01-01

    Cigarette smoke (CS) exposure induces mucus obstruction and the development of chronic bronchitis (CB). While many of these responses are determined genetically, little is known about the effects CS can exert on pulmonary epithelia at the protein level. We, therefore, tested the hypothesis that CS exerts direct effects on the CFTR protein, which could impair airway hydration, leading to the mucus stasis characteristic of both cystic fibrosis and CB. In vivo and in vitro studies demonstrated that CS rapidly decreased CFTR activity, leading to airway surface liquid (ASL) volume depletion (i.e., dehydration). Further studies revealed that CS induced internalization of CFTR. Surprisingly, CS-internalized CFTR did not colocalize with lysosomal proteins. Instead, the bulk of CFTR shifted to a detergent-resistant fraction within the cell and colocalized with the intermediate filament vimentin, suggesting that CS induced CFTR movement into an aggresome-like, perinuclear compartment. To test whether airway dehydration could be reversed, we used hypertonic saline (HS) as an osmolyte to rehydrate ASL. HS restored ASL height in CS-exposed, dehydrated airway cultures. Similarly, inhaled HS restored mucus transport and increased clearance in patients with CB. Thus, we propose that CS exposure rapidly impairs CFTR function by internalizing CFTR, leading to ASL dehydration, which promotes mucus stasis and a failure of mucus clearance, leaving smokers at risk for developing CB. Furthermore, our data suggest that strategies to rehydrate airway surfaces may provide a novel form of therapy for patients with CB.—Clunes, L. A., Davies, C. M., Coakley, R. D., Aleksandrov, A. A., Henderson, A. G., Zeman, K. L., Worthington, E. N., Gentzsch, M., Kreda, S. M., Cholon, D., Bennett, W. D., Riordan, J. R., Boucher, R. C., Tarran, R. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. PMID:21990373

  13. PAF mediates cigarette smoke-induced goblet cell metaplasia in guinea pig airways.

    PubMed

    Komori, M; Inoue, H; Matsumoto, K; Koto, H; Fukuyama, S; Aizawa, H; Hara, N

    2001-03-01

    Goblet cell metaplasia is an important morphological feature in the airways of patients with chronic airway diseases; however, the precise mechanisms that cause this feature are unknown. We investigated the role of endogenous platelet-activating factor (PAF) in airway goblet cell metaplasia induced by cigarette smoke in vivo. Guinea pigs were exposed repeatedly to cigarette smoke for 14 consecutive days. The number of goblet cells in each trachea was determined with Alcian blue-periodic acid-Schiff staining. Differential cell counts and PAF levels in bronchoalveolar lavage fluid were also evaluated. Cigarette smoke exposure significantly increased the number of goblet cells. Eosinophils, neutrophils, and PAF levels in bronchoalveolar lavage fluid were also significantly increased after cigarette smoke. Treatment with a specific PAF receptor antagonist, E-6123, significantly attenuated the increases in the number of airway goblet cells, eosinophils, and neutrophils observed after cigarette smoke exposure. These results suggest that endogenous PAF may play a key role in goblet cell metaplasia induced by cigarette smoke and that potential roles exist for inhibitors of PAF receptor in the treatment of hypersecretory airway diseases. PMID:11159026

  14. High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells

    PubMed Central

    Chen, Yu-Ching; Statt, Sarah; Wu, Reen; Chang, Hao-Teng; Liao, Jiunn-Wang; Wang, Chien-Neng; Shyu, Woei-Cherng; Lee, Chen-Chen

    2016-01-01

    Epithelial–mesenchymal transition (EMT) is implicated in bronchial remodeling and loss of lung function in chronic inflammatory airway diseases. Previous studies showed the involvement of the high mobility group box 1 (HMGB1) protein in the pathology of chronic pulmonary inflammatory diseases. However, the role of HMGB1 in EMT of human airway epithelial cells is still unclear. In this study, we used RNA sequencing to show that HMGB1 treatment regulated EMT-related gene expression in human primary-airway epithelial cells. The top five upregulated genes were SNAI2, FGFBP1, VIM, SPARC (osteonectin), and SERPINE1, while the downregulated genes included OCLN, TJP1 (ZO-1), FZD7, CDH1 (E-cadherin), and LAMA5. We found that HMGB1 induced downregulation of E-cadherin and ZO-1, and upregulation of vimentin mRNA transcription and protein translation in a dose-dependent manner. Additionally, we observed that HMGB1 induced AKT phosphorylation, resulting in GSK3β inactivation, cytoplasmic accumulation, and nuclear translocation of β-catenin to induce EMT in human airway epithelial cells. Treatment with PI3K inhibitor (LY294006) and β-catenin shRNA reversed HMGB1-induced EMT. Moreover, HMGB1 induced expression of receptor for advanced glycation products (RAGE), but not that of Toll-like receptor (TLR) 2 or TLR4, and RAGE shRNA inhibited HMGB1-induced EMT in human airway epithelial cells. In conclusion, we found that HMGB1 induced EMT through RAGE and the PI3K/AKT/GSK3β/β-catenin signaling pathway. PMID:26739898

  15. High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells.

    PubMed

    Chen, Yu-Ching; Statt, Sarah; Wu, Reen; Chang, Hao-Teng; Liao, Jiunn-Wang; Wang, Chien-Neng; Shyu, Woei-Cherng; Lee, Chen-Chen

    2016-01-01

    Epithelial-mesenchymal transition (EMT) is implicated in bronchial remodeling and loss of lung function in chronic inflammatory airway diseases. Previous studies showed the involvement of the high mobility group box 1 (HMGB1) protein in the pathology of chronic pulmonary inflammatory diseases. However, the role of HMGB1 in EMT of human airway epithelial cells is still unclear. In this study, we used RNA sequencing to show that HMGB1 treatment regulated EMT-related gene expression in human primary-airway epithelial cells. The top five upregulated genes were SNAI2, FGFBP1, VIM, SPARC (osteonectin), and SERPINE1, while the downregulated genes included OCLN, TJP1 (ZO-1), FZD7, CDH1 (E-cadherin), and LAMA5. We found that HMGB1 induced downregulation of E-cadherin and ZO-1, and upregulation of vimentin mRNA transcription and protein translation in a dose-dependent manner. Additionally, we observed that HMGB1 induced AKT phosphorylation, resulting in GSK3β inactivation, cytoplasmic accumulation, and nuclear translocation of β-catenin to induce EMT in human airway epithelial cells. Treatment with PI3K inhibitor (LY294006) and β-catenin shRNA reversed HMGB1-induced EMT. Moreover, HMGB1 induced expression of receptor for advanced glycation products (RAGE), but not that of Toll-like receptor (TLR) 2 or TLR4, and RAGE shRNA inhibited HMGB1-induced EMT in human airway epithelial cells. In conclusion, we found that HMGB1 induced EMT through RAGE and the PI3K/AKT/GSK3β/β-catenin signaling pathway. PMID:26739898

  16. Low level ozone exposure induces airways inflammation and modifies cell surface phenotypes in healthy humans

    EPA Science Inventory

    Background: The effects of low level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known, however much less is known about the inflammatory and immuno-modulatory effects oflow level ozone in the airways. Techniques such as induced sputum and flo...

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

    PubMed Central

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

    2014-01-01

    High levels of ambient environmental particulate matter (PM10 i.e. < 10 μm median aerodynamic diameter) have been linked to acute exacerbations of asthma. We examined the effects of delivering a single dose of Sydney PM10 by intranasal instillation to BALB/c mice that had been sensitized to ovalbumin and challenged repeatedly with a low (≈3 mg/m3) mass concentration of aerosolized ovalbumin for 4 weeks. Responses were compared to animals administered carbon black as a negative control, or a moderate (≈30 mg/m3) concentration of ovalbumin to simulate an allergen-induced acute exacerbation of airway inflammation. Delivery of PM10 to mice, in which experimental mild chronic asthma had previously been established, elicited characteristic features of enhanced allergic inflammation of the airways, including eosinophil and neutrophil recruitment, similar to that in the allergen-induced exacerbation. In parallel, there was increased expression of mRNA for interleukin (IL)-33 in airway tissues and an increased concentration of IL-33 in bronchoalveolar lavage fluid. Administration of a monoclonal neutralizing anti-mouse IL-33 antibody prior to delivery of particulates significantly suppressed the inflammatory response induced by Sydney PM10, as well as the levels of associated proinflammatory cytokines in lavage fluid. We conclude that IL-33 plays a key role in driving airway inflammation in this novel experimental model of an acute exacerbation of chronic allergic asthma induced by exposure to PM10. PMID:24730559

  18. EFFECTS OF SYSTEMIC NEUTROPHIL DEPLETION ON LPS-INDUCED AIRWAY DISEASE

    EPA Science Inventory

    Effects of Systemic Neutrophil Depletion on LPS-induced Airway Disease
    Jordan D. Savov, Stephen H. Gavett*, David M. Brass, Daniel L. Costa*, David A. Schwartz
    Pulmonary and Critical Care Division, Dept of Medicine ? Duke University Medical Center
    * National Health and E...

  19. NEUTROPHILS PLAY A CRITICAL ROLE IN THE DEVELOPMENT OF LPS-INDUCED AIRWAY DISEASE

    EPA Science Inventory

    ETD-02-045 (GAVETT) GPRA # 10108

    Neutrophils Play a Critical Role in the Development of LPS-Induced Airway Disease.
    Jordan D. Savov, Stephen H. Gavett*, David M. Brass, Daniel L. Costa*, and David A. Schwartz

    ABSTRACT
    We investigated the role of neutrophils...

  20. Vagotomy Reverses Established Allergen-Induced Airway Hyperreactivity to Methacholine in the Mouse

    EPA Science Inventory

    We evaluated the role of vagal reflexes in a mouse model of allergen-induced airway hyperreactivity. Mice were actively sensitized to ovalbumin then exposed to the allergen via inhalation. Prior to ovalbumin inhalation, mice also received intratracheally-instilled particulate ma...

  1. 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

  2. Airway cooling and rewarming. The second reaction sequence in exercise-induced asthma.

    PubMed Central

    Gilbert, I A; McFadden, E R

    1992-01-01

    To determine if a relationship exists among the magnitude and rate of airway rewarming, and the severity of bronchial obstruction in thermally induced asthma, we had seven subjects perform three- to four-point stimulus response curves with isocapnic hyperventilation of frigid air with and without pretreatment with inhaled norepinephrine. The latter was employed to alter the heat supplied to the airway walls by producing vasoconstriction. 1-s forced expiratory volume (FEV1) was measured before and 5 min after the cessation of each bout of hyperpnea and before and after norepinephrine. On a separate day, the subjects repeated the above challenges while the temperatures of the airstream in the intrathoracic airways were measured. Prenorepinephrine, FEV1 progressively decreased in a stimulus response fashion as ventilation rose, while norepinephrine shifted this curve to the right. As the level of ventilation increased, the size of the temperature difference between the cooling of hyperpnea and the rewarming of recovery followed suit, and their magnitude was linearly related to the severity of bronchial narrowing. Reducing the mucosal blood supply of the airways with norepinephrine limited rewarming and attenuated the obstructive response. These data demonstrate that the airway narrowing that develops following hyperpnea and the magnitude of the thermal differences are related, and that alterations in blood supply directly affect bronchial heat flux and influence obstruction. PMID:1522227

  3. Indomethacin inhibits the airway hyperresponsiveness but not the neutrophil influx induced by ozone in dogs

    SciTech Connect

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

    1984-08-01

    To determine whether oxygenation products of arachidonic acid may be involved in the airway hyperresponsiveness induced by ozone exposure, we studied whether ozone-induced hyperresponsiveness could be inhibited by the prostaglandin synthetase inhibitor, indomethacin, in dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance in 2 sets of experiments: in one set, 5 dogs were given no indomethacin treatment and were studied both before and after ozone exposure (3.0 ppm, 2 h); in another set, the same dogs were studied before indomethacin treatment or ozone exposure and then during treatment (1 mg/kg every 12 h for 4 days) both before and after ozone exposure. On each occasion, we also determined the number of neutrophils in biopsies of the airway epithelium. When the dogs were not treated with indomethacin, ozone caused a marked increase in responsiveness to acetylcholine and a marked increase in the number of neutrophils in the airway epithelium. When the dogs were given indomethacin, responsiveness was no different during treatment than before treatment, but more importantly, responsiveness did not increase significantly after they were exposed to ozone. Interestingly, indomethacin treatment did not affect either the baseline number of epithelial neutrophils before ozone exposure or the increase in the number of neutrophils after exposure. The results suggest that oxygenation products of arachidonic acid that are sensitive to inhibition by indomethacin play a role in ozone-induced hyperresponsiveness without affecting the influx of neutrophils.

  4. Mechanical consequences of allergic induced remodeling on mice airway resistance and compressibility.

    PubMed

    Novali, Mauro; Shalaby, Karim H; Robichaud, Annette; Benedetti, Andrea; Fereydoonzad, Liah; McGovern, Toby K; Schuessler, Thomas F; Martin, James G

    2015-11-01

    The effect of remodeling on airway function is uncertain. It may affect airway compressibility during forced expirations differently than airflow resistance, providing a tool for its assessment. The aim of the current study was to compare the effects of acute and chronic antigen challenge on methacholine-induced bronchoconstriction assessed from resistance and maximal tidal expiratory flow. Balb/C mice were sensitized with ovalbumin (OVA) and challenged either daily for three days with intra-nasal OVA or daily for 5 days and three times a week for 5 subsequent weeks. Acute and chronic allergen challenge induced airway hyperresponsiveness (AHR) to methacholine. However the relationship between maximal tidal expiratory flow and resistance during methacholine challenge was different between the two conditions, suggesting that the determinants of AHR are not identical following acute and chronic allergen exposure. We conclude that the contrast of changes in maximal tidal expiratory flow and respiratory resistance during methacholine-induced bronchoconstriction may allow the detection of the mechanical consequences of airway remodeling. PMID:26213118

  5. Effect of thromboxane antagonists on ozone-induced airway responses in dogs

    SciTech Connect

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

    1990-09-01

    Airway hyperresponsiveness after inhaled ozone in dogs may occur as a result of thromboxane release in the airway. In this study, two thromboxane receptor antagonists, L-655,240 and L-670,596, were used in doses that inhibit the response to an inhaled thromboxane mimetic, U-46619, to determine further the role of thromboxane in ozone-induced airway hyperresponsiveness. Dogs were studied on 2 days separated by 1 wk. On each day, the dogs inhaled ozone (3 ppm) for 30 min. On one randomly assigned day, 10 dogs received an infusion of L-655,240 (5 mg.kg-1.h-1) and 5 dogs received an infusion of L-670,596 (1 mg.kg-1.h-1); on the other day dogs received a control infusion. Airway responses to doubling doses of acetylcholine were measured before and after inhalation of ozone and were expressed as the concentration of acetylcholine giving a rise in resistance of 5 cmH2O.l-1.s from baseline (acetylcholine provocation concentration). The development of airway hyperresponsiveness after ozone was not inhibited by the thromboxane antagonists. The mean log difference in the acetylcholine provocative concentration before and after ozone on the L-655,240 treatment day was 0.62 +/- 0.12 (SE) and on the control day was 0.71 +/- 0.12 (P = 0.48); on the L-670,596 treatment day the mean log difference was 0.68 +/- 0.15 (SE) and on the control day it was 0.75 +/- 0.19 (P = 0.45). These results do not support an important role for thromboxane in causing ozone-induced airway hyperresponsiveness.

  6. 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.

  7. 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.

  8. The Lateral Position Improved Airway Patency in Anesthetized Patient With Burn-Induced Cervico-Mento-Sternal Scar Contracture

    PubMed Central

    Arai, Young-Chang P.; Kawanishi, Jun; Sakakima, Yoshikazu; Ohmoto, Koichi; Ito, Akihiro; Maruyama, Yuki; Ikemoto, Tatsunori

    2016-01-01

    A 78-year-old woman with burn-induced cervico-mento-sternal scar contracture was scheduled for laparoscopic cholecystectomy. During inhalational induction of sevoflurane, her airway patency deteriorated. The right lateral position and assist ventilation using a breathing bag dramatically improved her airway patency. PMID:27252906

  9. Neurogenic airway inflammation induced by repeated intra-esophageal instillation of HCl in guinea pigs.

    PubMed

    Liu, Chunli; Chen, Ruchong; Luo, Wei; Lai, Kefang; Zhong, Nanshan

    2013-04-01

    This study was conducted to investigate if repeated intra-esophageal acid administrations may induce neurogenic inflammation in the airways and nodose ganglion in a guinea pig model. Guinea pigs were sedated and perfused with 0.1 N HCl in the distal esophagus via a nasoesophageal catheter for 14 consecutive days. Substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and calcitonin gene-related peptide concentration were measured by ELISA or radioimmunoassay. Neuropeptide expression in the airways and nodose ganglion was detected by immunohistochemistry and assessed semi-quantitatively. Inflammation was found in the trachea and bronchi. There was a threefold increase in substance P concentration in the trachea, main bronchi, and lung homogenate and a twofold increase in NKA and NKB concentration in the main bronchi, lung homogenate, and bronchial alveolus lavage fluid, respectively. The SP and NKA expressions in the airways and nodose ganglion were also significantly increased. Chronic intra-esophageal acid instillation induces significant neurogenic inflammation in the airways and nodose ganglion in the vagus nerve in guinea pigs. PMID:23225164

  10. Secretory response induced by essential oils on airway surface fluid: a pharmacological MRI study.

    PubMed

    Nicolato, Elena; Boschi, Federico; Marzola, Pasquina; Sbarbati, Andrea

    2009-07-30

    Using pharmacological magnetic resonance imaging, we have performed an in vivo evaluation of the secretory response induced by essential oils in the rat airway. Aim of the work was to establish a computerized method to assess the efficacy of volatile compounds in spatially localized areas without the bias derived by subjective evaluation. Magnetic resonance experiments were carried out using a 4.7 T horizontal magnet. In the trachea, airway surface fluid was easily identified for its high intensity signal. The tracheal glands were also easily visible. The oesophageal lumen was usually collapsed and was identifiable only in the presence of intraluminal liquid. Scotch pine essential oil inhalation significantly increased the surface fluid in the middle portion of the trachea and the increase was visible at both 5 and 10 min. A lesser secretory response was detected after rosemary essential oil inhalation even though the response was significant with respect to the control in particular at 10 min. No secretory response was detected after peppermint essential oil inhalation both at 5 and 10 min. The data obtained in the present work demonstrate a chemically induced airway secretion. The availability of a pharmacological magnetic resonance imaging approach opens new perspectives to test the action of volatile compounds on the airway. PMID:19422906

  11. IL-33 Modulates Chronic Airway Resistance Changes Induced by Multi-Walled Carbon Nanotubes

    PubMed Central

    Wang, Xiaojia; Shannahan, Jonathan H.; Brown, Jared M.

    2015-01-01

    Objective Instillation of multi-walled carbon nanotubes (MWCNTs) in C57BL/6 mice results in decrements of pulmonary function specifically characterized by increases in airway resistance. In this study, we examined possible mechanisms responsible for these alterations following MWCNT exposure, including the roles of IL-33 and chronic inflammation. Materials and Methods To elucidate the role of IL-33, we assessed lung histology and pulmonary function in C57BL/6 and IL-33−/− mice 30 days following MWCNT instillation. In addition, the impact of MWCNT instillation on airway hyperresponsiveness (AHR) was assessed by methacholine challenges of C57BL/6 and IL-33−/− mice. To further understand the mechanisms by which MWCNTs may increase airway constriction, C57BL/6 mice were treated with aerosolized albuterol or injected with multiple doses of methylprednisolone via intra-peritoneal injections prior to the assessment of MWCNT-induced changes in pulmonary function. Results Total cell count, macrophages, and neutrophils were increased in the lavage fluid of C57BL/6 mice, but not in IL-33−/− mice, following MWCNT exposure. C57BL/6 mice displayed increased inflammation and fibrosis located proximal to the airways which was absent in IL-33−/− mice. Aerosolized methacholine increased parameters of airway resistance (R and Rn) in a dose-dependent manner in all groups, with MWCNT-instilled C57BL/6 mice responding more robustly compared to controls, while no differences were found in IL-33−/− mice due to MWCNT exposure. Treatment with methylprednisolone reduced both the MWCNT-induced histopathological changes and increases in R and Rn in C57BL/6 mice. Conclusion These findings suggest that IL-33 and chronic inflammation in general are critical in the pulmonary toxicity induced by MWCNT resulting in modified pulmonary function. PMID:24502429

  12. Intratracheal myriocin enhances allergen‐induced Th2 inflammation and airway hyper‐responsiveness

    PubMed Central

    Edukulla, Ramakrishna; Rehn, Kira Lee; Liu, Bo; McAlees, Jaclyn W.; Hershey, Gurjit K.; Wang, Yui Hsi; Lewkowich, Ian

    2016-01-01

    Introduction Ceramide is the central substrate of sphingolipid metabolism and plays a key role in cellular signal transduction pathways, regulating apoptosis, differentiation, and chemotaxis. Alterations in airway ceramide levels are observed in multiple pulmonary diseases and recent human genetic association studies have linked dysregulation of sphingolipid regulatory genes with asthma pathogenesis. Methods Utilizing myriocin, a potent inhibitor of sphingolipid synthesis, we evaluated the immune regulatory role of de novo ceramide generation in vitro and in vivo. Intratracheal myriocin was administered alone or during house dust mite sensitization (HDM) of BALB/C mice and airway hyper‐responsiveness (AHR) was evaluated by invasive plethysmography followed by bronchial lavage (BAL) cytology and cytokine quantification. Results Myriocin inhibits and HDM exposure activates de novo ceramide synthesis in bone marrow‐derived dendritic cells. Mice receiving intratracheal myriocin developed a mild airway neutrophilic infiltrate without inducing a significant increase in AHR. CXCL1 was elevated in the BAL fluid of myriocin‐treated mice while the neutrophilic chemotactic factors anaphylatoxin C5a, leukotriene B4, and IL‐17 were unaffected. HDM treatment combined with myriocin led to a dramatic enhancement of AHR (63% increase over HDM alone, p < 0.001) and increased granulocyte pulmonary infiltrates versus HDM or myriocin alone. Elevated Th2 T cell counts and Th2 cytokines/chemokines (IL5, IL13, CCL17) were observed in mice treated with combined HDM/myriocin compared to HDM alone. Myriocin‐treated pulmonary CD11c+ cells stimulated with HDM secreted significantly more CXCL1 than cells stimulated with HDM alone while HDM stimulated airway epithelial cells showed no change in CXCL1 secretion following myriocin treatment. Conclusions Intratracheal myriocin, likely acting via ceramide synthesis inhibition, enhances allergen‐induced airway inflammation

  13. The effects of cannabidiol on the antigen-induced contraction of airways smooth muscle in the guinea-pig.

    PubMed

    Dudášová, A; Keir, S D; Parsons, M E; Molleman, A; Page, C P

    2013-06-01

    (-)-Δ(9)-Tetrahydrocannabinol has been demonstrated to have beneficial effects in the airways, but its psychoactive effects preclude its therapeutic use for the treatment of airways diseases. In the present study we have investigated the effects of (-)-cannabidiol, a non-psychoactive component of cannabis for its actions on bronchial smooth muscle in vitro and in vivo. Guinea-pig bronchial smooth muscle contractions induced by exogenously applied spasmogens were measured isometrically. In addition, contractile responses of bronchial smooth muscle from ovalbumin-sensitized guinea-pigs were investigated in the absence or presence of (-)-cannabidiol. Furthermore, the effect of (-)-cannabidiol against ovalbumin-induced airway obstruction was investigated in vivo in ovalbumin-sensitized guinea-pigs. (-)-Cannabidiol did not influence the bronchial smooth muscle contraction induced by carbachol, histamine or neurokinin A. In contrast, (-)-cannabidiol inhibited anandamide- and virodhamine-induced responses of isolated bronchi. A fatty acid amide hydrolase inhibitor, phenylmethanesulfonyl fluoride reversed the inhibitory effect of (-)-cannabidiol on anandamide-induced contractions. In addition, (-)-cannabidiol inhibited the contractile response of bronchi obtained from allergic guinea-pigs induced by ovalbumin. In vivo, (-)-cannabidiol reduced ovalbumin-induced airway obstruction. In conclusion, our results suggest that cannabidiol can influence antigen-induced airway smooth muscle tone suggesting that this molecule may have beneficial effects in the treatment of obstructive airway disorders. PMID:23428645

  14. The Epithelial Anion Transporter Pendrin Is Induced by Allergy and Rhinovirus Infection, Regulates Airway Surface Liquid, and Increases Airway Reactivity and Inflammation in an Asthma Model1

    PubMed Central

    Nakagami, Yasuhiro; Favoreto, Silvio; Zhen, Guohua; Park, Sung-Woo; Nguyenvu, Louis T.; Kuperman, Douglas A.; Dolganov, Gregory M.; Huang, Xiaozhu; Boushey, Homer A.; Avila, Pedro C.; Erle, David J.

    2008-01-01

    Asthma exacerbations can be triggered by viral infections or allergens. The Th2 cytokines IL-13 and IL-4 are produced during allergic responses and cause increases in airway epithelial cell mucus, electrolyte and water secretion into the airway surface liquid (ASL). Since ASL dehydration can cause airway inflammation and obstruction, ion transporters could play a role in pathogenesis of asthma exacerbations. We previously reported that expression of the epithelial cell anion transporter pendrin is markedly increased in response to IL-13. Here we show that pendrin plays a role in allergic airway disease and in regulation of ASL thickness. Pendrin-deficient mice had less allergen-induced airway hyperreactivity and inflammation than control mice although other aspects of the Th2 response were preserved. In cultures of IL-13-stimulated mouse tracheal epithelial cells, pendrin deficiency caused an increase in ASL thickness, suggesting that reductions in allergen-induced hyperreactivity and inflammation in pendrin-deficient mice result from improved ASL hydration. To determine whether pendrin might also play a role in virus-induced exacerbations of asthma, we measured pendrin mRNA expression in human subjects with naturally occurring common colds caused by rhinovirus and found a 4.9-fold-increase in mean expression during colds. Studies of cultured human bronchial epithelial cells indicated that this increase could be explained by the combined effects of rhinovirus and IFN-γ, a Th1 cytokine induced during virus infection. We conclude that pendrin regulates ASL thickness and may be an important contributor to asthma exacerbations induced by viral infections or allergens. PMID:18641360

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

    PubMed Central

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

    2015-01-01

    Asthma is characterized by aberrant airways including epithelial thickening, goblet cell hyperplasia, and smooth muscle hypertrophy within the airway wall. The current study examined whether kaempferol inhibited mast cell degranulation and prostaglandin (PG) release leading to the development of aberrant airways, using an in vitro model of dinitrophenylated bovine serum albumin (DNP-BSA)-sensitized rat basophilic leukemia (RBL-2H3) mast cells and an in vivo model of BSA-challenged asthmatic mice. Nontoxic kaempferol at 10–20 μM suppressed β-hexosaminidase release and cyclooxygenase 2 (COX2)-mediated production of prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α) in sensitized mast cells. Oral administration of ≤20 mg/kg kaempferol blocked bovine serum albumin (BSA) inhalation-induced epithelial cell excrescence and smooth muscle hypertrophy by attenuating the induction of COX2 and the formation of PGD2 and PGF2α, together with reducing the anti-α-smooth muscle actin (α-SMA) expression in mouse airways. Kaempferol deterred the antigen-induced mast cell activation of cytosolic phospholipase A2 (cPLA2) responsive to protein kinase Cμ (PKCμ) and extracellular signal-regulated kinase (ERK). Furthermore, the antigen-challenged activation of Syk-phospholipase Cγ (PLCγ) pathway was dampened in kaempferol-supplemented mast cells. These results demonstrated that kaempferol inhibited airway wall thickening through disturbing Syk-PLCγ signaling and PKCμ-ERK-cPLA2-COX2 signaling in antigen-exposed mast cells. Thus, kaempferol may be a potent anti-allergic compound targeting allergic asthma typical of airway hyperplasia and hypertrophy. PMID:26694364

  16. Role of mitochondrial hydrogen peroxide induced by intermittent hypoxia in airway epithelial wound repair in vitro.

    PubMed

    Hamada, Satoshi; Sato, Atsuyasu; Hara-Chikuma, Mariko; Satooka, Hiroki; Hasegawa, Koichi; Tanimura, Kazuya; Tanizawa, Kiminobu; Inouchi, Morito; Handa, Tomohiro; Oga, Toru; Muro, Shigeo; Mishima, Michiaki; Chin, Kazuo

    2016-05-15

    The airway epithelium acts as a frontline barrier against various environmental insults and its repair process after airway injury is critical for the lung homeostasis restoration. Recently, the role of intracellular reactive oxygen species (ROS) as transcription-independent damage signaling has been highlighted in the wound repair process. Both conditions of continuous hypoxia and intermittent hypoxia (IH) induce ROS. Although IH is important in clinical settings, the roles of IH-induced ROS in the airway repair process have not been investigated. In this study, we firstly showed that IH induced mitochondrial hydrogen peroxide (H2O2) production and significantly decreased bronchial epithelial cell migration, prevented by catalase treatment in a wound scratch assay. RhoA activity was higher during repair process in the IH condition compared to in the normoxic condition, resulting in the cellular morphological changes shown by immunofluorescence staining: round cells, reduced central stress fiber numbers, pronounced cortical actin filament distributions, and punctate focal adhesions. These phenotypes were replicated by exogenous H2O2 treatment under the normoxic condition. Our findings confirmed the transcription-independent role of IH-induced intracellular ROS in the bronchial epithelial cell repair process and might have significant implications for impaired bronchial epithelial cell regeneration. PMID:27093911

  17. Vitamin D Treatment Modulates Organic Dust-Induced Cellular and Airway Inflammatory Consequences

    PubMed Central

    Golden, Gregory A.; Wyatt, Todd A.; Romberger, Debra J.; Reiff, Daniel; McCaskill, Michael; Bauer, Christopher; Gleason, Angela M.; Poole, Jill A.

    2014-01-01

    Exposure to organic dusts elicits airway inflammatory diseases. Vitamin D recently has been associated with various airway inflammatory diseases, but its role in agricultural organic dust exposures is unknown. This study investigated whether vitamin D reduces organic dust-induced inflammatory outcomes in cell culture and animal models. Organic dust extracts obtained from swine confinement facilities induced neutrophil chemokine production (human IL-8, murine CXCL1/CXCL2). Neutrophil chemokine induction was reduced in human blood monocytes, human bronchial epithelial cells and murine lung slices pretreated with 1,25-(OH)2D3. Intranasal inhalation of organic dust extract induced neutrophil influx and CXCL1/CXCL2 release also was decreased in mice fed a relatively high vitamin D diet as compared to mice fed a low vitamin D diet. These findings were associated with reduced tracheal epithelial cell PKCα and PKCε activity and whole lung TLR2 and TLR4 gene expression. Collectively, vitamin D plays a role in modulating organic dust-induced airway inflammatory outcomes. PMID:23281135

  18. Cyclooxygenase-2/prostaglandin D2/CRTH2 pathway mediates double-stranded RNA-induced enhancement of allergic airway inflammation.

    PubMed

    Shiraishi, Yoshiki; Asano, Koichiro; Niimi, Kyoko; Fukunaga, Koichi; Wakaki, Misa; Kagyo, Junko; Takihara, Takahisa; Ueda, Soichiro; Nakajima, Takeshi; Oguma, Tsuyoshi; Suzuki, Yusuke; Shiomi, Tetsuya; Sayama, Koichi; Kagawa, Shizuko; Ikeda, Eiji; Hirai, Hiroyuki; Nagata, Kinya; Nakamura, Masataka; Miyasho, Taku; Ishizaka, Akitoshi

    2008-01-01

    Respiratory RNA viruses responsible for the common cold often worsen airway inflammation and bronchial responsiveness, two characteristic features of human asthma. We studied the effects of dsRNA, a nucleotide synthesized during viral replication, on airway inflammation and bronchial hyperresponsiveness in murine models of asthma. Intratracheal instillation of poly I:C, a synthetic dsRNA, increased the airway eosinophilia and enhanced bronchial hyperresponsiveness to methacholine in OVA-sensitized, exposed rats. These changes were associated with induction of cyclooxygenase-2 (COX-2) expression and COX-2-dependent PGD2 synthesis in the lungs, particularly in alveolar macrophages. The direct intratracheal instillation of PGD2 enhanced the eosinophilic inflammation in OVA-exposed animals, whereas pretreatment with a dual antagonist against the PGD2 receptor-(CRTH2) and the thromboxane A2 receptor, but not with a thromboxane A2 receptor-specific antagonist, nearly completely eliminated the dsRNA-induced worsening of airway inflammation and bronchial hyperresponsiveness. CRTH2-deficient mice had the same degree of allergen-induced airway eosinophilia as wild-type mice, but they did not exhibit a dsRNA-induced increase in eosinophil accumulation. Our data demonstrate that COX-2-dependent production of PGD2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenetic factors responsible for the dsRNA-induced enhancement of airway inflammation and responsiveness. PMID:18097056

  19. Chlamydophila pneumoniae induces a sustained airway hyperresponsiveness and inflammation in mice

    PubMed Central

    Blasi, Francesco; Aliberti, Stefano; Allegra, Luigi; Piatti, Gioia; Tarsia, Paolo; Ossewaarde, Jacobus M; Verweij, Vivienne; Nijkamp, Frans P; Folkerts, Gert

    2007-01-01

    Background It has been reported that Chlamydophila (C.) pneumoniae is involved in the initiation and promotion of asthma and chronic obstructive pulmonary diseases (COPD). Surprisingly, the effect of C. pneumoniae on airway function has never been investigated. Methods In this study, mice were inoculated intranasally with C. pneumoniae (strain AR39) on day 0 and experiments were performed on day 2, 7, 14 and 21. Results We found that from day 7, C. pneumoniae infection causes both a sustained airway hyperresponsiveness and an inflammation. Interferon-γ (IFN-γ) and macrophage inflammatory chemokine-2 (MIP-2) levels in bronchoalveolar lavage (BAL)-fluid were increased on all experimental days with exception of day 7 where MIP-2 concentrations dropped to control levels. In contrast, tumor necrosis factor-α (TNF-α) levels were only increased on day 7. From day 7 to 21 epithelial damage and secretory cell hypertrophy was observed. It is suggested that, the inflammatory cells/mediators, the epithelial damage and secretory cell hypertrophy contribute to initiation of airway hyperresponsiveness. Conclusion Our study demonstrates for the first time that C. pneumoniae infection can modify bronchial responsiveness. This has clinical implications, since additional changes in airway responsiveness and inflammation-status induced by this bacterium may worsen and/or provoke breathlessness in asthma and COPD. PMID:18021431

  20. Protease inhibitor reduces airway response and underlying inflammation in cockroach allergen-induced murine model.

    PubMed

    Saw, Sanjay; Arora, Naveen

    2015-04-01

    Protease(s) enhances airway inflammation and allergic cascade. In the present study, effect of a serine protease inhibitor was evaluated in mouse model of airway disease. Mice were sensitized with cockroach extract (CE) or Per a 10 and treated with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) 1 h before or after challenge to measure airway response. Mice were euthanized to collect bronchoalveolar lavage fluid (BALF), blood, and lung to evaluate inflammation. AEBSF treatment significantly reduced the AHR in allergen-challenged mice in dose-dependent manner (p≤ 0.01). IgE (p≤0.05) and Th2 cytokines (p≤0.05) were significantly reduced in treated mice. AEBSF treatment lowered total cell (p≤0.05), eosinophil (p≤0.05), and neutrophil (p≤0.05) in BALF and lung tissue. Oxidative stress parameters were impaired on treatment in allergen-challenged mice (p≤0.05). AEBSF had therapeutic effect in allergen-induced airway resistance and underling inflammation and had potential for combination or as add-on therapy for respiratory diseases. PMID:25052477

  1. Role of EP2 and EP4 receptors in airway microvascular leak induced by prostaglandin E2

    PubMed Central

    Jones, Victoria C; Birrell, Mark A; Maher, Sarah A; Griffiths, Mark; Grace, Megan; O'Donnell, Valerie B; Clark, Stephen R

    2016-01-01

    Background and Purpose Airway microvascular leak (MVL) involves the extravasation of proteins from post‐capillary venules into surrounding tissue. MVL is a cardinal sign of inflammation and an important feature of airway inflammatory diseases such as asthma. PGE2, a product of COX‐mediated metabolism of arachidonic acid, binds to four receptors, termed EP1–4. PGE2 has a wide variety of effects within the airway, including modulation of inflammation, sensory nerve activation and airway tone. However, the effect of PGE2 on airway MVL and the receptor/s that mediate this have not been described. Experimental Approach Evans Blue dye was used as a marker of airway MVL, and selective EP receptor agonists and antagonists were used alongside EP receptor‐deficient mice to define the receptor subtype involved. Key Results PGE2 induced significant airway MVL in mice and guinea pigs. A significant reduction in PGE2‐induced MVL was demonstrated in Ptger2 −/− and Ptger4 −/− mice and in wild‐type mice pretreated simultaneously with EP2 (PF‐04418948) and EP4 (ER‐819762) receptor antagonists. In a model of allergic asthma, an increase in airway levels of PGE2 was associated with a rise in MVL; this change was absent in Ptger2 −/− and Ptger4 −/− mice. Conclusions and Implications PGE2 is a key mediator produced by the lung and has widespread effects according to the EP receptor activated. Airway MVL represents a response to injury and under ‘disease’ conditions is a prominent feature of airway inflammation. The data presented highlight a key role for EP2 and EP4 receptors in MVL induced by PGE2. PMID:26639895

  2. Thuja orientalis reduces airway inflammation in ovalbumin-induced allergic asthma.

    PubMed

    Shin, In-Sik; Shin, Na-Rae; Jeon, Chan-Mi; Kwon, Ok-Kyoung; Hong, Ju-Mi; Kim, Hui-Seong; Oh, Sei-Ryang; Ahn, Kyung-Seop

    2015-09-01

    Thuja orientalis (TO) may be used as a herbal remedy for the treatment of numerous inflammatory diseases. In the present study, the effects of TO were evaluated on airway inflammation in ovalbumin (OVA)‑induced allergic asthma and RAW264.7 murine macrophage cells. The effects of TO on the production of proinflammatory mediators, were determined in RAW264.7 cells that had been stimulated with lipopolysaccharide (LPS). Furthermore, an in vivo experiment was performed on mice that were sensitized to OVA and then received an OVA airway challenge. TO was administered by daily oral gavage at a dose of 30 mg/kg, 21‑23 days after the initial OVA sensitization. TO was shown to reduce nitric oxide production and reduce the relative mRNA expression levels of inducible nitric oxide synthase (iNOS), interleukin (IL)‑6, cyclooxygenase‑2, matrix metalloproteinase (MMP)‑9, and tumor necrosis factor‑α in RAW264.7 cells stimulated with LPS. In addition, TO markedly decreased the inflammatory cell counts in bronchial alveolar lavage fluid, reduced the levels of IL‑4, IL‑5, IL‑13, eotaxin and immunoglobulin E, and reduced airway hyperresponsivenes, in the OVA sensitized mice. Furthermore, TO attenuated airway inflammation and mucus hypersecretion, induced by the OVA challenge of the lung tissue. TO also reduced the expression of iNOS and MMP‑9 in lung tissue. In conclusion, TO exerted anti‑inflammatory effects in an OVA‑induced allergic asthma model, and in LPS‑stimulated RAW264.7 cells. These results suggest that TO may be a useful therapeutic agent for the treatment of inflammatory diseases, including allergic asthma. PMID:26063078

  3. 1,25-Dihydroxyvitamin D3 prevents toluene diisocyanate-induced airway epithelial barrier disruption.

    PubMed

    Li, Wenjia; Dong, Hangming; Zhao, Haijin; Song, Jiafu; Tang, Haixiong; Yao, Lihong; Liu, Laiyu; Tong, Wancheng; Zou, Mengchen; Zou, Fei; Cai, Shaoxi

    2015-07-01

    The loss of airway epithelial integrity contributes significantly to asthma pathogenesis. Evidence suggests that vitamin D plays an important role in the prevention and treatment of asthma. However, its role in airway epithelial barrier function remains uncertain. We have previously demonstrated impaired epithelial junctions in a model of toluene diisocyanate (TDI)-induced asthma. In the present study, we hypothesized that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] may prevent TDI-induced epithelial barrier disruption. Male BALB/c mice were dermally sensitized and then challenged with TDI. The mice were then administered 1,25(OH)2D3 intraperitoneally prior to challenge with TDI. For in vitro experiments, 16HBE bronchial epithelial cells were cultured and stimulated with TDI-human serum albumin (HSA). The results revealed that the mice treated with 1,25(OH)2D3 displayed decreased airway hyperresponsiveness (AHR), suppressed neutrophil and eosinophil infiltration into the airways, as well as an increased E-cadherin and zonula occludens-1 (ZO-1) expression at the cell-cell contact sites. In vitro, exposure of the cells to TDI-HSA induced a rapid decline in transepithelial electrical resistance (TER) and an increase in cell permeability, followed by a decrease in occludin expression and the redistribution of E-cadherin, accompanied by a significant upregulation in the levels of phosphorylated extracellular signal-regulated kinase (ERK)1/2. These effects were all partly reversed by treatment with either 1,25(OH)2D3 or an ERK1/2 inhibitor. In conclusion, the findings of our study demonstrate that 1,25(OH)2D3 prevents TDI-induced epithelial barrier disruption, and that the ERK1/2 pathway may play a role in this process. PMID:25998793

  4. Baicalin inhibits PDGF-induced proliferation and migration of airway smooth muscle cells

    PubMed Central

    Yang, Guang; Li, Jian-Qiang; Bo, Jian-Ping; Wang, Bei; Tian, Xin-Rui; Liu, Tan-Zhen; Liu, Zhuo-La

    2015-01-01

    Airway smooth muscle (ASM) cell proliferation and migration play important roles in airway remodeling in asthma. In vitro platelet-derived growth factor (PDGF) induced ASM cell proliferation and migration. Baicalin is one of flavonoid extracts from Scutellaria baicalensis, which has an anti-asthma effect. However, little is known about its role in PDGF-induced proliferation and migration in rat ASM (RASM) cells. In this study, we aimed to investigate the effects of baicalin on PDGF-induced RASM cell proliferation and migration. We also identified the signaling pathway by which baicalin influences RASM cell proliferation and migration. In the current study, we demonstrated that baicalin suppressed PDGF-induced RASM cell proliferation, arrested PDGF-induced cell-cycle progression. It also suppressed PDGF-induced RASM cell migration. Furthermore, baicalin suppressed PDGF-induced expression of phosphorylated p38, ERK1/2 and JNK in RASM cells. In summary, our study is the first to show that baicalin pretreatment can significantly inhibit PDGF-induced RASM cell proliferation and migration by suppressing the MAPK signaling pathway, and baicalin may be a useful chemotherapeutic agent for asthma. PMID:26884970

  5. Bone morphogenetic protein 4 inhibits liposaccharide-induced inflammation in the airway.

    PubMed

    Li, Zhengtu; Wang, Jian; Wang, Yan; Jiang, Hua; Xu, Xiaoming; Zhang, Chenting; Li, Defu; Xu, Chuyi; Zhang, Kedong; Qi, Yafei; Gong, Xuefang; Tang, Chun; Zhong, Nanshan; Lu, Wenju

    2014-11-01

    Bone morphogenetic protein 4 (BMP4) is a multifunctional growth factor that belongs to the TGF-β superfamily. The role of BMP4 in lung diseases is not fully understood. Here, we demonstrate that BMP4 was upregulated in lungs undergoing lipopolysaccharide (LPS)-induced inflammation, and in airway epithelial cells treated with LPS or TNF-α. BMP4 mutant (BMP4(+/-) ) mice presented with more severe lung inflammation in response to LPS or Pseudomonas aeruginosa, and lower bacterial load compared with that in BMP4(+/+) mice. Knockdown of BMP4 by siRNA increased LPS and TNF-α-induced IL-8 expression in 16HBE human airway epithelial cells and in primary human bronchial epithelial cells. Similarly, peritoneal macrophages from BMP4(+/-) mice produced greater levels of TNF-α and keratinocyte chemoattractant (KC) upon LPS treatment compared with cells from BMP4(+/+) mice. Administration of exogenous BMP4 attenuated the upregulation of TNF-α, IL-8, or KC induced by LPS and/or TNF-α in airway epithelial cells, and peritoneal macrophages. Finally, partial deficiency of BMP4 in BMP4(+/-) mice protected the animals from restrictive lung function reduction upon chronic LPS exposure. These results indicate that BMP4 plays an important anti-inflammatory role, controlling the strength and facilitating the resolution of acute lung inflammation; yet, BMP4 also contributes to lung function impairment during chronic lung inflammation. PMID:25142202

  6. Hyperoxia promotes polarization of the immune response in ovalbumin-induced airway inflammation, leading to a TH17 cell phenotype

    PubMed Central

    Nagato, Akinori C; Bezerra, Frank S; Talvani, André; Aarestrup, Beatriz J; Aarestrup, Fernando M

    2015-01-01

    Previous studies have demonstrated that hyperoxia-induced stress and oxidative damage to the lungs of mice lead to an increase in IL-6, TNF-α, and TGF-β expression. Together, IL-6 and TGF-β have been known to direct T cell differentiation toward the TH17 phenotype. In the current study, we tested the hypothesis that hyperoxia promotes the polarization of T cells to the TH17 cell phenotype in response to ovalbumin-induced acute airway inflammation. Airway inflammation was induced in female BALB/c mice by intraperitoneal sensitization and intranasal introduction of ovalbumin, followed by challenge methacholine. After the methacholine challenge, animals were exposed to hyperoxic conditions in an inhalation chamber for 24 h. The controls were subjected to normoxia or aluminum hydroxide dissolved in phosphate buffered saline. After 24 h of hyperoxia, the number of macrophages and lymphocytes decreased in animals with ovalbumin-induced airway inflammation, whereas the number of neutrophils increased after ovalbumin-induced airway inflammation. The results showed that expression of Nrf2, iNOS, T-bet and IL-17 increased after 24 of hyperoxia in both alveolar macrophages and in lung epithelial cells, compared with both animals that remained in room air, and animals with ovalbumin-induced airway inflammation. Hyperoxia alone without the induction of airway inflammation lead to increased levels of TNF-α and CCL5, whereas hyperoxia after inflammation lead to decreased CCL2 levels. Histological evidence of extravasation of inflammatory cells into the perivascular and peribronchial regions of the lungs was observed after pulmonary inflammation and hyperoxia. Hyperoxia promotes polarization of the immune response toward the TH17 phenotype, resulting in tissue damage associated with oxidative stress, and the migration of neutrophils to the lung and airways. Elucidating the effect of hyperoxia on ovalbumin-induced acute airway inflammation is relevant to preventing or

  7. Preexposure to ozone blocks the antigen-induced late asthmatic response of the canine peripheral airways

    SciTech Connect

    Turner, C.R.; Kleeberger, S.R.; Spannhake, E.W. )

    1989-01-01

    The influence of exposure of the airways to ozone on acute allergic responsiveness has been investigated in several species. Little is known, however, about the effect of this environmental pollutant on the late asthmatic response (LAR) in animals in which it is exhibited. The purpose of this study was to evaluate this effect in the canine peripheral airways and to assess the potential role of mast cells in modulating the effect. A series of experiments on seven mongrel dogs demonstrated that the numbers of mast cells at the base of the epithelial region of small subsegmental airways exposed to 1 ppm ozone for 5 min were significantly (p less than .01) increased 3 h following exposure compared to air exposed or nonexposed control airways. In a second series of experiments performed on eight additional mongrel dogs with inherent sensitivity to Ascaris suum antigen, antigen aerosol was administered to the sublobar segment 3 h following ozone preexposure when mast cell numbers were presumed to be increased. These experiments were performed to determine whether ozone preexposure could enhance the late-phase response to antigen by virtue of acutely increasing the number of mast cells available to bind the antigen. Four of the eight dogs tested displayed a late-phase response to antigen following air-sham preexposure. In these four dogs, simultaneous ozone preexposure of a contralateral lobe completely blocked the late-phase response to antigen. These results indicate that the consequences of a single exposure to ozone persist beyond its effects on acute antigen-induced bronchoconstriction and extend to the complex processes involved with the late response. This attenuating effect of ozone is seen under conditions where mast-cell numbers in the airways are increased above baseline levels.

  8. Effect of C-fiber-mediated, ozone-induced rapid shallow breathing on airway epithelial injury in rats.

    PubMed

    Schelegle, E S; Alfaro, M F; Putney, L; Stovall, M; Tyler, N; Hyde, D M

    2001-10-01

    We examined the relationship between C-fiber-mediated, ozone-induced rapid shallow breathing and airway epithelial cell injury at different airway sites within the lower respiratory tract of conscious Wistar rats (n = 24). We combined an acute 8-h ozone inhalation with vagal perineural capsaicin treatment, a selective C-fiber conduction block, and 5-bromo-2'-deoxyuridine (BrdU) labeling as an index of epithelial injury. Vehicle-treated rats that inhaled ozone developed a rapid shallow breathing pattern during ozone inhalation, whereas the capsaicin-treated rats that inhaled ozone showed no changes in respiratory frequency. In vehicle-treated, ozone-exposed rats that developed rapid shallow breathing, a progressive increase in BrdU-labeling density (no. of BrdU-labeled cells/mm(2) airway) was observed starting at the bifurcation of the left main stem bronchi (central airway) and going down either a short or long airway path. In vehicle-treated, ozone-exposed rats, terminal bronchioles supplied by short and long airway paths had a similar degree of BrdU-labeling density that was significantly (P < 0.05) greater than the BrdU-labeling density of the proximal airways that supply them. In contrast, the attenuation of rapid shallow breathing produced by capsaicin treatment resulted in a significantly reduced BrdU-labeling density in the terminal bronchioles supplied by short airway paths compared with the terminal bronchioles supplied by long airway paths. Our data indicate that ozone-induced rapid shallow breathing protects large conducting airways while producing a more even distribution of injury to terminal bronchioles. PMID:11568142

  9. Effects of chronic intermittent hypoxia on allergen-induced airway inflammation in rats.

    PubMed

    Broytman, Oleg; Braun, Rudolf K; Morgan, Barbara J; Pegelow, David F; Hsu, Pei-Ning; Mei, Linda S; Koya, Ajay K; Eldridge, Marlowe; Teodorescu, Mihaela

    2015-02-01

    Obstructive sleep apnea aggravates asthma, but its mechanisms are unknown. Chronic intermittent hypoxia is one hallmark feature of sleep apnea. In this study, we tested the effects of chronic intermittent hypoxia on allergen-induced inflammation in rats. Four groups (n = 9-11/group) of ovalbumin (OVA)-sensitized Brown-Norway rats underwent intermittent hypoxia (10% oxygen, 30 cycles/h, 10 h/d) or normoxia for 30 days concurrent with weekly OVA or vehicle challenges. Lung physiology, differential leukocyte counts from bronchoalveolar lavage, and histology (Picro Sirius Red staining for collagen content) were compared between groups 2 days after the last challenge. Gene expression in bronchoalveolar lavage cells was quantified by quantitative PCR. Compared with normoxia, chronic intermittent hypoxia reduced the FEV0.1/FVC ratio (P = 0.005), peak expiratory flow (P = 0.002), and mean midexpiratory flow (P = 0.004), predominantly in medium and large airways; decreased the baseline eosinophil number (P = 0.01) and amplified the effect of OVA on monocyte number (P = 0.02 for the interaction); in proximal airways, increased (P = 0.008), whereas in distal airways it decreased (P = 0.004), collagen density; induced qualitative emphysematous changes in lung periphery; and increased expression of the M2 macrophage marker YM-1 and augmented OVA-induced expression of plasminogen activator inhibitor-1. Chronic intermittent hypoxia alters immune response to allergen toward a more TH-1-predominant cellular phenotype with collagen deposition and matrix degradation, leading to airflow limitation. These findings highlight the potential of sleep apnea to aggravate airway dysfunction in patients with preexistent asthma. PMID:25004109

  10. Acute ozone-induced change in airway permeability: role of infiltrating leukocytes

    SciTech Connect

    Kleeberger, S.R.; Hudak, B.B. )

    1992-02-01

    The role of infiltrating polymorphonuclear leukocytes (PMNs) in acute lung injury and inflammation is still controversial. In inbred mice, acute ozone (O3) exposure induces airway inflammation that is characterized by a maximal influx of lavageable PMNs 6 h after exposure and a maximal increase in lung permeability 24 h after O3. We tested the hypothesis that O3-induced change in airway epithelial permeability of O3-susceptible C57BL/6J mice is due to infiltrating PMNs. Male mice (6-8 wk) were treated with a nonsteroidal anti-inflammatory drug (indomethacin), a chemotactic inhibitor (colchicine), or an immunosuppressant (cyclophosphamide) to deplete or inhibit PMNs from infiltrating the airways. After drug or vehicle treatment, mice were exposed for 3 h to 2 ppm O3 or filtered air, and pulmonary inflammation was assessed by inflammatory cell counts and total protein content (a marker of airway permeability) in bronchoalveolar lavage (BAL) fluid. Filtered air exposure did not affect the parameters of pulmonary inflammation at any time after exposure. Compared with vehicle controls, each of the drug treatments resulted in significant reduction of PMN influx 6 and 24 h after O3. However, total BAL protein content was not attenuated significantly by the three treatments at either 6 or 24 h postexposure. Results of these experiments suggest that the influx of PMNs and the change in total BAL protein are not mutually dependent events in this model and suggest that infiltrating PMNs do not play a major role in acute O3-induced changes in permeability of the murine lung.

  11. Effect of epithelium ATP release on cyclic pressure-induced airway mucus secretion

    PubMed Central

    Tong, Jin; Zhou, Xiang-dong; Perelman, Juliy M.; Kolosov, Victor P.

    2013-01-01

    The cyclic mechanical effect of airflow during breathing creates the optimal airway hydration state. MUC (mucin) 5AC is an important component of the airway mucus. The formation of MUC5AC is related to ATP and intracellular calcium in the epithelial cells. In this study, we evaluated the effect of ATP release from intracellular calcium in epithelial cells on cyclic pressure-induced mucus secretion in the airway. 16HBE (human bronchial epithelial cells) were cultured in vitro on cyclically tilted cultured plates and divided into five groups: control, tilt, tilt and BAPTA–AM (1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid–acetoxymethyl ester), tilt and EGTA and tilt and RB-2 (reactive blue-2). The shear stress and compressive stress were induced by the surface tension of the liquid, atmospheric pressure and liquid gravity. Cell activity, MUC5AC mRNA expression level, MUC5AC protein expression level and ATP release and intracellular calcium changes were measured with the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay, RT–PCR (reverse transcription–PCR), HPLC and inverted fluorescence microscope, respectively. We detected that cyclic pressure significantly increased MUC5AC secretion and ATP release. The enhanced ATP release could be inhibited by both BAPTA–AM and RB-2, while EGTA did not have a suppressive effect. BAPTA–AM, EGTA and RB-2 did not obviously inhibit MUC5AC mRNA expression. Cyclic pressure did not induce MUC5AC secretion in the airway mucus epithelium via Ca2+-dependent ATP release, and nearly all Ca2+ was provided by stored intracellular Ca2+. PMID:24329423

  12. Effect of epithelium ATP release on cyclic pressure-induced airway mucus secretion.

    PubMed

    Tong, Jin; Zhou, Xiang-Dong; Perelman, Juliy M; Kolosov, Victor P

    2013-12-16

    The cyclic mechanical effect of airflow during breathing creates the optimal airway hydration state. Mucin (MUC) 5AC is an impotent component of the airway mucus. The formation of MUC5AC is related to adenosine triphosphate (ATP) and intracellular calciumin the epithelial cells. In this study, we evaluated the effect of ATP release from and intracellular calcium in epithelial cells on cyclic pressure-induced mucus secretion in the airway. Human bronchial epithelial cells (16HBE) were cultured in vitro on cyclically tilted cultured plates and divided into 5 groups: control, tilt, tilt and BAPTA-AM, tilt and EGTA, and tilt and RB-2. The shear stress and compressive stress were induced by the surface tension of the liquid, atmospheric pressure and liquid gravity. Cell activity, MUC5AC mRNA expression level, MUC5AC protein expression level and ATP release, and intracellular calcium changes were measured with the MTT assay, RT-PCR, high performance liquid chromatography (HPLC) and inverted fluorescence microscope, respectively. We detected that cyclic pressure significantly increased MUC5AC secretion and ATP release. The enhanced ATP release could be inhibited by both BAPTA-AM and RB-2, while EGTA did not have a suppressive effect. BAPTA-AM, EGTA, and RB-2 did not obviously inhibit MUC5AC mRNA expression.Cyclic pressure did not induce MUC5AC secretion in the airway mucus epithelium via Ca2+-dependent ATP release, and nearly all Ca2+ was provided by stored intracellular Ca2+. PMID:24329423

  13. Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol.

    PubMed

    Khosravi, Ali Reza; Erle, David J

    2016-01-01

    Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin. PMID

  14. Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol

    PubMed Central

    Erle, David J.

    2016-01-01

    Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin. PMID

  15. Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle

    PubMed Central

    Aravamudan, Bharathi; Kiel, Alexander; Freeman, Michelle; Delmotte, Philippe; Thompson, Michael; Vassallo, Robert; Sieck, Gary C.; Pabelick, Christina M.

    2014-01-01

    The balance between mitochondrial fission and fusion is crucial for mitochondria to perform its normal cellular functions. We hypothesized that cigarette smoke (CS) disrupts this balance and enhances mitochondrial dysfunction in the airway. In nonasthmatic human airway smooth muscle (ASM) cells, CS extract (CSE) induced mitochondrial fragmentation and damages their networked morphology in a concentration-dependent fashion, via increased expression of mitochondrial fission protein dynamin-related protein 1 (Drp1) and decreased fusion protein mitofusin (Mfn) 2. CSE effects on Drp1 vs. Mfn2 and mitochondrial network morphology involved reactive oxygen species (ROS), activation of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C (PKC) and proteasome pathways, as well as transcriptional regulation via factors such as NF-κB and nuclear erythroid 2-related factor 2. Inhibiting Drp1 prevented CSE effects on mitochondrial networks and ROS generation, whereas blocking Mfn2 had the opposite, detrimental effect. In ASM from asmatic patients, mitochondria exhibited substantial morphological defects at baseline and showed increased Drp1 but decreased Mfn2 expression, with exacerbating effects of CSE. Overall, these results highlight the importance of mitochondrial networks and their regulation in the context of cellular changes induced by insults such as inflammation (as in asthma) or CS. Altered mitochondrial fission/fusion proteins have a further potential to influence parameters such as ROS and cell proliferation and apoptosis relevant to airway diseases. PMID:24610934

  16. Thymol attenuates allergic airway inflammation in ovalbumin (OVA)-induced mouse asthma.

    PubMed

    Zhou, Ershun; Fu, Yunhe; Wei, Zhengkai; Yu, Yuqiang; Zhang, Xichen; Yang, Zhengtao

    2014-07-01

    Thymol, a naturally occurring monocyclic phenolic compound derived from Thymus vulgaris (Lamiaceae), has been reported to exhibit anti-inflammatory property in vivo and vitro. However, the mechanism of thymol is not clear. The aim of the present study was to investigate the effects of thymol on allergic inflammation in OVA-induced mice asthma and explore its mechanism. The model of mouse asthma was established by the induction of OVA. Thymol was orally administered at a dose of 4, 8, and 16 mg/kg body weight 1h before OVA challenge. At 24h after the last challenge, mice were sacrificed, and the data were collected by various experimental methods. The results revealed that pretreatment with thymol reduced the level of OVA-specific IgE, inhibited recruitment of inflammatory cells into airway, and decreased the levels of IL-4, IL-5, and IL-13 in BALF. Moreover, the pathologic changes of lung tissues were obviously ameliorated and goblet cell hyperplasia was effectively inhibited by the pretreatment of thymol. In addition, thymol reduced the development of airway hyperresponsiveness and blocked the activation of NF-κB pathway. All data suggested that thymol ameliorated airway inflammation in OVA-induced mouse asthma, possibly through inhibiting NF-κB activation. These findings indicated that thymol may be used as an alternative agent for treating allergic asthma. PMID:24785965

  17. Prevention of Th2-like cell responses by coadministration of IL-12 and IL-18 is associated with inhibition of antigen-induced airway hyperresponsiveness, eosinophilia, and serum IgE levels.

    PubMed

    Hofstra, C L; Van Ark, I; Hofman, G; Kool, M; Nijkamp, F P; Van Oosterhout, A J

    1998-11-01

    Allergic asthma is thought to be regulated by Th2 cells, and inhibiting this response is a promising mode of intervention. Many studies have focused on differentiation of Th cells to the Th1 or Th2 subset in vitro. IL-4 is essential for Th2 development, while IL-12 induces Th1 development, which can be enhanced by IL-18. In the present study, we investigated whether IL-12 and IL-18 were able to interfere in Th2 development and the associated airway symptoms in a mouse model of allergic asthma. Mice were sensitized with OVA using a protocol that induces IgE production. Repeated challenges by OVA inhalation induced elevated serum levels of IgE, airway hyperresponsiveness, and a predominantly eosinophilic infiltrate in the bronchoalveolar lavage concomitant with the appearance of Ag-specific Th2-like cells in lung tissue and lung-draining lymph nodes. Whereas treatments with neither IL-12 nor IL-18 during the challenge period were effective, combined treatment of IL-12 and IL-18 inhibited Ag-specific Th2-like cell development. This inhibition was associated with an absence of IgE up-regulation, airway hyperresponsiveness, and cellular infiltration in the lavage. These data show that, in vivo, the synergistic action of IL-12 and IL-18 is necessary to prevent Th2-like cell differentiation, and consequently inhibits the development of airway symptoms in a mouse model of allergic asthma. PMID:9794443

  18. Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation

    SciTech Connect

    Svensson Holm, Ann-Charlotte B.; Bengtsson, Torbjoern; Grenegard, Magnus; Lindstroem, Eva G.

    2012-03-10

    Hyaluronic acid (HA) is one of the main components of the extracellular matrix (ECM) and is expressed throughout the body including the lung and mostly in areas surrounding proliferating and migrating cells. Furthermore, platelets have been implicated as important players in the airway remodelling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of HA, the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in platelet-induced ASMC proliferation. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and the HA synthase inhibitor 4-Methylumbelliferone (4-MU) significantly inhibited platelet-induced ASMC proliferation. The interaction between ASMC and platelets was studied by fluorescent staining of F-actin. In addition, the ability of ASMC to synthesise HA was investigated by fluorescent staining using biotinylated HA-binding protein and a streptavidin conjugate. We observed that ASMC produced HA and that a CD44 blocking antibody and 4-MU significantly inhibited platelet binding to the area surrounding the ASMC. Furthermore, the FAK-inhibitor PF 573228 inhibited platelet-induced ASMC proliferation. Co-culture of ASMC and platelets also resulted in increased phosphorylation of FAK as detected by Western blot analysis. In addition, 4-MU significantly inhibited the increased FAK-phosphorylation. In conclusion, our findings demonstrate that ECM has the ability to influence platelet-induced ASMC proliferation. Specifically, we propose that HA produced by ASMC is recognised by platelet CD44. The platelet/HA interaction is followed by FAK activation and increased proliferation of co-cultured ASMC. We also suggest that the mitogenic effect of platelets represents a potential important and novel mechanism that may contribute to airway remodelling.

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

    PubMed Central

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

    2016-01-01

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

  20. β2-Agonists Inhibit TNF-α-Induced ICAM-1 Expression in Human Airway Parasympathetic Neurons

    PubMed Central

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

    2012-01-01

    Background Major basic protein released from eosinophils to airway parasympathetic nerves blocks inhibitory M2 muscarinic receptors on the parasympathetic nerves, increasing acetylcholine release and potentiating reflex bronchoconstriction. Recruitment of eosinophils to airway parasympathetic neurons requires neural expression of both intercellular adhesion molecular-1 (ICAM-1) and eotaxin. We have shown that inflammatory cytokines induce eotaxin and ICAM-1 expression in parasympathetic neurons. Objective To test whether the β2 agonist albuterol, which is used to treat asthma, changes TNF-alpha-induced eotaxin and ICAM-1 expression in human parasympathetic neurons. Methods Parasympathetic neurons were isolated from human tracheas and grown in serum-free medium for one week. Cells were incubated with either (R)-albuterol (the active isomer), (S)-albuterol (the inactive isomer) or (R,S)-albuterol for 90 minutes before adding 2 ng/ml TNF-alpha for another 4 hours (for mRNA) or 24 hours (for protein). Results and Conclusions Baseline expression of eotaxin and ICAM-1 were not changed by any isomer of albuterol as measured by real time RT-PCR. TNF-alpha induced ICAM-1 expression was significantly inhibited by (R)-albuterol in a dose dependent manner, but not by (S) or (R,S)-albuterol. Eotaxin expression was not changed by TNF-alpha or by any isomer of albuterol. The β-receptor antagonist propranolol blocked the inhibitory effect of (R)-albuterol on TNF-alpha-induced ICAM-1 expression. Clinical Implication The suppressive effect of (R)-albuterol on neural ICAM-1 expression may be an additional mechanism for decreasing bronchoconstriction, since it would decrease eosinophil recruitment to the airway nerves. PMID:23049757

  1. Triptolide inhibits TGF-β1-induced cell proliferation in rat airway smooth muscle cells by suppressing Smad signaling

    SciTech Connect

    Chen, Ming; Lv, Zhiqiang; Huang, Linjie; Zhang, Wei; Lin, Xiaoling; Shi, Jianting; Zhang, Wei; Liang, Ruiyun; Jiang, Shanping

    2015-02-15

    Background: We have reported that triptolide can inhibit airway remodeling in a murine model of asthma via TGF-β1/Smad signaling. In the present study, we aimed to investigate the effect of triptolide on airway smooth muscle cells (ASMCs) proliferation and the possible mechanism. Methods: Rat airway smooth muscle cells were cultured and made synchronized, then pretreated with different concentration of triptolide before stimulated by TGF-β1. Cell proliferation was evaluated by MTT assay. Flow cytometry was used to study the influence of triptolide on cell cycle and apoptosis. Signal proteins (Smad2, Smad3 and Smad7) were detected by western blotting analysis. Results: Triptolide significantly inhibited TGF-β1-induced ASMC proliferation (P<0.05). The cell cycle was blocked at G1/S-interphase by triptolide dose dependently. No pro-apoptotic effects were detected under the concentration of triptolide we used. Western blotting analysis showed TGF-β1 induced Smad2 and Smad3 phosphorylation was inhibited by triptolide pretreatment, and the level of Smad7 was increased by triptolide pretreatment. Conclusions: Triptolide may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation via negative regulation of Smad signaling pathway. - Highlights: • In this study, rat airway smooth muscle cells were cultured and made synchronized. • Triptolide inhibited TGF-β1-induced airway smooth muscle cells proliferation. • Triptolide inhibited ASMCs proliferation via negative regulation of Smad signaling pathway.

  2. Side-stream tobacco smoke-induced airway hyperresponsiveness in early postnatal period is involved nerve growth factor.

    PubMed

    Wu, Z-X; Hunter, D D; Batchelor, T P; Dey, R D

    2016-03-01

    Epidemiological studies have shown that children are more susceptible to adverse respiratory effects of passive smoking than adults. The goal of this study is to elucidate the possible neural mechanism induced by exposure to passive smoking during early life. Postnatal day (PD) 2 and PD 21 mice were exposed to side-stream tobacco smoke (SS), a surrogate to secondhand smoke, or filtered air (FA) for 10 consecutive days. Pulmonary function, substance P (SP) airway innervation, neurotrophin gene expression in lung and nerve growth factor (NGF) release in bronchoalveolar lavage (BAL) fluid were measured at different times after the last SS or FA exposure. Exposure to SS significantly altered pulmonary function in PD2, accompanied with an enhanced SP innervation in airway. However, exposure to SS during the later developmental period (PD21) did not appear to affect pulmonary function and SP innervation of the airways. Interestingly, SS exposure in PD2 group significantly induced an increased gene expression on NGF, and decreased NGF receptor P75 in lung; parallel with high levels of NGF protein in BAL. Furthermore, pretreatment with NGF antibody significantly diminished SS-induced airway hyperresponsivenss and the increased SP airway innervation in the PD2 group. These findings suggest that enhanced NGF released in the lung contributes to SS-enhanced SP tracheal innervation and airway responsiveness in early life. PMID:26638730

  3. Vagotomy reverses established allergen-induced airway hyperreactivity to methacholine in the mouse✩

    PubMed Central

    McAlexander, M. Allen; Gavett, Stephen H.; Kollarik, Marian; Undem, Bradley J.

    2016-01-01

    We evaluated the role of vagal reflexes in a mouse model of allergen-induced airway hyperreactivity. Mice were actively sensitized to ovalbumin then exposed to the allergen via inhalation. Prior to ovalbumin inhalation, mice also received intratracheally-instilled particulate matter in order to boost the allergic response. In control mice, methacholine (i.v.) caused a dose-dependent increase in respiratory tract resistance (RT) that only modestly decreased if the vagi were severed bilaterally just prior to the methacholine challenge. Sensitized and challenged mice, however, manifested an airway reactivity increase that was abolished by severing the vagi prior to methacholine challenge. In an innervated ex vivo mouse lung model, methacholine selectively evoked action potential discharge in a subset of distension-sensitive A-fibers. These data support the hypothesis that the major component of the increased airway reactivity in inflamed mice is due to a vagal reflex initiated by activation of afferent fibers, even in response to a direct (i.e., smooth muscle)-acting muscarinic agonist. PMID:25842220

  4. Vagotomy reverses established allergen-induced airway hyperreactivity to methacholine in the mouse.

    PubMed

    McAlexander, M Allen; Gavett, Stephen H; Kollarik, Marian; Undem, Bradley J

    2015-07-01

    We evaluated the role of vagal reflexes in a mouse model of allergen-induced airway hyperreactivity. Mice were actively sensitized to ovalbumin then exposed to the allergen via inhalation. Prior to ovalbumin inhalation, mice also received intratracheally-instilled particulate matter in order to boost the allergic response. In control mice, methacholine (i.v.) caused a dose-dependent increase in respiratory tract resistance (RT) that only modestly decreased if the vagi were severed bilaterally just prior to the methacholine challenge. Sensitized and challenged mice, however, manifested an airway reactivity increase that was abolished by severing the vagi prior to methacholine challenge. In an innervated ex vivo mouse lung model, methacholine selectively evoked action potential discharge in a subset of distension-sensitive A-fibers. These data support the hypothesis that the major component of the increased airway reactivity in inflamed mice is due to a vagal reflex initiated by activation of afferent fibers, even in response to a direct (i.e., smooth muscle)-acting muscarinic agonist. PMID:25842220

  5. Early stages of Ascaris suum induce airway inflammation and hyperreactivity in a mouse model.

    PubMed

    Enobe, C S; Araújo, C A; Perini, A; Martins, M A; Macedo, M S; Macedo-Soares, M F

    2006-09-01

    The inflammatory and functional changes that occur in murine lung after infection with 2500 infective Ascaris suum eggs were studied in this work. A sequential influx of neutrophils, mononuclear cells and eosinophils occurred into airways concomitantly with migration of larvae from liver to the lungs. Histological analysis of the lung showed a severe intra-alveolar haemorrhage at the peak of larval migration (day 8) and the most intense inflammatory cell infiltrate on day 14. Ascaris L3 were found in alveolar spaces and inside bronchioles on day 8. The number of eosinophils was elevated in the blood on days 8 and 14. The peak of eosinophil influx into the lung was at day 14, as indicated by the high levels of eosinophil peroxidase activity, followed by their migration into the airways. The antibody response against egg and larval antigens consisted mainly of IgG1 and IgM, and also of IgE and anaphylactic IgG1, that cross-reacted with adult worm antigens. Total IgE levels were substantially elevated during the infection. Measurement of lung mechanical parameters showed airway hyperreactivity in infected mice. In conclusion, the murine model of A. suum infection mimics the Th2-induced parameters observed in pigs and humans and can be used to analyse the immunoregulatory properties of this helminth. PMID:16916369

  6. Autophagy plays an essential role in cigarette smoke-induced expression of MUC5AC in airway epithelium.

    PubMed

    Zhou, Jie-Sen; Zhao, Yun; Zhou, Hong-Bin; Wang, Yong; Wu, Yin-Fang; Li, Zhou-Yang; Xuan, Nan-Xia; Zhang, Chao; Hua, Wen; Ying, Song-Min; Li, Wen; Shen, Hua-Hao; Chen, Zhi-Hua

    2016-06-01

    Mucus hypersecretion is a common pathological feature of chronic airway inflammatory diseases including chronic obstructive pulmonary disease (COPD). However, the molecular basis for this condition remains incompletely understood. We have previously demonstrated a critical role of autophagy in COPD pathogenesis through mediating apoptosis of lung epithelial cells. In this study, we aimed to investigate the function of autophagy as well as its upstream and downstream signals in cigarette smoke-induced mucus production in human bronchial epithelial (HBE) cells and in mouse airways. Cigarette smoke extract (CSE), as well as the classical autophagy inducers starvation or Torin-1, significantly triggered MUC5AC expression, and inhibition of autophagy markedly attenuated CSE-induced mucus production. The CSE-induced autophagy was mediated by mitochondrial reactive oxygen species (mitoROS), which regulated mucin expression through the JNK and activator protein-1 pathway. Epidermal growth factor receptor (EGFR) was also required for CSE-induced MUC5AC in HBE cells, but it exerted inconsiderable effects on the autophagy-JNK signaling cascade. Airways of mice with dysfunctional autophagy-related genes displayed a markedly reduced number of goblet cells and attenuated levels of Muc5ac in response to cigarette smoke exposure. These results altogether suggest that mitoROS-dependent autophagy is essential for cigarette smoke-induced mucus hyperproduction in airway epithelial cells, and reemphasize autophagy inhibition as a novel therapeutic strategy for chronic airway diseases. PMID:27036871

  7. Basophils as a primary inducer of the T helper type 2 immunity in ovalbumin-induced allergic airway inflammation

    PubMed Central

    Zhong, Wenwei; Su, Wen; Zhang, Yanjie; Liu, Qi; Wu, Jinhong; Di, Caixia; Zhang, Zili; Xia, Zhenwei

    2014-01-01

    Antigen-induced allergic airway inflammation is mediated by T helper type 2 (Th2) cells and their cytokines, but the mechanism that initiates the Th2 immunity is not fully understood. Recent studies show that basophils play important roles in initiating Th2 immunity in some inflammatory models. Here we explored the role of basophils in ovalbumin (OVA) -induced airway allergic inflammation in BALB/c mice. We found that OVA sensitization and challenge resulted in a significant increase in the amount of basophils in blood and lung, along with the up-regulation of activation marker of CD200R. However, depletion of basophils with MAR-1 or Ba103 antibody attenuated airway inflammation, represented by the significantly decreased amount of the Th2 subset in spleen and draining lymph nodes, interlukin-4 level in lung and OVA-special immunoglobulin E (sIgE) levels in serum. On the other hand, adoptive transfer of basophils from OVA-challenged lung tissue to naive BALB/c mice provoked the Th2 immune response. In addition, pulmonary basophils from OVA-challenged mice were able to uptake DQ-OVA and express MHC class II molecules and CD40 in vivo, as well as to release interleukin-4 following stimulation by IgE–antigen complexes and promote Th2 polarization in vitro. These findings demonstrate that basophils may participate in Th2 immune responses in antigen-induced allergic airway inflammation and that they do so through facilitating antigen presentation and providing interleukin-4. PMID:24383680

  8. Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

    PubMed Central

    Hendry-Hofer, Tara B.; Loader, Joan E.; Rioux, Jacqueline S.; Garlick, Rhonda B.; White, Carl W.

    2013-01-01

    Sulfur mustard (SM) inhalation causes the rare but life-threatening disorder of plastic bronchitis, characterized by bronchial cast formation, resulting in severe airway obstruction that can lead to respiratory failure and death. Mortality in those requiring intubation is greater than 80%. To date, no antidote exists for SM toxicity. In addition, therapies for plastic bronchitis are solely anecdotal, due to lack of systematic research available to assess drug efficacy in improving mortality and/or morbidity. Adult rats exposed to SM analog were treated with intratracheal tissue plasminogen activator (tPA) (0.15–0.7 mg/kg, 5.5 and 6.5 h), compared with controls (no treatment, isoflurane, and placebo). Respiratory distress and pulse oximetry were assessed (for 12 or 48 h), and arterial blood gases were obtained at study termination (12 h). Microdissection of fixed lungs was done to assess airway obstruction by casts. Optimal intratracheal tPA treatment (0.7 mg/kg) completely eliminated mortality (0% at 48 h), and greatly improved morbidity in this nearly uniformly fatal disease model (90–100% mortality at 48 h). tPA normalized plastic bronchitis–associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress (i.e., clinical scores) while decreasing airway fibrin casts. Intratracheal tPA diminished airway-obstructive fibrin–containing casts while improving clinical respiratory distress, pulmonary gas exchange, tissue oxygenation, and oxygen utilization in our model of severe chemically induced plastic bronchitis. Most importantly, mortality, which was associated with hypoxemia and clinical respiratory distress, was eliminated. PMID:23258228

  9. Parainfluenza 3-Induced Cough Hypersensitivity in the Guinea Pig Airways.

    PubMed

    Zaccone, Eric J; Lieu, TinaMarie; Muroi, Yukiko; Potenzieri, Carl; Undem, Blair E; Gao, Peisong; Han, Liang; Canning, Brendan J; Undem, Bradley J

    2016-01-01

    The effect of respiratory tract viral infection on evoked cough in guinea pigs was evaluated. Guinea pigs were inoculated intranasally with either parainfluenza type 3 (PIV3) and cough was quantified in conscious animals. The guinea pigs infected with PIV3 (day 4) coughed nearly three times more than those treated with the viral growth medium in response to capsaicin, citric acid, and bradykinin. Since capsaicin, citric acid, and bradykinin evoked coughing in guinea pigs can be inhibited by drugs that antagonize the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), it was reasoned that the virally-induced hypertussive state may involve alterations in TPRV1 activity. PIV3 infection caused a phenotypic switch in tracheal nodose Aδ "cough receptors" such that nearly 50% of neurons began to express, de novo, TRPV1 mRNA. There was also an increase TRPV1 expression in jugular C-fiber neurons as determined by qPCR. It has previously been reported that tracheal-specific nodose neurons express the BDNF receptor TrkB and jugular neurons express the NGF receptor TrkA. Jugular neurons also express the artemin receptor GFRα3. All these neurotrophic factors have been associated with increases in TRPV1 expression. In an ex vivo perfused guinea pig tracheal preparation, we demonstrated that within 8 h of PIV3 infusion there was no change in NGF mRNA expression, but there was nearly a 10-fold increase in BDNF mRNA in the tissue, and a small but significant elevation in the expression of artemin mRNA. In summary, PIV3 infection leads to elevations in TRPV1 expression in the two key cough evoking nerve subtypes in the guinea pig trachea, and this is associated with a hypertussive state with respect to various TRPV1 activating stimuli. PMID:27213574

  10. Parainfluenza 3-Induced Cough Hypersensitivity in the Guinea Pig Airways

    PubMed Central

    Lieu, TinaMarie; Muroi, Yukiko; Potenzieri, Carl; Undem, Blair E.; Gao, Peisong; Han, Liang; Canning, Brendan J.

    2016-01-01

    The effect of respiratory tract viral infection on evoked cough in guinea pigs was evaluated. Guinea pigs were inoculated intranasally with either parainfluenza type 3 (PIV3) and cough was quantified in conscious animals. The guinea pigs infected with PIV3 (day 4) coughed nearly three times more than those treated with the viral growth medium in response to capsaicin, citric acid, and bradykinin. Since capsaicin, citric acid, and bradykinin evoked coughing in guinea pigs can be inhibited by drugs that antagonize the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), it was reasoned that the virally-induced hypertussive state may involve alterations in TPRV1 activity. PIV3 infection caused a phenotypic switch in tracheal nodose Aδ “cough receptors” such that nearly 50% of neurons began to express, de novo, TRPV1 mRNA. There was also an increase TRPV1 expression in jugular C-fiber neurons as determined by qPCR. It has previously been reported that tracheal-specific nodose neurons express the BDNF receptor TrkB and jugular neurons express the NGF receptor TrkA. Jugular neurons also express the artemin receptor GFRα3. All these neurotrophic factors have been associated with increases in TRPV1 expression. In an ex vivo perfused guinea pig tracheal preparation, we demonstrated that within 8 h of PIV3 infusion there was no change in NGF mRNA expression, but there was nearly a 10-fold increase in BDNF mRNA in the tissue, and a small but significant elevation in the expression of artemin mRNA. In summary, PIV3 infection leads to elevations in TRPV1 expression in the two key cough evoking nerve subtypes in the guinea pig trachea, and this is associated with a hypertussive state with respect to various TRPV1 activating stimuli. PMID:27213574

  11. Early events in the pathogenesis of chronic obstructive pulmonary disease. Smoking-induced reprogramming of airway epithelial basal progenitor cells.

    PubMed

    Shaykhiev, Renat; Crystal, Ronald G

    2014-12-01

    The airway epithelium is the primary site of the earliest pathologic changes induced by smoking, contributing to the development of chronic obstructive pulmonary disease (COPD). The normal human airway epithelium is composed of several major cell types, including differentiated ciliated and secretory cells, intermediate undifferentiated cells, and basal cells (BC). BC contain the stem/progenitor cell population responsible for maintenance of the normally differentiated airway epithelium. Although inflammatory and immune processes play a significant role in the pathogenesis of COPD, the earliest lesions include hyperplasia of the BC population, suggesting that the disease may start with this cell type. Apart from BC hyperplasia, smoking induces a number of COPD-relevant airway epithelial remodeling phenotypes that are likely initiated in the BC population, including mucous cell hyperplasia, squamous cell metaplasia, epithelial-mesenchymal transition, altered ciliated and nonmucous secretory cell differentiation, and suppression of junctional barrier integrity. Significant progress has been recently made in understanding the biology of human airway BC, including gene expression features, stem/progenitor, and other functions, including interaction with other airway cell types. Accumulating evidence suggests that human airway BC function as both sensors and cellular sources of various cytokines and growth factors relevant to smoking-associated airway injury, as well as the origin of various molecular and histological phenotypes relevant to the pathogenesis of COPD. In the context of these considerations, we suggest that early BC-specific smoking-induced molecular changes are critical to the pathogenesis of COPD, and these represent a candidate target for novel therapeutic approaches to prevent COPD progression in susceptible individuals. PMID:25525728

  12. Inhibitory effect of Platycodi Radix on ovalbumin-induced airway inflammation in a murine model of asthma.

    PubMed

    Choi, Jae Ho; Hwang, Yong Pil; Lee, Hyun Sun; Jeong, Hye Gwang

    2009-06-01

    Asthma is a chronic inflammatory disease of the airways characterized by an associated increase in airway responsiveness. In this study, we investigated the inhibitory effect of an aqueous extract from the root of Platycodi Radix (Changkil: CK) on airway inflammation in a murine model of asthma. Mice were sensitized and challenged by ovalbumin (OVA) inhalation to induce chronic airway inflammation and airway remodeling. CK markedly decreased the number of infiltrated inflammatory cells and the levels of Th1 and Th2 cytokines and chemokines compared with those in the OVA-induced group. In addition, CK reduced OVA-specific IgE levels in bronchoalveolar lavage (BAL) fluid. Based on lung histopathological studies, inflammatory cell infiltration and mucus hypersecretion were inhibited by CK administration compared to that in the OVA-induced group. Lung weight was reduced after CK administration. Also, increased generation of ROS in BAL fluid, as well as NF-kappaB nuclear translocation, by inhalation of OVA was diminished by CK. Moreover, CK reduced the OVA-induced upregulation of matrix metalloproteases activity. These findings indicate that oxidative stress may play a crucial role in the pathogenesis of bronchial asthma induced by OVA and that CK may be useful as an adjuvant therapy for the treatment of bronchial asthma. PMID:19264106

  13. Parasitic Nematode-Induced CD4+Foxp3+T Cells Can Ameliorate Allergic Airway Inflammation

    PubMed Central

    Kang, Shin Ae; Park, Mi-Kyung; Cho, Min Kyoung; Park, Sang Kyun; Jang, Min Seong; Yang, Bo-Gie; Jang, Myoung Ho; Kim, Dong-Hee; Yu, Hak Sun

    2014-01-01

    Background The recruitment of CD4+CD25+Foxp3+T (Treg) cells is one of the most important mechanisms by which parasites down-regulate the immune system. Methodology/Principal Findings We compared the effects of Treg cells from Trichinella spiralis-infected mice and uninfected mice on experimental allergic airway inflammation in order to understand the functions of parasite-induced Treg cells. After four weeks of T. spiralis infection, we isolated Foxp3-GFP-expressing cells from transgenic mice using a cell sorter. We injected CD4+Foxp3+ cells from T. spiralis-infected [Inf(+)Foxp3+] or uninfected [Inf(-)Foxp3+] mice into the tail veins of C57BL/6 mice before the induction of inflammation or during inflammation. Inflammation was induced by ovalbumin (OVA)-alum sensitization and OVA challenge. The concentrations of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchial alveolar lavage fluid and the levels of OVA-specific IgE and IgG1 in the serum were lower in mice that received intravenous application of Inf(+)Foxp3+ cells [IV(inf):+(+) group] than in control mice. Some features of allergic airway inflammation were ameliorated by the intravenous application of Inf(-)Foxp3+ cells [IV(inf):+(-) group], but the effects were less distinct than those observed in the IV(inf):+(+) group. We found that Inf(+)Foxp3+ cells migrated to inflammation sites in the lung and expressed higher levels of Treg-cell homing receptors (CCR5 and CCR9) and activation markers (Klrg1, Capg, GARP, Gzmb, OX40) than did Inf(-)Foxp3+ cells. Conclusion/Significance T. spiralis infection promotes the proliferation and functional activation of Treg cells. Parasite-induced Treg cells migrate to the inflammation site and suppress immune responses more effectively than non-parasite-induced Treg cells. The adoptive transfer of Inf(+)Foxp3+ cells is an effective method for the treatment and prevention of allergic airway diseases in mice and is a promising therapeutic approach for the treatment

  14. Dietary intervention in the treatment of patients with cough and symptoms suggestive of airways reflux as determined by Hull airways Reflux Questionnaire

    PubMed Central

    2013-01-01

    Background Chronic cough is a common and distressing symptom. Gastro-oesophageal reflux is a common cause of chronic cough however the symptom complex in cough is not confined to classic peptic symptoms. Dyspeptic symptoms have previously been shown to respond to dietary modifications and weight loss. We hypothesised that weight reduction maybe a useful non-pharmacological strategy in reducing reflux cough in the obese. Methods Subjects with cough were recruited from Hull Cough Clinic. They were randomised to one of two open parallel groups; one receiving the traditional dietary modifications and the other weight reduction advice in the form of an Energy Prescription (EP). Cough symptoms, using the Leicester cough questionnaire (LCQ) and dietary intake were measured at the start and end of the study. Results Thirty-three patients were recruited and 20 patients completed the study. Mean weight loss was 3.1 kg (p < 0.001) and reported an improvement in the LCQ (mean improvement 3.1); which is greater than the clinically significant score of 1.3. . Moreover, secondary outcomes showed a significant association between baseline high calorie (r = -0.24; p < 0.001) and fat intake (r = -0.36; p = 0.001), and LCQ scores. Conclusion A high calorie and fat intake is strongly correlated with cough score. Irrespective of diet, weight loss is associated with a reduction in cough symptoms. Asking patients to lose weight by reducing fat and calorie intake may be a simple strategy to ameliorate this intractable condition. Trial Registration The study was approved by the local research ethics committee (South Humber Local Research Ethics Committee; REC04/Q1105/62). The study was registered with the Research and Development Department, Clinical Governance Directorate, Hull and East Yorkshire Hospitals NHS Trust (reference number R0086). PMID:24380385

  15. 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

  16. Ozone-induced airway epithelial cell death, the neurokinin-1 receptor pathway, and the postnatal developing lung

    PubMed Central

    Murphy, Shannon R.; Oslund, Karen L.; Hyde, Dallas M.; Miller, Lisa A.; Van Winkle, Laura S.

    2014-01-01

    Children are uniquely susceptible to ozone because airway and lung growth continue for an extensive period after birth. Early-life exposure of the rhesus monkey to repeated ozone cycles results in region-specific disrupted airway/lung growth, but the mediators and mechanisms are poorly understood. Substance P (SP), neurokinin-1 receptor (NK-1R); and nuclear receptor Nur77 (NR4A1) are signaling pathway components involved in ozone-induced cell death. We hypothesize that acute ozone (AO) exposure during postnatal airway development disrupts SP/NK-1R/Nur77 pathway expression and that these changes correlate with increased ozone-induced cell death. Our objectives were to 1) spatially define the normal development of the SP/NK-1R/Nur77 pathway in conducting airways; 2) compare how postnatal age modulates responses to AO exposure; and 3) determine how concomitant, episodic ozone exposure modifies age-specific acute responses. Male infant rhesus monkeys were assigned at age 1 mo to two age groups, 2 or 6 mo, and then to one of three exposure subgroups: filtered air (FA), FA+AO (AO: 8 h/day × 2 days), or episodic biweekly ozone exposure cycles (EAO: 8 h/day × 5 days/14-day cycle+AO). O3 = 0.5 ppm. We found that 1) ozone increases SP/NK-1R/Nur77 pathway expression in conducting airways, 2) an ozone exposure cycle (5 days/cycle) delivered early at age 2 mo resulted in an airway that was hypersensitive to AO exposure at the end of 2 mo, and 3) continued episodic exposure (11 cycles) resulted in an airway that was hyposensitive to AO exposure at 6 mo. These observations collectively associate with greater overall inflammation and epithelial cell death, particularly in early postnatal (2 mo), distal airways. PMID:25063800

  17. ULTRAFINE CARBON PARTICLES INDUCE IL-8 EXPRESSION IN HUMAN AIRWAY EPITHELIAL CELLS THROUGH A POST-TRANSCRIPTIONAL MECHANISM

    EPA Science Inventory

    Ultrafine carbon particles induce IL-8 expression in human airway
    epithelial cells through a post-transcritpional mechanism
    Epidemiological studies suggest that ultrafine particles contribute to
    particulate matter (PM) - induced adverse health effects. IL-8 is an
    i...

  18. Fatty Acid Binding Protein 4 Regulates VEGF-Induced Airway Angiogenesis and Inflammation in a Transgenic Mouse Model

    PubMed Central

    Ghelfi, Elisa; Yu, Chen-Wei; Elmasri, Harun; Terwelp, Matthew; Lee, Chun G.; Bhandari, Vineet; Comhair, Suzy A.; Erzurum, Serpil C.; Hotamisligil, Gökhan S.; Elias, Jack A.; Cataltepe, Sule

    2014-01-01

    Neovascularization of the airways occurs in several inflammatory lung diseases, including asthma. Vascular endothelial growth factor (VEGF) plays an important role in vascular remodeling in the asthmatic airways. Fatty acid binding protein 4 (FABP4 or aP2) is an intracellular lipid chaperone that is induced by VEGF in endothelial cells. FABP4 exhibits a proangiogenic function in vitro, but whether it plays a role in modulation of angiogenesis in vivo is not known. We hypothesized that FABP4 promotes VEGF-induced airway angiogenesis and investigated this hypothesis with the use of a transgenic mouse model with inducible overexpression of VEGF165 under a CC10 promoter [VEGF-TG (transgenic) mice]. We found a significant increase in FABP4 mRNA levels and density of FABP4-expressing vascular endothelial cells in mouse airways with VEGF overexpression. FABP4−/− mouse airways showed a significant decrease in neovessel formation and endothelial cell proliferation in response to VEGF overexpression. These alterations in airway vasculature were accompanied by attenuated expression of proinflammatory mediators. Furthermore, VEGF-TG/FABP4−/− mice showed markedly decreased expression of endothelial nitric oxide synthase, a well-known mediator of VEGF-induced responses, compared with VEGF-TG mice. Finally, the density of FABP4-immunoreactive vessels in endobronchial biopsy specimens was significantly higher in patients with asthma than in control subjects. Taken together, these data unravel FABP4 as a potential target of pathologic airway remodeling in asthma. PMID:23391391

  19. Pharmacological modulation of inhaled sodium metabisulphite-induced airway microvascular leakage and bronchoconstriction in the guinea-pig.

    PubMed Central

    Sakamoto, T.; Elwood, W.; Barnes, P. J.; Chung, K. F.

    1992-01-01

    1. We have investigated the effects of chlorpheniramine, atropine and capsaicin pretreatment on inhaled sodium metabisulphite (MBS)-induced airway microvascular leakage and bronchoconstriction in anaesthetized guinea-pigs in order to clarify the mechanisms involved in these responses. The effects of frusemide and nedocromil sodium were also examined. 2. Lung resistance (RL) was measured for 6 min after inhalation of MBS (20, 40, 80 and 200 mM; 30 breaths), followed by measurement of extravasation of Evans blue dye into airway tissues, used as an index of airway microvascular leakage. MBS caused an increase in RL and leakage of dye at all airway levels in a dose-dependent manner. 3. Chlorpheniramine (10 mg kg-1, i.v.), atropine (1 mg kg-1, i.v.), their combination or inhaled nedocromil sodium (10 mg ml-1, 7 min) had no effect against the airway microvascular leakage induced by 80 mM MBS (30 breaths). Capsaicin pretreatment (50 mg kg-1, s.c.) caused a significant decrease in the leakage of dye in the main bronchi and inhaled frusemide (10 mg ml-1, 7 min) also in the main bronchi and proximal intrapulmonary airway. 4. Chlorpheniramine, atropine, their combination, capsaicin pretreatment and frusemide, but not nedocromil sodium, inhibited significantly the peak RL induced by 80 mM MBS (30 breaths) by approximately 50%. 5. We conclude that a cholinergic reflex and neuropeptides released from sensory nerve endings may participate in the mechanisms of MBS-induced airway responses. Frusemide but not nedocromil sodium may have an inhibitor effect on these neural mechanisms. The inhibitory effect of nedocromil sodium against lower doses of MBS is not excluded. PMID:1330180

  20. 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

  1. 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

  2. A prebiotic galactooligosaccharide mixture reduces severity of hyperpnoea-induced bronchoconstriction and markers of airway inflammation.

    PubMed

    Williams, Neil C; Johnson, Michael A; Shaw, Dominick E; Spendlove, Ian; Vulevic, Jelena; Sharpe, Graham R; Hunter, Kirsty A

    2016-09-01

    Gut microbes have a substantial influence on systemic immune function and allergic sensitisation. Manipulation of the gut microbiome through prebiotics may provide a potential strategy to influence the immunopathology of asthma. This study investigated the effects of prebiotic Bimuno-galactooligosaccharide (B-GOS) supplementation on hyperpnoea-induced bronchoconstriction (HIB), a surrogate for exercise-induced bronchoconstriction, and airway inflammation. A total of ten adults with asthma and HIB and eight controls without asthma were randomised to receive 5·5 g/d of either B-GOS or placebo for 3 weeks separated by a 2-week washout period. The peak fall in forced expiratory volume in 1 s (FEV1) following eucapnic voluntary hyperpnoea (EVH) defined HIB severity. Markers of airway inflammation were measured at baseline and after EVH. Pulmonary function remained unchanged in the control group. In the HIB group, the peak post-EVH fall in FEV1 at day 0 (-880 (sd 480) ml) was unchanged after placebo, but was attenuated by 40 % (-940 (sd 460) v. -570 (sd 310) ml, P=0·004) after B-GOS. In the HIB group, B-GOS reduced baseline chemokine CC ligand 17 (399 (sd 140) v. 323 (sd 144) pg/ml, P=0·005) and TNF-α (2·68 (sd 0·98) v. 2·18 (sd 0·59) pg/ml, P=0·040) and abolished the EVH-induced 29 % increase in TNF-α. Baseline C-reactive protein was reduced following B-GOS in HIB (2·46 (sd 1·14) v. 1·44 (sd 0·41) mg/l, P=0·015) and control (2·16 (sd 1·02) v. 1·47 (sd 0·33) mg/l, P=0·050) groups. Chemokine CC ligand 11 and fraction of exhaled nitric oxide remained unchanged. B-GOS supplementation attenuated airway hyper-responsiveness with concomitant reductions in markers of airway inflammation associated with HIB. PMID:27523186

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

    PubMed

    Mahajan, Shailaja G; Mehta, Anita A

    2008-08-01

    To determine the therapeutic potential of herbal medicine Moringa oleifera Lam. family: Moringaceae in the control of allergic diseases, the efficacy of the ethanolic extract of the seeds of the plant (MOEE) against ovalbumin (OVA)-induced airway inflammation in guinea pigs was examined. During the experimental period, the test drugs (MOEE or dexamethasone) were administered by oral route prior to challenge with aerosolized 0.5% OVA. Bronchoconstriction tests were performed and respiratory parameters (i.e., tidal volume and respiratory rate) were measured. At the end of experiment, blood was collected from each animal to perform total and differential counts and serum was used for assay of IL-4, IL-6, and TNFalpha. Lung lavage fluid (BAL) was collected for estimation of cellular content and cytokine levels. Lung tissue histamine assays were performed using the homogenate of one lobe from each animal; a separate lobe and the trachea were subjected to histopathology to measure the degree of any airway inflammation. The results suggest that in OVA-sensitized control animals that did not receive either drug, tidal volume (V(t)) was decreased, respiration rate (f) was increased, and both the total and differential cell counts in blood and BAL fluid were increased significantly. MOEE-treatment of sensitized hosts resulted in improvement in all parameters except BAL TNFalpha and IL-4. Moreover, MOEE-treatment also showed protection against acetylcholine-induced broncho-constriction and airway inflammation which was confirmed by histological observations. The results of these studies confirm the traditional claim for the usefulness of this herb in the treatment of allergic disorders like asthma. PMID:18686107

  4. 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

  5. [Risk factors and subjective symptoms of drug-induced leucopenia].

    PubMed

    Hayashi, Kyoko; Ohtsu, Fumiko; Yano, Reiko; Sakakibara, Jinsaku; Goto, Nobuyuki

    2011-01-01

    The present study investigated risk factors and subjective symptoms associated with drug-induced leucopenia. We selected 248 patients with drug-induced leucopenia from the Case Reports of Adverse Drug Reactions and Poisoning Information System (CARPIS) database of over 47000 case reports of adverse drug reactions and assigned them to a case group. We also randomly selected 743 cases of adverse drug reactions not associated with leucopenia as a control group. A comparison of patient characteristic data between the two groups using logistic-regression analysis revealed that female sex, autoimmune disease and renal damage were background risk factors for drug-induced leucopenia. In addition, thiamazole, ritodrine, propylthiouracil, ticlopidine, allopurinol, minocycline and captopril administration significantly increased the risk of drug-induced leucopenia. A significant association was also found for fever, chills and pharyngeal abnormalities. Based on these findings, we developed two estimated regression equations to help prevent drug-induced leucopenia in the community pharmacy setting. PMID:21212623

  6. Macrolides Inhibit Fusobacterium nucleatum-Induced MUC5AC Production in Human Airway Epithelial Cells

    PubMed Central

    Nagaoka, Kentaro; Harada, Yosuke; Yamada, Koichi; Migiyama, Yohei; Morinaga, Yoshitomo; Hasegawa, Hiroo; Izumikawa, Koichi; Kakeya, Hiroshi; Nishimura, Masaharu; Kohno, Shigeru

    2013-01-01

    Fusobacterium nucleatum is one of the most common anaerobic bacteria in periodontitis and is responsible for several extraoral infections, including respiratory tract diseases. In this study, we examined whether F. nucleatum induces mucin secretion in airway epithelial cells. We also examined the effects of macrolides on F. nucleatum-induced mucus production compared with the effects of other antibiotics that exert anti-anaerobic activities. The production of MUC5AC, the major core protein of mucin secreted from the airway surface epithelium, in bronchial epithelial cells after stimulation with culture supernatants (Sup) of F. nucleatum was analyzed by performing enzyme-linked immunosorbent assay and quantitative RT-PCR. The cell-signaling pathway of F. nucleatum Sup stimulation was also analyzed by Western blotting. For inhibition studies, cells were treated with azithromycin, clarithromycin, clindamycin (CLDM), and metronidazole (MTZ). The F. nucleatum Sup induced NCI-H292 cells to express MUC5AC at both the protein level and the mRNA level in both a time- and dose-dependent manner. Macrolides inhibited F. nucleatum Sup-induced MUC5AC production, while CLDM and MTZ were less effective. F. nucleatum Sup induced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and this induction was suppressed by macrolides. F. nucleatum Sup-induced MUC5AC production was blocked by the ERK pathway inhibitor U0126. F. nucleatum is likely to contribute to excessive mucin production, which suggests that periodontitis may correlate with the pathogenesis of chronic respiratory tract infection. Macrolides seem to reduce this mucin production and might represent an additional means of therapeutic intervention for F. nucleatum respiratory tract infections other than CLDM and MTZ. PMID:23380724

  7. Analysis of induced sputum to examine the effects of prednisone on airway inflammation in asthmatic subjects.

    PubMed

    Claman, D M; Boushey, H A; Liu, J; Wong, H; Fahy, J V

    1994-11-01

    To determine whether induced sputum samples might provide a useful means for evaluating the effects of therapy on airway mucosal inflammation, we examined induced sputum samples obtained before and after 6 days of treatment with prednisone (0.5 mg/kg/day) or placebo in a randomized, double-blind study of 24 asthmatic subjects. Induced sputum was analyzed for total and differential cell counts and for concentrations of eosinophil cationic protein, albumin, and mucin-like glycoprotein. We found that the mean (+/- SEM) percentage of eosinophils in sputum samples from the prednisone-treated group fell from 14.1% +/- 5.0% at baseline to 1.8% +/- 0.8% after treatment, a decrease significantly greater than in the placebo-treated group (from 10.3% +/- 4.9% to 11.1% +/- 4.0%; p = 0.002). The absolute number of eosinophils also decreased significantly more in the prednisone-treated group than in the placebo-treated group (p = 0.04). In addition, eosinophil cationic protein levels in induced sputum fell more in the prednisone-treated group than in the placebo-treated group (from 324 +/- 131 ng/ml to 144 +/- 84 ng/ml vs 173 +/- 50 ng/ml to 188 +/- 47 ng/ml; p = 0.002). Furthermore, prednisone treatment was associated with a significant increase in peak expiratory flow, an effect that was significantly correlated with the decrease in eosinophil percentage in induced sputum (rs = 0.64, p = 0.04). Prednisone treatment was not associated with any significant change in the concentrations of albumin or mucin-like glycoprotein. We conclude that analysis of induced sputum is a useful noninvasive method for studying the effects of asthma therapy on airway eosinophilic inflammation. PMID:7963155

  8. Angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter review and an algorithm for airway management.

    PubMed

    Chiu, A G; Newkirk, K A; Davidson, B J; Burningham, A R; Krowiak, E J; Deeb, Z E

    2001-09-01

    Angioedema is a nonpitting edema of which the presentation ranges from benign facial swelling to airway obstruction managed by intubation or tracheotomy. The presentation of this disease is reviewed, and a treatment algorithm based on initial signs and symptoms is proposed for proper airway management. We performed a retrospective review of 108 patients treated in 2 tertiary care centers in the Washington, DC, area over a 5-year period. Ninety-eight patients (90.7%) were African-American, and 81 (75%) were female. Seventy-four patients (68.5%) were taking angiotensin-converting enzyme inhibitors (ACEIs). A classification system was developed based on the location of the edema at initial presentation: 1) isolated facial swelling and oral cavity edema, excluding the floor of the mouth; 2) floor of mouth and/or oropharyngeal edema, and 3) oropharyngeal edema with glottic and/or supraglottic involvement. Fourteen patients (13%) needed airway intervention, 2 of whom underwent a cricothyrotomy after a failed intubation attempt. Eleven (78.6%) were taking ACEIs. The indication for each intubation was massive tongue and floor of mouth edema. The patients were extubated 48 to 72 hours later. No patient demonstrated symptom progression after medical treatment was initiated. Therapy included discontinuation of the ACEI or other inciting agent, a high-humidity face tent, an initial dose of intravenous antihistamines, and a continued course of intravenous steroids. Within 48 hours, most patients had a resolution of their edema. Only cases of significant tongue and oropharyngeal edema took longer than 48 hours to resolve. The ACEIs are a common cause of angioedema. Left untreated, angioedema may progress to involve the oropharynx and supraglottis, resulting in a life-threatening airway compromise. Marked floor of mouth and tongue edema are the indications for airway intervention. An algorithm based on the initial presentation is essential for proper airway and patient management

  9. Trichostatin A Inhibits Epithelial Mesenchymal Transition Induced by TGF-β1 in Airway Epithelium

    PubMed Central

    Shin, Jae-Min; Lee, Heung-Man

    2016-01-01

    Background and Objectives Tissue remodeling is believed to cause recalcitrant chronic rhinosinusitis (CRS). Epithelial-mesenchymal transition (EMT) is a novel clinical therapeutic target in many chronic airway diseases related with tissue remodeling. The aim of this study was to investigate the effect of trichostatin A (TSA) on transforming growth factor (TGF)-β1-induced EMT in airway epithelium and nasal tissue. Materials and Methods A549 cells, primary nasal epithelial cells (PNECs), or inferior nasal turbinate organ culture were exposed to TSA prior to stimulation with TGF-β1. Expression levels of E-cadherin, vimentin, fibronectin, α-smooth muscle actin (SMA), histone deacetylase 2 (HDAC2), and HDAC4 were determined by western blotting and/or immunofluorescent staining. Hyperacetylation of histone H2 and H4 by TSA was measured by western blotting. After siHDAC transfection, the effects of HDAC2 and HDAC4 silencing on expression of E-cadherin, vimentin, fibronectin, α-SMA, HDAC2, and HDAC4 in TGF-β1-induced A549 were determined by RT-PCR and/or western blotting. We assessed the change in migration capacity of A549 cells by using cell migration assay and transwell invasion assay. Results TGF-β1 altered mRNA and protein expression levels of EMT markers including E-cadherin, vimentin, fibronectin, α-SMA, slug, and snail in A549 cells. Inhibition and silencing of HDAC2 and HDAC4 by TSA and siRNA enhanced TGF-β1-induced EMT in A549 cells. TSA blocked the effect of TGF-β1 on the migratory ability of A549 cells. In experiments using PNECs and inferior turbinate organ cultures, TSA suppressed expression of EMT markers induced by TGF-β1. Conclusions We showed that EMT is induced by TGF-β1 in airway epithelial cells and nasal tissue via activation of HDAC2 and HDAC4, and that inhibition of HDAC2 and HDAC4 by TSA reduces TGF-β1-induced EMT. This observation indicates that histone deacetylase inhibitors such as TSA could be potential candidates for treatment of

  10. Attenuation of histamine-induced airway effects by intranasal application of levocetirizine in mice.

    PubMed

    Kitayama-Sugiyama, Chie; Mochizuki, Naoko; Murata, Hitomi; Katsura, Masashi; Kamei, Chiaki

    2013-10-01

    The present study was performed to investigate the histamine-induced airway effect of levocetirizine, an active enantiomer of cetirizine, by intranasal application using ddY mice. Nasal rubbing and sneezing after histamine application into the nasal cavity were used as an index of histamine-induced airway effect in mice. Intranasal application of levocetirizine inhibited both nasal rubbing and sneezing concentration-dependently, and the ED50 values were 0.62 (0.51-0.77) and 0.70 (0.51-1.02) %/site for nasal rubbing and sneezing, respectively. ED50 values of cetirizine were 1.24 (1.02-1.59) and 1.35 (1.02-2.08) %/site for nasal rubbing and sneezing, respectively. Levocetirizine also inhibited nasal rubbing and sneezing when administered orally. These results clearly indicate that levocetirizine was about two times more potent than cetirizine by intranasal application, similar to the findings of the former's affinity for human histamine H1 receptors. In addition, the present findings raise the expectation of the development of levocetirizine nasal drops. PMID:23855419

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  13. Prostaglandin E2 induces expression of MAPK phosphatase 1 (MKP-1) in airway smooth muscle cells.

    PubMed

    Rumzhum, Nowshin N; Ammit, Alaina J

    2016-07-01

    Prostaglandin E2 (PGE2) is a prostanoid with diverse actions in health and disease. In chronic respiratory diseases driven by inflammation, PGE2 has both positive and negative effects. An enhanced understanding of the receptor-mediated cellular signalling pathways induced by PGE2 may help us separate the beneficial properties from unwanted actions of this important prostaglandin. PGE2 is known to exert anti-inflammatory and bronchoprotective actions in human airways. To date however, whether PGE2 increases production of the anti-inflammatory protein MAPK phosphatase 1 (MKP-1) was unknown. We address this herein and use primary cultures of human airway smooth muscle (ASM) cells to show that PGE2 increases MKP-1 mRNA and protein upregulation in a concentration-dependent manner. We explore the signalling pathways responsible and show that PGE2-induces CREB phosphorylation, not p38 MAPK activation, in ASM cells. Moreover, we utilize selective antagonists of EP2 (PF-04418948) and EP4 receptors (GW 627368X) to begin to identify EP-mediated functional outcomes in ASM cells in vitro. Taken together with earlier studies, our data suggest that PGE2 increases production of the anti-inflammatory protein MKP-1 via cAMP/CREB-mediated cellular signalling in ASM cells and demonstrates that EP2 may, in part, be involved. PMID:27108790

  14. Leptin enhances ICAM-1 expression, induces migration and cytokine synthesis, and prolongs survival of human airway epithelial cells.

    PubMed

    Suzukawa, Maho; Koketsu, Rikiya; Baba, Shintaro; Igarashi, Sayaka; Nagase, Hiroyuki; Yamaguchi, Masao; Matsutani, Noriyuki; Kawamura, Masafumi; Shoji, Shunsuke; Hebisawa, Akira; Ohta, Ken

    2015-10-15

    There is rising interest in how obesity affects respiratory diseases, since epidemiological findings indicate a strong relationship between the two conditions. Leptin is a potent adipokine produced mainly by adipocytes. It regulates energy storage and expenditure and also induces inflammation. Previous studies have shown that leptin is able to activate inflammatory cells such as lymphocytes and granulocytes, but little is known about its effect on lung structural cells. The present study investigated the effects of leptin on human airway epithelial cells by using human primary airway epithelial cells and a human airway epithelial cell line, BEAS-2B. Flow cytometry showed enhanced ICAM-1 expression by both of those cells in response to leptin, and that effect was abrogated by dexamethasone or NF-κB inhibitor. Flow cytometry and quantitative PCR showed that airway epithelial cells expressed leptin receptor (Ob-R), whose expression level was downregulated by leptin itself. Multiplex cytokine analysis demonstrated enhanced production of CCL11, G-CSF, VEGF, and IL-6 by BEAS-2B cells stimulated with leptin. Furthermore, transfection of Ob-R small interference RNA decreased the effect of leptin on CCL11 production as assessed by quantitative PCR. Finally, leptin induced migration of primary airway epithelial cells toward leptin, suppressed BEAS-2B apoptosis induced with TNF-α and IFN-γ, and enhanced proliferation of primary airway epithelial cells. In summary, leptin was able to directly activate human airway epithelial cells by binding to Ob-R and by NF-κB activation, resulting in upregulation of ICAM-1 expression, induction of CCL11, VEGF, G-CSF, and IL-6 synthesis, induction of migration, inhibition of apoptosis, and enhancement of proliferation. PMID:26276826

  15. 2-O, 3-O-Desulfated Heparin Inhibits Neutrophil Elastase–Induced HMGB-1 Secretion and Airway Inflammation

    PubMed Central

    Griffin, Kathryn L.; Fischer, Bernard M.; Kummarapurugu, Apparao B.; Zheng, Shuo; Kennedy, Thomas P.; Rao, Narayanam V.; Foster, W. Michael

    2014-01-01

    Neutrophil elastase (NE) is a major inflammatory mediator in cystic fibrosis (CF) that is a robust predictor of lung disease progression. NE directly causes airway injury via protease activity, and propagates persistent neutrophilic inflammation by up-regulation of neutrophil chemokine expression. Despite its key role in the pathogenesis of CF lung disease, there are currently no effective antiprotease therapies available to patients with CF. Although heparin is an effective antiprotease and anti-inflammatory agent, its anticoagulant activity prohibits its use in CF, due to risk of pulmonary hemorrhage. In this report, we demonstrate the efficacy of a 2-O, 3-O-desulfated heparin (ODSH), a modified heparin with minimal anticoagulant activity, to inhibit NE activity and to block NE-induced airway inflammation. Using an established murine model of intratracheal NE-induced airway inflammation, we tested the efficacy of intratracheal ODSH to block NE-generated neutrophil chemoattractants and NE-triggered airway neutrophilic inflammation. ODSH inhibited NE-induced keratinocyte-derived chemoattractant and high-mobility group box 1 release in bronchoalveolar lavage. ODSH also blocked NE-stimulated high-mobility group box 1 release from murine macrophages in vitro, and inhibited NE activity in functional assays consistent with prior reports of antiprotease activity. In summary, this report suggests that ODSH is a promising antiprotease and anti-inflammatory agent that may be useful as an airway therapy in CF. PMID:24325600

  16. Evidence for basolateral but not apical membrane localization of outwardly rectifying depolarization-induced Cl(-) channel in airway epithelia.

    PubMed

    Hwang, T H; Lee, H J; Lee, N K; Choi, Y C

    2000-08-01

    The rat primary cultured-airway monolayer had been an excellent model for deciphering the ion channel after nystatin permeabilization of its basolateral or apical membrane (Hwang et al., 1996). After apical membrane permeabilization of rat primary cultured-airway monolayer, 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS)-sensitive outwardly rectifying depolarization-induced Cl(-) (BORDIC) currents were observed across the basolateral membrane in symmetrical NMG-Cl solution in this study. No significant Cl(-) current induced by the application of voltage clamping was observed across the apical membrane in symmetrical NMG-Cl solution after basolateral membrane permeabilization. The halide permeability sequence for BORDIC current was Br(-) = I(-) > Cl(-). BORDIC current was not affected by basolaterally applied bumetanide (0.5 mm). Basolateral DIDS (0.2 mm) but not apical DIDS inhibited CFTR mediated short-circuit current (I(sc)) in an intact monolayer of rat airway epithelia, a T84 human colonal epithelial cell line, and a Calu-3 human airway epithelial cell line. This is the first report showing that depolarization induced Cl(-) current is present on the basolateral membrane of airway epithelia. PMID:10931973

  17. 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.

  18. 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.

  19. Influenza A infection enhances antigen-induced airway inflammation and hyper-responsiveness in young but not aged mice

    PubMed Central

    Birmingham, Janette M.; Gillespie, Virginia L.; Srivastava, Kamal; Li, Xiu-Min; Busse, Paula J.

    2015-01-01

    Background Although morbidity and mortality rates from asthma are highest in patients > 65 years of age, the effect of older age on airway inflammation in asthma is not well established. Objective To investigate age-related differences in the promotion of allergic inflammation after influenza A viral respiratory infection on antigen specific IgE production, antigen-induced airway inflammation and airway hyper-responsiveness in mice. Methods To accomplish this objective, the following model system was used. Young (six-week) and aged (18-month) BALB/c mice were first infected with a non-lethal dose of influenza virus A (H/HK×31). Mice were then ovalbumin (OVA) sensitized during the acute-infection (3-days post inoculation) and then chronically underwent challenge to the airways with OVA. Forty-eight hours after the final OVA-challenge, airway hyperresponsiveness (AHR), bronchoalveolar fluid (BALF) cellular and cytokine profile, antigen-specific IgE and IgG1, and lung tissue inflammation were measured. Results Age-specific differences were noted on the effect of a viral infection, allergic sensitization, airway inflammation and airway hyperresponsiveness. Serum OVA-specific IgE was significantly increased in only the aged mice infected with influenza virus. Despite greater morbidity (e.g. weight loss and sickness scores) during the acute infection in the 18-month old mice that were OVA-sensitized there was little effect on the AHR and BALF cellular differential. In contrast, BALF neutrophils and AHR increased, but eosinophils decreased in 6-week mice that were OVA-sensitized during an acute influenza infection. Conclusion With increased age in a mouse model, viral infection prior to antigen sensitization affects the airway and systemic allergic response differently. These differences may reflect distinct phenotypic features of allergic inflammation in older patients with asthma PMID:25039815

  20. Neurokinin B- and specific tachykinin NK3 receptor agonists-induced airway hyperresponsiveness in the guinea-pig

    PubMed Central

    Daoui, Samira; Naline, Emmanuel; Lagente, Vincent; Emonds-Alt, Xavier; Advenier, Charles

    2000-01-01

    The aim of this study was to determine whether neurokinin B (NKB) or specific agonists of tachykinin NK3 receptors, [MePhe7]NKB and senktide, were able to induce airway hyperresponsiveness in guinea-pigs. The effects of these compounds were compared to those of substance P (SP), neurokinin A (NKA) and the preferential tachykinin NK1 ([Sar9, Met(02)11]SP) or NK2 ([βAla8]NKA (4-10)) receptor agonists.In guinea-pigs pretreated with phosphoramidon (10−4 M aerosol for 10 min) and salbutamol (8.7×10−3 M for 10 min), all tachykinins administrated by aerosol (3×10−7 to 10−4 M) induced airway hyperresponsiveness 24 h later, displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine (i.v.). The rank order of potency was: [βAla8]NKA (4-10)>NKA=NKB=senktide=[MePhe7]NKB=[Sar9,Met(02)11]SP>SP.Airway hyperresponsiveness induced by [MePhe7]NKB was prevented by the tachykinin NK3 (SR 142801) and NK2 (SR 48968) receptor antagonists.Bronchoconstriction induced by tachykinins administered by aerosol was also determined. SP, NKA, NKB and the tachykinin NK1 and NK2 receptor agonist induced bronchoconstriction. The rank order of potency was: NKA=[βAla8]NKA (4-10)>NKB=SP=[Sar9,Met(02)11]SP. Under similar conditions, and for concentrations which induce airway hyperresponsiveness, senktide and [MePhe7]NKB failed to induce bronchoconstriction.It is concluded that tachykinin NK3-receptor stimulation can induce airway hyperresponsiveness and that this effect is not related to the ability of tachykinins to induce bronchoconstriction. PMID:10780997

  1. Acetaminophen Attenuates House Dust Mite-Induced Allergic Airway Disease in Mice.

    PubMed

    Smith, Gregory J; Thrall, Roger S; Cloutier, Michelle M; Manautou, Jose E; Morris, John B

    2016-09-01

    Epidemiologic evidence suggests that N-acetyl-para-aminophenol (APAP) may play a role in the pathogenesis of asthma, likely through pro-oxidant mechanisms. However, no studies have investigated the direct effects of APAP on the development of allergic inflammation. To determine the likelihood of a causal relationship between APAP and asthma pathogenesis, we explored the effects of APAP on inflammatory responses in a murine house dust mite (HDM) model of allergic airway disease. We hypothesized that APAP would enhance the development of HDM-induced allergic inflammation. The HDM model consisted of once daily intranasal instillations for up to 2 weeks with APAP or vehicle administration 1 hour prior to HDM during either week 1 or 2. Primary assessment of inflammation included bronchoalveolar lavage (BAL), cytokine expression in lung tissue, and histopathology. Contrary to our hypothesis, the effects of HDM treatment were substantially diminished in APAP-treated groups compared with controls. APAP-treated groups had markedly reduced airway inflammation: including decreased inflammatory cells in the BAL fluid, lower cytokine expression in lung tissue, and less perivascular and peribronchiolar immune cell infiltration. The anti-inflammatory effect of APAP was not abrogated by an inhibitor of cytochrome P450 (P450) metabolism, suggesting that the effect was due to the parent compound or a non-P450 generated metabolite. Taken together, our studies do not support the biologic plausibility of the APAP hypothesis that APAP use may contribute to the causation of asthma. Importantly, we suggest the mechanism by which APAP modulates airway inflammation may provide novel therapeutic targets for asthma. PMID:27402277

  2. Anti-Siglec-F Antibody Reduces Allergen-Induced Eosinophilic Inflammation and Airway Remodeling1

    PubMed Central

    Song, Dae Jin; Cho, Jae Youn; Lee, Sang Yeub; Miller, Marina; Rosenthal, Peter; Soroosh, Pejman; Croft, Michael; Zhang, Mai; Varki, Ajit; Broide, David H.

    2009-01-01

    Siglec-F is a sialic acid-binding Ig superfamily receptor that is highly expressed on eosinophils. We have investigated whether administration of an anti-Siglec-F Ab to OVA-challenged wild-type mice would reduce levels of eosinophilic inflammation and levels of airway remodeling. Mice sensitized to OVA and challenged repetitively with OVA for 1 mo who were administered an anti-Siglec-F Ab had significantly reduced levels of peribronchial eosinophilic inflammation and significantly reduced levels of subepithelial fibrosis as assessed by either trichrome staining or lung collagen levels. The anti-Siglec-F Ab reduced the number of bone marrow, blood, and tissue eosinophils, suggesting that the anti-Siglec-F Ab was reducing the production of eosinophils. Administration of a F(ab′)2 fragment of an anti-Siglec-F Ab also significantly reduced levels of eosinophilic inflammation in the lung and blood. FACS analysis demonstrated increased numbers of apoptotic cells (annexin V+/CCR3+ bronchoalveolar lavage and bone marrow cells) in anti-Siglec-F Ab-treated mice challenged with OVA. The anti-Siglec-F Ab significantly reduced the number of peribronchial major basic protein+/TGF-β+ cells, suggesting that reduced levels of eosinophil-derived TGF-β in anti-Siglec-F Ab-treated mice contributed to reduced levels of peribronchial fibrosis. Administration of the anti-Siglec-F Ab modestly reduced levels of periodic acid-Schiff-positive mucus cells and the thickness of the smooth muscle layer. Overall, these studies suggest that administration of an anti-Siglec-F Ab can significantly reduce levels of allergen-induced eosinophilic airway inflammation and features of airway remodeling, in particular subepithelial fibrosis, by reducing the production of eosinophils and increasing the number of apoptotic eosinophils in lung and bone marrow. PMID:19783675

  3. Airway hyperresponsiveness to adenosine induced by lipopolysaccharide in Brown Norway rats

    PubMed Central

    Tigani, B; Hannon, J P; Rondeau, C; Mazzoni, L; Fozard, J R

    2002-01-01

    We have explored the effects of bacterial endotoxin (lipopolysaccharide; LPS) on the response of the airways of Brown Norway (BN) rats to adenosine. Comparisons have been drawn with the effects on responses to methacholine and 5-hydroxytryptamine.In vehicle-challenged animals, adenosine, given i.v. was only a weak bronchoconstrictor. In contrast, 1 h following intratracheal administration of LPS, 0.3 mg kg−1, bronchoconstrictor responses to adenosine were markedly and selectively enhanced. At this time point, there were no significant changes in leukocyte numbers, eosinophil peroxidase and myeloperoxidase activities or protein concentrations in bronchoalveolar lavage (BAL) fluid. Twenty-four hours after challenge, the sensitivity of the airways to both adenosine and methacholine was reduced relative to the earlier time point and there were substantial increases in each marker of inflammation in BAL fluid.The bronchoconstrictor response to adenosine was blocked selectively by methysergide, disodium cromoglycate and the broad-spectrum adenosine receptor antagonist, 8-SPT, but not by DPCPX or ZM 243185, selective antagonists for the A1 and A2A receptors, respectively.Thus, the response to adenosine augmented following LPS is mast cell mediated and involves a receptor which can be blocked by 8-SPT but not by selective A1 or A2A receptor antagonists. It thus bears similarity to the augmented response to adenosine induced by allergen challenge in actively sensitized BN rats. Exposure to LPS could be a factor along with allergen in determining the increased sensitivity of the airways of asthmatics to adenosine. PMID:11976275

  4. The effect of treating obstructive sleep apnea with positive airway pressure on depression and other subjective symptoms: A systematic review and meta-analysis.

    PubMed

    Gupta, Madhulika A; Simpson, Fiona C; Lyons, Danika C A

    2016-08-01

    Patients with obstructive sleep apnea (OSA) frequently present with symptoms of depression and anxiety. The objective of this study is to determine if treatment with positive airway pressure (PAP) improves symptoms of depression and anxiety. A systematic review was conducted to identify clinical trials of PAP that contained a validated measure of depression severity. Meta-analysis was conducted for depression, anxiety, excessive daytime sleepiness (EDS), quality of life (QoL) and respiratory variables. The systematic review included 33 reports. Pre-post-test analysis of PAP showed a moderate effect size (Hedge's g, 95% CI) for depression 0.524 [0.401-0.647], but a low effect size compared to oral placebo (0.355 [0.187-0.524]) and no effect when compared to dental appliances (0.107 [-0.72-0.287]) and sham PAP (-0.049 [-0.292-0.194]). Anxiety, EDS, and QoL showed similar improvement in pre-post-test analysis, but a lack of superiority to dental appliances and sham PAP. PAP was superior to all comparators for respiratory variables. PAP has a moderate clinical effect on symptoms of depression and anxiety in OSA, but it is not superior to dental appliances or sham PAP. The improvement in subjective symptoms, such as depression and anxiety, may be mediated by patient expectations and contact with healthcare providers. PMID:26454823

  5. Src regulates cigarette smoke-induced ceramide generation via neutral sphingomyelinase 2 in the airway epithelium.

    PubMed

    Chung, Samuel; Vu, Simon; Filosto, Simone; Goldkorn, Tzipora

    2015-06-01

    We previously demonstrated that the neutral sphingomyelinase (nSMase) 2 is the sole sphingomyelinase activated during cigarette smoke (CS)-induced oxidative stress of human airway epithelial cells, leading to ceramide generation and subsequent apoptosis of affected cells. Since then, we reported that nSMase2 is a phosphoprotein, the degree of enzymatic activity and stability of which are dictated by its degree of phosphorylation. Simultaneously, the non-receptor tyrosine kinase and proto-oncogene Src has increasingly become a target of interest in both smoking-related lung injury, such as chronic obstructive pulmonary disease, and lung cancer. Within this context, we tested and now present Src as a regulator of ceramide generation via modulation of nSMase2 phosphorylation and activity during CS-induced oxidative stress. Specifically, we provide evidence that Src activity is necessary for both CS-induced ceramide accumulation in vivo (129/Sv mice) and in vitro (human airway epithelial cells) and for nSMase2 activity during CS-induced oxidative stress. Moreover, because nSMase2 is exclusively phosphorylated on serines, we show that this occurs through Src-dependent activation of the serine/threonine kinase p38 mitogen-activated protein kinase during oxidative stress. Finally, we provide evidence that Src and p38 mitogen-activated protein kinase activities are critical for regulating nSMase2 phosphorylation. This study provides insights into a molecular target involved in smoking-related lung injury, represented here as nSMase2, and its modulation by the oncogene Src. PMID:25347576

  6. Src Regulates Cigarette Smoke–Induced Ceramide Generation via Neutral Sphingomyelinase 2 in the Airway Epithelium

    PubMed Central

    Chung, Samuel; Vu, Simon; Filosto, Simone

    2015-01-01

    We previously demonstrated that the neutral sphingomyelinase (nSMase) 2 is the sole sphingomyelinase activated during cigarette smoke (CS)–induced oxidative stress of human airway epithelial cells, leading to ceramide generation and subsequent apoptosis of affected cells. Since then, we reported that nSMase2 is a phosphoprotein, the degree of enzymatic activity and stability of which are dictated by its degree of phosphorylation. Simultaneously, the non–receptor tyrosine kinase and proto-oncogene Src has increasingly become a target of interest in both smoking-related lung injury, such as chronic obstructive pulmonary disease, and lung cancer. Within this context, we tested and now present Src as a regulator of ceramide generation via modulation of nSMase2 phosphorylation and activity during CS-induced oxidative stress. Specifically, we provide evidence that Src activity is necessary for both CS-induced ceramide accumulation in vivo (129/Sv mice) and in vitro (human airway epithelial cells) and for nSMase2 activity during CS-induced oxidative stress. Moreover, because nSMase2 is exclusively phosphorylated on serines, we show that this occurs through Src-dependent activation of the serine/threonine kinase p38 mitogen-activated protein kinase during oxidative stress. Finally, we provide evidence that Src and p38 mitogen-activated protein kinase activities are critical for regulating nSMase2 phosphorylation. This study provides insights into a molecular target involved in smoking-related lung injury, represented here as nSMase2, and its modulation by the oncogene Src. PMID:25347576

  7. Hesperetin, a Selective Phosphodiesterase 4 Inhibitor, Effectively Suppresses Ovalbumin-Induced Airway Hyperresponsiveness without Influencing Xylazine/Ketamine-Induced Anesthesia

    PubMed Central

    Shih, Chung-Hung; Lin, Ling-Hung; Hsu, Hsin-Te; Wang, Kuo-Hsien; Lai, Chi-Yin; Chen, Chien-Ming; Ko, Wun-Chang

    2012-01-01

    Hesperetin, a selective phosphodiesterase (PDE)4 inhibitor, is present in the traditional Chinese medicine, “Chen Pi.” Therefore, we were interested in investigating its effects on ovalbumin- (OVA-) induced airway hyperresponsiveness, and clarifying its rationale for ameliorating asthma and chronic obstructive pulmonary disease (COPD). Hesperetin was revealed to have a therapeutic (PDE4H/PDE4L) ratio of >11. Hesperetin (10 ~ 30 μmol/kg, intraperitoneally (i.p.)) dose-dependently and significantly attenuated the airway hyperresponsiveness induced by methacholine. It also significantly suppressed the increases in total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF). It dose-dependently and significantly suppressed total and OVA-specific immunoglobulin E levels in the BALF and serum. However, hesperetin did not influence xylazine/ketamine-induced anesthesia, suggesting that hesperetin has few or no emetic effects. In conclusion, the rationales for ameliorating allergic asthma and COPD by hesperetin are anti-inflammation, immunoregulation, and bronchodilation. PMID:22454667

  8. Chlamydia pneumoniae infection induced allergic airway sensitization is controlled by regulatory T-cells and plasmacytoid dendritic cells.

    PubMed

    Crother, Timothy R; Schröder, Nicolas W J; Karlin, Justin; Chen, Shuang; Shimada, Kenichi; Slepenkin, Anatoly; Alsabeh, Randa; Peterson, Ellena; Arditi, Moshe

    2011-01-01

    Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs. PMID:21695198

  9. 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

  10. Cocaine-induced psychotic symptoms in clinical setting.

    PubMed

    Vergara-Moragues, Esperanza; Araos Gómez, Pedro; González-Saiz, Francisco; Rodríguez-Fonseca, Fernando

    2014-06-30

    Cocaine use is significantly associated with psychiatric co-morbidities of which psychotic symptoms are the most typical. The primary goal of this study is to estimate the life-time prevalence of cocaine-induced psychotic symptoms (CIPS) in a sample of patients without a history of primary psychosis, who attended specific out-patient drug-dependence treatment centres (ODDTCs). This is an observational, cross-sectional design and a consecutive sampling technique. The Scale for Assessment of Positive Symptoms-Cocaine Induced Psychosis (SAPS-CIP) was used to interview 114 patients who request treatment at specific ODDTCs for problems related to cocaine use. Most patients, 89.5% (95% CIs: 83.8-95.2%) had dependence of cocaine and 84.2% (95% CIs: 77.5-90.9%) showed at least one CIPS. Patients with CIPS had used cocaine more times throughout their lives and had a more frequency of use during the period of higher abuse severity in the last year, had higher severity of dependence score and had fewer abstinence periods greater than 30 days compared with those without CIPS. Cocaine dependency severity scale scores were significantly greater in patients with CIPS compared with those without CIPS. PMID:24679995

  11. Personalized symptoms forecasting for pollen-induced allergic rhinitis sufferers

    NASA Astrophysics Data System (ADS)

    Voukantsis, D.; Berger, U.; Tzima, F.; Karatzas, K.; Jaeger, S.; Bergmann, K. C.

    2015-07-01

    Hay fever is a pollen-induced allergic reaction that strongly affects the overall quality of life of many individuals. The disorder may vary in severity and symptoms depending on patient-specific factors such as genetic disposition, individual threshold of pollen concentration levels, medication, former immunotherapy, and others. Thus, information services that improve the quality of life of hay fever sufferers must address the needs of each individual separately. In this paper, we demonstrate the development of information services that offer personalized pollen-induced symptoms forecasts. The backbone of these services consists of data of allergic symptoms reported by the users of the Personal Hay Fever Diary system and pollen concentration levels (European Aeroallergen Network) in several sampling sites. Data were analyzed using computational intelligence methods, resulting in highly customizable forecasting models that offer personalized warnings to users of the Patient Hay Fever Diary system. The overall system performance for the pilot area (Vienna and Lower Austria) reached a correlation coefficient of r = 0.71 ± 0.17 (average ± standard deviation) in a sample of 219 users with major contribution to the Pollen Hay Fever Diary system and an overall performance of r = 0.66 ± 0.18 in a second sample of 393 users, with minor contribution to the system. These findings provide an example of combining data from different sources using advanced data engineering in order to develop innovative e-health services with the capacity to provide more direct and personalized information to allergic rhinitis sufferers.

  12. CRTH2 antagonism significantly ameliorates airway hyperreactivity and downregulates inflammation-induced genes in a mouse model of airway inflammation.

    PubMed

    Lukacs, Nicholas W; Berlin, Aaron A; Franz-Bacon, Karin; Sásik, Roman; Sprague, L James; Ly, Tai Wei; Hardiman, Gary; Boehme, Stefen A; Bacon, Kevin B

    2008-11-01

    Prostaglandin D(2), the ligand for the G protein-coupled receptors DP1 and CRTH2, has been implicated in the pathogenesis of the allergic response in diseases such as asthma, rhinitis, and atopic dermatitis. This prostanoid also fulfills a number of physiological, anti-inflammatory roles through its receptor DP1. We investigated the role of PGD(2) and CRTH2 in allergic pulmonary inflammation by using a highly potent and specific antagonist of CRTH2. Administration of this antagonist ameliorated inflammation caused by either acute or subchronic sensitization using the cockroach egg antigen. Gene expression and ELISA analysis revealed that there was reduced proinflammatory cytokine mRNA or protein produced, as well as a wide array of genes associated with the Th2-type proinflammatory response. Importantly, the CRTH2 antagonist reduced antigen-specific IgE, IgG1, and IgG2a antibody levels as well as decreased mucus deposition and leukocyte infiltration in the large airways. Collectively, these findings suggest that the PGD(2)-CRTH2 activation axis has a pivotal role in mediating the inflammation and the underlying immune response in a T cell-driven model of allergic airway inflammation. PMID:18757520

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

    PubMed

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

    2016-01-01

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

  14. Bee venom phospholipase A2 suppresses allergic airway inflammation in an ovalbumin-induced asthma model through the induction of regulatory T cells.

    PubMed

    Park, Soojin; Baek, Hyunjung; Jung, Kyung-Hwa; Lee, Gihyun; Lee, Hyeonhoon; Kang, Geun-Hyung; Lee, Gyeseok; Bae, Hyunsu

    2015-12-01

    Bee venom (BV) is one of the alternative medicines that have been widely used in the treatment of chronic inflammatory diseases. We previously demonstrated that BV induces immune tolerance by increasing the population of regulatory T cells (Tregs) in immune disorders. However, the major component and how it regulates the immune response have not been elucidated. We investigated whether bee venom phospholipase A2 (bvPLA2) exerts protective effects that are mediated via Tregs in OVA-induced asthma model. bvPLA2 was administered by intraperitoneal injection into control and OVA-challenged mice. The Treg population, total and differential bronchoalveolar lavage fluid (BALF) cell count, Th2 cytokines, and lung histological features were assessed. Treg depletion was used to determine the involvement of Treg migration and the reduction of asthmatic symptoms. The CD206-dependence of bvPLA2-treated suppression of airway inflammation was evaluated in OVA-challenged CD206(-/-) mice. The bvPLA2 treatment induced the Tregs and reduced the infiltration of inflammatory cells into the lung in the OVA-challenged mice. Th2 cytokines in the bronchoalveolar lavage fluid (BALF) were reduced in bvPLA2-treated mice. Although bvPLA2 suppressed the number of inflammatory cells after OVA challenge, these effects were not observed in Treg-depleted mice. In addition, we investigated the involvement of CD206 in bvPLA2-mediated immune tolerance in OVA-induced asthma model. We observed a significant reduction in the levels of Th2 cytokines and inflammatory cells in the BALF of bvPLA2-treated OVA-induced mice but not in bvPLA2-treated OVA-induced CD206(-/-) mice. These results demonstrated that bvPLA2 can mitigate airway inflammation by the induction of Tregs in an OVA-induced asthma model. PMID:26734460

  15. Airborne lipid antigens mobilize resident intravascular NKT cells to induce allergic airway inflammation

    PubMed Central

    Scanlon, Seth T.; Thomas, Seddon Y.; Ferreira, Caroline M.; Bai, Li; Krausz, Thomas; Savage, Paul B.

    2011-01-01

    Airborne exposure to microbial cell wall lipids such as lipopolysaccharide triggers innate immune responses that regulate susceptibility to allergic airway inflammation. α-Glycosylceramides represent another widespread class of microbial lipids that directly stimulate innate-like, IL-4– and IL-13–producing, CD1d-restricted NKT cells. In this study, we demonstrate that NKT cells constitutively accumulate and reside in the microvasculature of the mouse lung. After a single airborne exposure to lipid antigen, they promptly extravasate to orchestrate the formation of peribronchiolar and interstitial lymphohistiocytic granulomas containing numerous eosinophils. Concomitant airborne exposure to ovalbumin (OVA) induces the priming of OVA-specific Th2 cells and IgE antibodies by the same dendritic cell coexpressing CD1d and MHC class II. Although NKT cell activation remains confined to the lipid-exposed lung and draining lymph nodes, Th2 cells recirculate and seed the lung of a parabiotic partner, conferring susceptibility to OVA challenge months after the initial exposure, in a manner independent of NKT cells and CD1d. Thus, transient recruitment and activation of lung-resident intravascular NKT cells can trigger long-term susceptibility to allergic airway inflammation. PMID:21930768

  16. Hazard of CO₂ laser-induced airway fire in laryngeal surgery: experimental data of contributing factors.

    PubMed

    Stuermer, Konrad Johannes; Ayachi, Stefan; Gostian, Antoniu-O; Beutner, Dirk; Hüttenbrink, Karl-Bernd

    2013-09-01

    In carbon dioxide (CO2) laser surgery of the larynx, the potentially dangerous combination of laser-induced heat in an oxygen-enriched atmosphere typically occurs when jet ventilation is used or due to an insufficiently blocked endotracheal tube. Until now, no limitations for safe oxygen concentrations or laser intervals have been established. The aim of this study was to investigate and quantify the factors that may contribute to an airway fire in laryngeal laser surgery. Fat, muscle and cartilage were irradiated with a CO2 laser at 2, 4, 6 and 8 W in five different oxygen concentrations with and without smoke exhaustion. The time to ignition was recorded for each different experimental setup. Fat burnt fastest, followed by cartilage and muscle. The elevation of laser energy or oxygen concentration reduced the time to inflammation of any tissue. The elevation of oxygen by 10 % increases the risk of inflammation more than the elevation of laser power by 2 W. Under smoke exhaustion, inflammation and burning occurred delayed or were even inhibited at lower oxygen concentrations. Lasing in more than 50 % oxygen is comparatively dangerous and can cause airway fire in less than 5 s, especially when laser energies of more than 5 W are applied. In equal or lower than 50 % oxygen, an irradiation interval of 5 s can be considered a comparatively safe time limit to prevent inflammation in laryngeal laser surgery. Smoke exhaustion should always be applied. PMID:23636479

  17. Effect of azelastine on sulphur dioxide induced impairment of ciliary motility in airway epithelium.

    PubMed Central

    Tamaoki, J; Chiyotani, A; Sakai, N; Takeyama, K; Konno, K

    1993-01-01

    OBJECTIVE--The effect of azelastine on airway mucociliary transport function was studied by measuring ciliary motility of human bronchial epithelium in vitro with a photoelectric method. METHOD--Bronchial epithelial cells were obtained by fibreoptic bronchoscopy, mounted in a Rose chamber, and perfused with Krebs-Henseleit solution. The preparations were placed on a microscope stage equipped with an illuminator, and the variations of light intensity caused by ciliary beating were detected by a photometer. RESULTS--The addition of azelastine to the perfusate increased ciliary beat frequency (CBF) in a dose dependent manner without ciliary discoordination. The mean (SE) maximal increase from the baseline value and the concentration required to produce a half maximal effect were 27.0 (4.2)% and 9.2 x 10(-6) mol/l, respectively. Exposure of the cells to the perfusate containing 3 ppm sulphur dioxide rapidly decreased CBF by 59.2 (5.0)%, and was accompanied by a reduction in intracellular cyclic AMP levels from 38.1 (4.3) to 10.1 (2.4) pmol/mg protein. This effect was prevented by pretreatment of cells with azelastine in a dose dependent manner. CONCLUSIONS--Azelastine not only stimulates ciliary motility of airway epithelium and hence mucociliary transport function, but may also protect against sulphur dioxide induced ciliary dysfunction, probably by inhibiting intracellular cyclic AMP loss. PMID:8322244

  18. TGF-β-mediated airway tolerance to allergens induced by peptide-based immunomodulatory mucosal vaccination.

    PubMed

    Michael, H; Li, Y; Wang, Y; Xue, D; Shan, J; Mazer, B D; McCusker, C T

    2015-11-01

    We sought to modulate mucosal immune responses using neonatal vaccination to avert the development of allergic airways disease (AAD). Pulmonary pathology in AAD is driven by T helper (TH)2 cytokines, in particular interleukin (IL)4 and IL13, the expression and actions of which are regulated by the transcription factor STAT6. We developed a peptide homolog of STAT6, STAT6-IP. Neonatal mice given, intranasally, STAT6-IP, in an effort to modulate de novo airways immune responses, developed tolerance following subsequent allergen sensitization, with either ovalbumin or ragweed allergens, as demonstrated by reduced TH2 cytokines and specific immunoglobulin (Ig)E and the significant increases in the latency-associated peptide (LAP)(+) T-regulatory (Treg) cell subset and expression of transforming growth factor (TGF)-β. This regulatory phenotype was transferrable by CD4(+) T cells or CD11c(+) dendritic cells (DCs) derived from STAT6-IP-vaccinated mice. Anti-TGF-β treatment during allergen sensitization, however, re-established the pro-inflammatory TH2 response. Thus, neonatal STAT6-IP vaccination induces prospective TGF-β-dependent tolerance to allergen and constitutes a novel highly effective immunomodulatory allergy prevention strategy. PMID:25783968

  19. Transgenic overexpression of interleukin-1β induces persistent lymphangiogenesis but not angiogenesis in mouse airways.

    PubMed

    Baluk, Peter; Hogmalm, Anna; Bry, Maija; Alitalo, Kari; Bry, Kristina; McDonald, Donald M

    2013-04-01

    These studies used bi-transgenic Clara cell secretory protein (CCSP)/IL-1β mice that conditionally overexpress IL-1β in Clara cells to determine whether IL-1β can promote angiogenesis and lymphangiogenesis in airways. Doxycycline treatment induced rapid, abundant, and reversible IL-1β production, influx of neutrophils and macrophages, and conspicuous and persistent lymphangiogenesis, but surprisingly no angiogenesis. Gene profiling showed many up-regulated genes, including chemokines (Cxcl1, Ccl7), cytokines (tumor necrosis factor α, IL-1β, and lymphotoxin-β), and leukocyte genes (S100A9, Aif1/Iba1). Newly formed lymphatics persisted after IL-1β overexpression was stopped. Further studies examined how IL1R1 receptor activation by IL-1β induced lymphangiogenesis. Inactivation of vascular endothelial growth factor (VEGF)-C and VEGF-D by adeno-associated viral vector-mediated soluble VEGFR-3 (VEGF-C/D Trap) completely blocked lymphangiogenesis, showing its dependence on VEGFR-3 ligands. Consistent with this mechanism, VEGF-C immunoreactivity was present in some Aif1/Iba1-immunoreactive macrophages. Because neutrophils contribute to IL-1β-induced lung remodeling in newborn mice, we examined their potential role in lymphangiogenesis. Triple-transgenic CCSP/IL-1β/CXCR2(-/-) mice had the usual IL-1β-mediated lymphangiogenesis but no neutrophil recruitment, suggesting that neutrophils are not essential. IL1R1 immunoreactivity was found on some epithelial basal cells and neuroendocrine cells, suggesting that these cells are targets of IL-1β, but was not detected on lymphatics, blood vessels, or leukocytes. We conclude that lymphangiogenesis triggered by IL-1β overexpression in mouse airways is driven by VEGF-C/D from macrophages, but not neutrophils, recruited by chemokines from epithelial cells that express IL1R1. PMID:23391392

  20. Naringin Protects Ovalbumin-Induced Airway Inflammation in a Mouse Model of Asthma.

    PubMed

    Guihua, Xiong; Shuyin, Liu; Jinliang, Gao; Wang, Shumin

    2016-04-01

    Many plant species containing flavonoids have been widely used in traditional Chinese medicine. Naringin, a well-known flavanone glycoside of citrus fruits, possesses antioxidant, anti-inflammatory, anti-apoptotic, anti-ulcer, anti-osteoporosis, and anti-carcinogenic properties. The aim of the study was to investigate the anti-asthmatic effects of naringin and the possible mechanisms. Asthma model was established by ovalbumin. A total of 50 mice were randomly assigned to five experimental groups: control, model, and dexamethasone (2 mg/kg, orally) and naringin (5 mg/kg, 10 mg/kg, orally). Airway resistance (Raw) were measured, histological studies were evaluated by the hematoxylin and eosin (HE) staining, OVA-specific serum and BALF IgE levels and Th1/Th2 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA), and Th1/Th2 cells was evaluated by flow cytometry (FCM). T-bet and GABA3 in the lung were evaluated by Western blot. Our study demonstrated that naringin inhibited OVA-induced increases in Raw and eosinophil count; OVA-induced effects on interleukin (IL)-4 and INF-gamma levels were blunted with naringin administration. Histological studies demonstrated that naringin substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue. Flow cytometry studies demonstrated that naringin substantially inhibited Th2 cells and enhanced Th1 cells. Naringin substantially inhibited GABA3 and increased T-bet. These findings suggest that naringin may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma. PMID:26920847

  1. Mechanism of airway hyperresponsiveness to adenosine induced by allergen challenge in actively sensitized Brown Norway rats

    PubMed Central

    Hannon, J P; Tigani, B; Williams, I; Mazzoni, L; Fozard, J R

    2001-01-01

    We have explored the role of allergen sensitization and challenge in defining the response of the airways of the Brown Norway (BN) rat to adenosine. In naïve animals or in rats sensitized to ovalbumin (OA) adenosine induced only weak bronchoconstrictor responses. Challenge of sensitized animals with OA induced a marked airway hyperresponsiveness to adenosine which was not seen with methacholine or bradykinin. The augmented bronchoconstrictor response to adenosine was not affected by acute bivagotomy or atropine nor mimicked by an i.v. injection of capsaicin. It was, however, blocked selectively by disodium cromoglycate methysergide or ketanserin and reduced in animals treated sub-chronically with compound 48/80. The augmented response to adenosine was associated with increases in the plasma concentrations of both histamine and 5-hydroxytryptamine (5-HT), which were attenuated by pretreatment with disodium cromoglycate, and degranulation of mast cells in the lung. Parenchymal strips from lungs removed from sensitized rats challenged with OA gave augmented bronchoconstrictor responses to adenosine relative to strips from sensitized animals challenged with saline. Responses were inhibited by methysergide and disodium cromoglycate. These data demonstrate a marked augmentation of the bronchoconstrictor response to adenosine in actively sensitized BN rats challenged with OA. The augmented response is primarily a consequence of mast cell activation, leading to the release of 5-HT, which in turn induces bronchoconstriction. Our data further suggest the involvement of a discrete lung-based population of mast cells containing and releasing mainly 5-HT and brought into play by prior exposure to allergen. PMID:11264245

  2. IL-17A induces signal transducers and activators of transcription-6-independent airway mucous cell metaplasia.

    PubMed

    Newcomb, Dawn C; Boswell, Madison G; Sherrill, Taylor P; Polosukhin, Vasiliy V; Boyd, Kelli L; Goleniewska, Kasia; Brody, Steven L; Kolls, Jay K; Adler, Kenneth B; Peebles, R Stokes

    2013-06-01

    Mucous cell metaplasia is a hallmark of asthma, and may be mediated by signal transducers and activators of transcription (STAT)-6 signaling. IL-17A is increased in the bronchoalveolar lavage fluid of patients with severe asthma, and IL-17A also increases mucus production in airway epithelial cells. Asthma therapeutics are being developed that inhibit STAT6 signaling, but the role of IL-17A in inducing mucus production in the absence of STAT6 remains unknown. We hypothesized that IL-17A induces mucous cell metaplasia independent of STAT6, and we tested this hypothesis in two murine models in which increased IL-17A protein expression is evident. In the first model, ovalbumin (OVA)-specific D011.10 Th17 cells were adoptively transferred into wild-type (WT) or STAT6 knockout (KO) mice, and the mice were challenged with OVA or PBS. WT-OVA and STAT6 KO-OVA mice demonstrated increased airway IL-17A and IL-13 protein expression and mucous cell metaplasia, compared with WT-PBS or STAT6 KO-PBS mice. In the second model, WT, STAT1 KO, STAT1/STAT6 double KO (DKO), or STAT1/STAT6/IL-17 receptor A (RA) triple KO (TKO) mice were challenged with respiratory syncytial virus (RSV) or mock viral preparation, and the mucous cells were assessed. STAT1 KO-RSV mice demonstrated increased airway mucous cell metaplasia compared with WT-RSV mice. STAT1 KO-RSV and STAT1/STAT6 DKO-RSV mice also demonstrated increased mucous cell metaplasia, compared with STAT1/STAT6/IL17RA TKO-RSV mice. We also treated primary murine tracheal epithelial cells (mTECs) from WT and STAT6 KO mice. STAT6 KO mTECs showed increased periodic acid-Schiff staining with IL-17A but not with IL-13. Thus, asthma therapies targeting STAT6 may increase IL-17A protein expression, without preventing IL-17A-induced mucus production. PMID:23392574

  3. Mycoplasma pneumoniae Modulates STAT3-STAT6/EGFR-FOXA2 Signaling To Induce Overexpression of Airway Mucins

    PubMed Central

    Hao, Yonghua; Kuang, Zhizhou; Jing, Jia; Miao, Jinfeng; Mei, Li Yu; Lee, Ryan J.; Kim, Susie; Choe, Shawn; Krause, Duncan C.

    2014-01-01

    Aberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced by M. pneumoniae remains unclear. This study aimed to determine the mechanism by which M. pneumoniae induces mucus hypersecretion by using M. pneumoniae infection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated that M. pneumoniae induced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure to M. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated that M. pneumoniae induces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways. PMID:25287927

  4. ZN2+-INDUCED IL-8 EXPRESSION INVOLVES AP-1, JNK, AND ERK ACTIVITIES IN HUMAN AIRWAY EPITHELIAL CELLS

    EPA Science Inventory

    Exposure to zinc-laden particulate matter (PM) in ambient and occupational settings has been associated with proinflammatory responses in the lung. IL-8 is an important proinflammatory cytokine in the human lung and is induced in human airway epithelial cells exposed to zin...

  5. Endotoxin-induced nitric oxide production rescues airway growth and maturation in atrophic fetal rat lung explants

    SciTech Connect

    Rae, C.; Cherry, J.I.; Land, F.M.; Land, S.C. . E-mail: s.c.land@dundee.ac.uk

    2006-10-13

    Inflammation induces premature maturation of the fetal lung but the signals causing this effect remain unclear. We determined if nitric oxide (NO) synthesis, evoked by Escherichia coli lipopolysaccharide (LPS, 2 {mu}g ml{sup -1}), participated in this process. Fetal rat lung airway surface complexity rose 2.5-fold over 96 h in response to LPS and was associated with increased iNOS protein expression and activity. iNOS inhibition by N6-(1-iminoethyl)-L-lysine-2HCl (L-NIL) abolished this and induced airway atrophy similar to untreated explants. Surfactant protein-C (SP-C) expression was also induced by LPS and abolished by L-NIL. As TGF{beta} suppresses iNOS activity, we determined if feedback regulation modulated NO-dependent maturation. LPS induced TGF{beta}1 release and SMAD4 nuclear translocation 96 h after treatment. Treatment of explants with a blocking antibody against TGF{beta}1 sustained NO production and airway morphogenesis whereas recombinant TGF{beta}1 antagonized these effects. Feedback regulation of NO synthesis by TGF{beta} may, thus, modulate airway branching and maturation of the fetal lung.

  6. Nickel Mobilizes Intracellular Zinc to Induce Metallothionein in Human Airway Epithelial Cells

    PubMed Central

    Nemec, Antonia A.; Leikauf, George D.; Pitt, Bruce R.; Wasserloos, Karla J.; Barchowsky, Aaron

    2009-01-01

    We recently reported that induction of metallothionein (MT) was critical in limiting nickel (Ni)-induced lung injury in intact mice. Nonetheless, the mechanism by which Ni induces MT expression is unclear. We hypothesized that the ability of Ni to mobilize zinc (Zn) may contribute to such regulation and therefore, we examined the mechanism for Ni-induced MT2A expression in human airway epithelial (BEAS-2B) cells. Ni induced MT2A transcript levels and protein expression by 4 hours. Ni also increased the activity of a metal response element (MRE) promoter luciferase reporter construct, suggesting that Ni induces MRE binding of the metal transcription factor (MTF-1). Exposure to Ni resulted in the nuclear translocation of MTF-1, and Ni failed to induce MT in mouse embryonic fibroblasts lacking MTF-1. As Zn is the only metal known to directly bind MTF-1, we then showed that Ni increased a labile pool of intracellular Zn in cells as revealed by fluorescence-activated cell sorter using the Zn-sensitive fluorophore, FluoZin-3. Ni-induced increases in MT2A mRNA and MRE-luciferase activity were sensitive to the Zn chelator, TPEN, supporting an important role for Zn in mediating the effect of Ni. Although neither the source of labile Zn nor the mechanism by which Ni liberates labile Zn was apparent, it was noteworthy that Ni increased intracellular reactive oxygen species (ROS). Although both N-acetyl cysteine (NAC) and ascorbic acid (AA) decreased Ni-induced increases in ROS, only NAC prevented Ni-induced increases in MT2A mRNA, suggesting a special role for interactions of Ni, thiols, and Zn release. PMID:19097988

  7. Lack of efficacy of pre bronchoscopy inhaled salbutamol on symptoms and lung functions in patients with pre-existing airway obstruction

    PubMed Central

    Mohan, Anant; Momin, Indrajit; Poulose, Rosemary; Mohan, Charu; Madan, Karan; Hadda, Vijay; Guleria, Randeep; Pandey, RM

    2016-01-01

    Background: Fiberoptic bronchoscopy (FOB) may exaggerate symptoms and lung functions in patients with pre-existing airway obstruction. Interventions which can alleviate or minimize this procedure-related bronchospasm, especially in this high-risk group are, therefore, required. Methods: A double-blinded randomized controlled trial was conducted to evaluate the efficacy of 400 μg of inhaled salbutamol on patients with spirometric evidence of airflow obstruction planned for FOB. Patient's dyspnea, procedure tolerability, and change in spirometry were assessed before and after the procedure. Results: A total of 50 patients were enrolled (78% males), with a mean (standard deviation) age of 49.8 (6.2) years. There was a significant fall in % predicted FEV1 within each group compared to their respective pre-bronchoscopy values. However, no significant difference in the % predicted or absolute FEV1 level was observed between the two groups. Similarly, although both groups experienced increased dyspnea immediately following FOB, this difference was not significant between the two groups either on the Borg or visual analog scale scales. Pre-FOB anxiety levels and the tolerability of the procedure as assessed by the bronchoscopist were similar in both groups. Conclusion: FOB in patients with pre-existing airway obstruction aggravates cough and dyspnea, with a concomitant decline in FEV1 and FVC. The administration of pre-FOB inhaled salbutamol does not have any significant beneficial effect on procedure-related outcomes. PMID:27578926

  8. Nevirapine-induced rash with eosinophilia and systemic symptoms (DRESS).

    PubMed

    Gill, Shaman; Sagar, Amitabh; Shankar, S; Nair, Velu

    2013-01-01

    Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an adverse reaction commonly occurring with antiepileptic agents. It was earlier referred to by various names such as dilantin hypersensitivity syndrome and anticonvulsant hypersensitivity syndrome. It is characterized by the triad of fever, skin eruption, and systemic involvement. DRESS syndrome has also been reported with a number of other drugs including allopurinol, minocycline, terbinafine, sulfonamides, azathioprine, dapsone, and antiretroviral agents such as abacavir and nevirapine. We describe a rare case of nevirapine-induced hypersensitivity syndrome that was successfully treated with oral steroids. PMID:24014920

  9. Effect of current exposure to Der p 1 on asthma symptoms, airway inflammation, and bronchial hyperresponsiveness in mite-allergic asthmatics.

    PubMed

    Alvarez, M J; Olaguibel, J M; Acero, S; García, B E; Tabar, A I; Urbiola, E

    2000-02-01

    The existence of a dose-response relationship between indoor allergen exposure and sensitization has been widely described, but the effect of allergen exposure on asthma activity (symptoms, bronchial hyperresponsiveness [BHR], and inflammation) is not clear. Our aim was to determine the existence of an association among current exposure to mite allergens and symptoms, BHR, and airway inflammation assessed in blood and sputum from asthmatic patients sensitized to Dermatophagoides pteronyssinus. We selected 31 mild and recently diagnosed (12-24 months) asthma patients sensitized to D. pteronyssinus. Allergenic exposure (Der p 1, Der 2) was assessed by a commercial assay based on monoclonal antibodies (mAb), carried out on the dust samples collected from patients' beds in a standardized way. Patients completed an asthma symptom questionnaire and underwent skin tests, methacholine bronchial challenge, and sputum induction. Sputum cell profile was analyzed and eosinophil cationic protein (ECP), tryptase, albumin, and interleukin(IL)-5 levels were quantified in sputum supernatant. Total eosinophil numbers and ECP levels were measured in blood samples. Most patients were exposed to Der p 1 levels under 2 microg/g of dust. Der p 1 exposure was higher among the subjects with positive sputum tryptase detection (P = 0.020). Der p 1 levels showed a trend toward correlation with asthma symptoms (P = 0.066, r = 0.36) and correlated with sputum tryptase levels (P = 0.032, r = 0.42). No relationship between BHR, eosinophilic inflammation, and allergenic exposure was found. Our results suggest that asthma symptoms and lung mast-cell activation are at least partially dependent on current allergen exposure. The lack of correlation between mite exposure, eosinophilic inflammation, and BHR supports the role of other factors that enhance the immunologic response initiated by allergen, increasing the activity of asthma. PMID:10726735

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

    PubMed Central

    2016-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Cho, Hye Youn

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

  12. Phospholipase A2 induced airway hyperreactivity to cooling and acetylcholine in rat trachea: pharmacological modulation.

    PubMed Central

    Chand, N.; Diamantis, W.; Mahoney, T. P.; Sofia, R. D.

    1988-01-01

    1. Rat isolated tracheal smooth muscle preparations respond to phospholipase A2 (PLA2) and phospholipase C (PLC) with contractile responses of highly variable magnitudes. Rat tracheae exposed to PLA2 or PLC for a period of 10-30 min, exhibit airway hyperreactivity (AH) to cooling (10 degrees C), i.e., respond with strong contractile responses. Phospholipase D neither contracted rat tracheae nor induced AH to cooling. 2. PLA2-induced AH to cooling was dependent on the presence of extracellular Ca2+ in the physiological solution. 3. Verapamil, azelastine, diltiazem and TMB-8 (each 10 microM) significantly attenuated PLA2-induced AH. This effect was not shared by nifedipine (10 microM). 4. Bepridil (10 microM), a Ca2+ and calmodulin antagonist, also significantly attenuated AH induced by PLA2. 5. Indomethacin (a cyclo-oxygenase inhibitor), AA-861 (a selective 5-lipoxygenase inhibitor), FPL 55712 (a leukotriene receptor antagonist), methysergide (a 5-hydroxytryptamine D-receptor antagonist) and pyrilamine (a histamine H1-receptor antagonist) exerted little or no effect on PLA2-induced AH to cooling. 6. Atropine significantly attenuated PLA2-induced AH suggesting the participation of acetylcholine. 7. Nordihydroguaiaretic acid (an antioxidant; 5-lipoxygenase inhibitor) and BW 755C (an antioxidant; a dual inhibitor of cyclo-oxygenase and 5-lipoxygenase) significantly attenuated PLA2-induced AH to cooling. 8. In conclusion, these data show that PLA2 (an enzyme involved in the synthesis of Paf-acether, prostaglandins, thromboxanes, leukotrienes, diacylglycerol, superoxide free radicals and lipid peroxides, etc.) induces AH to cooling and acetylcholine in rat trachea. The induction of AH to cooling is dependent on the presence of extracellular Ca2+ and is significantly attenuated by verapamil, diltiazem, bepridil, atropine and azelastine (an antiallergic/antiasthmatic drug). PMID:3207972

  13. 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. PMID:25010831

  14. Acute pulmonary inflammation induced by exposure of the airways to staphylococcal enterotoxin type B in rats

    SciTech Connect

    Desouza, Ivani A. . E-mail: ivanidesouza@fcm.unicamp.br; Franco-Penteado, Carla F.; Camargo, Enilton A.; Lima, Carmen S.P.; Teixeira, Simone A.; Muscara, Marcelo N.; De Nucci, Gilberto; Antunes, Edson

    2006-11-15

    Staphylocococcus aureus is a gram-positive bacterium that produces several enterotoxins, which are responsible for most part of pathological conditions associated to staphylococcal infections, including lung inflammation. This study aimed to investigate the underlying inflammatory mechanisms involved in leukocyte recruitment in rats exposed to staphylococcal enterotoxin B (SEB). Rats were anesthetized with pentobarbital sodium and intratracheally injected with either SEB or sterile phosphate-buffered saline (PBS, 0.4 ml). Airways exposition to SEB (7.5-250 ng/trachea) caused a dose- and time-dependent neutrophil accumulation in BAL fluid, the maximal effects of which were observed at 4 h post-SEB exposure (250 ng/trachea). Eosinophils were virtually absent in BAL fluid, whereas mononuclear cell counts increased only at 24 h post-SEB. Significant elevations of granulocytes in bone marrow (mature and immature forms) and peripheral blood have also been detected. In BAL fluid, marked elevations in the levels of lipid mediators (LTB{sub 4} and PGE{sub 2}) and cytokines (TNF-{alpha}, IL-6 and IL-10) were observed after SEB instillation. The SEB-induced neutrophil accumulation in BAL fluid was reduced by pretreatment with dexamethasone (0.5 mg/kg), the COX-2 inhibitor celecoxib (3 mg/kg), the selective iNOS inhibitor compound 1400 W (5 mg/kg) and the lipoxygenase inhibitor AA-861 (200 {mu}g/kg). In separate experiments carried out with rat isolated peripheral neutrophils, SEB failed to induce neutrophil adhesion to serum-coated plates and chemotaxis. In conclusion, rat airways exposition to SEB causes a neutrophil-dependent lung inflammation at 4 h as result of the release of proinflammatory (NO, PGE{sub 2}, LTB{sub 4}, TNF-{alpha}, IL-6) and anti-inflammatory mediators (IL-10)

  15. Real-time imaging of ATP release induced by mechanical stretch in human airway smooth muscle cells.

    PubMed

    Takahara, Norihiro; Ito, Satoru; Furuya, Kishio; Naruse, Keiji; Aso, Hiromichi; Kondo, Masashi; Sokabe, Masahiro; Hasegawa, Yoshinori

    2014-12-01

    Airway smooth muscle (ASM) cells within the airway walls are continually exposed to mechanical stimuli, and exhibit various functions in response to these mechanical stresses. ATP acts as an extracellular mediator in the airway. Moreover, extracellular ATP is considered to play an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease. However, it is not known whether ASM cells are cellular sources of ATP secretion in the airway. We therefore investigated whether mechanical stretch induces ATP release from ASM cells. Mechanical stretch was applied to primary human ASM cells cultured on a silicone chamber coated with type I collagen using a stretching apparatus. Concentrations of ATP in cell culture supernatants measured by luciferin-luciferase bioluminescence were significantly elevated by cyclic stretch (12 and 20% strain). We further visualized the stretch-induced ATP release from the cells in real time using a luminescence imaging system, while acquiring differential interference contrast cell images with infrared optics. Immediately after a single uniaxial stretch for 1 second, strong ATP signals were produced by a certain population of cells and spread to surrounding spaces. The cyclic stretch-induced ATP release was significantly reduced by inhibitors of Ca(2+)-dependent vesicular exocytosis, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester, monensin, N-ethylmaleimide, and bafilomycin. In contrast, the stretch-induced ATP release was not inhibited by a hemichannel blocker, carbenoxolone, or blockade of transient receptor potential vanilloid 4 by short interfering RNA transfection or ruthenium red. These findings reveal a novel property of ASM cells: mechanically induced ATP release may be a cellular source of ATP in the airway. PMID:24885163

  16. Cigarette smoke makes airway and early parenchymal asbestos-induced lung disease worse in the guinea pig

    SciTech Connect

    Tron, V.; Wright, J.L.; Harrison, N.; Wiggs, B.; Churg, A.

    1987-08-01

    In order to assess the effects of cigarette smoke and asbestos exposure, we divided guinea pigs into 4 groups: smoking or nonsmoking, and asbestos-exposed or not asbestos-exposed groups. Asbestos-exposed animals were given a single intratracheal instillation of 5 mg UICC amosite, a dose and method of administration that we have previously shown produces morphologic changes in the small airways as well as minimal interstitial fibrosis. Animals were smoked 5 days per week for 6 months. By itself, smoking did not affect lung collagen content, small airways wall thickness, or the volume fraction of tissue surrounding airways, but it did cause a significant increase in alveolar mean linear intercept (Lm). Asbestos alone increased collagen content, airway wall thickness, and tissue volume fraction surrounding airways, the latter measure used to assess interstitial fibrosis. An unexpected finding was that asbestos also increased Lm. The two agents administered together caused more severe changes of all types than were produced by either agent alone, and the interaction between the 2 was generally synergistic. Smoke-exposed animals retained 3 times the asbestos fiber burden of those not smoke-exposed; the increase in retention was greater for short than for long fibers. We conclude that cigarette smoke can potentiate the fibrosis induced by asbestos, possibly because of increased fiber retention. As well, in this model, asbestos or asbestos plus cigarette smoke produces increases in alveolar size.

  17. Furosemide-induced airway relaxation in guinea pigs: relation to Na-K-2Cl cotransporter function.

    PubMed

    Lavallee, S L; Iwamoto, L M; Claybaugh, J R; Dressel, M V; Sato, A K; Nakamura, K T

    1997-07-01

    This study tested the hypothesis that airway relaxation to furosemide is mediated via the Na-K-2Cl cotransporter. If this mechanism exists in airway smooth muscle like in vascular smooth muscle, changes in airway relaxation should be associated with changes in Na-K-2Cl cotransporter function, and both should be substrate dependent. Tracheal rings from newborn guinea pigs were bathed in standard (STD) or varying low Cl- concentration ([Cl-]) N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). Isometric relaxation to 300 microM furosemide or 10(-8) to 10(-5) M salbutamol was measured. Airway segments were incubated with rubidium-86 (86Rb) in STD or varying low [Cl-] HEPES, with and without 300 microM furosemide or 25 microM salbutamol. Furosemide was unable to reduce 86Rb uptake at 10 mM [Cl-], although relaxation was still observed in 10 mM [Cl-]. Salbutamol did not affect 86Rb uptake. This study demonstrated that there is a furosemide-sensitive Na-K-2Cl cotransporter in newborn guinea pig trachea. However, the effect of furosemide on cotransporter function did not always directly correspond to differences in relaxation, suggesting that the Na-K-2Cl cotransporter may play a major, but not exclusive, role in furosemide-induced airway relaxation. PMID:9252558

  18. Wood smoke enhances cigarette smoke-induced inflammation by inducing the aryl hydrocarbon receptor repressor in airway epithelial cells.

    PubMed

    Awji, Elias G; Chand, Hitendra; Bruse, Shannon; Smith, Kevin R; Colby, Jennifer K; Mebratu, Yohannes; Levy, Bruce D; Tesfaigzi, Yohannes

    2015-03-01

    Our previous studies showed that cigarette smokers who are exposed to wood smoke (WS) are at an increased risk for chronic bronchitis and reduced lung function. The present study was undertaken to determine the mechanisms for WS-induced adverse effects. We studied the effect of WS exposure using four cohorts of mice. C57Bl/6 mice were exposed for 4 or 12 weeks to filtered air, to 10 mg/m(3) WS for 2 h/d, to 250 mg/m(3) cigarette smoke (CS) for 6 h/d, or to CS followed by WS (CW). Inflammation was absent in the filtered air and WS groups, but enhanced by twofold in the bronchoalveolar lavage of the CW compared with CS group as measured by neutrophil numbers and levels of the neutrophil chemoattractant, keratinocyte-derived chemokine. The levels of the anti-inflammatory lipoxin, lipoxin A4, were reduced by threefold along with cyclo-oxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 in airway epithelial cells and PGE2 levels in the bronchoalveolar lavage of CW compared with CS mice. We replicated, in primary human airway epithelial cells, the changes observed in mice. Immunoprecipitations showed that WS blocked the interaction of aryl hydrocarbon receptor (AHR) with AHR nuclear transporter to reduce expression of COX-2 and mPGES-1 by increasing expression of AHR repressor (AHRR). Collectively, these studies show that exposure to low concentrations of WS enhanced CS-induced inflammation by inducing AHRR expression to suppress AHR, COX-2, and mPGES-1 expression, and levels of PGE2 and lipoxin A4. Therefore, AHRR is a potential therapeutic target for WS-associated exacerbations of CS-induced inflammation. PMID:25137396

  19. Wood Smoke Enhances Cigarette Smoke–Induced Inflammation by Inducing the Aryl Hydrocarbon Receptor Repressor in Airway Epithelial Cells

    PubMed Central

    Awji, Elias G.; Chand, Hitendra; Bruse, Shannon; Smith, Kevin R.; Colby, Jennifer K.; Mebratu, Yohannes; Levy, Bruce D.

    2015-01-01

    Our previous studies showed that cigarette smokers who are exposed to wood smoke (WS) are at an increased risk for chronic bronchitis and reduced lung function. The present study was undertaken to determine the mechanisms for WS-induced adverse effects. We studied the effect of WS exposure using four cohorts of mice. C57Bl/6 mice were exposed for 4 or 12 weeks to filtered air, to 10 mg/m3 WS for 2 h/d, to 250 mg/m3 cigarette smoke (CS) for 6 h/d, or to CS followed by WS (CW). Inflammation was absent in the filtered air and WS groups, but enhanced by twofold in the bronchoalveolar lavage of the CW compared with CS group as measured by neutrophil numbers and levels of the neutrophil chemoattractant, keratinocyte-derived chemokine. The levels of the anti-inflammatory lipoxin, lipoxin A4, were reduced by threefold along with cyclo-oxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 in airway epithelial cells and PGE2 levels in the bronchoalveolar lavage of CW compared with CS mice. We replicated, in primary human airway epithelial cells, the changes observed in mice. Immunoprecipitations showed that WS blocked the interaction of aryl hydrocarbon receptor (AHR) with AHR nuclear transporter to reduce expression of COX-2 and mPGES-1 by increasing expression of AHR repressor (AHRR). Collectively, these studies show that exposure to low concentrations of WS enhanced CS-induced inflammation by inducing AHRR expression to suppress AHR, COX-2, and mPGES-1 expression, and levels of PGE2 and lipoxin A4. Therefore, AHRR is a potential therapeutic target for WS-associated exacerbations of CS-induced inflammation. PMID:25137396

  20. Cyclic mechanical strain-induced proliferation and migration of human airway smooth muscle cells: role of EMMPRIN and MMPs.

    PubMed

    Hasaneen, Nadia A; Zucker, Stanley; Cao, Jian; Chiarelli, Christian; Panettieri, Reynold A; Foda, Hussein D

    2005-09-01

    Airway smooth muscle (ASM) proliferation and migration are major components of airway remodeling in asthma. Asthmatic airways are exposed to mechanical strain, which contributes to their remodeling. Matrix metalloproteinase (MMP) plays an important role in remodeling. In the present study, we examined if the mechanical strain of human ASM (HASM) cells contributes to their proliferation and migration and the role of MMPs in this process. HASM were exposed to mechanical strain using the FlexCell system. HASM cell proliferation, migration and MMP release, activation, and expression were assessed. Our results show that cyclic strain increased the proliferation and migration of HASM; cyclic strain increased release and activation of MMP-1, -2, and -3 and membrane type 1-MMP; MMP release was preceded by an increase in extracellular MMP inducer; Prinomastat [a MMP inhibitor (MMPI)] significantly decreased cyclic strain-induced proliferation and migration of HASM; and the strain-induced increase in the release of MMPs was accompanied by an increase in tenascin-C release. In conclusion, cyclic mechanical strain plays an important role in HASM cell proliferation and migration. This increase in proliferation and migration is through an increase in MMP release and activation. Pharmacological MMPIs should be considered in the pursuit of therapeutic options for airway remodeling in asthma. PMID:16014803

  1. R-134a (1,1,1,2-Tetrafluoroethane) Inhalation Induced Reactive Airways Dysfunction Syndrome.

    PubMed

    Doshi, Viral; Kham, Nang; Kulkarni, Shreedhar; Kapitan, Kent; Henkle, Joseph; White, Peter

    2016-01-01

    R-134a (1,1,1,2-tetrafluoroethane) is widely used as a refrigerant and as an aerosol propellant. Inhalation of R-134a can lead to asphyxia, transient confusion, and cardiac arrhythmias. We report a case of reactive airways dysfunction syndrome secondary to R-134a inhalation. A 60-year-old nonsmoking man without a history of lung disease was exposed to an air conditioner refrigerant spill while performing repairs beneath a school bus. Afterward, he experienced worsening shortness of breath with minimal exertion, a productive cough, and wheezing. He was also hypoxic. He was admitted to the hospital for further evaluation. Spirometry showed airflow obstruction with an FEV1 1.97 L (45% predicted). His respiratory status improved with bronchodilators and oral steroids. A repeat spirometry 2 weeks later showed improvement with an FEV1 2.5 L (60% predicted). Six months after the incident, his symptoms had improved, but he was still having shortness of breath on exertion and occasional cough. PMID:25137406

  2. Involvement of Syk kinase in TNF-induced nitric oxide production by airway epithelial cells

    SciTech Connect

    Ulanova, Marina . E-mail: marina.ulanova@normed.ca; Marcet-Palacios, Marcelo; Munoz, Samira; Asfaha, Samuel; Kim, Moo-Kyung; Schreiber, Alan D.; Befus, A. Dean

    2006-12-15

    We have recently found that Syk is widely expressed in lung epithelial cells (EC) and participates in {beta}1 integrin signaling. In this study, we assessed the role of Syk in regulation of NO production. Stimulation of human bronchial EC line HS-24 by TNF caused an increased expression of inducible nitric oxide synthase (iNOS). Inhibition of Syk using siRNA or piceatannol down-regulated the iNOS expression and reduced NO production. This effect occurred in EC simultaneously stimulated via {beta}1 integrins, suggesting that TNF and {beta}1 integrins provide co-stimulatory signals. Inhibition of Syk down-regulated TNF-induced p38 and p44/42 MAPK phosphorylation and nuclear translocation of p65 NF-{kappa}B. Thus, TNF-induced activation of pro-inflammatory signaling in EC leading to enhanced expression of iNOS and NO production was dependent on Syk. Syk-mediated signaling regulates NO production at least partly via activating the MAPK cascade. Understanding the role of Syk in airway EC may help in developing new therapeutic tools for inflammatory lung disorders.

  3. Identification of human metapneumovirus-induced gene networks in airway epithelial cells by microarray analysis

    SciTech Connect

    Bao, X.; Sinha, M. |; Liu, T.; Hong, C.; Luxon, B.A. |; Garofalo, R.P. ||; Casola, A. ||

    2008-04-25

    Human metapneumovirus (hMPV) is a major cause of lower respiratory tract infections in infants, elderly and immunocompromised patients. Little is known about the response to hMPV infection of airway epithelial cells, which play a pivotal role in initiating and shaping innate and adaptive immune responses. In this study, we analyzed the transcriptional profiles of airway epithelial cells infected with hMPV using high-density oligonucleotide microarrays. Of the 47,400 transcripts and variants represented on the Affimetrix GeneChip Human Genome HG-U133 plus 2 array, 1601 genes were significantly altered following hMPV infection. Altered genes were then assigned to functional categories and mapped to signaling pathways. Many up-regulated genes are involved in the initiation of pro-inflammatory and antiviral immune responses, including chemokines, cytokines, type I interferon and interferon-inducible proteins. Other important functional classes up-regulated by hMPV infection include cellular signaling, gene transcription and apoptosis. Notably, genes associated with antioxidant and membrane transport activity, several metabolic pathways and cell proliferation were down-regulated in response to hMPV infection. Real-time PCR and Western blot assays were used to confirm the expression of genes related to several of these functional groups. The overall result of this study provides novel information on host gene expression upon infection with hMPV and also serves as a foundation for future investigations of genes and pathways involved in the pathogenesis of this important viral infection. Furthermore, it can facilitate a comparative analysis of other paramyxoviral infections to determine the transcriptional changes that are conserved versus the one that are specific to individual pathogens.

  4. Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction.

    PubMed

    Borthwick, L A; Suwara, M I; Carnell, S C; Green, N J; Mahida, R; Dixon, D; Gillespie, C S; Cartwright, T N; Horabin, J; Walker, A; Olin, E; Rangar, M; Gardner, A; Mann, J; Corris, P A; Mann, D A; Fisher, A J

    2016-06-01

    Bacterial infections after lung transplantation cause airway epithelial injury and are associated with an increased risk of developing bronchiolitis obliterans syndrome. The damaged epithelium is a source of alarmins that activate the innate immune system, yet their ability to activate fibroblasts in the development of bronchiolitis obliterans syndrome has not been evaluated. Two epithelial alarmins were measured longitudinally in bronchoalveolar lavages from lung transplant recipients who developed bronchiolitis obliterans syndrome and were compared to stable controls. In addition, conditioned media from human airway epithelial cells infected with Pseudomonas aeruginosa was applied to lung fibroblasts and inflammatory responses were determined. Interleukin-1 alpha (IL-1α) was increased in bronchoalveolar lavage of lung transplant recipients growing P. aeruginosa (11.5 [5.4-21.8] vs. 2.8 [0.9-9.4] pg/mL, p < 0.01) and was significantly elevated within 3 months of developing bronchiolitis obliterans syndrome (8.3 [1.4-25.1] vs. 3.6 [0.6-17.1] pg/mL, p < 0.01), whereas high mobility group protein B1 remained unchanged. IL-1α positively correlated with elevated bronchoalveolar lavage IL-8 levels (r(2)  = 0.6095, p < 0.0001) and neutrophil percentage (r(2)  = 0.25, p = 0.01). Conditioned media from P. aeruginosa infected epithelial cells induced a potent pro-inflammatory phenotype in fibroblasts via an IL-1α/IL-1R-dependent signaling pathway. In conclusion, we propose that IL-1α may be a novel therapeutic target to limit Pseudomonas associated allograft injury after lung transplantation. PMID:26714197

  5. Exercise-induced asthma

    MedlinePlus

    Wheezing - exercise-induced; Reactive airway disease - exercise ... Having asthma symptoms when you exercise does not mean you cannot or should not exercise. But be aware of your EIA triggers. Cold or dry air may ...

  6. Prevention of antigen-induced bronchial hyperreactivity and airway inflammation in sensitized guinea-pigs by tacrolimus.

    PubMed Central

    Lapa e Silva, J R; Ruffié, C; Lefort, J; Nahori, M A; Vargaftig, B B; Pretolani, M

    1999-01-01

    We examined the effect of the immunosuppressive agent, tacrolimus (FK506), on antigen-induced bronchial hyperreactivity to acetylcholine and leukocyte infiltration into the airways of ovalbumin-challenged guinea-pigs. Subcutaneous injection of 0.5 mg/kg of FK506, 1 h before and 5 h after intra-nasal antigen challenge prevented bronchial hyperreactivity to aerosolized acetylcholine, eosinophilia in bronchoalveolar lavage (BAL) fluid and bronchial tissue and the invasion of the bronchial wall by CD4+ T-lymphocytes. FK506 also suppressed ovalbumin-induced increase in the number of leukocytes adhering to the pulmonary vascular endothelium and expressing alpha4-integrins. Inhibition by FK506 of antigen-induced bronchial hyperreactivity in sensitized guinea-pigs may thus relate to its ability to prevent the emergence of important inflammatory components of airway inflammation, such as eosinophil accumulation, as well as CD4+ T-lymphocyte infiltration into the bronchial tissue. PMID:10704085

  7. p110γ/δ Double-Deficiency Induces Eosinophilia and IgE Production but Protects from OVA-Induced Airway Inflammation

    PubMed Central

    Ammon-Treiber, Susanne; Schwab, Matthias; Piekorz, Roland P.; Hirsch, Emilio; Nürnberg, Bernd; Beer-Hammer, Sandra

    2016-01-01

    The catalytical isoforms p110γ and p110δ of phosphatidylinositide 3-kinase γ (PI3Kγ) and PI3Kδ play an important role in the pathogenesis of asthma. Two key elements in allergic asthma are increased levels of eosinophils and IgE. Dual pharmacological inhibition of p110γ and p110δ reduces asthma-associated eosinophilic lung infiltration and ameliorates disease symptoms, whereas the absence of enzymatic activity in p110γKOδD910A mice increases IgE and basal eosinophil counts. This suggests that long-term inhibition of p110γ and p110δ might exacerbate asthma. Here, we analysed mice genetically deficient for both catalytical subunits (p110γ/δ-/-) and determined basal IgE and eosinophil levels and the immune response to ovalbumin-induced asthma. Serum concentrations of IgE, IL-5 and eosinophil numbers were significantly increased in p110γ/δ-/- mice compared to single knock-out and wildtype mice. However, p110γ/δ-/- mice were protected against OVA-induced infiltration of eosinophils, neutrophils, T and B cells into lung tissue and bronchoalveolar space. Moreover, p110γ/δ-/- mice, but not single knock-out mice, showed a reduced bronchial hyperresponsiveness. We conclude that increased levels of eosinophils and IgE in p110γ/δ-/- mice do not abolish the protective effect of p110γ/δ-deficiency against OVA-induced allergic airway inflammation. PMID:27442134

  8. In vivo pharmacological evaluation of compound 48/80-induced airways oedema by MRI

    PubMed Central

    Karmouty-Quintana, H; Blé, F-X; Cannet, C; Zurbruegg, S; Fozard, J R; Page, C P; Beckmann, N

    2008-01-01

    Background and purpose: Allergen-induced airways oedema in actively sensitized rats has been studied earlier by magnetic resonance imaging (MRI). We used MRI to follow the consequences of non-immunological mast cell activation induced by compound 48/80 in the rat lungs in vivo. Experimental approach: Male naïve rats were scanned by MRI prior to and at several time points following intratracheal administration of the mast cell secretagogue, compound 48/80. The effects of a range of drugs on the response induced by compound 48/80 were studied. Key results: Strong fluid signals were detected by MRI in the lungs at 24 h after compound 48/80, correlating with increased protein concentration and inflammatory cell infiltration in bronchoalveolar lavage, and with perivascular oedema observed histologically. Pharmacological intervention demonstrated that the increase in MRI signal volume induced by compound 48/80 24 h after challenge was blocked by disodium cromoglycate and the glucocorticoid, budesonide. Pretreatment with wortmannin, capsazepine, DNK333 (a dual neurokinin (NK) 1 and NK2 antagonist) or the anti-allergy drug CGS8515, but not indomethacin, resulted in partial inhibition. Conclusions and implications: Compound 48/80 induced a complex inflammatory reaction which did not solely involve mast cell degranulation but also activation of sensory nerves and was qualitatively similar to allergen challenge. Changes observed by MRI correlated with decreases in protein concentration in BAL fluid. However, the magnitude of the changes detected was greater using MRI. Our results demonstrate that MRI is a sensitive and efficient tool to assess the effects of drugs on lung inflammation. PMID:18469845

  9. Methylglyoxal Induces Systemic Symptoms of Irritable Bowel Syndrome

    PubMed Central

    Zhang, Shuang; Jiao, Taiwei; Chen, Yushuai; Gao, Nan; Zhang, Lili; Jiang, Min

    2014-01-01

    Patients with irritable bowel syndrome (IBS) show a wide range of symptoms including diarrhea, abdominal pain, changes in bowel habits, nausea, vomiting, headache, anxiety, depression and cognitive impairment. Methylglyoxal has been proved to be a potential toxic metabolite produced by intestinal bacteria. The present study was aimed at investigating the correlation between methylglyoxal and irritable bowel syndrome. Rats were treated with an enema infusion of methylglyoxal. Fecal water content, visceral sensitivity, behavioral tests and serum 5-hydroxytryptamine (5-HT) were assessed after methylglyoxal exposure. Our data showed that fecal water content was significantly higher than controls after methylglyoxal exposure except that of 30 mM group. Threshold volumes on balloon distension decreased in the treatment groups. All exposed rats showed obvious head scratching and grooming behavior and a decrease in sucrose preference. The serum 5-HT values were increased in 30, 60, 90 mM groups and decreased in 150 mM group. Our findings suggested that methylglyoxal could induce diarrhea, visceral hypersensitivity, headache as well as depression-like behaviors in rats, and might be the key role in triggering systemic symptoms of IBS. PMID:25157984

  10. Methylglyoxal induces systemic symptoms of irritable bowel syndrome.

    PubMed

    Zhang, Shuang; Jiao, Taiwei; Chen, Yushuai; Gao, Nan; Zhang, Lili; Jiang, Min

    2014-01-01

    Patients with irritable bowel syndrome (IBS) show a wide range of symptoms including diarrhea, abdominal pain, changes in bowel habits, nausea, vomiting, headache, anxiety, depression and cognitive impairment. Methylglyoxal has been proved to be a potential toxic metabolite produced by intestinal bacteria. The present study was aimed at investigating the correlation between methylglyoxal and irritable bowel syndrome. Rats were treated with an enema infusion of methylglyoxal. Fecal water content, visceral sensitivity, behavioral tests and serum 5-hydroxytryptamine (5-HT) were assessed after methylglyoxal exposure. Our data showed that fecal water content was significantly higher than controls after methylglyoxal exposure except that of 30 mM group. Threshold volumes on balloon distension decreased in the treatment groups. All exposed rats showed obvious head scratching and grooming behavior and a decrease in sucrose preference. The serum 5-HT values were increased in 30, 60, 90 mM groups and decreased in 150 mM group. Our findings suggested that methylglyoxal could induce diarrhea, visceral hypersensitivity, headache as well as depression-like behaviors in rats, and might be the key role in triggering systemic symptoms of IBS. PMID:25157984

  11. Reactive airways dysfunction syndrome following metal fume fever.

    PubMed

    Dube, Daniel; Puruckherr, Michael; Byrd, Ryland P; Roy, Thomas M

    2002-06-01

    Metal fume fever (MFF) is an acute response to the inhalation of heavy metals used in industry. The patient typically experiences symptoms of cough, fever, chills, malaise, and myalgia that are self-limited and of short duration. Wheezing may occur and pulmonary function may be acutely impaired with a decrease in lung volumes and diffusing capacity of carbon monoxide. Nevertheless, respiratory function quickly returns to normal, and persistent pulmonary insufficiency is unusual. Irritant-induced asthma is a non-immunogenic form of airway injury that may be associated with industrial inhalation exposure. In this situation, the direct toxic effect on the airways causes persistent airway inflammation and bronchial hyperreactivity. The two conditions are considered distinct entities, but we report a previously healthy worker who had classic MFF and was left with irritant-induced asthma or reactive airways dysfunction syndrome (RADS). PMID:12056129

  12. Particulate matter (PM₁₀) induces metalloprotease activity and invasion in airway epithelial cells.

    PubMed

    Morales-Bárcenas, Rocío; Chirino, Yolanda I; Sánchez-Pérez, Yesennia; Osornio-Vargas, Álvaro Román; Melendez-Zajgla, Jorge; Rosas, Irma; García-Cuellar, Claudia María

    2015-09-17

    Airborne particulate matter with an aerodynamic diameter ≤ 10 μm (PM10) is a risk factor for the development of lung diseases and cancer. The aim of this work was to identify alterations in airway epithelial (A549) cells induced by PM10 that could explain how subtoxic exposure (10 μg/cm(2)) promotes a more aggressive in vitro phenotype. Our results showed that cells exposed to PM10 from an industrial zone (IZ) and an urban commercial zone (CZ) induced an increase in protease activity and invasiveness; however, the cell mechanism is different, as only PM10 from CZ up-regulated the activity of metalloproteases MMP-2 and MMP-9 and disrupted E-cadherin/β-catenin expression after 48 h of exposure. These in vitro findings are relevant in terms of the mechanism action of PM10 in lung epithelial cells, which could be helpful in understanding the pathogenesis of some human illness associated with highly polluted cities. PMID:26047787

  13. Mitochondrial alteration in malignantly transformed human small airway epithelial cells induced by alpha particles

    PubMed Central

    Zhang, Suping; Wen, Gengyun; Huang, Sarah XL; Wang, Jianrong; Tong, Jian; Hei, Tom K.

    2012-01-01

    Human small airway epithelial cells (SAECs) immortalized with human telomerase reverse transcriptase (h-TERT) were exposed to either a single or multiple doses of α particles. Irradiated cells showed a dose-dependent cytotoxicity and progressive neoplastic transformation phenotype. These included an increase in saturation density of growth, a greater resistance to PALA, faster anchorage-independent growth, reinforced cell invasion and c-Myc expression. In addition, the transformed cells formed progressively growing tumors upon inoculation into athymic nude mice. Specifically, α-irradiation induced damage to both mitochondrial DNA (mtDNA) and mitochondrial functions in transformed cells as evidenced by increased mtDNA copy number and common deletion, decreased oxidative phosphorylation (OXPHOS) activity as measured by cytochrome C oxidase (COX) activity and oxygen consumption. There was a linear correlation between mtDNA copy number, common deletion, COX activity and cellular transformation represented by soft agar colony formation and c-Myc expression. These results suggest that mitochondria are associated with neoplastic transformation of SAEC cells induced by α particles, and that the oncogenesis process may depend not only on the genomes inside the nucleus, but also on the mitochondrial DNA outside the nucleus. PMID:22644783

  14. IL-13 Augments Compressive Stress-Induced Tissue Factor Expression in Human Airway Epithelial Cells.

    PubMed

    Mitchel, Jennifer A; Antoniak, Silvio; Lee, Joo-Hyeon; Kim, Sae-Hoon; McGill, Maureen; Kasahara, David I; Randell, Scott H; Israel, Elliot; Shore, Stephanie A; Mackman, Nigel; Park, Jin-Ah

    2016-04-01

    Tissue factor (TF) is best known as a cellular initiator of coagulation, but it is also a multifunctional protein that has been implicated in multiple pathophysiologic conditions, including asthma. In the lung, airway epithelial cells express TF, but it is unknown how TF expression is regulated by asthma-associated mediators. We investigated the role of IL-13, a type 2 cytokine, alone and in combination with compressive stress, which mimics asthmatic bronchoconstriction, on TF expression and release of TF-positive extracellular vesicles from primary normal human bronchial epithelial cells. Well-differentiated normal human bronchial epithelial cells were treated with IL-13 and compressive stress, alone and in combination. TF mRNA, protein and activity were measured in the cells and conditioned media. TF was also measured in the bronchoalveolar lavage (BAL) fluid of allergen-challenged mice and patients with asthma. IL-13 and compressive stress increased TF expression, but only compressive stress induced TF-positive extracellular vesicle release. Pretreatment with IL-13 augmented compressive stress-induced TF expression and release. TF protein and activity in BAL fluid were increased in allergen-sensitized and -challenged mice. TF was elevated in the BAL fluid of patients with mild asthma after an allergen challenge. Our in vitro and in vivo data indicate close cooperation between mechanical and inflammatory stimuli on TF expression and release of TF-positive extracellular vesicles in the lungs, which may contribute to pathophysiology of asthma. PMID:26407210

  15. OZONE-INDUCED RELEASE OF CYTOKINES AND FIBRONECTIN BY ALVEOLAR MACROPHAGES AND AIRWAY EPITHELIAL CELLS

    EPA Science Inventory

    Although airway epithelial cells appear damaged following exposure of humans and animals to ozone, the contribution of these cells to inflammation observed after ozone exposure is unclear. ince human airway cells are infrequently available for in vitro studies, we have investigat...

  16. Hyperosmolar solution effects in guinea pig airways. IV. Lipopolysaccharide-induced alterations in airway reactivity and epithelial bioelectric responses to methacholine and hyperosmolarity.

    PubMed

    Johnston, Richard A; Van Scott, Michael R; Kommineni, Choudari; Millecchia, Lyndell L; Dortch-Carnes, Juanita; Fedan, Jeffrey S

    2004-01-01

    We investigated the in vivo and in vitro effects of lipopolysaccharide (LPS) treatment (4 mg/kg i.p.) on guinea pig airway smooth muscle reactivity and epithelial bioelectric responses to methacholine (MCh) and hyperosmolarity. Hyperosmolar challenge of the epithelium releases epithelium-derived relaxing factor (EpDRF). Using a two-chamber, whole body plethysmograph 18 h post-treatment, animals treated with LPS were hyporeactive to inhaled MCh aerosol. This could involve an increase in the release and/or actions of EpDRF, because LPS treatment enhanced EpDRF-induced smooth muscle relaxation in vitro in the isolated perfused trachea apparatus. In isolated perfused tracheas the basal transepithelial potential difference (Vt) was increased after LPS treatment. The increase in Vt was inhibited by amiloride and indomethacin. Concentration-response curves for changes in Vt in response to serosally and mucosally applied MCh were biphasic (hyperpolarization, <3 x 10(-7)M; depolarization, >3 x 10(-7)M); MCh was more potent when applied serosally. The hyperpolarization response to MCh, but not the depolarization response, was potentiated after LPS treatment. In both treatment groups, mucosally applied hyperosmolar solution (using added NaCl) depolarized the epithelium; this response was greater in tracheas from LPS-treated animals. The results of this study indicate that airway hyporeactivity in vivo after LPS treatment is accompanied by an increase in the release and/or actions of EpDRF in vitro. These changes may involve LPS-induced bioelectric alterations in the epithelium. PMID:14566002

  17. Role of Neprilysin in Airway Inflammation Induced by Diesel Exhaust Emissions

    PubMed Central

    Wong, Simon S.; Sun, Nina N.; Fastje, Cynthia D.; Witten, Mark L.; Lantz, R. Clark; Lu, Bao; Sherrill, Duane L.; Gerard, Craig J.; Burgess, Jefferey L.

    2016-01-01

    In this study, we examined the role of neprilysin (NEP*), a key membrane-bound endopeptidase, in the inflammatory response induced by diesel exhaust emissions (DEE) in the airways through a number of approaches: in vitro, animal, and controlled human exposure. Our specific aims were (1) to examine the role of NEP in inflammatory injury induced by diesel exhaust particles (DEP) using Nep-intact (wild-type) and Nep-null mice; (2) to examine which components of DEP are associated with NEP downregulation in vitro; (3) to determine the molecular impact of DEP exposure and decreased NEP expression on airway epithelial cells’ gene expression in vitro, using a combination of RNA interference (RNAi) and microarray approaches; and (4) to evaluate the effects on NEP activity of human exposure to DEE. We report four main results: First, we found that exposure of normal mice to DEP consisting of standard reference material (SRM) 2975 via intratracheal installation can downregulate NEP expression in a concentration-dependent manner. The changes were accompanied by increases in the number of macrophages and epithelial cells, as well as proinflammatory cytokines, examined in bronchoalveolar lavage (BAL) fluid and cells. Nep-null mice displayed increased and/or additional inflammatory responses when compared with wild-type mice, especially in response to exposure to the higher dose of DEP that we used. These in vivo findings suggest that loss of NEP in mice could cause increased susceptibility to injury or exacerbate inflammatory responses after DEP exposure via release of specific cytokines from the lungs. Second, we found evidence, using in vitro studies, that downregulation of NEP by DEP in cultured human epithelial BEAS-2B cells was mostly attributable to DEP-adsorbed organic compounds, whereas the carbonaceous core and transition metal components of DEP had little or no effect on NEP messenger RNA (mRNA) expression. This NEP downregulation was not a specific response to DEP

  18. IgE induces proliferation in human airway smooth muscle cells: role of MAPK and STAT3 pathways.

    PubMed

    Redhu, Naresh Singh; Shan, Lianyu; Al-Subait, Duaa; Ashdown, Heather L; Movassagh, Hesam; Lamkhioued, Bouchaib; Gounni, Abdelilah S

    2013-01-01

    Airway remodeling is not specifically targeted by current asthma medications, partly owing to the lack of understanding of remodeling mechanisms, altogether posing great challenges in asthma treatment. Increased airway smooth muscle (ASM) mass due to hyperplasia/hypertrophy contributes significantly to overall airway remodeling and correlates with decline in lung function. Recent evidence suggests that IgE sensitization can enhance the survival and mediator release in inflammatory cells. Human ASM (HASM) cells express both low affinity (FcεRII/CD23) and high affinity IgE Fc receptors (FcεRI), and IgE can modulate the contractile and synthetic function of HASM cells. IgE was recently shown to induce HASM cell proliferation but the detailed mechanisms remain unknown. We report here that IgE sensitization induces HASM cell proliferation, as measured by 3H-thymidine, EdU incorporation, and manual cell counting. As an upstream signature component of FcεRI signaling, inhibition of spleen tyrosine kinase (Syk) abrogated the IgE-induced HASM proliferation. Further analysis of IgE-induced signaling depicted an IgE-mediated activation of Erk 1/2, p38, JNK MAPK, and Akt kinases. Lastly, lentiviral-shRNA-mediated STAT3 silencing completely abolished the IgE-mediated HASM cell proliferation. Collectively, our data provide mechanisms of a novel function of IgE which may contribute, at least in part, to airway remodeling observed in allergic asthma by directly inducing HASM cell proliferation. PMID:24499258

  19. Increased transforming growth factor beta 1 expression mediates ozone-induced airway fibrosis in mice

    PubMed Central

    Katre, Ashwini; Ballinger, Carol; Akhter, Hasina; Fanucchi, Michelle; Kim, Dae-Kee; Postlethwait, Edward; Liu, Rui-Ming

    2013-01-01

    Ozone (O3), a commonly encountered environmental pollutant, has been shown to induce pulmonary fibrosis in different animal models; the underlying mechanism, however, remains elusive. To investigate the molecular mechanism underlying O3-induced pulmonary fibrosis, 6- to 8-week-old C57BL/6 male mice were exposed to a cyclic O3 exposure protocol consisting of 2 days of filtered air and 5 days of O3 exposure (0.5 ppm, 8 h/day) for 5 and 10 cycles with or without intraperitoneal injection of IN-1233, a specific inhibitor of the type 1 receptor of transforming growth factor beta (TGF-β), the most potent profibrogenic cytokine. The results showed that O3 exposure for 5 or 10 cycles increased the TGF-β protein level in the epithelial lining fluid (ELF), associated with an increase in the expression of plasminogen activator inhibitor 1 (PAI-1), a TGF-β-responsive gene that plays a critical role in the development of fibrosis under various pathological conditions. Cyclic O3 exposure also increased the deposition of collagens and alpha smooth muscle actin (α-SMA) in airway walls. However, these fibrotic changes were not overt until after 10 cycles of O3 exposure. Importantly, blockage of the TGF-β signaling pathway with IN-1233 suppressed O3-induced Smad2/3 phosphorylation, PAI-1 expression, as well as collagens and α-SMA deposition in the lung. Our data demonstrate for the first time that O3 exposure increases TGF-β expression and activates TGF-β signaling pathways, which mediates O3-induced lung fibrotic responses in vivo. PMID:21689010

  20. Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates.

    PubMed

    Cabrera-Benítez, Nuria E; Pérez-Roth, Eduardo; Ramos-Nuez, Ángela; Sologuren, Ithaisa; Padrón, José M; Slutsky, Arthur S; Villar, Jesús

    2016-06-01

    Inflammation and apoptosis are crucial mechanisms for the development of the acute respiratory distress syndrome (ARDS). Currently, there is no specific pharmacological therapy for ARDS. We have evaluated the ability of a new family of 1,2,3,5-tetrasubstituted pyrrol compounds for attenuating lipopolysaccharide (LPS)-induced inflammation and apoptosis in an in vitro LPS-induced airway epithelial cell injury model based on the first steps of the development of sepsis-induced ARDS. Human alveolar A549 and human bronchial BEAS-2B cells were exposed to LPS, either alone or in combination with the pyrrol derivatives. Rhein and emodin, two representative compounds with proven activity against the effects of LPS, were used as reference compounds. The pyrrol compound that was termed DTA0118 had the strongest inhibitory activity and was selected as the lead compound to further explore its properties. Exposure to LPS caused an intense inflammatory response and apoptosis in both A549 and BEAS-2B cells. DTA0118 treatment downregulated Toll-like receptor-4 expression and upregulated nuclear factor-κB inhibitor-α expression in cells exposed to LPS. These anti-inflammatory effects were accompanied by a significantly lower secretion of interleukin-6 (IL-6), IL-8, and IL-1β. The observed antiapoptotic effect of DTA0118 was associated with the upregulation of antiapoptotic Bcl-2 and downregulation of proapoptotic Bax and active caspase-3 protein levels. Our findings demonstrate the potent anti-inflammatory and antiapoptotic properties of the pyrrol DTA0118 compound and suggest that it could be considered as a potential drug therapy for the acute phase of sepsis and septic ARDS. Further investigations are needed to examine and validate these mechanisms and effects in a clinically relevant animal model of sepsis and sepsis-induced ARDS. PMID:26999659

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

    PubMed Central

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

    2015-01-01

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

  2. Arylhydrocarbon receptor (AhR) activation in airway epithelial cells induces MUC5AC via reactive oxygen species (ROS) production.

    PubMed

    Chiba, Takahito; Uchi, Hiroshi; Tsuji, Gaku; Gondo, Hisaki; Moroi, Yoichi; Furue, Masutaka

    2011-02-01

    The dioxins and dioxin-like compounds in cigarette smoke regulate various immunological responses via the arylhydrocarbon receptor (AhR). These environmental toxicants are known to cause bronchitis, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. Recent studies have demonstrated that AhR activation upregulates the expression of mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) in the airway epithelial cell line. However, the mechanism for the production of mucin has not been clarified. In this study, we investigated the role and pathway of AhR in airway epithelial cells by using selective agonists and antagonists. After stimulation with or without benzopyrene (B[a]P), an AhR agonist, MUC5AC expression was measured by real-time RT-PCR. The mechanism of AhR-induced MUC5AC expression in airway epithelial cells was studied in terms of the production of cytokine and reactive oxygen species (ROS). Treatment with B[a]P increased ROS generation in NCI-H₂₉₂ cells. Furthermore, B[a]P-induced MUC5AC upregulation and mucin production were inhibited by AhR siRNA or the use of an antioxidative agent. These results suggest that the AhR-induced increase of mucin production is partially mediated by ROS generation. An antioxidant therapy approach may help to cure AhR-induced mucus hypersecretory diseases. PMID:20709182

  3. Ozone-induced lung function decrements do not correlate with early airway inflammatory or antioxidant responses.

    PubMed

    Blomberg, A; Mudway, I S; Nordenhäll, C; Hedenström, H; Kelly, F J; Frew, A J; Holgate, S T; Sandström, T

    1999-06-01

    This study sought to clarify the early events occurring within the airways of healthy human subjects performing moderate intermittent exercise following ozone challenge. Thirteen healthy nonsmoking subjects were exposed in a single blinded, crossover control fashion to 0.2 parts per million (ppm) O3 and filtered air for 2 h, using a standard intermittent exercise and rest protocol. Lung function was assessed pre- and immediately post-exposure. Bronchoscopy was performed with endobronchial mucosal biopsies, bronchial wash (BW) and bronchoalveolar lavage (BAL) 1.5 h after the end of the exposure period. Respiratory tract lining fluid (RTLF) redox status was assessed by measuring a range of antioxidants and oxidative damage markers in BW and BAL fluid samples. There was a significant upregulation after O3 exposure in the expression of vascular endothelial P-selectin (p<0.005) and intercellular adhesion molecule-1 (p<0.005). This was associated with a 2-fold increase in submucosal mast cells (p<0.005) in biopsy samples, without evidence of neutrophilic inflammation, and a decrease in BAL fluid macrophage numbers (1.6-fold, p<0.005), with an activation of the remaining macrophage subset (2.5-fold increase in % human leukocyte antigen (HLA)-DR+ cells, p<0.005). In addition, exposure led to a 4.5-fold and 3.1-fold increase of reduced glutathione (GSH) concentrations, in BW and BAL fluid respectively (p<0.05), with alterations in urate and alpha-tocopherol plasma/RTLF partitioning ratios (p<0.05). Spirometry showed reductions in forced vital capacity (p<0.05) and forced expiratory volume in one second (p<0.01), with evidence of small airway narrowing using forced expiratory flow values (p<0.005). Evidence was found of O3-induced early adhesion molecule upregulation, increased submucosal mast cell numbers and alterations to the respiratory tract lining fluid redox status. No clear relationship was demonstrable between changes in these early markers and the lung function

  4. Fatty acid binding protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma.

    PubMed

    Ghelfi, Elisa; Yu, Chen-Wei; Elmasri, Harun; Terwelp, Matthew; Lee, Chun G; Bhandari, Vineet; Comhair, Suzy A; Erzurum, Serpil C; Hotamisligil, Gökhan S; Elias, Jack A; Cataltepe, Sule

    2013-04-01

    Neovascularization of the airways occurs in several inflammatory lung diseases, including asthma. Vascular endothelial growth factor (VEGF) plays an important role in vascular remodeling in the asthmatic airways. Fatty acid binding protein 4 (FABP4 or aP2) is an intracellular lipid chaperone that is induced by VEGF in endothelial cells. FABP4 exhibits a proangiogenic function in vitro, but whether it plays a role in modulation of angiogenesis in vivo is not known. We hypothesized that FABP4 promotes VEGF-induced airway angiogenesis and investigated this hypothesis with the use of a transgenic mouse model with inducible overexpression of VEGF165 under a CC10 promoter [VEGF-TG (transgenic) mice]. We found a significant increase in FABP4 mRNA levels and density of FABP4-expressing vascular endothelial cells in mouse airways with VEGF overexpression. FABP4(-/-) mouse airways showed a significant decrease in neovessel formation and endothelial cell proliferation in response to VEGF overexpression. These alterations in airway vasculature were accompanied by attenuated expression of proinflammatory mediators. Furthermore, VEGF-TG/FABP4(-/-) mice showed markedly decreased expression of endothelial nitric oxide synthase, a well-known mediator of VEGF-induced responses, compared with VEGF-TG mice. Finally, the density of FABP4-immunoreactive vessels in endobronchial biopsy specimens was significantly higher in patients with asthma than in control subjects. Taken together, these data unravel FABP4 as a potential target of pathologic airway remodeling in asthma. PMID:23391391

  5. Natural killer T cells are dispensable in the development of allergen-induced airway hyperresponsiveness, inflammation and remodelling in a mouse model of chronic asthma.

    PubMed

    Koh, Y-I; Shim, J-U; Lee, J-H; Chung, I-J; Min, J-J; Rhee, J H; Lee, H C; Chung, D H; Wi, J-O

    2010-07-01

    Natural killer T (NK T) cells have been shown to play an essential role in the development of allergen-induced airway hyperresponsiveness (AHR) and/or airway inflammation in mouse models of acute asthma. Recently, NK T cells have been reported to be required for the development of AHR in a virus induced chronic asthma model. We investigated whether NK T cells were required for the development of allergen-induced AHR, airway inflammation and airway remodelling in a mouse model of chronic asthma. CD1d-/- mice that lack NK T cells were used for the experiments. In the chronic model, AHR, eosinophilic inflammation, remodelling characteristics including mucus metaplasia, subepithelial fibrosis and increased mass of the airway smooth muscle, T helper type 2 (Th2) immune response and immunoglobulin (Ig)E production were equally increased in both CD1d-/- mice and wild-type mice. However, in the acute model, AHR, eosinophilic inflammation, Th2 immune response and IgE production were significantly decreased in the CD1d-/- mice compared to wild-type. CD1d-dependent NK T cells may not be required for the development of allergen-induced AHR, eosinophilic airway inflammation and airway remodelling in chronic asthma model, although they play a role in the development of AHR and eosinophilic inflammation in acute asthma model. PMID:20456411

  6. Rhinovirus-Induced Airway Disease: A Model to Understand the Antiviral and Th2 Epithelial Immune Dysregulation in Childhood Asthma

    PubMed Central

    Perez, Geovanny F.; Rodriguez-Martinez, Carlos E.; Nino, Gustavo

    2015-01-01

    Rhinovirus (RV) infections account for most asthma exacerbations among children and adults, yet the fundamental mechanism responsible for why asthmatics are more susceptible to RV than otherwise healthy individuals remains largely unknown. Nonetheless, the use of models to understand the mechanisms of RV-induced airway disease in asthma has dramatically expanded our knowledge about the cellular and molecular pathogenesis of the disease. For instance, ground-breaking studies have recently established that the susceptibility to RV in asthmatic subjects is associated with a dysfunctional airway epithelial inflammatory response generated after innate recognition of viral-related molecules, such as double stranded (ds) RNA. This review summarizes the novel cardinal features of the asthmatic condition identified in the past few years through translational and experimental RV-based approaches. Specifically, we discuss the evidence demonstrating the presence of an abnormal innate antiviral immunity (airway epithelial secretion of type I and III interferons), exaggerated production of the master Th2 molecule thymic stromal lymphopoietin (TSLP), and altered antimicrobial host defense in the airways of asthmatic individuals with acute RV infection. PMID:26057561

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

    PubMed

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

    2016-06-01

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

  8. Home dampness, childhood asthma, hay fever, and airway symptoms in Shanghai, China: associations, dose-response relationships, and lifestyle's influences.

    PubMed

    Hu, Y; Liu, W; Huang, C; Zou, Z J; Zhao, Z H; Shen, L; Sundell, J

    2014-10-01

    Numerous studies of associations between dampness and respiratory diseases have been conducted, but their implications remain inconclusive. In this study of 13,335 parent-reported questionnaires (response rate: 85.3%), we analyzed associations between home dampness and asthma and related symptoms in 4- to 6-year-old children in a cross-sectional study of Shanghai. Indicators of home dampness were strongly and significantly associated with dry cough, wheeze, and rhinitis symptoms. In the current residence, children with visible mold spots (VMS) exposure had 32% higher risk of asthma (adjusted OR, 95% CI: 1.32, 1.07-1.64); damp clothing and/or bedding (frequently) was strongly associated with dry cough (1.78, 1.37-2.30); condensation on windows was strongly associated with hay fever (1.60, 1.27-2.01). In the early-life residence, VMS or damp stains (frequently) were strongly associated with dry cough (2.20, 1.55-3.11) and rhinitis ever (1.57, 1.11-2.21). Associations between dampness and diseases among children with or without family history of atopy were similar. The total number of dampness indicators had strong dose-response relationships with investigated health outcomes. Actions, including opening windows of the child's room at night and cleaning the child's room frequently, could potentially mitigate 25% of home VMS, thereby preventing more than 1.5% of attributable risk of the studied symptoms. PMID:24571077

  9. TRP channels and temperature in airway disease—clinical significance

    PubMed Central

    Millqvist, Eva

    2015-01-01

    Temperatures above and below what is generally regarded as “comfortable” for the human being have long been known to induce various airway symptoms, especially in combination with exercise in cold climate with temperatures below 0°C, which is naturally since exercise is followed by enhanced ventilation and thus greater amounts of inhaled cold air. The aim was to highlight the knowledge we have today on symptoms from the airways (here also including the eyes) arisen from various temperatures; the mechanisms, the pathophysiology and their clinical significance. The most common eye and airway conditions related to temperature changes are dry eye disease, rhinitis, laryngeal dysfunction, asthma, chronic obstructive pulmonary disease and chronic cough. Transient receptor potential (TRP) ion channels are probably involved in all temperature induced airway symptoms but via different pathways, which are now beginning to be mapped out. In asthma, the most persuasive hypothesis today is that cold-induced asthmatic bronchoconstriction is induced by dehydration of the airway mucosa, from which it follows that provocations with osmotic stimuli like hypertonic saline and mannitol can be used as a surrogate for exercise provocation as well as dry air inhalation. In chronic unexplained cough there seems to be a direct influence of cold air on the TRP ion channels followed by coughing and increased cough sensitivity to inhaled capsaicin. Revelations in the last decades of the ability of several airway TRP ion channels to sense and react to ambient air temperature have opened new windows for the understanding of the pathogenesis in a diversity of airway reactions appearing in many common respiratory diseases. PMID:27227021

  10. TRP channels and temperature in airway disease-clinical significance.

    PubMed

    Millqvist, Eva

    2015-01-01

    Temperatures above and below what is generally regarded as "comfortable" for the human being have long been known to induce various airway symptoms, especially in combination with exercise in cold climate with temperatures below 0°C, which is naturally since exercise is followed by enhanced ventilation and thus greater amounts of inhaled cold air. The aim was to highlight the knowledge we have today on symptoms from the airways (here also including the eyes) arisen from various temperatures; the mechanisms, the pathophysiology and their clinical significance. The most common eye and airway conditions related to temperature changes are dry eye disease, rhinitis, laryngeal dysfunction, asthma, chronic obstructive pulmonary disease and chronic cough. Transient receptor potential (TRP) ion channels are probably involved in all temperature induced airway symptoms but via different pathways, which are now beginning to be mapped out. In asthma, the most persuasive hypothesis today is that cold-induced asthmatic bronchoconstriction is induced by dehydration of the airway mucosa, from which it follows that provocations with osmotic stimuli like hypertonic saline and mannitol can be used as a surrogate for exercise provocation as well as dry air inhalation. In chronic unexplained cough there seems to be a direct influence of cold air on the TRP ion channels followed by coughing and increased cough sensitivity to inhaled capsaicin. Revelations in the last decades of the ability of several airway TRP ion channels to sense and react to ambient air temperature have opened new windows for the understanding of the pathogenesis in a diversity of airway reactions appearing in many common respiratory diseases. PMID:27227021

  11. β2-Adrenoceptor involved in smoking-induced airway mucus hypersecretion through β-arrestin-dependent signaling.

    PubMed

    Zhou, Yujiao; Zhang, Yuan; Guo, Yang; Zhang, Youyi; Xu, Ming; He, Bei

    2014-01-01

    Progression of chronic obstructive pulmonary disease is associated with small airway obstruction by accumulation of inflammatory mucous exudates. However, the mechanism of mucin hypersecretion after exposure to cigarette smoke (CS) is still not clear. In this study, we explored the contribution of β2-adrenoceptor (β2-AR) signaling to CS extract (CSE)-induced mucus hypersecretion in vitro and examined the effect of a β-blocker on airway mucin hypersecretion in vivo. NCI-H292 epithelial cell line was used to determine the contribution of β2-AR signaling to CSE-induced MUC5AC production by treatment with β2-AR antagonists propranolol and ICI118551 and β2-AR-targeted small interfering RNA. The effect of propranolol on airway mucus hypersecretion was examined in a rat model exposed to CS. MUC5AC expression was assayed by real-time PCR, immunohistochemistry and ELISA. β2-AR and its downstream signaling were detected by western blot analysis. We found that pretreating NCI-H292 cells with propranolol, ICI118551 for 30 min or β2AR-targeted siRNA for 48 h reduced MUC5AC mRNA and protein levels stimulated by CSE. However,inhibiting the classical β2AR-cAMP-PKA pathway didn't attenuate CSE-induced MUC5AC production, while silencing β-arretin2 expression significantly decreased ERK and p38MAPK phosphorylation, thus reduced the CSE-stimulated MUC5AC production. In vivo, we found that administration of propranolol (25 mg kg(-1) d(-1)) for 28 days significantly attenuated the airway goblet cell metaplasia, mucus hypersecretion and MUC5AC expression of rats exposed to CS. From the study, β2-AR-β-arrestin2-ERK1/2 signaling was required for CS-induced airway MUC5AC expression. Chronic propranolol administration ameliorated airway mucus hypersecretion and MUC5AC expression in smoking rats. The exploration of these mechanisms may contribute to the optimization of β2-AR target therapy in chronic obstructive pulmonary disease. PMID:24905583

  12. Persistent rhinitis and epithelial remodeling induced by cyclic ozone exposure in the nasal airways of infant monkeys

    PubMed Central

    Ballinger, Carol A.; Plopper, Charles G.; McDonald, Ruth J.; Bartolucci, Alfred A.; Postlethwait, Edward M.; Harkema, Jack R.

    2011-01-01

    Children chronically exposed to high levels of ozone (O3), the principal oxidant pollutant in photochemical smog, are more vulnerable to respiratory illness and infections. The specific factors underlying this differential susceptibility are unknown but may be related to air pollutant-induced nasal alterations during postnatal development that impair the normal physiological functions (e.g., filtration and mucociliary clearance) serving to protect the more distal airways from inhaled xenobiotics. In adult animal models, chronic ozone exposure is associated with adaptations leading to a decrease in airway injury. The purpose of our study was to determine whether cyclic ozone exposure induces persistent morphological and biochemical effects on the developing nasal airways of infant monkeys early in life. Infant (180-day-old) rhesus macaques were exposed to 5 consecutive days of O3 [0.5 parts per million (ppm), 8 h/day; “1-cycle”] or filtered air (FA) or 11 biweekly cycles of O3 (FA days 1–9; 0.5 ppm, 8 h/day on days 10–14; “11-cycle”). The left nasal passage was processed for light microscopy and morphometric analysis. Mucosal samples from the right nasal passage were processed for GSH, GSSG, ascorbate (AH2), and uric acid (UA) concentration. Eleven-cycle O3 induced persistent rhinitis, squamous metaplasia, and epithelial hyperplasia in the anterior nasal airways of infant monkeys, resulting in a 39% increase in the numeric density of epithelial cells. Eleven-cycle O3 also induced a 65% increase in GSH concentrations at this site. The persistence of epithelial hyperplasia was positively correlated with changes in GSH. These results indicate that early life ozone exposure causes persistent nasal epithelial alterations in infant monkeys and provide a potential mechanism for the increased susceptibility to respiratory illness exhibited by children in polluted environments. PMID:21131400

  13. Persistent rhinitis and epithelial remodeling induced by cyclic ozone exposure in the nasal airways of infant monkeys.

    PubMed

    Carey, Stephan A; Ballinger, Carol A; Plopper, Charles G; McDonald, Ruth J; Bartolucci, Alfred A; Postlethwait, Edward M; Harkema, Jack R

    2011-02-01

    Children chronically exposed to high levels of ozone (O(3)), the principal oxidant pollutant in photochemical smog, are more vulnerable to respiratory illness and infections. The specific factors underlying this differential susceptibility are unknown but may be related to air pollutant-induced nasal alterations during postnatal development that impair the normal physiological functions (e.g., filtration and mucociliary clearance) serving to protect the more distal airways from inhaled xenobiotics. In adult animal models, chronic ozone exposure is associated with adaptations leading to a decrease in airway injury. The purpose of our study was to determine whether cyclic ozone exposure induces persistent morphological and biochemical effects on the developing nasal airways of infant monkeys early in life. Infant (180-day-old) rhesus macaques were exposed to 5 consecutive days of O(3) [0.5 parts per million (ppm), 8 h/day; "1-cycle"] or filtered air (FA) or 11 biweekly cycles of O(3) (FA days 1-9; 0.5 ppm, 8 h/day on days 10-14; "11-cycle"). The left nasal passage was processed for light microscopy and morphometric analysis. Mucosal samples from the right nasal passage were processed for GSH, GSSG, ascorbate (AH(2)), and uric acid (UA) concentration. Eleven-cycle O(3) induced persistent rhinitis, squamous metaplasia, and epithelial hyperplasia in the anterior nasal airways of infant monkeys, resulting in a 39% increase in the numeric density of epithelial cells. Eleven-cycle O(3) also induced a 65% increase in GSH concentrations at this site. The persistence of epithelial hyperplasia was positively correlated with changes in GSH. These results indicate that early life ozone exposure causes persistent nasal epithelial alterations in infant monkeys and provide a potential mechanism for the increased susceptibility to respiratory illness exhibited by children in polluted environments. PMID:21131400

  14. Airway epithelial cell PPARγ modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice.

    PubMed

    Solleti, Siva Kumar; Simon, Dawn M; Srisuma, Sorachai; Arikan, Meltem C; Bhattacharya, Soumyaroop; Rangasamy, Tirumalai; Bijli, Kaiser M; Rahman, Arshad; Crossno, Joseph T; Shapiro, Steven D; Mariani, Thomas J

    2015-08-01

    Chronic obstructive pulmonary disease (COPD) is a highly prevalent, chronic inflammatory lung disease with limited existing therapeutic options. While modulation of peroxisome proliferator-activating receptor (PPAR)-γ activity can modify inflammatory responses in several models of lung injury, the relevance of the PPARG pathway in COPD pathogenesis has not been previously explored. Mice lacking Pparg specifically in airway epithelial cells displayed increased susceptibility to chronic cigarette smoke (CS)-induced emphysema, with excessive macrophage accumulation associated with increased expression of chemokines, Ccl5, Cxcl10, and Cxcl15. Conversely, treatment of mice with a pharmacological PPARγ activator attenuated Cxcl10 and Cxcl15 expression and macrophage accumulation in response to CS. In vitro, CS increased lung epithelial cell chemokine expression in a PPARγ activation-dependent fashion. The ability of PPARγ to regulate CS-induced chemokine expression in vitro was not specifically associated with peroxisome proliferator response element (PPRE)-mediated transactivation activity but was correlated with PPARγ-mediated transrepression of NF-κB activity. Pharmacological or genetic activation of PPARγ activity abrogated CS-dependent induction of NF-κB activity. Regulation of NF-κB activity involved direct PPARγ-NF-κB interaction and PPARγ-mediated effects on IKK activation, IκBα degradation, and nuclear translocation of p65. Our data indicate that PPARG represents a disease-relevant pathophysiological and pharmacological target in COPD. Its activation state likely contributes to NF-κB-dependent, CS-induced chemokine-mediated regulation of inflammatory cell accumulation. PMID:26024894

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

    PubMed Central

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

    2014-01-01

    Several low weight molecules have often been implicated in the induction of occupational asthma. Glyphosate, a small molecule herbicide, is widely used in the world. There is a controversy regarding a role of glyphosate in developing asthma and rhinitis among farmers, the mechanism of which is unexplored. The aim of this study was to explore the mechanisms of glyphosate induced pulmonary pathology by utilizing murine models and real environmental samples. C57BL/6, TLR4−/−, and IL-13−/− mice inhaled extracts of glyphosate-rich air samples collected on farms during spraying of herbicides or inhaled different doses of glyphosate and ovalbumin. The cellular response, humoral response, and lung function of exposed mice were evaluated. Exposure to glyphosate-rich air samples as well as glyphosate alone to the lungs increased: eosinophil and neutrophil counts, mast cell degranulation, and production of IL-33, TSLP, IL-13, and IL-5. In contrast, in vivo systemic IL-4 production was not increased. Co-administration of ovalbumin with glyphosate did not substantially change the inflammatory immune response. However, IL-13-deficiency resulted in diminished inflammatory response but did not have a significant effect on airway resistance upon methacholine challenge after 7 or 21 days of glyphosate exposure. Glyphosate-rich farm air samples as well as glyphosate alone were found to induce pulmonary IL-13-dependent inflammation and promote Th2 type cytokines, but not IL-4 for glyphosate alone. This study, for the first time, provides evidence for the mechanism of glyphosate-induced occupational lung disease. PMID:25172162

  16. Obesity Increases Airway Hyperresponsiveness via the TNF-α Pathway and Treating Obesity Induces Recovery

    PubMed Central

    Kim, Joo Young; Sohn, Jung-Ho; Lee, Jae-Hyun; Park, Jung-Won

    2015-01-01

    Obesity is a known risk factor for allergic asthma. It has been recognized as a key player in the pathogenesis of several inflammatory disorders via activation of macrophages, which is also vital to the development of allergic asthma. We investigated the mechanism of obesity-related asthma and whether treating obesity through exercise or diet ameliorates the severity of asthma in the obesity-related asthma model. We generated diet-induced obesity (DIO) in C57BL/6 mice by high-fat-feeding and ovalbumin-induced asthma (lean-OVA or DIO-OVA). The DIO-OVA mice were then treated with tumor necrosis factor (TNF)-α neutralizing antibody as a TNF-α blockade or a Cl2MDP-containing liposome to induce an alveolar macrophage deficiency. To treat obesity, the DIO-OVA mice were under dietary restrictions or exercised. The pathophysiological and immunological responses were analyzed. Airway hyperresponsiveness (AHR), serum IgE and TNF-α levels in the lung tissue increased in the DIO-OVA mice compared to the lean-OVA mice. Both the TNF-α blockade and depletion of alveolar macrophages in the DIO-OVA mice decreased AHR compared to the DIO-OVA mice. Treating obesity by exercise or through dietary means also reduced pulmonary TNF-α levels and AHR in the DIO-OVA mice. These results suggest that restoring normal body weight is an appropriate strategy for reducing TNF-α levels, and controlling inflammation may help improve asthma severity and control in obesity-related asthma. PMID:25658739

  17. S-Nitrosoglutathione Reductase Inhibition Regulates Allergen-Induced Lung Inflammation and Airway Hyperreactivity

    PubMed Central

    Bassett, David J. P.; Bradley, Matthews O.; Jaffar, Zeina

    2013-01-01

    Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation. PMID:23936192

  18. 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.

  19. Allergen-induced airway remodeling is impaired in galectin-3 deficient mice1

    PubMed Central

    Ge, Xiao Na; Bahaie, Nooshin S.; Kang, Bit Na; Hosseinkhani, Reza M.; Ha, Sung Gil; Frenzel, Elizabeth M.; Liu, Fu-Tong; Rao, Savita P.; Sriramarao, P.

    2010-01-01

    The role played by the β-galactoside-binding lectin galectin-3 (Gal-3) in airway remodeling, a characteristic feature of asthma that leads to airway dysfunction and poor clinical outcome in humans, was investigated in a murine model of chronic allergic airway inflammation. Wild-type (WT) and Gal-3 knock-out (KO) mice were subjected to repetitive allergen challenge with ovalbumin (OVA) up to 12 weeks and bronchoalveolar lavage fluid (BALF) and lung tissue collected after the last challenge were evaluated for cellular features associated with airway remodeling. Compared to WT mice, chronic OVA challenge in Gal-3 KO mice resulted in diminished remodeling of the airways with significantly reduced mucus secretion, sub-epithelial fibrosis, smooth muscle thickness, and peribronchial angiogenesis. The higher degree of airway remodeling in WT mice was associated with higher Gal-3 expression in the BALF as well as lung tissue. Cell counts in BALF and lung immunohistology demonstrated that eosinophil infiltration in OVA-challenged Gal-3 KO mice was significantly reduced compared to WT mice. Evaluation of cellular mediators associated with eosinophil recruitment and airway remodeling revealed that levels of eotaxin-1, IL-5, IL-13, FIZZ1 and TGF-β were substantially lower in Gal-3 KO mice. Finally, leukocytes from Gal-3 KO mice demonstrated decreased trafficking (rolling) on vascular endothelial adhesion molecules compared to WT cells. Overall, these studies demonstrate that Gal-3 is an important lectin that promotes airway remodeling via airway recruitment of inflammatory cells, specifically eosinophils, and the development of a Th2 phenotype as well as increased expression of eosinophil-specific chemokines, pro-fibrogenic and angiogenic mediators. PMID:20543100

  20. Levofloxacin decreased chest wall mechanical inhomogeneities and airway and vascular remodeling in rats with induced hepatopulmonary syndrome.

    PubMed

    Gaio, Eduardo; Amado, Veronica; Rangel, Leonardo; Huang, Wilson; Storck, Rodrigo; Melo-Silva, César Augusto

    2013-12-01

    The administration of antibiotics decreases bacterial translocation, reduces the activity of nitric oxide synthase and improves the gas exchange of hepatopulmonary syndrome (HPS) in rats. We hypothesized that levofloxacin could reduce HPS-induced respiratory mechanical inhomogeneities and airway and pulmonary vascular remodeling. We assessed the respiratory mechanical properties and lung tissue structure in 24 rats assigned to the control, HPS (eHPS) and HPS+levofloxacin (eHPS+L) groups. The administration of levofloxacin reduced the HPS-induced chest wall but not the lung mechanical inhomogeneities. The eHPS airway proportion of elastic fibers increased 20% but was similar between the control and eHPS+L groups. The eHPS vascular collagen increased 25% in eHPS but was similar between the control and eHPS+L groups. Compared to the control group, the vascular proportion of elastic fibers of the eHPS and eHPS+L groups increased by 60% and 16%, respectively. The administration of levofloxacin decreased the HPS-induced chest wall mechanical inhomogeneities and airway and vascular remodeling. PMID:23994178

  1. Evidence of prednisolone induced mood change ('steroid euphoria') in patients with chronic obstructive airways disease.

    PubMed Central

    Swinburn, C R; Wakefield, J M; Newman, S P; Jones, P W

    1988-01-01

    1. It is a clinical impression that some patients given oral corticosteroids develop a sense of wellbeing that is 'inappropriate' to improvements in physical health. This has been termed steroid 'euphoria', but unlike steroid-induced psychosis it has not been documented. 2. To test for the size and frequency of this phenomenon, 20 patients with severe chronic obstructive airways disease (mean FEV1 0.86 l) were given 30 mg of prednisolone for 14 days, after a period of placebo administration in a single-blind study. 3. Lung spirometry and arterial saturation during exercise were measured serially, together with established measures of mood state. 4. No changes in spirometry or arterial saturation during exercise were detected until 7 days of active therapy. 5. Mood state did not change during the placebo period, but small significant reductions in anxiety and depression were measured after 3 days of prednisolone and before any measurable improvement in lung function. Mood state did not then further improve, despite measurable improvements in lung spirometry. 6. This is evidence that prednisolone may produce a mild 'inappropriate' sense of wellbeing within a population receiving the drug, rather than as an occasional idiosyncratic response. PMID:3242575

  2. 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

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

    PubMed

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

    2014-02-01

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

  4. 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. PMID:18160846

  5. THE SPONTANEOUSLY HYPERTENSIVE RAT: AN EXPERIMENTAL MODEL OF SULFUR DIOXIDE-INDUCED AIRWAYS DISEASE

    EPA Science Inventory

    Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction, inflammation and mucus hypersecretion; features that capture bronchitis, emphysema and often asthma. However, current rodent models do not reflect this human disease. Because genetically predisp...

  6. ROLE OF NEPRILYSIN IN AIRWAY INFLAMMATION INDUCED BY DIESEL EXHAUST EMISSIONS

    EPA Science Inventory

    The investigators intend to evaluate airway inflammatory responses and expression of the enzyme neprilysin in response to diesel exhaust particle exposure. Dr. Wong and colleagues anticipate that their research will reveal that components of diesel exhaust decrease neprilys...

  7. Copper Oxide Nanoparticles Induce Oxidative Stress and Cytotoxicity in Airway Epithelial Cells

    PubMed Central

    Fahmy, Baher; Cormier, Stephania A.

    2009-01-01

    Metal oxide nanoparticles are often used as industrial catalysts and elevated levels of these particles have been clearly demonstrated at sites surrounding factories. To date, limited toxicity data on metal oxide nanoparticles are available. To understand the impact of these airborne pollutants on the respiratory system, airway epithelial (HEp-2) cells were exposed to increasing doses of silicon oxide (SiO2), ferric oxide (Fe2O3) and copper oxide (CuO) nanoparticles, the leading metal oxides found in ambient air surrounding factories. CuO induced the greatest amount of cytotoxicity in a dose dependent manner; while even high doses (400 µg/cm2) of SiO2 and Fe2O3 were non-toxic to HEp-2 cells. Although all metal oxide nanoparticles were able to generate ROS in HEp-2 cells, CuO was better able to overwhelm antioxidant defenses (e.g. catalase and glutathione reductase). A significant increase in the level of 8-isoprostanes and in the ratio of GSSG to total glutathione in cells exposed to CuO suggested that ROS generated by CuO induced oxidative stress in HEp-2 cells. Co-treatment of cells with CuO and the antioxidant resveratrol increased cell viability suggesting that oxidative stress may be the cause of the cytotoxic effect of CuO. These studies demonstrated that there is a high degree of variability in the cytotoxic effects of metal oxides, that this variability is not due to the solubility of the transition metal, and that this variability appears to involve sustained oxidative stress possibly due to redox cycling. PMID:19699289

  8. Asian sand dust enhances ovalbumin-induced eosinophil recruitment in the alveoli and airway of mice

    SciTech Connect

    Hiyoshi, Kyoko; Ichinose, Takamichi; Sadakane, Kaori; Takano, Hirohisa; Nishikawa, Masataka; Mori, Ikuko; Yanagisawa, Rie; Yoshida, Seiichi; Kumagai, Yoshito; Tomura, Shigeo; Shibamoto, Takayuki . E-mail: tshibamoto@ucdavis.edu

    2005-11-15

    Asian sand dust (ASD) containing sulfate (SO{sub 4} {sup 2-}) reportedly causes adverse respiratory health effects but there is no experimental study showing the effect of ASD toward allergic respiratory diseases. The effects of ASD and ASD plus SO{sub 4} {sup 2-} toward allergic lung inflammation induced by ovalbumin (OVA) were investigated in this study. ICR mice were administered intratracheally with saline; ASD alone (sample from Shapotou desert); and ASD plus SO{sub 4} {sup 2-} (ASD-SO{sub 4}); OVA+ASD; OVA+ASD-SO{sub 4}. ASD or ASD-SO{sub 4} alone caused mild nutrophilic inflammation in the bronchi and alveoli. ASD and ASD-SO{sub 4} increased pro-inflammatory mediators, such as Keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-1 alpha, in bronchoalveolar lavage fluids (BALF). ASD and ASD-SO{sub 4} enhanced eosinophil recruitment induced by OVA in the alveoli and in the submucosa of the airway, which has a goblet cell proliferation in the bronchial epithelium. However, a further increase of eosinophils by addition of SO{sub 4} {sup 2-} was not observed. The two sand dusts synergistically increased interleukin-5 (IL-5) and monocyte chemotactic protein-1 (MCP-1), which were associated with OVA, in BALF. However, the increased levels of IL-5 were lower in the OVA+ASD-SO{sub 4} group than in the OVA+ASD group. ASD caused the adjuvant effects to specific-IgG1 production by OVA, but not to specific-IgE. These results suggest that the enhancement of eosinophil recruitment in the lung is mediated by synergistically increased IL-5 and MCP-1. IgG1 antibodies may play an important role in the enhancement of allergic reaction caused by OVA and sand dust. However, extra sulfate may not contribute to an increase of eosinophils.

  9. Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure.

    PubMed

    Zychowski, Katherine E; Lucas, Selita N; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J

    2016-08-15

    Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability. PMID:27286659

  10. A model of surfactant-induced surface tension effects on the parenchymal tethering of pulmonary airways.

    PubMed

    Fujioka, Hideki; Halpern, David; Gaver, Donald P

    2013-01-18

    We developed a computational model of lung parenchyma, which is comprised of individual alveolar chamber models. Each alveolus is modeled by a truncated octahedron. Considering the force balance between the elastin and collagen fibers laying on the alveolar membrane and the pressures acting on the membrane, we computed the deformations of the parenchyma with a finite element method. We focused on the effect of surfactant on the force of parenchymal tethering an airway. As the lung inflates, the parenchyma becomes stiffer and the tethering force becomes stronger. As the alveolar surfactant concentration is reduced, the lung volume at a fixed alveolar pressure decreases, and thus, the tethering force becomes weaker. The distortion of parenchyma caused by the deformation of an airway extends widely around the airway. The displacement of parenchyma decays with distance from the airway wall, but deviates from the prediction based on a theory for a continuum material. Using results obtained from the present lung parenchyma model, we also developed a simple 1-dimensional model for parenchyma tethering force on an airway, which could be utilized for the analysis of liquid/gas transports in an axis-symmetric elastic airway. The effective shear modulus was calculated from the pressure-volume relation of parenchyma. By manipulating the pressure-volume curve, this simple model may be used to predict the parenchyma tethering force in diseased lungs. PMID:23235110

  11. Adoptive transfer of allergen-specific CD4+ T cells induces airway inflammation and hyperresponsiveness in brown-Norway rats.

    PubMed

    Haczku, A; Macary, P; Huang, T J; Tsukagoshi, H; Barnes, P J; Kay, A B; Kemeny, D M; Chung, K F; Moqbel, R

    1997-06-01

    Following allergen exposure, sensitized Brown-Norway rats develop airway hyperresponsiveness (AHR) and eosinophilic inflammation together with an increase in activated T cells (CD25+) in the airways. We tested the hypothesis that CD4+ T cells are involved directly in the acquisition of AHR. Spleen T cells from animals that were injected intraperitoneally on three consecutive days with ovalbumin/Al(OH)3, showed a dose-dependent proliferative response in vitro to ovalbumin, but not to bovine serum albumin, as measured by [3H]thymidine uptake. For total T-cell transfer, spleen cells obtained from donor rats 4 days after sensitization were depleted of adherent cells by a nylon wool column separation. CD4+ and CD8+ T cells were purified by immunomagnetic beads cell separation. Recipient naive rats were injected intravenously with 50 x 10(6) total T cells, 20 x 10(6) and 5 x 10(6) CD4+ cells, and 5 x 10(6) CD8+ cells, and were exposed to ovalbumin aerosol 24 hr afterwards. After a further 24 hr, airway responsiveness to acetylcholine (ACh) was measured and provocative concentration (PC) values PC100, PC200 and PC300) (the ACh concentration needed to achieve 100, 200 and 300% increase in lung resistance above baseline) were calculated. Airway responsiveness was significantly increased in recipients of sensitized total T cells compared with recipients of cells from saline-injected donor rats (P < 0.05). There were significantly increased eosinophil major basic protein (MBP)+ cell counts/mm2 in airway submucosal tissue in the hyperreactive rats and a significant correlation was found between the number of MBP+ cells and PC100 (r = 0.75; P < 0.03) in recipients of sensitized total T cells. Purified CD4+ T cells from sensitized donors induced AHR in naive recipients (P < 0.05), while sensitized CD8+ and naive CD4+ cells failed to do so. Our data indicate that T cells may induce AHR through an eosinophilic airway inflammation and that CD4+ T cells may have a direct effect in

  12. Ozone-induced oxygen radical release from bronchoalveolar lavage cells and airway hyper-responsiveness in dogs.

    PubMed Central

    Stevens, W H; Conlon, P D; O'Byrne, P M

    1995-01-01

    1. Ozone inhalation causes airway hyper-responsiveness and airway inflammation in dogs. The purpose of this study was to determine whether these effects are associated with increases in oxygen radical production from bronchoalveolar lavage (BAL) cells. 2. Twelve randomly selected dogs were studied twice, 4 weeks apart. On each study day, acetylcholine (ACh) airway responsiveness was measured before and 1 h after ozone (3 p.p.m., 30 min) or dry air inhalation, followed by BAL. The response to ACh was expressed as the concentration causing an increase in lung resistance of 5 cmH2O l-1 s-1 above baseline. Spontaneous and phorbol myristate acetate (PMA) (2.4 mumol l-1)-stimulated oxygen radical release from washed BAL cells (4 x 10(6) cells ml-1) was measured by luminol-enhanced chemiluminescence in a luminometer at 37 degrees C. 3. Ozone inhalation caused airway hyper-responsiveness. The concentration of ACh causing an increase in lung resistance of 5 cmH2O l-1 s-1 (the 'provocative' concentration) fell from 4.68 mg ml-1 (% S.E.M., 1.43) before, to 0.48 mg ml-1 (% S.E.M., 1.60) after ozone (P < 0.0001). Spontaneous chemiluminescence area under the curve (AUC) significantly increased after ozone from 4.08 mV (10 min) (% S.E.M., 1.28) after dry air to 8.25 mV (10 min; % S.E.M., 1.29) after ozone (P = 0.007). Ozone inhalation also increased PMA-stimulated chemiluminescence AUC from 18.97 mV (10 min; % S.E.M., 1.18) after dry air to 144.03 mV (10 min; % S.E.M., 1.45) after ozone (P = 0.0001). The increase in PMA-stimulated chemiluminescence was significantly correlated with ozone-induced ACh airway hyper-responsiveness (r = 0.83, P < 0.001). 4. These results indicate that inhaled ozone increases oxygen radical release from BAL cells and suggest that oxygen radicals are important in causing ozone-induced airway hyper-responsiveness. PMID:7562641

  13. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE2

    PubMed Central

    Kim, Yun-Gi; Udayanga, Kankanam Gamage Sanath; Totsuka, Naoya; Weinberg, Jason B.; Núñez, Gabriel; Shibuya, Akira

    2014-01-01

    SUMMARY Although imbalances in gut microbiota composition, or “dysbiosis”, are associated with many diseases, the effects of gut dysbiosis on host systemic physiology are less well characterized. We report that gut dysbiosis induced by antibiotic (Abx)-treatment promotes allergic airway inflammation by shifting macrophage polarization in the lung toward the alternatively activated M2 phenotype. Adoptive transfer of alveolar macrophages derived from Abx-treated mice was sufficient to increase allergic airway inflammation. Abx-treatment resulted in the overgrowth of a commensal fungal Candida species in the gut and increased plasma concentrations of prostaglandin E2 (PGE2), which induced M2 macrophage polarization in the lung. Suppression of PGE2 synthesis by the cyclooxygenase inhibitors aspirin and celecoxib suppressed M2 macrophage polarization and decreased allergic airway inflammatory cell infiltration in Abx-treated mice. Thus, Abx-treatment can cause overgrowth of particular fungal species in the gut and promote M2 macrophage activation at distant sites to influence systemic responses including allergic inflammation. PMID:24439901

  14. Continuous Exposure to Low-Dose-Rate Gamma Irradiation Reduces Airway Inflammation in Ovalbumin-Induced Asthma.

    PubMed

    Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Seung Sook; Park, Sun Hoo; Lee, Hae June; Lee, Soong In; Lee, Chang Geun; Kim, Sung Dae; Jo, Wol Soon; Kim, Sung Ho; Shin, In Sik

    2015-01-01

    Although safe doses of radiation have been determined, concerns about the harmful effects of low-dose radiation persist. In particular, to date, few studies have investigated the correlation between low-dose radiation and disease development. Asthma is a common chronic inflammatory airway disease that is recognized as a major public health problem. In this study, we evaluated the effects of low-dose-rate chronic irradiation on allergic asthma in a murine model. Mice were sensitized and airway-challenged with ovalbumin (OVA) and were exposed to continuous low-dose-rate irradiation (0.554 or 1.818 mGy/h) for 24 days after initial sensitization. The effects of chronic radiation on proinflammatory cytokines and the activity of matrix metalloproteinase-9 (MMP-9) were investigated. Exposure to low-dose-rate chronic irradiation significantly decreased the number of inflammatory cells, methylcholine responsiveness (PenH value), and the levels of OVA-specific immunoglobulin E, interleukin (IL)-4, and IL-5. Furthermore, airway inflammation and the mucus production in lung tissue were attenuated and elevated MMP-9 expression and activity induced by OVA challenge were significantly suppressed. These results indicate that low-dose-rate chronic irradiation suppresses allergic asthma induced by OVA challenge and does not exert any adverse effects on asthma development. Our findings can potentially provide toxicological guidance for the safe use of radiation and relieve the general anxiety about exposure to low-dose radiation. PMID:26588845

  15. Continuous Exposure to Low-Dose-Rate Gamma Irradiation Reduces Airway Inflammation in Ovalbumin-Induced Asthma

    PubMed Central

    Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Seung Sook; Park, Sun Hoo; Lee, Hae June; Lee, Soong In; Lee, Chang Geun; Kim, Sung Dae; Jo, Wol Soon; Kim, Sung Ho; Shin, In Sik

    2015-01-01

    Although safe doses of radiation have been determined, concerns about the harmful effects of low-dose radiation persist. In particular, to date, few studies have investigated the correlation between low-dose radiation and disease development. Asthma is a common chronic inflammatory airway disease that is recognized as a major public health problem. In this study, we evaluated the effects of low-dose-rate chronic irradiation on allergic asthma in a murine model. Mice were sensitized and airway-challenged with ovalbumin (OVA) and were exposed to continuous low-dose-rate irradiation (0.554 or 1.818 mGy/h) for 24 days after initial sensitization. The effects of chronic radiation on proinflammatory cytokines and the activity of matrix metalloproteinase-9 (MMP-9) were investigated. Exposure to low-dose-rate chronic irradiation significantly decreased the number of inflammatory cells, methylcholine responsiveness (PenH value), and the levels of OVA-specific immunoglobulin E, interleukin (IL)-4, and IL-5. Furthermore, airway inflammation and the mucus production in lung tissue were attenuated and elevated MMP-9 expression and activity induced by OVA challenge were significantly suppressed. These results indicate that low-dose-rate chronic irradiation suppresses allergic asthma induced by OVA challenge and does not exert any adverse effects on asthma development. Our findings can potentially provide toxicological guidance for the safe use of radiation and relieve the general anxiety about exposure to low-dose radiation. PMID:26588845

  16. Methacholine-Induced Variations in Airway Volume and the Slope of the Alveolar Capnogram Are Distinctly Associated with Airflow Limitation and Airway Closure

    PubMed Central

    Plantier, Laurent; Marchand-Adam, Sylvain; Boyer, Laurent; Taillé, Camille; Delclaux, Christophe

    2015-01-01

    Mechanisms driving alteration of lung function in response to inhalation of a methacholine aerosol are incompletely understood. To explore to what extent large and small airways contribute to airflow limitation and airway closure in this context, volumetric capnography was performed before (n = 93) and after (n = 78) methacholine provocation in subjects with an intermediate clinical probability of asthma. Anatomical dead space (VDaw), reflecting large airway volume, and the slope of the alveolar capnogram (slope3), an index of ventilation heterogeneity linked to small airway dysfunction, were determined. At baseline, VDaw was positively correlated with lung volumes, FEV1 and peak expiratory flow, while slope3 was not correlated with any lung function index. Variations in VDaw and slope3 following methacholine stimulation were correlated to a small degree (R2 = -0.20). Multivariate regression analysis identified independent associations between variation in FEV1 and variations in both VDaw (Standardized Coefficient-SC = 0.66) and Slope3 (SC = 0.35). By contrast, variation in FVC was strongly associated with variations in VDaw (SC = 0.8) but not Slope3. Thus, alterations in the geometry and/or function of large and small airways were weakly correlated and contributed distinctly to airflow limitation. While both large and small airways contributed to airflow limitation as assessed by FEV1, airway closure as assessed by FVC reduction mostly involved the large airways. PMID:26599006

  17. Methacholine-Induced Variations in Airway Volume and the Slope of the Alveolar Capnogram Are Distinctly Associated with Airflow Limitation and Airway Closure.

    PubMed

    Plantier, Laurent; Marchand-Adam, Sylvain; Boyer, Laurent; Taillé, Camille; Delclaux, Christophe

    2015-01-01

    Mechanisms driving alteration of lung function in response to inhalation of a methacholine aerosol are incompletely understood. To explore to what extent large and small airways contribute to airflow limitation and airway closure in this context, volumetric capnography was performed before (n = 93) and after (n = 78) methacholine provocation in subjects with an intermediate clinical probability of asthma. Anatomical dead space (VDaw), reflecting large airway volume, and the slope of the alveolar capnogram (slope3), an index of ventilation heterogeneity linked to small airway dysfunction, were determined. At baseline, VDaw was positively correlated with lung volumes, FEV1 and peak expiratory flow, while slope3 was not correlated with any lung function index. Variations in VDaw and slope3 following methacholine stimulation were correlated to a small degree (R2 = -0.20). Multivariate regression analysis identified independent associations between variation in FEV1 and variations in both VDaw (Standardized Coefficient-SC = 0.66) and Slope3 (SC = 0.35). By contrast, variation in FVC was strongly associated with variations in VDaw (SC = 0.8) but not Slope3. Thus, alterations in the geometry and/or function of large and small airways were weakly correlated and contributed distinctly to airflow limitation. While both large and small airways contributed to airflow limitation as assessed by FEV1, airway closure as assessed by FVC reduction mostly involved the large airways. PMID:26599006

  18. Zinc deficiency induces depression-like symptoms in adult rats.

    PubMed

    Tassabehji, Nadine M; Corniola, Rikki S; Alshingiti, Almamoun; Levenson, Cathy W

    2008-10-20

    There is mounting evidence suggesting a link between serum zinc levels and clinical depression. Not only is serum zinc negatively correlated with the severity of symptoms, but zinc levels appear to be lowest in patients who do not respond to antidepressant drug therapy. It is not known if reduced zinc levels are contributing to depression, or the result of dietary or other factors associated with major depression. Thus, we designed this study to test the hypothesis that dietary zinc deficiency would induce depression-like behaviors in rats. Two-month-old male rats were fed zinc adequate (ZA, 30 ppm), deficient (ZD, 1 ppm), or supplemented (ZS, 180 ppm) diets for 3 weeks. Consistent with the development of depression, ZD rats displayed anorexia (p<0.001), anhedonia (reduced saccharin:water intake, p< 0.001), and increased anxiety-like behaviors in a light-dark box test (p<0.05). Furthermore, the antidepressant drug fluoxetine (10 mg/kg body wt) reduced behavioral despair, as measured by the forced swim test, in rats fed the ZA and ZS rats (p<0.05), but was ineffective in ZD rats. Together these studies suggest that zinc deficiency leads to the development of depression-like behaviors that may be refractory to antidepressant treatment. PMID:18655800

  19. Tachykinin NK(3) receptor agonists induced microvascular leakage hypersensitivity in the guinea-pig airways.

    PubMed

    Daoui, S; Ahnaou, A; Naline, E; Emonds-Alt, X; Lagente, V; Advenier, C

    2001-12-21

    Microvascular leakage hypersensitivity is a main component of neurogenic inflammation and of tachykinin effects. The aim of this study was to examine the ability of neurokinin B and of the tachykinin NK(3) receptor agonists, [MePhe(7)]neurokinin B or senktide, to potentiate when given by aerosol the microvascular leakage induced by histamine in guinea-pig airways and to compare their effects to those of tachykinin NK(1) (substance P, [Sar(9),Met(O(2))(11)]substance P) or tachykinin NK(2) (neurokinin A, [betaAla(8)]neurokinin A (4-10)) receptor agonists. Guinea-pigs were pretreated successively for 10 min with aerolized salbutamol and phosphoramidon; 15 min later, they were exposed for 30 min to an aerosolized solution of tachykinin receptor agonists; 24 h later, the animals were anaesthetized and vascular permeability was quantified by extravasation of Evans blue dye. Neurokinin B, [MePhe(7)]neurokinin B and senktide (3 x 10(-6)-3 x 10(-5)M) induced a potentiation of the effects of histamine on the vascular permeability in the trachea and main bronchi. Compared to other tachykinin NK(1) and NK(2) receptor agonists, the order of potency was: senktide>neurokinin B=[Sar(9),Met(O(2))(11)]substance P=[betaAla(8)]neurokinin A (4-10)=[MePhe(7)]neurokinin B>neurokinin A>substance P. The potentiation by [MePhe(7)]neurokinin B of histamine-induced microvascular leakage was abolished by the tachykinin NK(1) receptor antagonist SR140333 ([(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidin-3-yl]etyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane, chloride]) or the tachykinin NK(3) receptor antagonists SR 142801 ([(R)-(N)-(1-(3-(l-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide]) and SB 223412 ([(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide]). In conclusion, these results suggest that tachykinin NK(3) receptors might be involved in the potentiation of histamine-induced increase in microvascular

  20. Protective effects of anisodamine on cigarette smoke extract-induced airway smooth muscle cell proliferation and tracheal contractility

    SciTech Connect

    Xu, Guang-Ni; Yang, Kai; Xu, Zu-Peng; Zhu, Liang; Hou, Li-Na; Qi, Hong; Chen, Hong-Zhuan Cui, Yong-Yao

    2012-07-01

    Anisodamine, an antagonist of muscarinic acetylcholine receptors (mAChRs), has been used therapeutically to improve smooth muscle function, including microvascular, intestinal and airway spasms. Our previous studies have revealed that airway hyper-reactivity could be prevented by anisodamine. However, whether anisodamine prevents smoking-induced airway smooth muscle (ASM) cell proliferation remained unclear. In this study, a primary culture of rat ASM cells was used to evaluate an ASM phenotype through the ability of the cells to proliferate and express contractile proteins in response to cigarette smoke extract (CSE) and intervention of anisodamine. Our results showed that CSE resulted in an increase in cyclin D1 expression concomitant with the G0/G1-to-S phase transition, and high expression of M2 and M3. Functional studies showed that tracheal hyper-contractility accompanied contractile marker α-SMA high-expression. These changes, which occur only after CSE stimulation, were prevented and reversed by anisodamine, and CSE-induced cyclin D1 expression was significantly inhibited by anisodamine and the specific inhibitor U0126, BAY11-7082 and LY294002. Thus, we concluded that the protective and reversal effects and mechanism of anisodamine on CSE-induced events might involve, at least partially, the ERK, Akt and NF-κB signaling pathways associated with cyclin D1 via mAChRs. Our study validated that anisodamine intervention on ASM cells may contribute to anti-remodeling properties other than bronchodilation. -- Highlights: ► CSE induces tracheal cell proliferation, hyper-contractility and α-SMA expression. ► Anisodamine reverses CSE-induced tracheal hyper-contractility and cell proliferation. ► ERK, PI3K, and NF-κB pathways and cyclin D1 contribute to the reversal effect.

  1. Putting the Squeeze on Airway Epithelia.

    PubMed

    Park, Jin-Ah; Fredberg, Jeffrey J; Drazen, Jeffrey M

    2015-07-01

    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

  2. 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

  3. Anti-Inflammatory Effects of Levalbuterol-Induced 11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Airway Epithelial Cells

    PubMed Central

    Randall, Matthew J.; Kostin, Shannon F.; Burgess, Edward J.; Hoyt, Laura R.; Ather, Jennifer L.; Lundblad, Lennart K.; Poynter, Matthew E.

    2015-01-01

    Airway epithelial NF-κB activation is observed in asthmatic subjects and is a cause of airway inflammation in mouse models of allergic asthma. Combination therapy with inhaled short-acting β2-agonists and corticosteroids significantly improves lung function and reduces inflammation in asthmatic subjects. Corticosteroids operate through a number of mechanisms to potently inhibit NF-κB activity. Since β2-agonists can induce expression of 11β-HSD1, which converts inactive 11-keto corticosteroids into active 11-hydroxy corticosteroids, thereby potentiating the effects of endogenous glucocorticoids, we examined whether this mechanism is involved in the inhibition of NF-κB activation induced by the β-agonist albuterol in airway epithelial cells. Treatment of transformed murine Club cells (MTCC) with (R)-albuterol (levalbuterol), but not with (S)- or a mixture of (R + S)- (racemic) albuterol, augmented mRNA expression of 11β-HSD1. MTCC were stably transfected with luciferase (luc) reporter constructs under transcriptional regulation by NF-κB (NF-κB/luc) or glucocorticoid response element (GRE/luc) consensus motifs. Stimulation of NF-κB/luc MTCC with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNFα) induced luc activity, which was inhibited by pretreatment with (R)-, but not (S)- or racemic albuterol. Furthermore, pretreatment of GRE/luc MTCC with (R)-, but not with (S)- or racemic albuterol, augmented 11-keto corticosteroid (cortisone) induced luc activity, which was diminished by the 11β-HSD inhibitor glycyrrhetinic acid (18β-GA), indicating that there was a conversion of inactive 11-keto to active 11-hydroxy corticosteroids. LPS- and TNFα-induced NF-κB/luc activity was diminished in MTCC cells treated with a combination of cortisone and (R)-albuterol, an effect that was inhibited by 18β-GA. Finally, pretreatment of MTCC cells with the combination of cortisone and (R)-albuterol diminished LPS- and TNFα-induced pro-inflammatory cytokine

  4. Anti-inflammatory effects of levalbuterol-induced 11β-hydroxysteroid dehydrogenase type 1 activity in airway epithelial cells.

    PubMed

    Randall, Matthew J; Kostin, Shannon F; Burgess, Edward J; Hoyt, Laura R; Ather, Jennifer L; Lundblad, Lennart K; Poynter, Matthew E

    2014-01-01

    Airway epithelial NF-κB activation is observed in asthmatic subjects and is a cause of airway inflammation in mouse models of allergic asthma. Combination therapy with inhaled short-acting β2-agonists and corticosteroids significantly improves lung function and reduces inflammation in asthmatic subjects. Corticosteroids operate through a number of mechanisms to potently inhibit NF-κB activity. Since β2-agonists can induce expression of 11β-HSD1, which converts inactive 11-keto corticosteroids into active 11-hydroxy corticosteroids, thereby potentiating the effects of endogenous glucocorticoids, we examined whether this mechanism is involved in the inhibition of NF-κB activation induced by the β-agonist albuterol in airway epithelial cells. Treatment of transformed murine Club cells (MTCC) with (R)-albuterol (levalbuterol), but not with (S)- or a mixture of (R + S)- (racemic) albuterol, augmented mRNA expression of 11β-HSD1. MTCC were stably transfected with luciferase (luc) reporter constructs under transcriptional regulation by NF-κB (NF-κB/luc) or glucocorticoid response element (GRE/luc) consensus motifs. Stimulation of NF-κB/luc MTCC with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNFα) induced luc activity, which was inhibited by pretreatment with (R)-, but not (S)- or racemic albuterol. Furthermore, pretreatment of GRE/luc MTCC with (R)-, but not with (S)- or racemic albuterol, augmented 11-keto corticosteroid (cortisone) induced luc activity, which was diminished by the 11β-HSD inhibitor glycyrrhetinic acid (18β-GA), indicating that there was a conversion of inactive 11-keto to active 11-hydroxy corticosteroids. LPS- and TNFα-induced NF-κB/luc activity was diminished in MTCC cells treated with a combination of cortisone and (R)-albuterol, an effect that was inhibited by 18β-GA. Finally, pretreatment of MTCC cells with the combination of cortisone and (R)-albuterol diminished LPS- and TNFα-induced pro-inflammatory cytokine

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

    PubMed

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

    2013-12-01

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

  6. Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response

    PubMed Central

    Legendre, Claire; Reen, F. Jerry; Woods, David F.; Mooij, Marlies J.; Adams, Claire

    2014-01-01

    Gastroesophageal reflux (GER) frequently occurs in patients with respiratory disease and is particularly prevalent in patients with cystic fibrosis. GER is a condition in which the duodenogastric contents of the stomach leak into the esophagus, in many cases resulting in aspiration into the respiratory tract. As such, the presence of GER-derived bile acids (BAs) has been confirmed in the bronchoalveolar lavage fluid and sputum of affected patients. We have recently shown that bile causes cystic fibrosis-associated bacterial pathogens to adopt a chronic lifestyle and may constitute a major host trigger underlying respiratory infection. The current study shows that BAs elicit a specific response in humans in which they repress hypoxia-inducible factor 1α (HIF-1α) protein, an emerging master regulator in response to infection and inflammation. HIF-1α repression was shown to occur through the 26S proteasome machinery via the prolyl hydroxylase domain (PHD) pathway. Further analysis of the downstream inflammatory response showed that HIF-1α repression by BAs can significantly modulate the immune response of airway epithelial cells, correlating with a decrease in interleukin-8 (IL-8) production, while IL-6 production was strongly increased. Importantly, the effects of BAs on cytokine production can also be more dominant than the bacterium-mediated effects. However, the effect of BAs on cytokine levels cannot be fully explained by their ability to repress HIF-1α, which is not surprising, given the complexity of the immune regulatory network. The suppression of HIF-1 signaling by bile acids may have a significant influence on the progression and outcome of respiratory disease, and the molecular mechanism underpinning this response warrants further investigation. PMID:24914220

  7. Reactive oxygen species induce a Ca(2+)-spark increase in sensitized murine airway smooth muscle cells.

    PubMed

    Tuo, Qing-Rong; Ma, Yun-Fei; Chen, Weiwei; Luo, Xiao-Jing; Shen, Jinhua; Guo, Donglin; Zheng, Yun-Min; Wang, Yong-Xiao; Ji, Guangju; Liu, Qing-Hua

    2013-05-10

    The level of reactive oxygen species (ROS) and the activity of spontaneous, transient, localized Ca(2+) increases (known as Ca(2+) sparks) in tracheal smooth muscle cells (TSMCs) in an experimental allergic asthma mouse model has not yet been investigated. We used laser confocal microscopy and fluorescent dyes to measure ROS levels and Ca(2+) sparks, and we found that both events were significantly increased in TSMCs obtained from ovalbumin (OVA)-sensitized/-challenged mice compared with control mice. ROS levels began to increase in TSMCs after the first OVA challenge, and this increase was sustained. However, this elevation and Ca(2+)-spark increase was abolished after the administration of the ROS scavenger N-acetylcysteine amide (NACA) for 5days. Furthermore, a similar inhibition was also observed following the direct perfusion of NACA into cells isolated from the (OVA)-sensitized mice that were not treated with NACA. Moreover, we used 0.1-mM caffeine treatment to increase the Ca(2+) sparks in single TSMCs and observed cell shortening. In addition, we did not find increases in the mRNA levels of ryanodine (RyRs) and inositol 1,4,5-trisphosphate (IP3Rs) receptors in the tracheal smooth muscle cells of (OVA)-sensitized mice compared with controls. We concluded that ROS and Ca(2+) sparks increased in (OVA)-sensitized TSMCs. We found that ROS induces Ca(2+) sparks, and increased Ca(2+) sparks resulted in the contraction of (OVA)-sensitized TSMCs, resulting in the generation of airway hyperresponsiveness (AHR). This effect may represent a novel mechanism for AHR pathogenesis and might provide insight into new methods for the clinical prevention and treatment of asthma and asthmatic AHR. PMID:23583396

  8. Comprehensive evaluation of poly(I:C) induced inflammatory response in an airway epithelial model

    PubMed Central

    Lever, Amanda R; Park, Hyoungshin; Mulhern, Thomas J; Jackson, George R; Comolli, James C; Borenstein, Jeffrey T; Hayden, Patrick J; Prantil-Baun, Rachelle

    2015-01-01

    Respiratory viruses invade the upper airway of the lung, triggering a potent immune response that often exacerbates preexisting conditions such as asthma and COPD. Poly(I:C) is a synthetic analog of viral dsRNA that induces the characteristic inflammatory response associated with viral infection, such as loss of epithelial integrity, and increased production of mucus and inflammatory cytokines. Here, we explore the mechanistic responses to poly(I:C) in a well-defined primary normal human bronchial epithelial (NHBE) model that recapitulates in vivo functions and responses. We developed functional and quantifiable methods to evaluate the physiology of our model in both healthy and inflamed states. Through gene and protein expression, we validated the differentiation state and population of essential cell subtypes (i.e., ciliated, goblet, club, and basal cells) as compared to the human lung. Assays for total mucus production, cytokine secretion, and barrier function were used to evaluate in vitro physiology and response to viral insult. Cells were treated apically with poly(I:C) and evaluated 48 h after induction. Results revealed a dose-dependent increase in goblet cell differentiation, as well as, an increase in mucus production relative to controls. There was also a dose-dependent increase in secretion of IL-6, IL-8, TNF-α, and RANTES. Epithelial barrier function, as measured by TEER, was maintained at 1501 ± 355 Ω*cm² postdifferentiation, but dropped significantly when challenged with poly(I:C). This study provides first steps toward a well-characterized model with defined functional methods for understanding dsRNA stimulated inflammatory responses in a physiologically relevant manner. PMID:25847914

  9. Cold-inducible RNA binding protein regulates mucin expression induced by cold temperatures in human airway epithelial cells.

    PubMed

    Ran, DanHua; Chen, LingXiu; Xie, WenYue; Xu, Qing; Han, Zhong; Huang, HuaPing; Zhou, XiangDong

    2016-08-01

    Mucus overproduction is an important manifestation of chronic airway inflammatory diseases, however, the mechanisms underlying the association between cold air and mucus overproduction remain unknown. We found that the expression of the cold-inducible RNA binding protein (CIRP) was increased in patients with chronic obstructive pulmonary disease (COPD). In the present study, we tested whether CIRP was involved in inflammatory factors and mucin5AC (MUC5AC) expression after cold stimulation and investigated the potential signaling pathways involved in this process. We found that CIRP was highly expressed in the bronchi of COPD patients. The expression of CIRP, interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) were increased, and the CIRP was localized in cytoplasm after cold stimulation. MUC5AC mRNA and protein expression levels were elevated in a temperature- and time-dependent manner after cold stimulation and were associated with the phosphorylation of ERK and NF-κB, which reflected their activation. These responses were suppressed by knockdown of CIRP with a specific siRNA or the ERK and NF-κB inhibitors. These results demonstrated that CIRP was expressed in the bronchi of human COPD patients and was involved in inflammatory factors and MUC5AC expression after cold stimulation through the ERK and NF-κB pathways. PMID:27184164

  10. Mechanisms of surface-tension-induced epithelial cell damage in a model of pulmonary airway reopening.

    PubMed

    Bilek, Anastacia M; Dee, Kay C; Gaver, Donald P

    2003-02-01

    Airway collapse and reopening due to mechanical ventilation exerts mechanical stress on airway walls and injures surfactant-compromised lungs. The reopening of a collapsed airway was modeled experimentally and computationally by the progression of a semi-infinite bubble in a narrow fluid-occluded channel. The extent of injury caused by bubble progression to pulmonary epithelial cells lining the channel was evaluated. Counterintuitively, cell damage increased with decreasing opening velocity. The presence of pulmonary surfactant, Infasurf, completely abated the injury. These results support the hypotheses that mechanical stresses associated with airway reopening injure pulmonary epithelial cells and that pulmonary surfactant protects the epithelium from this injury. Computational simulations identified the magnitudes of components of the stress cycle associated with airway reopening (shear stress, pressure, shear stress gradient, or pressure gradient) that may be injurious to the epithelial cells. By comparing these magnitudes to the observed damage, we conclude that the steep pressure gradient near the bubble front was the most likely cause of the observed cellular damage. PMID:12433851

  11. Symptoms induced by environmental irritants and health-related quality of life in patients with chronic cough - A cross-sectional study

    PubMed Central

    2011-01-01

    Background Chronic cough is a common condition, but some patients have no evident medical explanation for their symptoms. A group of patients has been identified, characterized by upper and lower airway symptoms triggered by chemicals and scents, and heightened cough sensitivity to inhaled capsaicin. Chronic cough is usually a prominent symptom in these patients, and it has been suggested that they suffer from sensory hyperreactivity. Our main aim was to analyse, in a group of patients with chronic cough, the presence of symptoms induced by environmental factors such as chemicals, scents, and cold air, and to measure the social and emotional influences of these symptoms in relation to quality of life. A second aim was to pilot-test a Swedish translation of a cough-specific questionnaire. Methods A total of 119 patients with chronic cough were asked to answer three different questionnaires: a local symptom questionnaire, the Chemical Sensitivity Scale for Sensory Hyperreactivity (CSS-SHR), and the Nottingham Health Profile (NHP). In addition, a Swedish version of the Hull Airway Reflux Questionnaire (HARQ) was developed and answered by a subgroup of patients and healthy controls. Results Sixty-two patients (52%) with mean cough duration of 10.6 years answered the local symptom questionnaire, the CSS-SHR, and the NHP. Of these, 39 (63%) claimed to have cough and other symptoms induced by chemicals and scents. Compared to population-based findings, the patients scored higher on the CSS-SHR, and the CSS-SHR score was significantly higher among chemical-sensitive individuals (p < 0.001). The NHP showed that the patients had a significantly reduced quality of life, which was most pronounced among chemical-sensitive individuals. The 31 patients who answered the HARQ had significantly higher scores (p < 0.0001) than 59 healthy controls. Conclusions Among patients with chronic cough, a majority claimed that environmental factors induced coughing. Both the CSS-SHR and the

  12. Myeloid Differentiation Factor 88–Dependent Signaling Is Critical for Acute Organic Dust–Induced Airway Inflammation in Mice

    PubMed Central

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

    2013-01-01

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

  13. Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations.

    PubMed

    Pardo-Saganta, Ana; Law, Brandon M; Tata, Purushothama Rao; Villoria, Jorge; Saez, Borja; Mou, Hongmei; Zhao, Rui; Rajagopal, Jayaraj

    2015-02-01

    Following injury, stem cells restore normal tissue architecture by producing the proper number and proportions of differentiated cells. Current models of airway epithelial regeneration propose that distinct cytokeratin 8-expressing progenitor cells, arising from p63(+) basal stem cells, subsequently differentiate into secretory and ciliated cell lineages. We now show that immediately following injury, discrete subpopulations of p63(+) airway basal stem/progenitor cells themselves express Notch pathway components associated with either secretory or ciliated cell fate commitment. One basal cell population displays intracellular Notch2 activation and directly generates secretory cells; the other expresses c-myb and directly yields ciliated cells. Furthermore, disrupting Notch ligand activity within the basal cell population at large disrupts the normal pattern of lineage segregation. These non-cell-autonomous effects demonstrate that effective airway epithelial regeneration requires intercellular communication within the broader basal stem/progenitor cell population. These findings have broad implications for understanding epithelial regeneration and stem cell heterogeneity. PMID:25658372

  14. House dust mite allergen induces asthma via TLR4 triggering of airway structural cells

    PubMed Central

    HAMMAD, Hamida; CHIEPPA, Marcello; PERROS, Frederic; WILLART, Monique A.; GERMAIN, Ronald N.; LAMBRECHT, Bart N.

    2009-01-01

    Barrier epithelial cells and airway dendritic cells (DC) make up the first line of defence against inhaled substances like house dust mite (HDM) allergen and endotoxin. We hypothesized that these cells need to communicate to cause allergic disease. Using irradiated chimeric mice, we demonstrate that TLR4 expression on radioresistant lung structural cells is required and sufficient for DC activation in the lung and for priming of effector T helper responses to HDM. TLR4 triggering on structural cells caused production of the innate proallergic cytokines thymic stromal lymphopoietin, granulocyte-macrophage colony stimulating factor, interleukin-25 and IL-33. The absence of TLR4 on structural cells, but not on hematopoietic cells, abolished HDM driven allergic airway inflammation. Finally, inhalation of a TLR4 antagonist to target exposed epithelial cells suppressed the salient features of asthma including bronchial hyperreactivity. Our data identify an innate immune function of airway epithelial cells that drives allergic inflammation via activation of mucosal DCs. PMID:19330007

  15. Videomicroscopy of methacholine-induced contraction of individual airways in precision-cut lung slices.

    PubMed

    Martin, C; Uhlig, S; Ullrich, V

    1996-12-01

    Contraction of airways of different size can be studied in viable lung slices by videomicroscopy. However, at present, application of this technique is limited by the heterogeneous responses obtained. We investigated the use of precision-cut lung slices to examine contraction of individual airways. Lung slices of 250 +/- 20 microns were prepared from Wistar rats and cultured in a roller incubator in serum-free minimum essential medium (MEM). Under these conditions, the slices were viable for at least 70 h, as indicated by leakage of lactate dehydrogenase into the supernatant, thymidine incorporation and ciliary beating. The slices were placed in a newly developed incubation chamber and mounted by a nylon thread that was fixed to a platinum wire. The whole chamber was positioned on a microscope stage, and contraction of single airways was followed under a microscope that was coupled to a CCD-camera. Reduction in airway area was taken as an index of bronchoconstriction and was determined by a computer program. Addition of methacholine resulted in a concentration-dependent (concentration producing half the maximal effect (EC50) = 0.64 +/- 0.08 (mean +/- SD) microM; n = 64) contraction of single airways. In the presence of hydrocortisone, the EC50 was about six times greater, i.e. 3.7 +/- 0.9 microM (n = 7), and the effect of the steroid was largely abolished by propanolol (EC50 = 1.1 +/- 0.1 microM; n = 7). Airways with an area smaller than 35,000 microns2 were nearly nine times more sensitive to methacholine (EC50 = 0.1 +/- 0.03 microM; n = 20) than larger ones (EC50 = 87 +/- 0.27 microM; n = 22). We conclude that cultured precision-cut lung slices are a useful model for routine study of contraction of individual airways of various sizes. The measurements were precise and reproducible and showed that smaller airways are more sensitive to methacholine than larger ones. PMID:8980957

  16. Virus-induced airway hyperresponsiveness in the guinea-pig: possible involvement of histamine and inflammatory cells.

    PubMed Central

    Folkerts, G.; De Clerck, F.; Reijnart, I.; Span, P.; Nijkamp, F. P.

    1993-01-01

    1. Guinea-pig tracheal contractions by histamine and by the cholinoceptor agonist, arecoline, are significantly enhanced (30% and 20%, respectively), 96 h after intra-tracheal inoculation with Parainfluenza-3 (PI-3) virus. 2. The airway hyperresponsiveness in animals inoculated with virus coincides with a significant increase in the number of broncho-alveolar cells (82%), and in the albumin concentration (121%) in lung lavage fluid, relative to values obtained in guinea-pigs challenged with control solution. 3. The chemiluminescence production by isolated broncho-alveolar cells, obtained from virus-infected guinea-pigs 96 h after inoculation stimulated with PI-3 virus in vitro, is significantly reduced by 42% relative to broncho-alveolar cells obtained from animals inoculated with control solution. This diminution was not specific for stimulation by PI-3 virus since the chemiluminescence production was also significantly reduced by 30% in response to zymosan. 4. Pretreatment of the guinea-pigs with the anti-allergic drugs, oxatomide (2.5 mg kg-1) or nedocromil (2.5 mg kg-1), or the specific H1-histamine receptor antagonist, levocabastine (0.25 mg kg-1), administered intra-peritoneally twice a day for five successive days, inhibits the virus-induced airway hyperresponsiveness, suppresses the influx of broncho-alveolar cells and increase in albumin content, and corrects the reduced chemiluminescence production by broncho-alveolar cells in response to zymosan. 5. In contrast, the cyclo-oxygenase inhibitor, suprofen (5.0 mg kg-1), the 5-HT2 receptor antagonist, ketanserin (0.63 mg kg-1), or the Ca2+ overload blocker, flunarizine (2.5 mg kg-1) do not modify the above mentioned processes. 6. The platelet-activating factor receptor antagonist, WEB 2170 (10 mg kg-1), reduces virus-induced airway hyperresponsiveness and influx of broncho-alveolar cells into the lungs but does not attenuate the increase of albumin in the bronchial lavage fluid. 7. Guinea-pigs nebulized with

  17. Adaptation to vection-induced symptoms of motion sickness

    NASA Technical Reports Server (NTRS)

    Stern, Robert M.; Hu, Senqi; Vasey, Michael W.; Koch, Kenneth L.

    1989-01-01

    The effects of repeated exposures to a rotating circular vection drum on the symptoms of motion sickness and tachygastria in humans were investigated. Subjects were sitting in a drum and were exposed to 15 min baseline (no rotation), followed by 15 min drum rotation at 60 deg/s, and, then, by 15 min recovery. Gastric myoelectric activity was continuously recorded with the electrogastrogram. Subjects who were exposed to the drum three times with intervals of 4-24 days all showed symptoms of tachygastria and failed to show an amelioration of motion sickness symptoms. On the other hand subjects who had only 48 h between the three sessions of drum exposure, experienced a reduction in motion-sickness symptoms and in tachygastsria upon repeated exposure to the drum, indicating that training effected a symptomatic and physiological adaptation. It is suggested that preflight adaptation to visual-vestibular sensory mismatch may reduce motion sickness in astronauts.

  18. Airway surface liquid volume expansion induces rapid changes in amiloride-sensitive Na+ transport across upper airway epithelium-Implications concerning the resolution of pulmonary edema

    PubMed Central

    Azizi, Fouad; Arredouani, Abdelilah; Mohammad, Ramzi M

    2015-01-01

    During airway inflammation, airway surface liquid volume (ASLV) expansion may result from the movement of plasma proteins and excess liquid into the airway lumen due to extravasation and elevation of subepithelial hydrostatic pressure. We previously demonstrated that elevation of submucosal hydrostatic pressure increases airway epithelium permeability resulting in ASLV expansion by 500 μL cm−2 h−1. Liquid reabsorption by healthy airway epithelium is regulated by active Na+ transport at a rate of 5 μL cm−2 h−1. Thus, during inflammation the airway epithelium may be submerged by a large volume of luminal liquid. Here, we have investigated the mechanism by which ASLV expansion alters active epithelial Na+ transport, and we have characterized the time course of the change. We used primary cultures of tracheal airway epithelium maintained under air interface (basal ASLV, depth is 7 ± 0.5 μm). To mimic airway flooding, ASLV was expanded to a depth of 5 mm. On switching from basal to expanded ASLV conditions, short-circuit current (Isc, a measure of total transepithelial active ion transport) declined by 90% with a half-time (t1/2) of 1 h. 24 h after the switch, there was no significant change in ATP concentration nor in the number of functional sodium pumps as revealed by [3H]-ouabain binding. However, amiloride-sensitive uptake of 22Na+ was reduced by 70% upon ASLV expansion. This process is reversible since after returning cells back to air interface, Isc recovered with a t1/2 of 5–10 h. These results may have important clinical implications concerning the development of Na+ channels activators and resolution of pulmonary edema. PMID:26333829

  19. 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

  20. Involvement of preprotachykinin A gene-encoded peptides and the neurokinin 1 receptor in endotoxin-induced murine airway inflammation.

    PubMed

    Helyes, Zsuzsanna; Elekes, Krisztián; Sándor, Katalin; Szitter, István; Kereskai, László; Pintér, Erika; Kemény, Agnes; Szolcsányi, János; McLaughlin, Lynn; Vasiliou, Sylvia; Kipar, Anja; Zimmer, Andreas; Hunt, Stephen P; Stewart, James P; Quinn, John P

    2010-10-01

    Tachykinins encoded by the preprotachykinin A (TAC1) gene such as substance P (SP) and neurokinin A (NKA) are involved in neurogenic inflammatory processes via predominantly neurokinins 1 and 2 (NK1 and NK2) receptor activation, respectively. Endokinins and hemokinins encoded by the TAC4 gene also have remarkable selectivity and potency for the NK1 receptors and might participate in inflammatory cell functions. The aim of the present study was to investigate endotoxin-induced airway inflammation and consequent bronchial hyper-reactivity in TAC1(-/-), NK1(-/-) and also in double knockout (TAC1(-/-)/NK1(-/-)) mice. Sub-acute interstitial lung inflammation was evoked by intranasal Escherichia coli lipopolysaccharide (LPS) in the knockout mice and their wildtype C57BL/6 counterparts 24 h before measurement. Respiratory parameters were measured with unrestrained whole body plethysmography. Bronchoconstriction was induced by inhalation of the muscarinic receptor agonist carbachol and Penh (enhanced pause) correlating with airway resistance was calculated. Lung interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured with ELISA. Histological evaluation was performed and a composite morphological score was determined. Myeloperoxidase (MPO) activity in the lung was measured with spectrophotometry to quantify the number of infiltrating neutrophils/macrophages. Airway hyper-reactivity was significantly reduced in the TAC1(-/-) as well as the TAC1(-/-)/NK1(-/-) groups. However, LPS-induced histological inflammatory changes (perivascular/peribronchial oedema, neutrophil infiltration and goblet cell hyperplasia), MPO activity and TNF-alpha concentration were markedly diminished only in TAC1(-/-) mice. Interestingly, the concentrations of both cytokines, IL-1beta and TNF-alpha, were significantly greater in the NK1(-/-) group. These data clearly demonstrated on the basis of histology, MPO and cytokine measurements that TAC1 gene

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

    PubMed Central

    Gu, Wen; Guo, Xue-jun

    2016-01-01

    The aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family, has recently been demonstrated to regulate T cell differentiation. Whether AhR activation participates in allergic airway inflammation remains unknown. In the current study, using a non-eosinophilic asthma model, we demonstrate that 2, 3, 7, 8-tetrachlorodibenzo-P-dioxin (TCDD), a potent AhR ligand, reduced the airway infiltration of neutrophils, airway hyperresponsiveness and Th17 cytokine expression. Furthermore, stimulation with TCDD promoted Treg differentiation and inhibited Th17 differentiation. However, the maturation of dendritic cells may not be inhibited by AhR activation. This study thus indicates a critical role of TCDD-induced AhR activation in the regulation of non-eosinophilic airway inflammation. PMID:26938767

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

    PubMed

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

    2016-01-01

    The aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family, has recently been demonstrated to regulate T cell differentiation. Whether AhR activation participates in allergic airway inflammation remains unknown. In the current study, using a non-eosinophilic asthma model, we demonstrate that 2, 3, 7, 8-tetrachlorodibenzo-P-dioxin (TCDD), a potent AhR ligand, reduced the airway infiltration of neutrophils, airway hyperresponsiveness and Th17 cytokine expression. Furthermore, stimulation with TCDD promoted Treg differentiation and inhibited Th17 differentiation. However, the maturation of dendritic cells may not be inhibited by AhR activation. This study thus indicates a critical role of TCDD-induced AhR activation in the regulation of non-eosinophilic airway inflammation. PMID:26938767

  3. ROLE OF OXIDANTS IN INFLUENZA-INDUCED AIRWAY HYPERREACTIVITY IN RATS

    EPA Science Inventory

    Airway hyperreactivity (AHR) to intravenous acetylcholine has been demonstrated 3d after F-344 rats were intranasally instilled with a rat-adapted influenza virus (ARRD, A657:1990). -acetyl cysteine (NAC), an oxidant scavenger, was able to lock AHR if orally administered (1% in t...

  4. Inhalation of stable dust extract prevents allergen induced airway inflammation and hyperresponsiveness

    PubMed Central

    Peters, M; Kauth, M; Schwarze, J; Körner‐Rettberg, C; Riedler, J; Nowak, D; Braun‐Fahrländer, C; von Mutius, E; Bufe, A; Holst, O

    2006-01-01

    Background Recent epidemiological studies have shown that growing up on a traditional farm provides protection from the development of allergic disorders such as hay fever and allergic asthma. We present experimental evidence that substances providing protection from the development of allergic diseases can be extracted from dust collected in stables of animal farms. Methods Stable dust was collected from 30 randomly selected farms located in rural regions of the Alps (Austria, Germany and Switzerland). The dust was homogenised with glass beads and extracted with physiological sodium chloride solution. This extract was used to modulate immune response in a well established mouse model of allergic asthma. Results Treatment of mice by inhalation of stable dust extract during sensitisation to ovalbumin inhibited the development of airway hyperresponsiveness and airway eosinophilia upon challenge, as well as the production of interleukin 5 by splenocytes and of antigen specific IgG1 and IgE. Dust extract also suppressed the generation of human dendritic cells in vitro. The biological activity of the dust extract was not exclusively mediated by lipopolysaccharide. Conclusions Stable dust from animal farms contains strong immune modulating substances. These substances can interfere with the development of both cellular and humoral immunity against allergens, thus suppressing allergen sensitisation, airway inflammation, and airway hyperresponsiveness in a murine model of allergic asthma. PMID:16244088

  5. A Novel Nonhuman Primate Model of Cigarette Smoke–Induced Airway Disease

    PubMed Central

    Polverino, Francesca; Doyle-Eisele, Melanie; McDonald, Jacob; Wilder, Julie A.; Royer, Christopher; Laucho-Contreras, Maria; Kelly, Emer M.; Divo, Miguel; Pinto-Plata, Victor; Mauderly, Joe; Celli, Bartolome R.; Tesfaigzi, Yohannes; Owen, Caroline A.

    2016-01-01

    Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)–exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD. PMID:25542772

  6. A novel nonhuman primate model of cigarette smoke-induced airway disease.

    PubMed

    Polverino, Francesca; Doyle-Eisele, Melanie; McDonald, Jacob; Wilder, Julie A; Royer, Christopher; Laucho-Contreras, Maria; Kelly, Emer M; Divo, Miguel; Pinto-Plata, Victor; Mauderly, Joe; Celli, Bartolome R; Tesfaigzi, Yohannes; Owen, Caroline A

    2015-03-01

    Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)-exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD. PMID:25542772

  7. Mast cell-derived neurotrophin 4 mediates allergen-induced airway hyperinnervation in early life

    PubMed Central

    Patel, Kruti R.; Aven, Linh; Shao, Fengzhi; Krishnamoorthy, Nandini; Duvall, Melody G.; Levy, Bruce D.; Ai, Xingbin

    2016-01-01

    Asthma often progresses from early episodes of insults. How early life events connect to long-term airway dysfunction remains poorly understood. We demonstrated previously that increased neurotrophin 4 (NT4) levels following early life allergen exposure cause persistent changes in airway smooth muscle (ASM) innervation and airway hyper-reactivity (AHR) in mice. Herein, we identify pulmonary mast cells as a key source of aberrant NT4 expression following early insults. NT4 is selectively expressed by ASM and mast cells in mice, nonhuman primates and humans. We show in mice that mast cell-derived NT4 is dispensable for ASM innervation during development. However, upon insults, mast cells expand in number and degranulate to release NT4 and thus become the major source of NT4 under pathological condition. Adoptive transfer of wild type mast cells, but not NT4−/− mast cells restores ASM hyperinnervation and AHR in KitW-sh/W-sh mice following early life insults. Notably, an infant nonhuman primate model of asthma also exhibits ASM hyperinnervation associated with the expansion and degranulation of mast cells. Together, these findings identify an essential role of mast cells in mediating ASM hyperinnervation following early life insults by producing NT4. This role may be evolutionarily conserved in linking early insults to long-term airway dysfunction. PMID:26860818

  8. PROINFLAMMATORY OXIDANT HYPOCHLOROUS ACID (HOCL) INDUCES DUAL SIGNALING PATHWAYS IN AIRWAY EPITHELIAL CELLS

    EPA Science Inventory

    In the airway of inflammatory diseases such as bacterial infection, cystic fibrosis and COPD, high level of HOCL (local concentration of up to 5mM) can be generated through a reaction catalyzed by leukocyte granule enzyme- Myeloperoxidase (MPO). HOCL is a very potent oxidative ag...

  9. A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice

    PubMed Central

    Kozy, Heather M.; Lum, Jeremy A.; Sweetwood, Rosemary; Chu, Mabel; Cunningham, Cameron R.; Salamon, Hugh; Lloyd, Clare M.; Coffman, Robert L.; Hessel, Edith M.

    2015-01-01

    Background CpG-containing oligodeoxynucleotides (CpG-ODN) are potent inhibitors of Th2-mediated allergic airway disease in sensitized mice challenged with allergen. A single treatment has transient effects but a limited series of treatments has potential to achieve clinically meaningful sustained inhibition of allergic airway disease. Objective To optimize the treatment regimen and determine the mechanisms of action in mice of an inhaled form of CpG-ODN being developed for human asthma treatment. Methods A limited series of weekly intranasal 1018 ISS (CpG-ODN; B-class) treatments were given to ragweed allergen-sensitized mice chronically exposed to allergen during and after the 1018 ISS treatment regimen. Treatment effects were evaluated by measuring effect on lung Th2 cytokines and eosinophilia as well as lung dendritic cell function and T cell responses. Results Twelve intranasal 1018 ISS treatments induced significant suppression of BAL eosinophilia and IL-4, IL-5, and IL-13 levels and suppression was maintained through 13 weekly ragweed exposures administered after treatment cessation. At least 5 treatments were required for lasting Th2 suppression. CpG-ODN induced moderate Th1 responses but Th2 suppression did not require IFN-γ. Th2 suppression was associated with induction of a regulatory T cell response. Conclusion A short series of CpG-ODN treatments results in sustained suppression of allergic lung inflammation induced by a clinically relevant allergen. PMID:24464743

  10. Deficiency of RAMP1 Attenuates Antigen-Induced Airway Hyperresponsiveness in Mice

    PubMed Central

    Hua, Xiaoyang; Tilley, Stephen L.; Oswald, Erin; Krummel, Matthew F.; Caron, Kathleen M.

    2014-01-01

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

  11. Inhibition of airway epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced epithelial cells and ovalbumin-sensitized mice.

    PubMed

    Gong, Ju-Hyun; Cho, In-Hee; Shin, Daekeun; Han, Seon-Young; Park, Sin-Hye; Kang, Young-Hee

    2014-03-01

    Chronic airway remodeling is characterized by structural changes within the airway wall, including smooth muscle hypertrophy, submucosal fibrosis and epithelial shedding. Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism of organ fibrosis, which can be induced by TGF-β. In the in vitro study, we investigated whether 1-20 μM kaempferol inhibited lipopolysaccharide (LPS)-induced bronchial EMT in BEAS-2B cells. The in vivo study explored demoting effects of 10-20 mg/kg kaempferol on airway fibrosis in BALB/c mice sensitized with ovalbumin (OVA). LPS induced airway epithelial TGF-β1 signaling that promoted EMT with concurrent loss of E-cadherin and induction of α-smooth muscle actin (α-SMA). Nontoxic kaempferol significantly inhibited TGF-β-induced EMT process through reversing E-cadherin expression and retarding the induction of N-cadherin and α-SMA. Consistently, OVA inhalation resulted in a striking loss of epithelial morphology by displaying myofibroblast appearance, which led to bronchial fibrosis with submucosal accumulation of collagen fibers. Oral administration of kaempferol suppressed collagen deposition, epithelial excrescency and goblet hyperplasia observed in the lung of OVA-challenged mice. The specific inhibition of TGF-β entailed epithelial protease-activated receptor-1 (PAR-1) as with 20 μM kaempferol. The epithelial PAR-1 inhibition by SCH-79797 restored E-cadherin induction and deterred α-SMA induction, indicating that epithelial PAR-1 localization was responsible for resulting in airway EMT. These results demonstrate that dietary kaempferol alleviated fibrotic airway remodeling via bronchial EMT by modulating PAR1 activation. Therefore, kaempferol may be a potential therapeutic agent targeting asthmatic airway constriction. PMID:24378645

  12. Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells

    SciTech Connect

    Matsuzaki, Shinichi; Ishizuka, Tamotsu; Yamada, Hidenori; Kamide, Yosuke; Hisada, Takeshi; Ichimonji, Isao; Aoki, Haruka; Yatomi, Masakiyo; Komachi, Mayumi; Tsurumaki, Hiroaki; Ono, Akihiro; Koga, Yasuhiko; Dobashi, Kunio; Mogi, Chihiro; Sato, Koichi; Tomura, Hideaki; Mori, Masatomo; Okajima, Fumikazu

    2011-10-07

    Highlights: {yields} The involvement of extracellular acidification in airway remodeling was investigated. {yields} Extracellular acidification alone induced CTGF production in human ASMCs. {yields} Extracellular acidification enhanced TGF-{beta}-induced CTGF production in human ASMCs. {yields} Proton-sensing receptor OGR1 was involved in acidic pH-stimulated CTGF production. {yields} OGR1 may play an important role in airway remodeling in asthma. -- Abstract: Asthma is characterized by airway inflammation, hyper-responsiveness and remodeling. Extracellular acidification is known to be associated with severe asthma; however, the role of extracellular acidification in airway remodeling remains elusive. In the present study, the effects of acidification on the expression of connective tissue growth factor (CTGF), a critical factor involved in the formation of extracellular matrix proteins and hence airway remodeling, were examined in human airway smooth muscle cells (ASMCs). Acidic pH alone induced a substantial production of CTGF, and enhanced transforming growth factor (TGF)-{beta}-induced CTGF mRNA and protein expression. The extracellular acidic pH-induced effects were inhibited by knockdown of a proton-sensing ovarian cancer G-protein-coupled receptor (OGR1) with its specific small interfering RNA and by addition of the G{sub q/11} protein-specific inhibitor, YM-254890, or the inositol-1,4,5-trisphosphate (IP{sub 3}) receptor antagonist, 2-APB. In conclusion, extracellular acidification induces CTGF production through the OGR1/G{sub q/11} protein and inositol-1,4,5-trisphosphate-induced Ca{sup 2+} mobilization in human ASMCs.

  13. EBM84 attenuates airway inflammation and mucus hypersecretion in an ovalbumin-induced murine model of asthma.

    PubMed

    Shin, In Sik; Lee, Mee Young; Jeon, Woo Young; Shin, Na Ra; Seo, Chang Seob; Ha, Hyekyung

    2013-04-01

    EBM84 is a traditional herbal medicine and a combination of extracts obtained from Pinellia ternata and Zingiber officinale. It is traditionally used to treat vomiting, nausea, sputum and gastrointestinal disorders, and functions is an effective expectorant. In this study, we evaluated the protective effects of EBM84 on asthmatic responses, particularly mucus hypersecretion in an ovalbumin (OVA)-induced murine model of asthma. We also analyzed EBM84 composition using high performance liquid chromatography. Animals were sensitized on days 0 and 14 via intraperitoneal injection using 20 µg OVA. On days 21, 22 and 23 after initial sensitization, the mice received an airway challenge with OVA (1% w/v in PBS) for 1 h using an ultrasonic nebulizer (NE-U12). EBM84 was administered by gavage to the mice at doses of 16.9, 33.8 and 67.5 mg/kg once daily from days 18 to 23. EBM84 administration significantly lowered elevated levels of interleukin (IL)-4, IL-13, eotaxin and immunoglobulin (Ig)E in the bronchoalveolar lavage fluid or plasma. Airway inflammation and mucus hypersecretion were attenuated following EBM84 administration. EBM84 also inhibited the overexpression of mucin 5AC (MUC5AC) induced by OVA challenge in lung tissue. This result was consistent with the immunohistochemistry results. Our results indicate that EBM84 effectively inhibited airway inflammation and mucus hypersecretion via the downregulation of T helper 2 (Th2) cytokines, which reduced MUC5AC expression. Therefore, EBM84 has potential as a useful medicine for the treatment of allergic asthma. PMID:23403738

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

    PubMed Central

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

    2016-01-01

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

  15. Fructose-induced symptoms beyond malabsorption in FGID.

    PubMed

    Biesiekierski, Jessica R

    2014-02-01

    The dietary carbohydrate fructose can be incompletely absorbed in the small intestine and is sometimes associated with gastrointestinal symptoms that include motility disturbances and abdominal pain. Fructose malabsorption has been well documented in variable but similar proportions of healthy and populations with functional gastrointestinal disorders. Recent work into the expression of the main intestinal fructose transporter proteins highlight that our understanding of the mechanistic basis for fructose malabsorption and how it differentiates in gastrointestinal patients is incomplete. Until we have further mechanistic insight, restricting dietary fructose intake and other poorly absorbed short-chain carbohydrates and polyols remains an efficacious approach for managing functional gastrointestinal symptoms. PMID:24918003

  16. 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

  17. OZONE-INDUCED RESPIRATORY SYMPTOMS: EXPOSURE-RESPONSE MODELS AND ASSOCIATION WITH LUNG FUNCTION

    EPA Science Inventory

    Ozone-induced respiratory symptoms are known to be functions of concentration, minute ventilation, and duration of exposure. The purposes of this study were to identify an exposure-response model for symptoms, to determine whether response was related to age, and to assess the re...

  18. Relation of Symptom-Induced Impairment with Other Illness Parameters in Clinic-Referred Youth

    ERIC Educational Resources Information Center

    Gadow, Kenneth D.; Kaat, Aaron J.; Lecavalier, Luc

    2013-01-01

    Objective: To examine the relation of caregiver ratings of psychiatric symptom-induced impairment with number and severity of symptoms and informant agreement in consecutive child psychiatry outpatient referrals. Methods: Parents and teachers completed a broadband "DSM-IV"-referenced rating scale with disorder-specific impairment for 636…

  19. Induced coronary spasm without electrocardiographic signs or symptoms of myocardial ischemia

    SciTech Connect

    Cipriano, P.R.

    1983-03-01

    Angiographic studies have shown that coronary artery spasm can be induced with ergonovine maleate. Coronary artery spasm induced by ergonovine maleate in these studies was nearly always accompanied by chest pain and electrocardiographic changes of myocardial ischemia. This report demonstrates that coronary artery spasm induced by ergonovine maleate may be diagnosed by angiography in the absence of these signs or symptoms.

  20. Farmer's Lung: Causes and Symptoms of Mold and Dust Induced Respiratory Illness

    MedlinePlus

    ... Educational Resources Farmer's Lung: Causes and Symptoms of Mold and Dust Induced Respiratory Illness ID 442-602 ( ... noninfectious allergic disease that is caused by inhaling mold spores in the dust from moldy hay, straw, ...

  1. Three-Dimensional Mapping of Ozone-Induced Injury in the Nasal Airways of Monkeys Using Magnetic Resonance Imaging and Morphometric Techniques

    SciTech Connect

    Carey, Stephen A.; Minard, Kevin R.; Trease, Lynn L.; Wagner, James G.; Garcia, Guilherme M.; Ballinger, Carol A.; Kimbell, Julia; Plopper, Charles G.; Corley, Rick A.; Postlewait, Ed; Harkema, Jack R.

    2007-03-01

    ABSTRACT Age-related changes in gross and microscopic structure of the nasal cavity can alter local tissue susceptibility as well as the dose of inhaled toxicant delivered to susceptible sites. This article describes a novel method for the use of magnetic resonance imaging, 3-dimensional airway modeling, and morphometric techniques to characterize the distribution and magnitude of ozone-induced nasal injury in infant monkeys. Using this method, we are able to generate age-specific, 3-dimensional, epithelial maps of the nasal airways of infant Rhesus macaques. The principal nasal lesions observed in this primate model of ozone-induced nasal toxicology were neutrophilic rhinitis, along with necrosis and exfoliation of the epithelium lining the anterior maxilloturbinate. These lesions, induced by acute or cyclic (episodic) exposures, were examined by light microscopy, quantified by morphometric techniques, and mapped on 3-dimensional models of the nasal airways. Here, we describe the histopathologic, imaging, and computational biology methods developed to efficiently characterize, localize, quantify, and map these nasal lesions. By combining these techniques, the location and severity of the nasal epithelial injury were correlated with epithelial type, nasal airway geometry, and local biochemical and molecular changes on an individual animal basis. These correlations are critical for accurate predictive modeling of exposure-dose-response relationships in the nasal airways, and subsequent extrapolation of nasal findings in animals to humans for developing risk assessment.

  2. Ozone-Induced Type 2 Immunity in Nasal Airways. Development and Lymphoid Cell Dependence in Mice.

    PubMed

    Ong, Chee Bing; Kumagai, Kazuyoshi; Brooks, Phillip T; Brandenberger, Christina; Lewandowski, Ryan P; Jackson-Humbles, Daven N; Nault, Rance; Zacharewski, Timothy R; Wagner, James G; Harkema, Jack R

    2016-03-01

    Inhalation exposures to ozone commonly encountered in photochemical smog cause airway injury and inflammation. Elevated ambient ozone concentrations have been epidemiologically associated with nasal airway activation of neutrophils and eosinophils. In the present study, we elucidated the temporal onset and lymphoid cell dependency of eosinophilic rhinitis and associated epithelial changes in mice repeatedly exposed to ozone. Lymphoid cell-sufficient C57BL/6 mice were exposed to 0 or 0.5 parts per million (ppm) ozone for 1, 2, 4, or 9 consecutive weekdays (4 h/d). Lymphoid cell-deficient, Rag2(-/-)Il2rg(-/-) mice were similarly exposed for 9 weekdays. Nasal tissues were taken at 2 or 24 hours after exposure for morphometric and gene expression analyses. C57BL/6 mice exposed to ozone for 1 day had acute neutrophilic rhinitis, with airway epithelial necrosis and overexpression of mucosal Ccl2 (MCP-1), Ccl11 (eotaxin), Cxcl1 (KC), Cxcl2 (MIP-2), Hmox1, Il1b, Il5, Il6, Il13, and Tnf mRNA. In contrast, 9-day ozone exposure elicited type 2 immune responses in C57BL/6 mice, with mucosal mRNA overexpression of Arg1, Ccl8 (MCP-2), Ccl11, Chil4 (Ym2), Clca1 (Gob5), Il5, Il10, and Il13; increased density of mucosal eosinophils; and nasal epithelial remodeling (e.g., hyperplasia/hypertrophy, mucous cell metaplasia, hyalinosis, and increased YM1/YM2 proteins). Rag2(-/-)Il2rg(-/-) mice exposed to ozone for 9 days, however, had no nasal pathology or overexpression of transcripts related to type 2 immunity. These results provide a plausible paradigm for the activation of eosinophilic inflammation and type 2 immunity found in the nasal airways of nonatopic individuals subjected to episodic exposures to high ambient ozone. PMID:26203683

  3. T-bet is induced by interferon-γ to mediate chemokine secretion and migration in human airway smooth muscle cells

    PubMed Central

    2011-01-01

    An inappropriate balance between T-helper (Th)1 and Th2 cytokine production underlies inflammatory changes that result in airway disease. Expression of the T-box transcription factor T-bet regulates differentiation of Th cells and production of Th1 cytokines, particularly IFNγ. T-bet-deficient mice develop airway hyperreactivity, undergo airway remodeling, and exhibit defects in IFNγ production while overproducing Th2 cytokines. T-bet is also reduced in the airways of asthmatic patients, suggesting loss of T-bet expression or activity promotes development of inflammatory airway disease. We present novel data demonstrating T-bet expression is induced in human airway smooth muscle cells (ASMC) by IFNγ. This IFNγ-stimulated expression of T-bet is dependent on signaling through JAK2 and signal transducers and activators of transcription 1 (STAT1) and activates T-bet-dependent DNA binding activity. Expression of T-bet stimulates IFNγ-stimulated IFNγ expression, secretion, and promoter activity, while inhibiting IFNγ-stimulated release of chemokines including monocyte chemoattractant protein (MCP)-1/CCL2, regulated on activation normal T-expressed and secreted (RANTES)/CCL5, and eotaxin/CCL11. This is accompanied by changes in expression of the chemokine receptors CCR3 and IL12Rβ2 and TNFα. T-bet expression also reduces chemotactic migration of ASMC in response to serum and PDGF, which contributes to airway hyperplasia. These results are the first to identify T-bet expression and activity in a structural cell of the lung and may provide new insights into therapeutic targets for inflammatory airway disease. PMID:21239533

  4. Administration of Pigment Epithelium-Derived Factor Inhibits Airway Inflammation and Remodeling in Chronic OVA-Induced Mice via VEGF Suppression

    PubMed Central

    Zha, Wangjian; Su, Mei; Huang, Mao; Cai, Jiankang

    2016-01-01

    Purpose Pigment epithelium-derived factor (PEDF) is a recently discovered antiangiogenesis protein. PEDF possesses powerful anti-inflammatory, antioxidative, antiangiogenic, and antifibrosis properties. It has been reported that PEDF can regulate vascular endothelial growth factor (VEGF) expression. This study aimed to evaluate whether recombinant PEDF protein could attenuate allergic airway inflammation and airway remodeling via the negative regulation of VEGF using a murine model of chronic ovalbumin (OVA)-induced asthma and BEAS-2B human bronchial epithelial cells. Methods In an in vivo experiment, mice sensitized with OVA were chronically airway challenged with aerosolized 1% OVA solution for 8 weeks. Treated mice were given injections of recombinant PEDF protein (50 or 100 µg/kg body weight) via the tail vein. In an in vitro experiment, we investigated the effects of recombinant PEDF protein on VEGF release levels in BEAS-2B cells stimulated with IL-1β. Results Recombinant PEDF protein significantly inhibited eosinophilic airway inflammation, airway hyperresponsiveness, and airway remodeling, including goblet cell hyperplasia, subepithelial collagen deposition, and airway smooth muscle hypertrophy. In addition, recombinant PEDF protein suppressed the enhanced expression of VEGF protein in lung tissue and bronchoalveolar lavage fluid (BALF) in OVA-challenged chronically allergic mice. In the in vitro experiment, VEGF expression was increased after IL-1β stimulation. Pretreatment with 50 and 100 ng/mL of recombinant PEDF protein significantly attenuated the increase in VEGF release levels in a concentration-dependent manner in BEAS-2B cells stimulated by IL-1β. Conclusions These results suggest that recombinant PEDF protein may abolish the development of characteristic features of chronic allergic asthma via VEGF suppression, providing a potential treatment option for chronic airway inflammation diseases such as asthma. PMID:26739410

  5. Effect of Obesity on Acute Ozone-Induced Changes in Airway Function, Reactivity, and Inflammation in Adult Females

    PubMed Central

    Bennett, William D.; Ivins, Sally; Alexis, Neil E.; Wu, Jihong; Bromberg, Philip A.; Brar, Sukhdev S.; Travlos, Gregory; London, Stephanie J.

    2016-01-01

    We previously observed greater ozone-induced lung function decrements in obese than non-obese women. Animal models suggest that obesity enhances ozone-induced airway reactivity and inflammation. In a controlled exposure study, we compared the acute effect of randomized 0.4ppm ozone and air exposures (2 h with intermittent light exercise) in obese (N = 20) (30induced-sputum (4h post-exposures and on 24h pre-exposure training day, no exercise): measures of C reactive protein (CRP) (blood only), leptin (blood only), adiponectin, interleukins IL-6, IL-1b, and IL-8, and tumor necrosis factor alpha, and sputum cell differential cell counts. The pre- to post-exposure decrease in forced vital capacity after ozone (adjusted for the change after air exposure) was significantly greater in the obese group (12.5+/-7.5 vs. 8.0+/-5.8%, p<0.05). Post ozone exposure, 6 obese and 6 non-obese subjects responded to methacholine at ≤ 10mg/ml (the maximum dose); the degree of hyperresponsiveness was similar for the two groups. Both BMI groups showed similar and significant ozone-induced increases in sputum neutrophils. Plasma IL-6 was increased by exercise (4 hr post air exposure vs. pre) only in the obese but returned to pre-air exposure levels at 20hr post-exposure. Plasma IL-6 was significantly increased at 4hr post ozone exposure in both groups and returned to pre-exposure levels by 20h post-exposure. These results confirm our previous findings of greater post-ozone spirometric decrements in obese young women. However, acute ozone-induced airway reactivity to methacholine and airway inflammation did not differ by obesity at the exposure and exercise levels used. PMID:27513854

  6. Effect of Obesity on Acute Ozone-Induced Changes in Airway Function, Reactivity, and Inflammation in Adult Females.

    PubMed

    Bennett, William D; Ivins, Sally; Alexis, Neil E; Wu, Jihong; Bromberg, Philip A; Brar, Sukhdev S; Travlos, Gregory; London, Stephanie J

    2016-01-01

    We previously observed greater ozone-induced lung function decrements in obese than non-obese women. Animal models suggest that obesity enhances ozone-induced airway reactivity and inflammation. In a controlled exposure study, we compared the acute effect of randomized 0.4ppm ozone and air exposures (2 h with intermittent light exercise) in obese (N = 20) (30induced-sputum (4h post-exposures and on 24h pre-exposure training day, no exercise): measures of C reactive protein (CRP) (blood only), leptin (blood only), adiponectin, interleukins IL-6, IL-1b, and IL-8, and tumor necrosis factor alpha, and sputum cell differential cell counts. The pre- to post-exposure decrease in forced vital capacity after ozone (adjusted for the change after air exposure) was significantly greater in the obese group (12.5+/-7.5 vs. 8.0+/-5.8%, p<0.05). Post ozone exposure, 6 obese and 6 non-obese subjects responded to methacholine at ≤ 10mg/ml (the maximum dose); the degree of hyperresponsiveness was similar for the two groups. Both BMI groups showed similar and significant ozone-induced increases in sputum neutrophils. Plasma IL-6 was increased by exercise (4 hr post air exposure vs. pre) only in the obese but returned to pre-air exposure levels at 20hr post-exposure. Plasma IL-6 was significantly increased at 4hr post ozone exposure in both groups and returned to pre-exposure levels by 20h post-exposure. These results confirm our previous findings of greater post-ozone spirometric decrements in obese young women. However, acute ozone-induced airway reactivity to methacholine and airway inflammation did not differ by obesity at the exposure and exercise levels used. PMID:27513854

  7. Prevalence, codetection and seasonal distribution of upper airway viruses and bacteria in children with acute respiratory illnesses with cough as a symptom.

    PubMed

    O'Grady, K F; Grimwood, K; Sloots, T P; Whiley, D M; Acworth, J P; Phillips, N; Goyal, V; Chang, A B

    2016-06-01

    Most studies exploring the role of upper airway viruses and bacteria in paediatric acute respiratory infections (ARI) focus on specific clinical diagnoses and/or do not account for virus-bacteria interactions. We aimed to describe the frequency and predictors of virus and bacteria codetection in children with ARI and cough, irrespective of clinical diagnosis. Bilateral nasal swabs, demographic, clinical and risk factor data were collected at enrollment in children aged <15 years presenting to an emergency department with an ARI and where cough was a symptom. Swabs were tested by polymerase chain reaction for 17 respiratory viruses and seven respiratory bacteria. Logistic regression was used to investigate associations between child characteristics and codetection of the organisms of interest. Between December 2011 and August 2014, swabs were collected from 817 (93.3%) of 876 enrolled children, median age 27.7 months (interquartile range 13.9-60.3 months). Overall, 740 (90.6%) of 817 specimens were positive for any organism. Both viruses and bacteria were detected in 423 specimens (51.8%). Factors associated with codetection were age (adjusted odds ratio (aOR) for age <12 months = 4.9, 95% confidence interval (CI) 3.0, 7.9; age 12 to <24 months = 6.0, 95% CI 3.7, 9.8; age 24 to <60 months = 2.4, 95% CI 1.5, 3.9), male gender (aOR 1.46; 95% CI 1.1, 2.0), child care attendance (aOR 2.0; 95% CI 1.4, 2.8) and winter enrollment (aOR 2.0; 95% CI 1.3, 3.0). Haemophilus influenzae dominated the virus-bacteria pairs. Virus-H. influenzae interactions in ARI should be investigated further, especially as the contribution of nontypeable H. influenzae to acute and chronic respiratory diseases is being increasingly recognized. PMID:26916343

  8. Levetiracetam Induced Drug Reaction with Eosinophilia and Systemic Symptom Syndrome

    PubMed Central

    Dar, Waseem Raja; Sofi, Najeebullah; Latief, Muzamil; Dar, Imtiyaz Ahmad; Kasana, Basharat Ahmad

    2016-01-01

    Drug reaction with eosinophilia and systemic symptom syndrome (DRESS) is a hypersensitivity drug reaction, most frequently associated with antiepileptic drugs, characterized by skin rash, fever, pharyngitis, lymphadenopathy, and visceral organ involvement, typically presenting within 8 weeks of initiation of therapy. Management involves prompt withdrawal of the offending drug and use of systemic corticosteroids. We here present a rare case of DRESS secondary to levetiracetam. Only few case reports of DRESS secondary to levetiracetam have been published so far. PMID:27057042

  9. Levetiracetam Induced Drug Reaction with Eosinophilia and Systemic Symptom Syndrome.

    PubMed

    Dar, Waseem Raja; Sofi, Najeebullah; Latief, Muzamil; Dar, Imtiyaz Ahmad; Kasana, Basharat Ahmad

    2016-01-01

    Drug reaction with eosinophilia and systemic symptom syndrome (DRESS) is a hypersensitivity drug reaction, most frequently associated with antiepileptic drugs, characterized by skin rash, fever, pharyngitis, lymphadenopathy, and visceral organ involvement, typically presenting within 8 weeks of initiation of therapy. Management involves prompt withdrawal of the offending drug and use of systemic corticosteroids. We here present a rare case of DRESS secondary to levetiracetam. Only few case reports of DRESS secondary to levetiracetam have been published so far. PMID:27057042

  10. Dopamine-induced nonmotor symptoms of Parkinson's disease.

    PubMed

    Park, Ariane; Stacy, Mark

    2011-01-01

    Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease. PMID:21603184

  11. Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease

    PubMed Central

    Park, Ariane; Stacy, Mark

    2011-01-01

    Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease. PMID:21603184

  12. Nasal administration of interleukin-33 induces airways angiogenesis and expression of multiple angiogenic factors in a murine asthma surrogate.

    PubMed

    Shan, Shan; Li, Yan; Wang, Jingjing; Lv, Zhe; Yi, Dawei; Huang, Qiong; Corrigan, Chris J; Wang, Wei; Quangeng, Zhang; Ying, Sun

    2016-05-01

    The T-helper cell type 2-promoting cytokine interleukin-33 (IL-33) has been implicated in asthma pathogenesis. Angiogenesis is a feature of airways remodelling in asthma. We hypothesized that IL-33 induces airways angiogenesis and expression of angiogenic factors in an established murine surrogate of asthma. In the present study, BALB/c mice were subjected to serial intranasal challenge with IL-33 alone for up to 70 days. In parallel, ovalbumin (OVA) -sensitized mice were subjected to serial intranasal challenge with OVA or normal saline to serve as positive and negative controls, respectively. Immunohistochemical analysis of expression of von Willebrand factor and erythroblast transformation-specific-related gene, both blood vessel markers, and angiogenic factors angiogenin, insulin-like growth factor-1, endothelin-1, epidermal growth factor and amphiregulin was performed in lung sections ex vivo. An established in-house assay was used to test whether IL-33 was able to induce microvessel formation by human vascular endothelial cells. Results showed that serial intranasal challenge of mice with IL-33 or OVA resulted in proliferation of peribronchial von Willebrand factor-positive blood vessels to a degree closely related to the total expression of the angiogenic factors amphiregulin, angiogenin, endothelin-1, epidermal growth factor and insulin-like growth factor-1. IL-33 also induced microvessel formation by human endothelial cells in a concentration-dependent fashion in vitro. Our data are consistent with the hypothesis that IL-33 has the capacity to induce angiogenesis at least partly by increasing local expression of multiple angiogenic factors in an allergen-independent murine asthma surrogate, and consequently that IL-33 or its receptor is a potential novel molecular target for asthma therapy. PMID:27035894

  13. Acamprosate-induced Extrapyramidal Symptoms in an Elderly Patient with Alcohol Dependence.

    PubMed

    Woo, Jungmin; Rim, Hyo-Deog

    2014-08-01

    Acamprosate reduces the craving for alcohol by decreasing glutamate activity and increasing gamma-aminobutyric acid (GABA) action in patients with alcohol dependence. Acamprosate has tolerable side effects that include diarrhea, headache, dizziness and pruritus. In this study, we report acamprosate-induced extrapyramidal symptoms in an elderly patient with no history of neurologic disease. Severe extrapyramidal symptoms developed two days after the administration of acamprosate and improved over one week after the acamprosate was stopped. Extrapyramidal symptoms are commonly associated with dopamine receptor antagonists. However, there have been several reports of extrapyramidal symptoms occurring with drugs targeting other systems, including GABA, glutamate and serotonin. Acamprosate may decrease dopamine levels in the ventral tegmental area mediated by glutamatergic action and thus cause extrapyramidal symptoms. We suggest that acamprosate carries the risk of causing extrapyramidal symptoms. PMID:25191510

  14. Measuring and imaging small airways dysfunction in asthma

    PubMed Central

    2013-01-01

    Asthma is a chronic inflammatory disorder of the airways causing typical symptoms, and the diagnosis is supported by evidence of airflow obstruction which is variable, reversible or inducible. However, standard assessment of lung function with spirometry does not measure dysfunction in small airways which are < 2 mm in diameter towards the periphery of the lung. These airways make only a small contribution to airway resistance under normal circumstances. Nevertheless, there is mounting evidence that pathology and dysfunction in these small airways are implicated in the pathogenesis and natural history of asthma. Using forced oscillation and the multibreath nitrogen washout techniques, uneven ventilation (ventilation heterogeneity) due to small airways dysfunction has been shown to be an important marker of asthma disease activity, even in the absence of abnormalities in standard spirometric measurements. Recent advances in imaging research, particularly with hyperpolarised gas magnetic resonance imaging, have also given insights into the significance and dynamic nature of ventilation heterogeneity in asthma. The challenge is to integrate these new physiological and imaging insights to further our understanding of asthma and facilitate potential new treatments. PMID:24260727

  15. Asthma, Airway Symptoms and Rhinitis in Office Workers in Malaysia: Associations with House Dust Mite (HDM) Allergy, Cat Allergy and Levels of House Dust Mite Allergens in Office Dust

    PubMed Central

    Lim, Fang Lee; Hashim, Zailina; Than, Leslie Thian Lung; Md Said, Salmiah; Hisham Hashim, Jamal; Norbäck, Dan

    2015-01-01

    A prevalence study was conducted among office workers in Malaysia (N= 695). The aim of this study was to examine associations between asthma, airway symptoms, rhinitis and house dust mites (HDM) and cat allergy and HDM levels in office dust. Medical data was collected by a questionnaire. Skin prick tests were performed for HDM allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae) and cat allergen Felis domesticus. Indoor temperature and relative air humidity (RH) were measured in the offices and vacuumed dust samples were analyzed for HDM allergens. The prevalence of D. pteronyssinus, D. farinae and cat allergy were 50.3%, 49.0% and 25.5% respectively. Totally 9.6% had doctor-diagnosed asthma, 15.5% had current wheeze and 53.0% had current rhinitis. The Der p 1 (from D. pteronyssinus) and Der f 1 (from D. farinae) allergens levels in dust were 556 ng/g and 658 ng/g respectively. Statistical analysis was conducted by multilevel logistic regression, adjusting for age, gender, current smoking, HDM or cat allergy, home dampness and recent indoor painting at home. Office workers with HDM allergy had more wheeze (p= 0.035), any airway symptoms (p= 0.032), doctor-diagnosed asthma (p= 0.005), current asthma (p= 0.007), current rhinitis (p= 0.021) and rhinoconjuctivitis (p< 0.001). Cat allergy was associated with wheeze (p= 0.021), wheeze when not having a cold (p= 0.033), any airway symptoms (p= 0.034), doctor-diagnosed asthma (p= 0.010), current asthma (p= 0.020) and nasal allergy medication (p= 0.042). Der f 1 level in dust was associated with daytime breathlessness (p= 0.033) especially among those with HDM allergy. Der f 1 levels were correlated with indoor temperature (p< 0.001) and inversely correlated with RH (p< 0.001). In conclusion, HDM and cat allergies were common and independently associated with asthma, airway symptoms and rhinitis. Der f 1 allergen can be a risk factor for daytime breathlessness. PMID:25923543

  16. Absence of c-Jun NH2-terminal kinase 1 protects against house dust mite-induced pulmonary remodeling but not airway hyperresponsiveness and inflammation

    PubMed Central

    van der Velden, Jos L. J.; Hoffman, Sidra M.; Alcorn, John F.; Tully, Jane E.; Chapman, David G.; Lahue, Karolyn G.; Guala, Amy S.; Lundblad, Lennart K. A.; Aliyeva, Minara; Daphtary, Nirav; Irvin, Charles G.

    2014-01-01

    Chronic allergic asthma leads to airway remodeling and subepithelial fibrosis via mechanisms not fully understood. Airway remodeling is amplified by profibrotic mediators, such as transforming growth factor-β1 (TGF-β1), which plays a cardinal role in various models of fibrosis. We recently have identified a critical role for c-Jun-NH2-terminal-kinase (JNK) 1 in augmenting the profibrotic effects of TGF-β1, linked to epithelial-to-mesenchymal transition of airway epithelial cells. To examine the role of JNK1 in house dust mite (HDM)-induced airway remodeling, we induced allergic airway inflammation in wild-type (WT) and JNK1−/− mice by intranasal administration of HDM extract. WT and JNK1−/− mice were sensitized with intranasal aspirations of HDM extract for 15 days over 3 wk. HDM caused similar increases in airway hyperresponsiveness, mucus metaplasia, and airway inflammation in WT and JNK1−/− mice. In addition, the profibrotic cytokine TGF-β1 and phosphorylation of Smad3 were equally increased in WT and JNK1−/− mice. In contrast, increases in collagen content in lung tissue induced by HDM were significantly attenuated in JNK1−/− mice compared with WT controls. Furthermore HDM-induced increases of α-smooth muscle actin (α-SMA) protein and mRNA expression as well as the mesenchymal markers high-mobility group AT-hook 2 and collagen1A1 in WT mice were attenuated in JNK1−/− mice. The let-7 family of microRNAs has previously been linked to fibrosis. HDM exposure in WT mice and primary lung epithelial cells resulted in striking decreases in let-7g miRNA that were not observed in mice or primary lung epithelial cells lacking JNK1−/− mice. Overexpression of let-7g in lung epithelial cells reversed the HDM-induced increases in α-SMA. Collectively, these findings demonstrate an important requirement for JNK1 in promoting HDM-induced fibrotic airway remodeling. PMID:24610935

  17. Zerumbone enhances the Th1 response and ameliorates ovalbumin-induced Th2 responses and airway inflammation in mice.

    PubMed

    Shieh, Ying-Hua; Huang, Huei-Mei; Wang, Ching-Chiung; Lee, Chen-Chen; Fan, Chia-Kwung; Lee, Yueh-Lun

    2015-02-01

    Zerumbone is a sesquiterpene compound isolated from the rhizome of wild ginger, Zingiber zerumbet Smith. The rhizomes of the plant are used as a spice and traditional medicine. Zerumbone was shown to possess anticarcinogenic, anti-inflammatory, and antioxidant properties. However, the antiallergic activity and the underlying mechanism of zerumbone have not been reported. Herein, we investigated the immunomodulatory effects of zerumbone on antigen-presenting dendritic cells (DCs) in vitro and its potential therapeutic effects against ovalbumin (OVA)-induced T helper 2 (Th2)-mediated asthma in mice. In the presence of zerumbone, lipopolysaccharide-activated bone marrow-derived DCs enhanced T cell proliferation and Th1 cell polarization in an allogeneic mixed lymphocyte reaction. In animal experiments, mice were sensitized and challenged with OVA, and were orally treated with different doses of zerumbone after sensitization. Circulating titers of OVA-specific antibodies, airway hyperresponsiveness to methacholine, histological changes in lung tissues, the cell composition and cytokine levels in bronchoalveolar lavage fluid, and cytokine profiles of spleen cells were assessed. Compared to OVA-induced hallmarks of asthma, oral administration of zerumbone induced lower OVA-specific immunoglobulin E (IgE) and higher IgG2a antibody production, attenuated airway hyperresponsiveness, prevented eosinophilic pulmonary infiltration, and ameliorated mucus hypersecretion. Zerumbone treatment also reduced the production of eotaxin, keratinocyte-derived chemokine (KC), interleukin (IL)-4, IL-5, IL-10, and IL-13, and promoted Th1 cytokine interferon (IFN)-γ production in asthmatic mice. Taken together, these results suggest that zerumbone exhibits an antiallergic effect via modulation of Th1/Th2 cytokines in an asthmatic mouse model. PMID:25573403

  18. A mouse model of airway disease: oncostatin M-induced pulmonary eosinophilia, goblet cell hyperplasia, and airway hyperresponsiveness are STAT6 dependent, and interstitial pulmonary fibrosis is STAT6 independent.

    PubMed

    Fritz, Dominik K; Kerr, Christine; Fattouh, Ramzi; Llop-Guevara, Alba; Khan, Waliul I; Jordana, Manel; Richards, Carl D

    2011-01-15

    Oncostatin M (OSM), a pleiotropic cytokine of the gp130 cytokine family, has been implicated in chronic allergic inflammatory and fibrotic disease states associated with tissue eosinophilia. Mouse (m)OSM induces airway eosinophilic inflammation and interstitial pulmonary fibrosis in vivo and regulates STAT6 activation in vitro. To determine the requirement of STAT6 in OSM-induced effects in vivo, we examined wild-type (WT) and STAT6-knockout (STAT6(-/-)) C57BL/6 mouse lung responses to transient ectopic overexpression of mOSM using an adenoviral vector (AdmOSM). Intratracheal AdmOSM elicited persistent eosinophilic lung inflammation that was abolished in STAT6(-/-) mice. AdmOSM also induced pronounced pulmonary remodeling characterized by goblet cell hyperplasia and parenchymal interstitial fibrosis. Goblet cell hyperplasia was STAT6 dependent; however, parenchymal interstitial fibrosis was not. OSM also induced airway hyperresponsiveness in WT mice that was abolished in STAT6(-/-) mice. OSM stimulated an inflammatory signature in the lungs of WT mice that demonstrated STAT6-dependent regulation of Th2 cytokines (IL-4, IL-13), chemokines (eotaxin-1/2, MCP-1, keratinocyte chemoattractant), and extracellular matrix modulators (tissue inhibitor of matrix metalloproteinase-1, matrix metalloproteinase-13), but STAT6-independent regulation of IL-4Rα, total lung collagen, collagen-1A1, -1A2 mRNA, and parenchymal collagen and α smooth muscle actin accumulation. Thus, overexpression of mOSM induces STAT6-dependent pulmonary eosinophilia, mucous/goblet cell hyperplasia, and airway hyperresponsiveness but STAT6-independent mechanisms of lung tissue extracellular matrix accumulation. These results also suggest that eosinophil or neutrophil accumulation in mouse lungs is not required for OSM-induced lung parenchymal collagen deposition and that OSM may have unique roles in the pathogenesis of allergic and fibrotic lung disease. PMID:21160052

  19. Mucosal production of uric acid by airway epithelial cells contributes to particulate matter-induced allergic sensitization.

    PubMed

    Gold, M J; Hiebert, P R; Park, H Y; Stefanowicz, D; Le, A; Starkey, M R; Deane, A; Brown, A C; Liu, G; Horvat, J C; Ibrahim, Z A; Sukkar, M B; Hansbro, P M; Carlsten, C; VanEeden, S; Sin, D D; McNagny, K M; Knight, D A; Hirota, J A

    2016-05-01

    Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM10-induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma. PMID:26509876

  20. Lipoxygenase Pathway Mediates Increases of Airway Resistance and Lung Inflation Induced by Exposure to Nanotitanium Dioxide in Rats

    PubMed Central

    Lee, Jyu-Feng; Tung, Shu-Ping; Wang, David; Yeh, Diana Yuwung; Fong, Yao; Young, Yu-Chung; Leu, Fur-Jiang

    2014-01-01

    Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal injury. After inhalation of nTiO2, we monitored changes in 5-lipoxygenase, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) mRNA in rat lung tissue. Lung function parameters include specific airway resistance (SRaw), peak expiratory flow rate (PEF), functional residual capacity (FRC), and lung compliance (Cchord); blood white blood cell count (WBC), nitric oxide (NO), hydrogen peroxide, and lactic dehydrogenase (LDH); and lung lavage leukotriene C4, interleukin 6 (IL6), tumor necrotic factor α (TNFα), hydroxyl radicals, and NO. Leukotriene receptor antagonist MK571 and 5-lipoxygenase inhibitor MK886 were used for pharmacologic intervention. Compared to control, nTiO2 exposure induced near 5-fold increase in 5-lipoxygenase mRNA expression in lung tissue. iNOS mRNA increased while eNOS mRNA decreased. Lavage leukotriene C4; IL6; TNFα; NO; hydroxyl radicals; and blood WBC, NO, hydrogen peroxide, and LDH levels rose. Obstructive ventilatory insufficiency was observed. MK571 and MK886 both attenuated the systemic inflammation and lung function changes. We conclude that inhaled nTiO2 induces systemic inflammation, cytokine release, and oxidative and nitrosative stress in the lung. The lipoxygenase pathway products, mediated by oxygen radicals and WBC, play a critical role in the obstructive ventilatory insufficiency induced by nTiO2. PMID:24693335

  1. Differential Roles of Hydrogen Peroxide in Adaptive and Inflammatory Gene Expression Induced by Exposure of Human Airway Epithelial Cells to Zn2+

    EPA Science Inventory

    Oxidant stress is believed to play an important role in particulate matter (PM)–mediated toxicity in the respiratory tract. Zinc (Zn2+) is a ubiquitous component of PM that has been shown to induce adverse responses such as inflammatory and adaptive gene expression in airway epit...

  2. Polyinosinic:polycytidylic acid induces protein kinase D–dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells

    PubMed Central

    Rezaee, Fariba; Meednu, Nida; Emo, Jason A.; Saatian, Bahman; Chapman, Timothy J.; Naydenov, Nayden G.; De Benedetto, Anna; Beck, Lisa A.; Ivanov, Andrei I.; Georas, Steve N.

    2011-01-01

    Background Disruption of the epithelial barrier might be a risk factor for allergen sensitization and asthma. Viral respiratory tract infections are strongly associated with asthma exacerbation, but the effects of respiratory viruses on airway epithelial barrier function are not well understood. Many viruses generate double-stranded RNA, which can lead to airway inflammation and initiate an antiviral immune response. Objectives We investigated the effects of the synthetic double-stranded RNA polyinosinic:polycytidylic acid (polyI:C) on the structure and function of the airway epithelial barrier in vitro. Methods 16HBE14o- human bronchial epithelial cells and primary airway epithelial cells at an air-liquid interface were grown to confluence on Transwell inserts and exposed to polyI:C. We studied epithelial barrier function by measuring transepithelial electrical resistance and paracellular flux of fluorescent markers and structure of epithelial apical junctions by means of immunofluorescence microscopy. Results PolyI:C induced a profound decrease in transepithelial electrical resistance and increase in paracellular permeability. Immunofluorescence microscopy revealed markedly reduced junctional localization of zonula occludens-1, occludin, E-cadherin, β-catenin, and disorganization of junction-associated actin filaments. PolyI:C induced protein kinase D (PKD) phosphorylation, and a PKD antagonist attenuated polyI:C-induced disassembly of apical junctions and barrier dysfunction. Conclusions PolyI:C has a powerful and previously unsuspected disruptive effect on the airway epithelial barrier. PolyI:C-dependent barrier disruption is mediated by disassembly of epithelial apical junctions, which is dependent on PKD signaling. These findings suggest a new mechanism potentially underlying the associations between viral respiratory tract infections, airway inflammation, and allergen sensitization. PMID:21996340

  3. The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation.

    PubMed

    Larsson, Olivia J; Manson, Martijn L; Starkhammar, Magnus; Fuchs, Barbara; Adner, Mikael; Kumlien Georén, Susanna; Cardell, Lars-Olaf

    2016-06-01

    Toll-like receptor (TLR) 7 agonists are known to reduce allergic airway inflammation. Their recently reported ability to rapidly relax airways has further increased their interest in the treatment of pulmonary disease. However, the mechanisms behind this effect are not fully understood. The present study, therefore, aimed to determine whether airway smooth muscle (ASM)-dependent mechanisms could be identified. TLR7 agonists were added to guinea pig airways following precontraction with carbachol in vitro or histamine in vivo. Pharmacological inhibitors were used to dissect conventional pathways of bronchodilation; tetrodotoxin was used or bilateral vagotomy was performed to assess neuronal involvement. Human ASM cells (HASMCs) were employed to determine the effect of TLR7 agonists on intracellular Ca(2+) ([Ca(2+)]i) mobilization. The well-established TLR7 agonist imiquimod rapidly relaxed precontracted airways in vitro and in vivo. This relaxation was demonstrated to be independent of nitric oxide, carbon monoxide, and cAMP signaling, as well as neuronal activity. A limited role for prostanoids could be detected. Imiquimod induced [Ca(2+)]i release from endoplasmic reticulum stores in HASMCs, inhibiting histamine-induced [Ca(2+)]i The TLR7 antagonist IRS661 failed to inhibit relaxation, and the structurally dissimilar agonist CL264 did not relax airways or inhibit [Ca(2+)]i This study shows that imiquimod acts directly on ASM to induce bronchorelaxation, via a TLR7-independent release of [Ca(2+)]i The effect is paralleled by other bronchorelaxant compounds, like chloroquine, which, like imiquimod, but unlike CL264, contains the chemical structure quinoline. Compounds with quinoline moieties may be of interest in the development of multifunctional drugs to treat pulmonary disease. PMID:27084847

  4. Upper airway resistance syndrome.

    PubMed

    Hasan, N; Fletcher, E C

    1998-07-01

    Many clinicians are familiar with the clinical symptoms and signs of obstructive sleep apnea (OSA). In its most blatant form, OSA is complete airway obstruction with repetitive, prolonged pauses in breathing, arterial oxyhemoglobin desaturation; followed by arousal with resumption of breathing. Daytime symptoms of this disorder include excessive daytime somnolence, intellectual dysfunction, and cardiovascular effects such as systemic hypertension, angina, myocardial infarction, and stroke. It has been recently recognized that increased pharyngeal resistance with incomplete obstruction can lead to a constellation of symptoms identical to OSA called "upper airway resistance syndrome" (UARS). The typical findings of UARS on sleep study are: (1) repetitive arousals from EEG sleep coinciding with a (2) waxing and waning of the respiratory airflow pattern and (3) increased respiratory effort as measured by esophageal pressure monitoring. There may be few, if any, obvious apneas or hypopneas with desaturation, but snoring may be a very prominent finding. Treatment with nasal positive airway pressure (NCPAP) eliminates the symptoms and confirms the diagnosis. Herein we describe two typical cases of UARS. PMID:9676067

  5. Interleukin-33 from Monocytes Recruited to the Lung Contributes to House Dust Mite-Induced Airway Inflammation in a Mouse Model

    PubMed Central

    Tashiro, Hiroki; Takahashi, Koichiro; Hayashi, Shinichiro; Kato, Go; Kurata, Keigo; Kimura, Shinya; Sueoka-Aragane, Naoko

    2016-01-01

    Background Interleukin-33 (IL-33) activates group 2 innate lymphoid cells (ILC2), resulting in T-helper-2 inflammation in bronchial asthma. Airway epithelial cells were reported as sources of IL-33 during apoptosis and necrosis. However, IL-33 is known to be from sources other than airway epithelial cells such as leukocytes, and the mechanisms of IL-33 production and release are not fully understood. The aim of this study was to clarify the role of IL-33 production by monocytes in airway inflammation. Methods BALB/c mice were sensitized and challenged with a house dust mite (HDM) preparation. Airway inflammation was assessed by quantifying inflammatory cells in bronchoalveolar lavage (BAL) fluid, and IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) levels in lung. Immunohistochemistry for IL-33 in lung sections was also performed. Ly6c, CD11b, and CD11c expression was examined by flow cytometry. Clodronate liposomes were used in the HDM-airway inflammation model to deplete circulating monocytes. Results The IL-33, but not IL-25 or TSLP, level in lung homogenates was markedly increased in HDM mice compared to control mice. IL-33-positive cells in the lungs were identified using immunohistochemistry and were increased in areas surrounding bronchi and vasculature. Furthermore, IL-33 levels were increased in mononuclear cells derived from lungs of HDM mice compared to controls. The expression of Ly6c in mononuclear cells was significantly higher in HDM mice than in controls. Treatment with clodronate liposomes led to inhibition of not only inflammatory cells in BAL fluid, airway hyper reactivity and Th2 cytokines in lung, but also IL-33 in lung. Conclusion IL-33 from monocytes recruited to the lung may contribute to the pathogenesis of HDM-induced airway inflammation. PMID:27310495

  6. Mitotic Asynchrony Induces Transforming Growth Factor-β1 Secretion from Airway Epithelium

    PubMed Central

    Alcala, Sarah E.; Benton, Angela S.; Watson, Alan M.; Kureshi, Suraiya; Reeves, Erica M. K.; Damsker, Jesse; Wang, Zuyi; Nagaraju, Kanneboyina; Anderson, Julia; Williams, Aaron M.; Lee, Amber J. Y.; Hayes, Kathleen; Rose, Mary C.; Hoffman, Eric P.

    2014-01-01

    We recently proposed that mitotic asynchrony in repairing tissue may underlie chronic inflammation and fibrosis, where immune cell infiltration is secondary to proinflammatory cross-talk among asynchronously repairing adjacent tissues. Building on our previous finding that mitotic asynchrony is associated with proinflammatory/fibrotic cytokine secretion (e.g., transforming growth factor [TGF]-β1), here we provide evidence supporting cause-and-effect. Under normal conditions, primary airway epithelial basal cell populations undergo mitosis synchronously and do not secrete proinflammatory or profibrotic cytokines. However, when pairs of nonasthmatic cultures were mitotically synchronized at 12 hours off-set and then combined, the mixed cell populations secreted elevated levels of TGF-β1. This shows that mitotic asynchrony is not only associated with but is also causative of TGF-β1 secretion. The secreted cytokines and other mediators from asthmatic cells were not the cause of asynchronous regeneration; synchronously mitotic nonasthmatic epithelia exposed to conditioned media from asthmatic cells did not show changes in mitotic synchrony. We also tested if resynchronization of regenerating asthmatic airway epithelia reduces TGF-β1 secretion and found that pulse-dosed dexamethasone, simvastatin, and aphidicolin were all effective. We therefore propose a new model for chronic inflammatory and fibrotic conditions where an underlying factor is mitotic asynchrony. PMID:24669775

  7. 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.

  8. A bovine whey protein extract can induce the generation of regulatory T cells and shows potential to alleviate asthma symptoms in a murine asthma model.

    PubMed

    Chen, Jiunn-Horng; Huang, Po-Han; Lee, Chen-Chen; Chen, Pin-Yu; Chen, Hui-Chen

    2013-05-28

    The number of people with asthma has dramatically increased over the past few decades and the cost of care is more than $11·3 billion per year. The use of steroids is the major treatment to control asthma symptoms, but the side effects are often devastating. Seeking new drugs or new strategies to reduce the dose of steroid taken has always been an important task. A bovine whey protein extract (WPE), which is enriched in transforming growth factor-β (TGF-β), has been demonstrated to have the potential for reducing symptoms associated with mild-to-moderate T-helper cell type 1-mediated psoriasis in human subjects. However, whether WPE also has potential for inhibiting T-helper cell type 2 (Th2)-mediated disease remains unclear. In the present study, using a murine asthma model, we found that sensitised mice fed WPE daily, before they were challenged, resulted in reducing airway inflammation, serum ovalbumin-specific IgE, Th2-related cytokine production and airway hyperresponsiveness. Increase in the regulatory T cell (Treg) population in vitro and in vivo was observed when treated with WPE. According to the results from the TGF-β-blocking antibody study, we suggest that TGF-β is the main component that endows WPE with the potential to reduce the generation of Treg. Thus, the present data suggest that WPE has the potential to alleviate the symptoms of asthma by inducing the generation of Treg. Therefore, regular administration of WPE might be potentially beneficial for patients with asthma. PMID:23068908

  9. Th2 cell-specific cytokine expression and allergen-induced airway inflammation depend on JunB

    PubMed Central

    Hartenstein, Bettina; Teurich, Sibylle; Hess, Jochen; Schenkel, Johannes; Schorpp-Kistner, Marina; Angel, Peter

    2002-01-01

    Naïve CD4+ T cells differentiate into effector T helper 1 (Th1) or Th2 cells, which are classified by their specific set of cytokines. Here we demonstrate that loss of JunB in in vitro polarized Th2 cells led to a dysregulated expression of the Th2-specific cytokines IL-4 and IL-5. These cells produce IFN-γ and express T-bet, the key regulator of Th1 cells. In line with the essential role of Th2 cells in the pathogenesis of allergic asthma, mice with JunB-deficient CD4+ T cells exhibited an impaired allergen-induced airway inflammation. This study demonstrates novel functions of JunB in the development of Th2 effector cells, for a normal Th2 cytokine expression pattern and for a complete Th2-dependent immune response in mice. PMID:12456639

  10. Symptom-dependent taste aversion induced by an anticoagulant rodenticide in the brown rat (Rattus norvegicus).

    PubMed

    Smith, P; Inglis, I R; Cowan, D P; Kerins, G M; Bull, D S

    1994-09-01

    In a series of 3 experiments with different experimental paradigms, feeding patterns of laboratory rats (Rattus norvegicus) were monitored in 2-choice feeding tests after intubation with a sublethal dose of an anticoagulant rodenticide. We report for the first time that contrary to accepted wisdom, anticoagulants can induce taste aversions. Furthermore, we report behavioral symptoms within the 1st day after dosing. Our data suggest that the taste aversion is induced through an inhibition of the vitamin K cycle and is transient, attenuating over the same period as the levels of vitamin K-dependent proteins return to normal. Because the taste aversion is expressed most strongly when symptoms are most pronounced and is not expressed after symptoms have disappeared, we term this novel form of control symptom-dependent taste aversion. PMID:7924258

  11. BET Bromodomains Regulate Transforming Growth Factor-β-induced Proliferation and Cytokine Release in Asthmatic Airway Smooth Muscle*

    PubMed Central

    Perry, Mark M.; Durham, Andrew L.; Austin, Philip J.; Adcock, Ian M.; Chung, Kian Fan

    2015-01-01

    Airway smooth muscle (ASM) mass is increased in asthma, and ASM cells from patients with asthma are hyperproliferative and release more IL-6 and CXCL8. The BET (bromo- and extra-terminal) family of proteins (Brd2, Brd3, and Brd4) govern the assembly of histone acetylation-dependent chromatin complexes. We have examined whether they modulate proliferation and cytokine expression in asthmatic ASM cells by studying the effect of BET bromodomain mimics JQ1/SGCBD01 and I-BET762. ASM cells from healthy individuals and nonsevere and severe asthmatics were pretreated with JQ1/SGCBD01 and I-BET762 prior to stimulation with FCS and TGF-β. Proliferation was measured by BrdU incorporation. IL-6 and CXCL8 release was measured by ELISA, and mRNA expression was measured by quantitative RT-PCR. ChIP using a specific anti-Brd4 antibody and PCR primers directed against the transcriptional start site of IL-6 and CXCL8 gene promoters was performed. Neither JQ1/SGCBD01 nor I-BET762 had any effect on ASM cell viability. JQ1/SGCBD01 and I-BET762 inhibited FCS+TGF-β-induced ASM cell proliferation and IL-6 and CXCL8 release in healthy individuals (≥ 30 nm) and in nonsevere and severe asthma patients (≥100 nm), with the latter requiring higher concentrations of these mimics. JQ1/SGCBD01 reduced Brd4 binding to IL8 and IL6 promoters induced by FCS+TGF-β. Mimics of BET bromodomains inhibit aberrant ASM cell proliferation and inflammation with lesser efficiency in those from asthmatic patients. They may be effective in reducing airway remodeling in asthma. PMID:25697361

  12. Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation.

    PubMed

    Cardoso, L S; Oliveira, S C; Góes, A M; Oliveira, R R; Pacífico, L G; Marinho, F V; Fonseca, C T; Cardoso, F C; Carvalho, E M; Araujo, M I

    2010-05-01

    Schistosoma mansoni infection has been associated with protection against allergies. The mechanisms underlying this association may involve regulatory cells and cytokines. We evaluated the immune response induced by the S. mansoni antigens Sm22.6, PIII and Sm29 in a murine model of ovalbumin (OVA)-induced airway inflammation. BALB/c mice were sensitized with subcutaneously injected OVA-alum and challenged with aerolized OVA. Mice were given three doses of the different S. mansoni antigens. Lung histopathology, cellularity of bronchoalveolar lavage (BAL) and eosinophil peroxidase activity in lung were evaluated. Immunoglobulin (Ig)E levels in serum and cytokines in BAL were also measured. Additionally, we evaluated the frequency of CD4+forkhead box P3 (FoxP3)+ T cells in cultures stimulated with OVA and the expression of interleukin (IL)-10 by these cells. The number of total cells and eosinophils in BAL and the levels of OVA-specific IgE were reduced in the immunized mice. Also, the levels of IL-4 and IL-5 in the BAL of mice immunized with PIII and Sm22.6 were decreased, while the levels of IL-10 were higher in mice immunized with Sm22.6 compared to the non-immunized mice. The frequency of CD4+FoxP3+ T cells was higher in the groups of mice who received Sm22.6, Sm29 and PIII, being the expression of IL-10 by these cells only higher in mice immunized with Sm22.6. We concluded that the S. mansoni antigens used in this study are able to down-modulate allergic inflammatory mediators in a murine model of airway inflammation and that the CD4+FoxP3+ T cells, even in the absence of IL-10 expression, might play an important role in this process. PMID:20132231

  13. Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation

    PubMed Central

    Cardoso, L S; Oliveira, S C; Góes, A M; Oliveira, R R; Pacífico, L G; Marinho, F V; Fonseca, C T; Cardoso, F C; Carvalho, E M; Araujo, M I

    2010-01-01

    Schistosoma mansoni infection has been associated with protection against allergies. The mechanisms underlying this association may involve regulatory cells and cytokines. We evaluated the immune response induced by the S. mansoni antigens Sm22·6, PIII and Sm29 in a murine model of ovalbumin (OVA)-induced airway inflammation. BALB/c mice were sensitized with subcutaneously injected OVA-alum and challenged with aerolized OVA. Mice were given three doses of the different S. mansoni antigens. Lung histopathology, cellularity of bronchoalveolar lavage (BAL) and eosinophil peroxidase activity in lung were evaluated. Immunoglobulin (Ig)E levels in serum and cytokines in BAL were also measured. Additionally, we evaluated the frequency of CD4+forkhead box P3 (FoxP3)+ T cells in cultures stimulated with OVA and the expression of interleukin (IL)-10 by these cells. The number of total cells and eosinophils in BAL and the levels of OVA-specific IgE were reduced in the immunized mice. Also, the levels of IL-4 and IL-5 in the BAL of mice immunized with PIII and Sm22·6 were decreased, while the levels of IL-10 were higher in mice immunized with Sm22·6 compared to the non-immunized mice. The frequency of CD4+FoxP3+ T cells was higher in the groups of mice who received Sm22·6, Sm29 and PIII, being the expression of IL-10 by these cells only higher in mice immunized with Sm22·6. We concluded that the S. mansoni antigens used in this study are able to down-modulate allergic inflammatory mediators in a murine model of airway inflammation and that the CD4+FoxP3+ T cells, even in the absence of IL-10 expression, might play an important role in this process. PMID:20132231

  14. Depressive Symptoms Are Associated with Mental Stress-Induced Myocardial Ischemia after Acute Myocardial Infarction

    PubMed Central

    Wei, Jingkai; Pimple, Pratik; Shah, Amit J.; Rooks, Cherie; Bremner, J. Douglas; Nye, Jonathon A.; Ibeanu, Ijeoma; Murrah, Nancy; Shallenberger, Lucy; Raggi, Paolo; Vaccarino, Viola

    2014-01-01

    Objectives Depression is an adverse prognostic factor after an acute myocardial infarction (MI), and an increased propensity toward emotionally-driven myocardial ischemia may play a role. We aimed to examine the association between depressive symptoms and mental stress-induced myocardial ischemia in young survivors of an MI. Methods We studied 98 patients (49 women and 49 men) age 38–60 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging at rest, after mental stress (speech task), and after exercise or pharmacological stress. A summed difference score (SDS), obtained with observer-independent software, was used to quantify myocardial ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, which were analyzed as overall score, and as separate somatic and cognitive depressive symptom scores. Results There was a significant positive association between depressive symptoms and SDS with mental stress, denoting more ischemia. After adjustment for demographic and lifestyle factors, disease severity and medications, each incremental depressive symptom was associated with 0.14 points higher SDS. When somatic and cognitive depressive symptoms were examined separately, both somatic [β = 0.17, 95% CI: (0.04, 0.30), p = 0.01] and cognitive symptoms [β = 0.31, 95% CI: (0.07, 0.56), p = 0.01] were significantly associated with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress. Conclusion Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with physical (exercise or pharmacological) stress. PMID:25061993

  15. Lipopolysaccharide stimulation of dendritic cells induces interleukin-10 producing allergen-specific T cells in vitro but fails to prevent allergic airway disease.

    PubMed

    Ahrens, Birgit; Freund, Tobias; Rha, Ro-Dug; Dittrich, Anna-Maria; Quarcoo, David; Hutloff, Andreas; Hamelmann, Eckard

    2009-05-01

    Dendritic cells (DCs) play an important role in directing naive T cells towards a Th1/Th2 or regulatory T cells (Treg) cell phenotype. In this context, interleukin (IL)-10 has been shown to exhibit immune regulatory capacities. The aim of this study was to delineate the influence of high-IL-10-producing DCs on DC-T-cell interactions in inhibiting allergen-induced airway inflammation and hyperreactivity in a murine model of allergic airway disease. Bone marrow-derived dendritic cells (BMDCs) were generated from hemopoietic progenitors by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF), and stimulated with ovalbumin (OVA) +/- lipopolysaccharide (LPS). The effects of ovalbumin-pulsed BMDCs on cytokine production by allergen-specific naive T cells were studied in vitro. The development of airway inflammation in Balb/c mice was determined after intranasal administration of BMDCs in vivo. LPS stimulation of BMDCs strongly enhanced IL-10 production. Coculture of LPS-modulated DCs exhibiting increased IL-10 production with allergen-specific naive T cells reduced the production of interferon (IFN)-gamma and IL-5, but enhanced the production of IL-10. After blockade with anti-IL-10 plus anti-IL-10-receptor antibodies, the level of IFN-gamma and IL-5 production by cocultured T cells was restored, underlining the regulatory function of IL-10. Intranasal administration of high-IL-10-producing LPS-stimulated, OVA-primed BMDCs prior to repetitive airway allergen challenges resulted in an even enhanced airway inflammation. These data demonstrate that increased IL-10 production by DCs may be a critical element for T-cell activation and differentiation in the context of allergen-induced immune responses in vitro. However, this DC modulation did not translate into suppression of allergic airway disease in vivo. PMID:19415548

  16. Larynx during exercise: the unexplored bottleneck of the airways.

    PubMed

    Røksund, Ola Drange; Heimdal, John-Helge; Olofsson, Jan; Maat, Robert Christiaan; Halvorsen, Thomas

    2015-09-01

    Exercise-induced shortness of breath is not uncommon in otherwise healthy young people. Based on the presenting symptoms alone, it is challenging to distinguish exercise-induced asthma (EIA) from exercise-induced obstruction of central airways, sometimes leading to diagnostic errors and inadequate treatment. Central airway obstruction usually presents with exercise-induced inspiratory symptoms (EIIS) during ongoing exercise. EIIS tends to peak towards the end of an exercise session or immediately after its completion, contradicting symptoms of EIA typically peaking 3-15 min after the exercise has stopped. EIIS is usually associated with some form of laryngeal obstruction. Transnasal flexible laryngoscopy performed continuously throughout an incremental exercise test from rest to exhaustion or to intolerable symptoms is usually diagnostic, and also provides information that is important for further handling and treatment. Reflecting the complex anatomy and functional features of the larynx, exercise-induced laryngeal obstruction (EILO) appears to be a heterogeneous condition. Contradicting previous beliefs, recent literature suggests that laryngeal adduction in a majority of cases starts in supraglottic structures and that vocal cord adduction (VCD) most often occurs as a secondary phenomenon. However, EILO is poorly understood and more and better research is needed to unravel causal mechanisms. The evidence base for treatment of EILO is weak. Speech therapy, psychotherapy, biofeedback, muscle training, anticholinergic aerosols have all been applied, as has laser supraglottoplasty. Randomized controlled trials with well-defined and verifiable inclusion and success criteria are required to establish evidence-based treatment schemes. PMID:25033930

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

    PubMed Central

    Kim, Jiwook; Kim, Bokyoum; Kim, Joowon; Shin, Yusom; Kim, Judeok; Ryu, Siejeong; Yang, Yu-Mi

    2016-01-01

    Mucus secretion is often uncontrolled in many airway inflammatory diseases of humans. Identifying the regulatory pathway(s) of mucus gene expression, mucus overproduction, and hypersecretion is important to alleviate airway inflammation in these diseases. However, the regulatory signaling pathway controlling mucus overproduction has not been fully identified yet. In this study, we report that the ATP/P2Y2 complex secretes many cytokines and chemokines to regulate airway inflammation, among which IL-1 receptor antagonist (IL-1ra) downregulates MUC5AC gene expression via the inhibition of Gαq-induced Ca2+ signaling. IL-1ra inhibited IL-1α protein expression and secretion, and vice versa. Interestingly, ATP/P2Y2-induced IL-1ra and IL-1α secretion were both mediated by PLCβ3. A dominant-negative mutation in the PDZ-binding domain of PLCβ3 inhibited ATP/P2Y2-induced IL-1ra and IL-1α secretion. IL-1α in the presence of the ATP/P2Y2 complex activated the ERK1/2 pathway in a greater degree and for a longer duration than the ATP/P2Y2 complex itself, which was dramatically inhibited by IL-1ra. These findings suggest that secreted IL-1ra exhibits a regulatory effect on ATP/P2Y2-induced MUC5AC gene expression, through inhibition of IL-1α secretion, to maintain the mucus homeostasis in the airway. Therefore, IL-1ra could be an excellent modality for regulating inflamed airway microenvironments in respiratory diseases. PMID:27034593

  18. Adalimumab ameliorates OVA-induced airway inflammation in mice: Role of CD4(+) CD25(+) FOXP3(+) regulatory T-cells.

    PubMed

    Elsakkar, Mohamed G; Sharaki, Olla A; Abdallah, Dina M; Mostafa, Dalia K; Shekondali, Fadia T

    2016-09-01

    Asthma is a chronic inflammatory heterogeneous disorder initiated by a dysregulated immune response which drives disease development in susceptible individuals. Though T helper 2 (TH2) biased responses are usually linked to eosinophilic asthma, other Th cell subsets induce neutrophilic airway inflammation which provokes the most severe asthmatic phenotypes. A growing evidence highlights the role of T regulatory (Treg) cells in damping abnormal Th responses and thus inhibiting allergy and asthma. Therefore, strategies to induce or augment Treg cells hold promise for treatment and prevention of allergic airway inflammation. Recently, the link between Tumor necrosis factor-α (TNF-α) and Treg has been uncovered, and TNF-α antagonists are increasingly used in many autoimmune diseases. Yet, their benefits in allergic airway inflammation is not clarified. We investigated the effect of Adalimumab, a TNF-α antagonist, on Ovalbumin (OVA)-induced allergic airway inflammation in CD1 mice and explored its impact on Treg cells. Our results showed that Adalimumab treatment attenuated the OVA-induced increase in serum IgE, TH2 and TH1 derived inflammatory cytokines (IL-4 and IFN-γ, respectively) in bronchoalveolar lavage (BAL) fluid, suppressed recruitment of inflammatory cells in BAL fluid and lung, and inhibited BAL fluid neutrophilia. It also ameliorated goblet cell metaplasia and bronchial fibrosis. Splenocytes flow cytometry revealed increased percentage of CD4(+) CD25(+) FOXP3(+) Treg cells by Adalimumab that was associated with increase in their suppressive activity as shown by elevated BAL fluid IL-10. We conclude that the beneficial effects of Adalimumab in this CD1 neutrophilic model of allergic airway inflammation are attributed to augmentation of Treg cell number and activity. PMID:27262379

  19. Transcription Factor Runx3 Is Induced by Influenza A Virus and Double-Strand RNA and Mediates Airway Epithelial Cell Apoptosis

    PubMed Central

    Gan, Huachen; Hao, Qin; Idell, Steven; Tang, Hua

    2015-01-01

    Influenza A virus (IAV) targets airway epithelial cells and exploits the host cell machinery to replicate, causing respiratory illness in annual epidemics and pandemics of variable severity. The high rate of antigenic drift (viral mutation) and the putative antigenic shift (reassortant strains) have raised the need to find the host cell inducible factors modulating IAV replication and its pathogenesis to develop more effective antiviral treatment. In this study, we found for the first time that transcription factor Runx3, a developmental regulator and tumor suppressor, was induced by IAV H1N1 and H3N2, viral RNA, a synthetic analog of viral double-stranded RNA (dsRNA) polyinosinic-polycytidylic acid, and type-II interferon-γ (IFNγ) in human airway epithelial cells. Whereas Runx3 was essentially not induced by type-I IFNα and type-III IFNλ, we show that Runx3 induction by IAV infection and viral RNA is mediated through the innate immune receptor MDA5 and the IκB kinase-β−NF-κB pathway. Moreover, we provide substantial evidence indicating that Runx3 plays a crucial role in airway epithelial cell apoptosis induced by IAV infection and dsRNA through the activation of extrinsic and intrinsic apoptosis pathways. Thus, we have identified Runx3 as an inducible and important transcription factor modulating IAV-induced host epithelial cell apoptosis. PMID:26643317

  20. Biochanin A, a Phytoestrogenic Isoflavone with Selective Inhibition of Phosphodiesterase 4, Suppresses Ovalbumin-Induced Airway Hyperresponsiveness

    PubMed Central

    Ko, Wun-Chang; Lin, Ling-Hung; Shen, Hsin-Yi; Lai, Chi-Yin; Chen, Chien-Ming; Shih, Chung-Hung

    2011-01-01

    The present study investigated the potential of biochanin A, a phytoestrogenic isoflavone of red clover (Triflolium pratense), for use in treating asthma or chronic obstructive pulmonary disease (COPD). Biochanin A (100 μmol/kg, orally (p.o.)) significantly attenuated airway resistance (RL), enhanced pause (Penh), and increased lung dynamic compliance (Cdyn) values induced by methacholine (MCh) in sensitized and challenged mice. It also significantly suppressed an increase in the number of total inflammatory cells, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, and tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid (BALF) of the mice. However, it did not influence interferon (IFN)-γ levels. Biochanin A (100 μmol/kg, p.o.) also significantly suppressed the total and ovalbumin (OVA)-specific immunoglobulin E (IgE) levels in the serum and BALF, and enhanced the total IgG2a level in the serum of these mice. The PDE4H/PDE4L value of biochanin A was calculated as >35. Biochanin A did not influence xylazine/ketamine-induced anesthesia. Biochanin A (10~30 μM) significantly reduced cumulative OVA (10~100 μg/mL)-induced contractions in the isolated guinea pig trachealis, suggesting that it inhibits degranulation of mast cells. In conclusion, red clover containing biochanin A has the potential for treating allergic asthma and COPD. PMID:21437195

  1. Upper airway collapse during drug induced sleep endoscopy: head rotation in supine position compared with lateral head and trunk position.

    PubMed

    Safiruddin, Faiza; Koutsourelakis, Ioannis; de Vries, Nico

    2015-02-01

    Drug induced sedated sleep endoscopy (DISE) is often employed to determine the site, severity and pattern of obstruction in patients with sleep apnea. DISE is usually performed in supine position. We recently showed that the obstruction pattern is different when DISE is performed in lateral position. In this study, we compared the outcomes of DISE performed in supine position with head rotated, with the outcomes of DISE performed with head and trunk in lateral position. The Prospective study design was used in the present study. Sixty patients with OSA (44 male; mean apnea hypopnea index (AHI) 20.8 ± 17.5 events/h) underwent DISE under propofol sedation. Patients were placed in lateral position, and the upper airway collapse was evaluated. The patients were then placed in supine position with the head rotated to the right side. DISE outcomes were scored using the VOTE classification system. In lateral position, nine patients (15.0%) had a complete antero-posterior (A-P) collapse at the level of the velum, nine had a partial A-P collapse. During head rotation and trunk in supine position, at the level of the velum, four patients (6.7%) had a complete A-P collapse, while two patients (3.3%) had a partial A-P collapse. For all other sites, the patterns of collapse were not significantly different between head rotation and lateral position. During DISE, rotation of the head in supine position, and lateral head and trunk position present similar sites, severity and patterns of upper airway collapse, with the exception of collapse at the level of the velum. Here the severity of A-P collapse is less severe during head rotation than in lateral head and trunk position. PMID:25142078

  2. Comparative Study of Protective Effects of Salbutamol and Beclomethasone against Insulin Induced Airway Hyper-reactivity on Isolated Tracheal Smooth Muscle of Guinea Pig

    PubMed Central

    Sharif, Mahjabeen; Tayyaba Khan, Bushra; Bakhtiar, Salman; Anwar, Mohammad Asim

    2015-01-01

    Inhalational insulin was withdrawn from the market due to its potential to produce airway hyper-reactivity and bronchoconstriction. So the present study was designed to explore the acute effects of insulin on airway reactivity of guinea pigs and protective effects of salbutamol and beclomethasone against insulin induced airway hyper-responsiveness on isolated tracheal smooth muscle of guinea pig. Effects of varying concentrations of insulin (10-7 to 10-3 M), insulin pretreated with fixed concentration of salbutamol (10-7 M) and beclomethasone (10-6 M) were studied on isolated tracheal tissue of guinea pig by constructing cumulative concentration response curves. Changes in tracheal smooth muscle contractions were recorded on four channel oscillograph. The mean ± SEM of maximum amplitudes of contraction with increasing concentrations of insulin, insulin pretreated with fixed concentration of salbutamol and beclomethasone were 35 ± 1.13 mm, 14.55 ± 0.62 mm and 22 ± 1.154 mm respectively. Although salbutamol and beclomethasone both had a profound inhibitory effect on insulin induced airway hyper-reactivity, yet salbutamol is more efficacious than beclomethasone. So we suggest that pretreatment of inhaled insulin with salbutamol may be preferred over beclomethasone in amelioration of its potential respiratory adverse effects such as bronchoconstriction. PMID:25901165

  3. Chenodeoxycholic acid attenuates ovalbumin-induced airway inflammation in murine model of asthma by inhibiting the T(H)2 cytokines.

    PubMed

    Shaik, Firdose Begum; Panati, Kalpana; Narasimha, Vydyanath R; Narala, Venkata Ramireddy

    2015-08-01

    Asthma is a complex highly prevalent airway disease that is a major public health problem for which current treatment options are inadequate. Recently, farnesoid X receptor (FXR) has been shown to exert anti-inflammatory actions in various disease conditions, but there have been no reported investigations of Chenodeoxycholic acid (CDCA), a natural FXR agonist, in allergic airway inflammation. To test the CDCA effectiveness in airway inflammation, ovalbumin (OVA)-induced acute murine asthma model was established. We found that lung tissue express FXR and CDCA administration reduced the severity of the murine allergic airway disease as assessed by pathological and molecular markers associated with the disease. CDCA treatment resulted in fewer infiltrations of cells into the airspace and peribronchial areas, and decreased goblet cell hyperplasia, mucus secretion and serum IgE levels which was increased in mice with OVA-induced allergic asthma. The CDCA treatment further blocked the secretion of TH2 cytokines (IL-4, IL-5 and IL-13) and proinflammatory cytokine TNF-α indicate that the FXR and its agonists may have potential for treating allergic asthma. PMID:26067554

  4. Eosinophil accumulation in pulmonary airways of guinea-pigs induced by exposure to an aerosol of platelet-activating factor: effect of anti-asthma drugs.

    PubMed Central

    Sanjar, S.; Aoki, S.; Boubekeur, K.; Chapman, I. D.; Smith, D.; Kings, M. A.; Morley, J.

    1990-01-01

    1. Exposure of guinea-pigs to aerosols of platelet activating factor (PAF) (0.01 to 100 micrograms ml-1) induced a dose-dependent increased incidence of eosinophils in bronchoalveolar lavage fluid (BAL) at 48 h. Total leucocyte numbers and the percentages of lymphocytes and neutrophils were unchanged in BAL fluid. 2. Increased numbers of eosinophils were detected in BAL 1 h after exposure to PAF but eosinophilia was not maximal until 48 h. One week after exposure to PAF, the percentage of eosinophils in BAL was within the normal range. 3. Depletion of circulating platelets or neutrophils by intravenous injection of specific antisera did not modify accumulation of eosinophils in the airway lumen following inhalation of PAF (10 micrograms ml-1). 4. PAF-induced pulmonary airway eosinophil accumulation was inhibited by treatment with SDZ 64-412, a selective PAF-antagonist, whether the compound was administered before, or 30 min after, inhalation of PAF. 5. Pulmonary airway eosinophil accumulation due to inhaled PAF (10 micrograms ml-1) was inhibited by prior treatment with aminophylline, cromoglycate, ketotifen, dexamethasone and AH 21-132. 6. Pulmonary airway eosinophil accumulation due to inhaled PAF (10 micrograms ml-1) was not inhibited by prior treatment with indomethacin, salbutamol or mepyramine. PMID:2328394

  5. The effects of inhaled corticosteroids on intrinsic responsiveness and histology of airways from infant monkeys exposed to house dust mite allergen and ozone

    SciTech Connect

    Joad, Jesse P. Kott, Kayleen S.; Bric, John M.; Schelegle, Edward S.; Gershwin, Laurel J.; Plopper, Charles G.; Peake, Janice L.; Pinkerton, Kent E.

    2008-01-15

    Inhaled corticosteroids (ICS) are recommended to treat infants with asthma, some with intermittent asthma. We previously showed that exposing infant monkeys to allergen/ozone resulted in asthma-like characteristics of their airways. We evaluated the effects of ICS on histology and intrinsic responsiveness of allergen/ozone-exposed and normal infant primate airways. Infant monkeys were exposed by inhalation to (1) filtered air and saline, (2) house dust mite allergen (HDMA) + ozone and saline, (3) filtered air and ICS (budesonide) or (4) HDMA + ozone and ICS. Allergen/ozone exposures started at 1 month and ICS at 3 months of age. At 6 months of age, methacholine-induced changes in luminal area of airways in proximal and distal lung slices were determined using videomicrometry, followed by histology of the same slices. Proximal airway responsiveness was increased by allergen/ozone and by ICS. Eosinophil profiles were increased by allergen/ozone in both proximal and distal airways, an effect that was decreased by ICS in distal airways. In both allergen/ozone- and air-exposed monkeys, ICS increased the number of alveolar attachments in distal airways, decreased mucin in proximal airways and decreased epithelial volume in both airways. ICS increased smooth muscle in air-exposed animals while decreasing it in allergen/ozone-exposed animals in both airways. In proximal airways, there was a small but significant positive correlation between smooth muscle and airway responsiveness, as well as between alveolar attachments and responsiveness. ICS change morphology and function in normal airways as well as allergen/ozone-exposed airways, suggesting that they should be reserved for infants with active symptoms.

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

    PubMed

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

    2011-04-22

    Asthma is characterized by Th2-mediated inflammation, resulting in airway hyperresponsiveness (AHR) through airway remodeling. Recent epidemiological and experimental reports have suggested an inverse relationship between the development of allergy and helminth infections. Infection by Clonorchis sinensis, a liver fluke that resides in the bile duct of humans, is endemic predominantly in Asia including Korea and China. Using a murine model for asthma, we investigated the effects of C. sinensis-derived total protein (Cs-TP) on allergen-induced airway inflammation and the mechanism underlying the protective effects of Cs-TP administration on asthma. Treatment with Cs-TP attenuated OVA-induced airway inflammation and methacholine-induced AHR, as well as eosinophilia development, lymphocyte infiltration into the lung, and goblet cell metaplasia. This protective effect of Cs-TP is associated with markedly reduced OVA-specific IgE and Th1/Th2 cytokine production. Moreover, Cs-TP increased the number of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells as well as their suppressive activity. In fact, proliferation of OVA-restimulated splenocytes was suppressed significantly. Cs-TP also inhibited the expression of such co-stimulatory molecules as CD80, CD86, and CD40 in LPS- or OVA-stimulated dendritic cells (DCs), suggesting that Cs-TP could interfere with the capacity of airway DCs to prime naïve T cells. These data demonstrate the capacity of C. sinensis to ameliorate allergic asthma and broaden our understanding of the paradoxical relationship between the allergic immune response and helminth infection. PMID:21440530

  7. Primary renal magnesium wasting: an unusual clinical picture of exercise-induced symptoms.

    PubMed

    Stark, Christopher M; Nylund, Cade M; Gorman, Gregory H; Lechner, Brent L

    2016-04-01

    Magnesium is one of the most abundant cations in the human body and plays a key role as a metabolic enzyme cofactor and regulatory ion for neurons and cardiomyocytes. Hypomagnesemia due to isolated primary renal magnesium wasting is a rare clinical condition typically associated with neurological hyperexcitability. Exercise-related gastrointestinal symptoms are caused by ischemic, mechanical, or neurohormonal changes. The role of hypomagnesemia in gastrointestinal symptoms is not well understood. We present a case of a 15-year-old male who presented with exercise-induced abdominal pain, nausea, and vomiting, who was found to have profound hypomagnesemia and inappropriately elevated fractional excretion of magnesium (FEMg). Testing for multiple intrinsic and extrinsic etiologies of renal magnesium wasting was inconclusive. He was diagnosed with primary renal magnesium wasting and his symptoms resolved acutely with intravenous magnesium sulfate and with long-term oral magnesium chloride. Primary renal magnesium wasting is a rare clinical entity that can cause extreme hypomagnesemia. It has not been associated previously with exercise-induced gastrointestinal symptoms. The effects of hypomagnesemia on the human gastrointestinal tract are not well established. This case offers unique insights into the importance of magnesium homeostasis in the gastrointestinal tract. Exercise-induced splanchnic hypoperfusion may contribute to gastrointestinal symptoms observed in this chronically hypomagnesemic patient. PMID:27117800

  8. Esophageal Submucosal Injection of Capsaicin but Not Acid Induces Symptoms in Normal Subjects

    PubMed Central

    Lee, Robert H; Korsapati, Hariprasad; Bhalla, Vikas; Varki, Nissi; Mittal, Ravinder K

    2016-01-01

    Background/Aims Transient receptor potential vanilloid-1 (TRPV1) is a candidate for mediating acid-induced symptoms in the esophagus. We conducted studies to determine if the presence of acid in the mucosa/submucosa and direct activation of TRPV1 by capsaicin elicited symptoms in normal healthy subjects. We also studied the presence of TRPV1 receptors in the esophagus. Methods Unsedated endoscopy was performed on healthy subjects with no symptoms. Using a sclerotherapy needle, normal saline (pH 2.0–7.5) was injected into the mucosa/submucosa, 5 cm above the Z line. In a separate group of healthy subjects, injection of capsaicin and vehicle was also studied. Quality of symptoms was reported using the McGill Pain Questionnaire, and symptom intensity using the visual analogue scale (VAS). Immunohistochemistry was performed on 8 surgical esophagus specimens using TRPV1 antibody. Results Acid injection either did not elicit or elicited mild symptoms in subjects at all pH solutions. Capsaicin but not the vehicle elicited severe heartburn/chest pain in all subjects. Mean VAS for capsaicin was 91 ± 3 and symptoms lasted for 25 ± 1 minutes. Immunohistochemistry revealed a linear TRPV1 staining pattern between the epithelial layer and the submucosa that extended into the papillae. Eighty-five percent of papillae stained positive for TRPV1 with a mean 1.1 positive papillae per high-powered field. Conclusions The mechanism of acid-induced heartburn and chest pain is not the simple interaction of hydrogen ions with afferents located in the esophageal mucosa and submucosa. TRPV1 receptors are present in the lamina propria and their activation induces heartburn and chest pain. PMID:26932896

  9. A mannose receptor mediates mannosyl-rich glycoprotein-induced mitogenesis in bovine airway smooth muscle cells.

    PubMed Central

    Lew, D B; Songu-Mize, E; Pontow, S E; Stahl, P D; Rattazzi, M C

    1994-01-01

    The putative mannose receptor (MR), previously implicated in mannosyl-rich glycoprotein-induced mitogenesis in bovine airway smooth muscle (ASM) cells, was studied to determine its properties. Specific binding of the mitogenic neoglycoprotein, mannosylated bovine serum albumin (Man-BSA) to ASM cells was saturable, with an apparent Kd = 5.0 x 10(-8) M. Cell-bound ManBSA-colloidal gold conjugate was localized by electron microscopy to clathrin-coated pits on the cell surface, and was found to undergo internalization to endosomes; this was inhibitable by weak bases and swainsonine, that also inhibited ligand-induced mitogenesis. The ASM-MR, isolated by mannose-affinity chromatography, had the same apparent molecular mass as the macrophage (Mø) MR (M(r) = 175 kD), and was immunoprecipitated by an anti-MøMR immune serum. This antiserum blocked 125I-labeled-ManBSA binding to intact ASM cells, stimulated mitogenesis, and immunolocalized the ASM-MR in cytoplasmic vesicles compatible with endosomes. A monoclonal antibody directed against the MøMR also reacted with the ASM-MR; like the polyclonal antibodies, it stimulated mitogenesis as effectively as beta-hexosaminidases. These data indicate that the ASM-MR shares a number of functional and structural properties with the MøMR and suggest that similar receptors may have different main functions in different cells. Images PMID:7962531

  10. Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase

    PubMed Central

    Mishra, Amarjit; Brown, Alexandra L.; Yao, Xianglan; Yang, Shutong; Park, Sung-Jun; Liu, Chengyu; Dagur, Pradeep K.; McCoy, J. Philip; Keeran, Karen J.; Nugent, Gayle Z.; Jeffries, Kenneth R.; Qu, Xuan; Yu, Zu-Xi; Levine, Stewart J.; Chung, Jay H.

    2015-01-01

    DNA-dependent protein kinase (DNA-PK) mediates double stranded DNA break repair, V(D)J recombination, and immunoglobulin class switch recombination, as well as innate immune and pro-inflammatory responses. However, there is limited information regarding the role of DNA-PK in adaptive immunity mediated by dendritic cells (DCs), which are the primary antigen-presenting cells in allergic asthma. Here we show that house dust mite induces DNA-PK phosphorylation, which is a marker of DNA-PK activation, in DCs via the generation of intracellular reactive oxygen species. We also demonstrate that pharmacological inhibition of DNA-PK, as well as the specific deletion of DNA-PK in DCs, attenuates the induction of allergic sensitization and Th2 immunity via a mechanism that involves the impaired presentation of mite antigens. Furthermore, pharmacological inhibition of DNA-PK following antigen priming similarly reduces the manifestations of mite-induced airway disease. Collectively, these findings suggest that DNA-PK may be a potential target for treatment of allergic asthma. PMID:25692509

  11. Suppression of ovalbumin-induced airway inflammatory responses in a mouse model of asthma by Mimosa pudica extract.

    PubMed

    Yang, Eun Ju; Lee, Ji-Sook; Yun, Chi-Young; Ryang, Yong Suk; Kim, Jong-Bae; Kim, In Sik

    2011-01-01

    Asthma is an inflammatory airway disease. The pathogenic mechanisms of asthma include the infiltration of leukocytes and release of cytokines. Mimosa pudica (Mp) has been used traditionally for the treatment of insomnia, diarrhea and inflammatory diseases. Although Mp extract has various therapeutic properties, the effect of this extract on asthma has not yet been reported. This study investigated the suppressive effects of Mp extract on asthmatic responses both in vitro and in vivo. Mp extract was acquired from dried and powdered whole plants of M. pudica using 80% ethanol. BALB/c mice were used for the mouse model of asthma induced by ovalbumin. Mp extract significantly inhibited the HMC-1 cell migration induced by stem cell factor and blocked the release of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) in EoL-1 cells. Leukocytosis, eosinophilia and mucus hypersecretion in asthmatic lung were significantly suppressed by Mp extract. The release of ovalbumin-specific IgE in bronchoalveolar lavage fluid and serum was also decreased. Mp extract treatment resulted in no liver cytotoxicity. The Mp extract has inhibitory properties on asthma and may be used as a potent therapeutic agent for allergic lung inflammation. PMID:20623591

  12. Gene expression profiling reveals insight into how distinct viruses induce symptoms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant viruses induce a wide array of disease symptoms and cytopathic effects including alterations of chloroplasts, ribosomes, and cellular architecture. While some of these changes are virus specific, many are common even among diverse viruses, and in most cases, the molecular determinants respons...

  13. Child and parent perceived food-induced gastrointestinal symptoms and quality of life in children with functional gastrointestinal disorders

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It is unknown whether children with functional gastrointestinal (GI) disorders identify specific foods that exacerbate their GI symptoms. The objectives of this study were to determine the perceived role of food on GI symptoms and to determine the impact of food-induced symptoms on quality of life (...

  14. Viruses as precipitants of asthma symptoms. II. Physiology and mechanisms.

    PubMed

    Bardin, P G; Johnston, S L; Pattemore, P K

    1992-09-01

    The upper and lower airways have complimentary roles in the ultimate object of supplying the body with oxygen whilst removing waste products of metabolism. Pathology in one area may trigger a response in another, the physiology of which, in the case of virus-induced asthma exacerbations remains poorly characterized. Viral infection of the upper airways by common cold viruses frequently triggers a response in the lower airways leading to prolonged morbidity, especially in subjects with significant pre-existing airway disease. The induction or amplification of BHR may be an important mechanism whereby asthmatic symptoms are produced although the cellular and tissue events or reflex mechanisms activated by viral illnesses and underlying BHR changes are poorly defined and may be dependent on the type and the severity of infection. Children and asthmatics tend to develop frequent colds setting in motion a sequence of events culminating in airway obstruction and symptoms of wheezing, coughing and chest tightness. This may reflect independent inflammatory changes caused by a simply additive effect of viral damage to the mucosa superimposed upon pre-existing allergic inflammation (Fig. 1). Few if any symptoms will develop in normal subjects with a mild cold whereas significant symptoms may ensue if the cold is severe and induces marked lower airway swelling, secretions and smooth muscle contraction; pathology to which children who have small calibre airways may be particularly susceptible. In asthmatics even a mild cold frequently induces exacerbation of symptoms, while serious life-threatening asthma attacks may occur associated with a severe cold. Some studies have suggested that this effect is not only additive but also synergistic and brought about by release of the mediators already present in increased quantities, the induction of IgE synthesis, or by the potentiation of neural and epithelial damage. The combined effect of both asthma and viruses may thus be

  15. Involvement of the MAPK and PI3K pathways in chitinase 3-like 1-regulated hyperoxia-induced airway epithelial cell death

    SciTech Connect

    Kim, Mi Na; Lee, Kyung Eun; Hong, Jung Yeon; Heo, Won Il; Kim, Kyung Won; Kim, Kyu Earn; Sohn, Myung Hyun

    2012-05-18

    Highlights: Black-Right-Pointing-Pointer Hyperoxia induces apoptosis and chitinase 3-like 1 expression in human airway epithelial cells. Black-Right-Pointing-Pointer Presence of chitinase 3-like 1 affects airway epithelial cell death after hyperoxic exposure. Black-Right-Pointing-Pointer Silencing chitinase 3-like 1 manipulate the phosphorylation of ERK, p38 and Akt. -- Abstract: Background: Exposure to 100% oxygen causes hyperoxic acute lung injury characterized by cell death and injury of alveolar epithelial cells. Recently, the role of chitinase 3-like 1 (CHI3L1), a member of the glycosyl hydrolase 18 family that lacks chitinase activity, in oxidative stress was demonstrated in murine models. High levels of serum CHI3L1 have been associated with various diseases of the lung, such as asthma, chronic obstructive pulmonary disease, and cancer. However, the role of CHI3L1 in human airway epithelial cells undergoing oxidative stress remains unknown. In addition, the signaling pathways associated with CHI3L1 in this process are poorly understood. Purpose: In this study, we demonstrate the role of CHI3L1, along with the MAPK and PI3K signaling pathways, in hyperoxia-exposed airway epithelial cells. Method: The human airway epithelial cell line, BEAS-2B, was exposed to >95% oxygen (hyperoxia) for up to 72 h. Hyperoxia-induced cell death was determined by assessing cell viability, Annexin-V FITC staining, caspase-3 and -7 expression, and electron microscopy. CHI3L1 knockdown and overexpression studies were conducted in BEAS-2B cells to examine the role of CHI3L1 in hyperoxia-induced apoptosis. Activation of the MAPK and PI3K pathways was also investigated to determine the role of these signaling cascades in this process. Results: Hyperoxia exposure increased CHI3L1 expression and apoptosis in a time-dependent manner. CHI3L1 knockdown protected cells from hyperoxia-induced apoptosis. In contrast, CHI3L1 overexpression promoted cell death after hyperoxia exposure. Finally

  16. Alternaria-Induced Release of IL-18 from Damaged Airway Epithelial Cells: An NF-κB Dependent Mechanism of Th2 Differentiation?

    PubMed Central

    Wild, Jim; Dharajiya, Nilesh; Vaidya, Swapnil; Kalita, Anjana; Bacsi, Attila; Corry, David; Kurosky, Alexander; Brasier, Allan; Boldogh, Istvan; Sur, Sanjiv

    2012-01-01

    Background A series of epidemiologic studies have identified the fungus Alternaria as a major risk factor for asthma. The airway epithelium plays a critical role in the pathogenesis of allergic asthma. These reports suggest that activated airway epithelial cells can produce cytokines such as IL-25, TSLP and IL-33 that induce Th2 phenotype. However the epithelium-derived products that mediate the pro-asthma effects of Alternaria are not well characterized. We hypothesized that exposure of the airway epithelium to Alternaria releasing cytokines that can induce Th2 differentiation. Methodology/Principal Finding We used ELISA to measure human and mouse cytokines. Alternaria extract (ALT-E) induced rapid release of IL-18, but not IL-4, IL-9, IL-13, IL-25, IL-33, or TSLP from cultured normal human bronchial epithelial cells; and in the BAL fluids of naïve mice after challenge with ALT-E. Both microscopic and FACS indicated that this release was associated with necrosis of epithelial cells. ALT-E induced much greater IL-18 release compared to 19 major outdoor allergens. Culture of naïve CD4 cells with rmIL-18 induced Th2 differentiation in the absence of IL-4 and STAT6, and this effect was abrogated by disrupting NF- κB p50 or with a NEMO binding peptide inhibitor. Conclusion/Significance Rapid and specific release of IL-18 from Alternaria-exposed damaged airway epithelial cells can directly initiate Th2 differentiation of naïve CD4+ T-cells via a unique NF-κB dependent pathway. PMID:22347372

  17. Virulence Factors of Pseudomonas aeruginosa Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells.

    PubMed

    van 't Wout, Emily F A; van Schadewijk, Annemarie; van Boxtel, Ria; Dalton, Lucy E; Clarke, Hanna J; Tommassen, Jan; Marciniak, Stefan J; Hiemstra, Pieter S

    2015-06-01

    Pseudomonas aeruginosa infection can be disastrous in chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. Its toxic effects are largely mediated by secreted virulence factors including pyocyanin, elastase and alkaline protease (AprA). Efficient functioning of the endoplasmic reticulum (ER) is crucial for cell survival and appropriate immune responses, while an excess of unfolded proteins within the ER leads to "ER stress" and activation of the "unfolded protein response" (UPR). Bacterial infection and Toll-like receptor activation trigger the UPR most likely due to the increased demand for protein folding of inflammatory mediators. In this study, we show that cell-free conditioned medium of the PAO1 strain of P. aeruginosa, containing secreted virulence factors, induces ER stress in primary bronchial epithelial cells as evidenced by splicing of XBP1 mRNA and induction of CHOP, GRP78 and GADD34 expression. Most aspects of the ER stress response were dependent on TAK1 and p38 MAPK, except for the induction of GADD34 mRNA. Using various mutant strains and purified virulence factors, we identified pyocyanin and AprA as inducers of ER stress. However, the induction of GADD34 was mediated by an ER stress-independent integrated stress response (ISR) which was at least partly dependent on the iron-sensing eIF2α kinase HRI. Our data strongly suggest that this increased GADD34 expression served to protect against Pseudomonas-induced, iron-sensitive cell cytotoxicity. In summary, virulence factors from P. aeruginosa induce ER stress in airway epithelial cells and also trigger the ISR to improve cell survival of the host. PMID:26083346

  18. Cold-inducible RNA-binding protein mediates airway inflammation and mucus hypersecretion through a post-transcriptional regulatory mechanism under cold stress.

    PubMed

    Juan, Yang; Haiqiao, Wu; Xie, Wenyao; Huaping, Huang; Zhong, Han; Xiangdong, Zhou; Kolosov, Victor P; Perelman, Juliy M

    2016-09-01

    Acute or chronic cold exposure exacerbates chronic inflammatory airway diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Cold-inducible RNA-binding protein (CIRP) is a cold-shock protein and is induced by various environmental stressors, such as hypothermia and hypoxia. In this study, we showed that CIRP gene and protein levels were significantly increased in patients with COPD and in rats with chronic airway inflammation compared with healthy subjects. Similarly, inflammatory cytokine production and MUC5AC secretion were up-regulated in rats following cigarette smoke inhalation. Cold temperature-induced CIRP overexpression and translocation were shown to be dependent on arginine methylation in vitro. CIRP overexpression promoted stress granule (SG) assembly. In the cytoplasm, the stability of pro-inflammatory cytokine mRNAs was increased through specific interactions between CIRP and mediator mRNA 3'-UTRs; these interactions increased the mRNA translation, resulting in MUC5AC overproduction in response to cold stress. Conversely, CIRP silencing and a methyltransferase inhibitor (adenosine dialdehyde) promoted cytokine mRNA degradation and inhibited the inflammatory response and mucus hypersecretion. These findings indicate that cold temperature can induce an airway inflammatory response and excess mucus production via a CIRP-mediated increase in mRNA stability and protein translation. PMID:27477308

  19. Corticosteroid administration modifies ozone-induced increases in sheep airway blood flow

    SciTech Connect

    Gunther, R.A.; Yousef, M.A.; Schelegle, E.S.; Cross, C.E. )

    1992-09-01

    Recently, we have shown that exposure of intubated conscious sheep to 3 to 4 ppm ozone (O3) for 3 h increases bronchial blood flow (Qbr). The purpose of the present study was to assess the potential role of corticosteroids in modulating this increase. Six nasally intubated sheep were exposed to filtered room air, 3.5 ppm O3 on two separate occasions, and 3.5 ppm O3 plus methyl-prednisone, for 3 h. Qbr was measured using a chronically implanted 20 MHz pulsed Doppler flow probe. Qbr, mean aortic pressure, cardiac output, pulmonary artery pressure, arterial blood gases, and core temperature were monitored. After 3 h of 3.5 ppm O3, Qbr increased from 3.2 +/- 0.5 (mean +/- SEM) to 8.5 +/- 1.6 KHz, whereas bronchial vascular resistance (BVR) decreased from the baseline value of 43.6 +/- 8.0 to 15.0 +/- 3 mm Hg/KHz. With corticosteroids, baseline Qbr was 3.2 +/- 0.6 and BVR was 44.2 +/- 9.7; after 3 h of 3.5 ppm O3, Qbr was 3.3 +/- 0.5 KHz and BVR was 39.0 +/- 8.0 mm Hg/KHz. The two 3.5-ppm O3 exposures without corticosteroids were impressively reproducible. Except for Qbr and BVR, no other measured cardiovascular parameters were affected by O3. The results indicate that corticosteroids are capable of interfering with mediator, neurohumoral, or inflammatory cell mechanisms responsible for vasodilation of the airway microcirculation after O3 exposure, but do not specifically address the specific processes whereby this attenuation occurs.

  20. Inhibition of antigen-induced airway inflammation and hyperresponsiveness in guinea pigs by a selective antagonist of "chemoattractant receptor homologous molecule expressed on Th2 cells" (CRTH2).

    PubMed

    Tasaki, Mamoru; Kobayashi, Miki; Tenda, Yoshiyuki; Tsujimoto, Susumu; Nakazato, Shoko; Numazaki, Mako; Hirano, Yasuno; Matsuda, Hiroshi; Terasaka, Tadashi; Miyao, Yasuhiro; Shimizu, Yasuaki; Hirayama, Yoshitaka

    2013-06-14

    Chemoattractant receptor homologous molecule expressed on T helper type 2 cells (CRTH2) is a PGD2 receptor found on eosinophils, basophils, and Th2 type T cells which exhibits chemotaxis and functions in activation cascades. However, while a number of CRTH2 antagonists, including ramatroban, are known to exert activity in certain animal models, activity in a guinea pig model of EA-induced airway hyperresponsiveness has not been demonstrated. The newly developed CRTH2 antagonist ASP5642 has shown antagonistic activity against human and guinea pig CRTH2 in previous studies and has also been found effective in treating guinea pig models of airway inflammation and airway hyperresponsiveness. While previous studies have used animals such as rats and mice to evaluate CRTH2 antagonist effects, ours is the first attempt to evaluate CRTH2 function in a guinea pig asthma model, which may prove useful in evaluating the compound's effects in humans, given the comparable airway function between the two species taken together, these data from the present study strongly suggest the utility of ASP5642 in investigating the role of CRTH2 in inflammatory responses and as a drug treatment for human asthma. PMID:23624353

  1. MEMBRANE PERMEABILITY AS A DETERMINANT OF ZN2+-INDUCED SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS

    EPA Science Inventory

    Zinc (Zn2+) is an essential micronutrient but also a common metallic constituent of ambient air particulate matter (PM) that may play a role in PM-induced adverse health effects. In vivo and in vitro studies have shown that Zn2+ exposure induces inflammatory responses in the airw...

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

    SciTech Connect

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

    2011-04-22

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

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

    PubMed Central

    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.

    2008-01-01

    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. PMID:17470619

  4. Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ-Induced IL-27 and Airway Hyperresponsiveness in Mice.

    PubMed

    Liao, Wupeng; Tan, W S Daniel; Wong, W S Fred

    2016-06-01

    LPS and IFN-γ alone or in combination have been implicated in the development of steroid resistance. Combined LPS/IFN-γ strongly upregulates IL-27 production, which has been linked to steroid-resistant airway hyperresponsiveness (AHR). Andrographolide, a bioactive molecule isolated from the plant Andrographis paniculata, has demonstrated anti-inflammatory and antioxidant properties. The present study investigated whether andrographolide could restore steroid sensitivity to block LPS/IFN-γ-induced IL-27 production and AHR via its antioxidative property. The mouse macrophage cell line Raw 264.7, mouse primary lung monocytes/macrophages, and BALB/c mice were treated with LPS/IFN-γ, in the presence and absence of dexamethasone and/or andrographolide. Levels of IL-27 in vitro and in vivo were examined and mouse AHR was assessed. Dexamethasone alone failed to inhibit LPS/IFN-γ-induced IL-27 production and AHR in mice. Andrographolide significantly restored the suppressive effect of dexamethasone on LPS/IFN-γ-induced IL-27 mRNA and protein levels in the macrophage cell line and primary lung monocytes/macrophages, mouse bronchoalveolar lavage fluid and lung tissues, and AHR in mice. LPS/IFN-γ markedly reduced the nuclear level of histone deacetylase (HDAC)2, an essential epigenetic enzyme that mediates steroid anti-inflammatory action. LPS/IFN-γ also decreased total HDAC activity but increased the total histone acetyltransferase/HDAC activity ratio in mouse lungs. Andrographolide significantly restored nuclear HDAC2 protein levels and total HDAC activity, and it diminished the total histone acetyltransferase/HDAC activity ratio in mouse lungs exposed to LPS/IFN-γ, possibly via suppression of PI3K/Akt/HDAC2 phosphorylation, and upregulation of the antioxidant transcription factor NF erythroid-2-related factor 2 level and DNA binding activity. Our data suggest that andrographolide may have therapeutic value in resensitizing steroid action in respiratory disorders

  5. Functional Effects of WNT1-Inducible Signaling Pathway Protein-1 on Bronchial Smooth Muscle Cell Migration and Proliferation in OVA-Induced Airway Remodeling.

    PubMed

    Yang, Mingjin; Du, Yuejun; Xu, Zhibo; Jiang, Youfan

    2016-02-01

    Upregulation of WISP1 has been demonstrated in lung remodeling. Moreover, it has been recently found that some signaling components of WNT pathway can activate GSK3β signaling to mediate remodeling of airway smooth muscle (ASM) in asthma. Therefore, we hypothesized that WISP1, a signaling molecule downstream of the WNT signaling pathway, is involved in PI3K/GSK3β signaling to mediate ASM remodeling in asthma. Our results showed that WISP1 depletion partly suppressed OVA-induced ASM hypertrophy in vivo. In vitro, WISP1 could induce hBSMC hypertrophy and proliferation, accompanied by upregulation of levels of PI3K, p-Akt, p-GSK3β, and its own expression. TGF-β treatment could increase expression of PI3K, p-Akt, p-GSK3β, and WISP1. SH-5 treatment could partly suppress TGF-β-induced hypertrophy and proliferation of hBSMC, and depress expression of p-GSK3β and WISP1. In conclusion, WISP1 may be a potential inducer of ASM proliferation and hypertrophy in asthma. The pro-remodeling effect of WISP1 is likely due to be involved in PI3K-GSK3β-dependent noncanonical TGF-β signaling. PMID:26242865

  6. A Selective Irreversible Inhibitor of Furin Does Not Prevent Pseudomonas Aeruginosa Exotoxin A-Induced Airway Epithelial Cytotoxicity

    PubMed Central

    Walker, Brian; Hamilton, Robert A.; Martin, S. Lorraine

    2016-01-01

    Many bacterial and viral pathogens (or their toxins), including Pseudomonas aeruginosa exotoxin A, require processing by host pro-protein convertases such as furin to cause disease. We report the development of a novel irreversible inhibitor of furin (QUB-F1) consisting of a diphenyl phosphonate electrophilic warhead coupled with a substrate-like peptide (RVKR), that also includes a biotin tag, to facilitate activity-based profiling/visualisation. QUB-F1 displays greater selectivity for furin, in comparison to a widely used exemplar compound (furin I) which has a chloromethylketone warhead coupled to RVKR, when tested against the serine trypsin-like proteases (trypsin, prostasin and matriptase), factor Xa and the cysteine protease cathepsin B. We demonstrate QUB-F1 does not prevent P. aeruginosa exotoxin A-induced airway epithelial cell toxicity; in contrast to furin I, despite inhibiting cell surface furin-like activity to a similar degree. This finding indicates additional proteases, which are sensitive to the more broad-spectrum furin I compound, may be involved in this process. PMID:27459298

  7. Neuroleptic-induced extrapyramidal symptoms with fever. Heterogeneity of the 'neuroleptic malignant syndrome'.

    PubMed

    Levinson, D F; Simpson, G M

    1986-09-01

    From 39 reported cases of the "neuroleptic malignant syndrome," three groups were identified: those with concurrent medical problems that could cause fever that accompanied the extrapyramidal symptoms; those with medical problems less clearly related to fever; and those without other medical disorders. Dehydration, infection, pulmonary embolus, and rhabdomyolysis were the common complications of untreated extrapyramidal symptoms. Three patients died, all with medical complications. In 14 cases, no medical cause of fever was identified. Hypotheses about mechanisms for fever include psychiatric illness, disruption of dopaminergic aspects of thermoregulation, and peripheral and central effects on muscle contraction leading to excess heat production. Neuroleptic-induced rigidity should be treated vigorously, with prompt discontinuation of neuroleptic therapy and administration of dopamine agonists in severe cases with or without fever. The cases of extrapyramidal symptoms with fever are too heterogeneous to justify the assumption of a unitary and "malignant" syndrome. PMID:2875701

  8. Regulation of Th17/Treg function contributes to the attenuation of chronic airway inflammation by icariin in ovalbumin-induced murine asthma model.

    PubMed

    Wei, Ying; Liu, Baojun; Sun, Jing; Lv, Yubao; Luo, Qingli; Liu, Feng; Dong, Jingcheng

    2015-06-01

    Icariin which is a flavonoid glucoside isolated from Epimedium brevicornu Maxim, has been reported to have anti-osteoporotic, anti-inflammatory and anti-depressant-like activities. In this study, we observed the effect of icariin on airway inflammation of ovalbumin (OVA)-induced murine asthma model and the associated regulatory mode on T-helper (Th)17 and regulatory T (Treg) cell function. Our data revealed that chronic OVA inhalation induced a dramatic increase in airway resistance (RL) and decrease in the lung dynamic compliance (Cdyn), and icariin and DEX treatment caused significant attenuation of such airway hyperresponsiveness (AHR). BALF cell counts demonstrated that icariin and DEX led to a prominent reduction in total leukocyte as well as lymphocyte, eosinophil, neutrophil, basophil and monocyte counts. Histological analysis results indicated that icariin and DEX alleviated the inflammatory cells infiltrating into the peribronchial tissues and goblet cells hyperplasia and mucus hyper-production. Flow cytometry test demonstrated that icariin or DEX administration resulted in a significant percentage reduction in CD4+RORγt+ T cells and elevation of CD4+Foxp3+ T cells in BALF. Furthermore, icariin or DEX caused a significant reduction in IL-6, IL-17 and TGF-β level in BALF. Unfortunately, icariin had no effect on IL-10 level in BALF. Western blot assay found that icariin or DEX suppressed RORγt and promoted Foxp3 expression in the lung tissue. qPCR analysis revealed that icariin and DEX resulted in a notable decrease in RORγt and increase in Foxp3 mRNA expression in isolated spleen CD4+ T cell. In conclusion, our results suggested that icariin was effective in the attenuation of AHR and chronic airway inflammatory changes in OVA-induced murine asthma model, and this effect was associated with regulation of Th17/Treg responses, which indicated that icariin may be used as a potential therapeutic method to treat asthma with Th17/Treg imbalance phenotype

  9. A survey of visually induced symptoms and associated factors in spectators of three dimensional stereoscopic movies

    PubMed Central

    2012-01-01

    Background The increasing popularity of commercial movies showing three dimensional (3D) computer generated images has raised concern about image safety and possible side effects on population health. This study aims to (1) quantify the occurrence of visually induced symptoms suffered by the spectators during and after viewing a commercial 3D movie and (2) to assess individual and environmental factors associated to those symptoms. Methods A cross-sectional survey was carried out using a paper based, self administered questionnaire. The questionnaire includes individual and movie characteristics and selected visually induced symptoms (tired eyes, double vision, headache, dizziness, nausea and palpitations). Symptoms were queried at 3 different times: during, right after and after 2 hours from the movie. Results We collected 953 questionnaires. In our sample, 539 (60.4%) individuals reported 1 or more symptoms during the movie, 392 (43.2%) right after and 139 (15.3%) at 2 hours from the movie. The most frequently reported symptoms were tired eyes (during the movie by 34.8%, right after by 24.0%, after 2 hours by 5.7% of individuals) and headache (during the movie by 13.7%, right after by 16.8%, after 2 hours by 8.3% of individuals). Individual history for frequent headache was associated with tired eyes (OR = 1.34, 95%CI = 1.01-1.79), double vision (OR = 1.96; 95%CI = 1.13-3.41), headache (OR = 2.09; 95%CI = 1.41-3.10) during the movie and of headache after the movie (OR = 1.64; 95%CI = 1.16-2.32). Individual susceptibility to car sickness, dizziness, anxiety level, movie show time, animation 3D movie were also associated to several other symptoms. Conclusions The high occurrence of visually induced symptoms resulting from this survey suggests the need of raising public awareness on possible discomfort that susceptible individuals may suffer during and after the vision of 3D movies. PMID:22974235

  10. Interaction between haemopoietic regulation and airway inflammation.

    PubMed

    O'Byrne, P M; Gauvreau, G M; Wood, L J

    1999-06-01

    Asthma is characterized by reversible airway narrowing, by airway hyperresponsiveness, and by airway inflammation. Inhaled allergens are the most important of the stimuli known to cause asthma. Methods for studying inhaled allergen in the laboratory have been well standardized and extensively used for the investigation of the pathophysiology and the pharmacological modulation of allergen-induced airway responses. Allergen inhalation by a sensitized subject results in an early asthmatic response, and, in the majority of subjects, a late asthmatic response and airway hyperresponsiveness. The late response and airway hyperresponsiveness are associated with increases in airway eosinophils and metachromatic cells. Allergen-induced airway inflammation in dogs (predominantly neutrophilic) is associated with increased granulocyte-macrophage progenitors in bone marrow, which is dependent on the effects of a circulating serum factor stimulating the bone marrow. The newly formed cells traffic to the airways. These increases in granulocyte-macrophage progenitors are blocked by inhaled corticosteroids. In human subjects, allergen-induced eosinophilic inflammation is associated with increases in Eo/B progenitors, mediated through up-regulation if the IL-5 receptor on progenitors and increases responsiveness to IL-5. Inhaled corticosteroids also attenuate all allergen-induced physiological responses and airway inflammation, an effect possibly mediated, in part, through inhibition of eosinophil and basophil maturation or release from the bone marrow. PMID:10421819

  11. [Reactive airways dysfunction syndrome].

    PubMed

    Costa, R; Orriols, R

    2005-01-01

    Reactive airways dysfunction syndrome, better known as RADS, was described as a clinical entity consisting in the appearance of bronchial asthma due to massive toxic inhalation. The term was coined and recognised for the first time in 1985. Since then different publications have verified new cases as well as different causal agents. It usually arises from an accident at the work place and in closed or poorly ventilated spaces, where high concentrations of irritant products are inhaled in the form of gas, smoke or vapour. In the following minutes or hours symptoms of bronchial obstruction appear in an acute form, with bronchial hyperresponsiveness persisting for months or years. The affected patients do not show a recurrence of symptoms following exposure to non-toxic doses of the same agent that started the symptoms. This is why diagnosis is based on clinical manifestations as it is not reproducible through a provocation test. PMID:15915173

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

    EPA Science Inventory

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

  13. SPONTANEOUSLY HYPERTENSIVE RATS ARE SUSCEPTIBLE TO AIRWAY DISEASE INDUCED BY SULFUR DIOXIDE

    EPA Science Inventory

    Rodent models of chronic pulmonary diseases induced by sulfur dioxide (SO2), elastase or tobacco smoke have limited utility because of their lack of chronicity of inflammation, and they demonstrate limited sensitivity to a given experimental manipulation. We hypothesized that dis...

  14. 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.

  15. Airway Pressure Release Ventilation and High-Frequency Oscillatory Ventilation: Potential Strategies to Treat Severe Hypoxemia and Prevent Ventilator-Induced Lung Injury.

    PubMed

    Facchin, Francesca; Fan, Eddy

    2015-10-01

    Although lifesaving, mechanical ventilation can itself be responsible for damage to lung parenchyma. This ventilator-induced lung injury is especially observed in already injured lungs of patients with ARDS. New ventilatory approaches are needed to safely treat patients with ARDS, and recent studies have suggested the potential utility of open-lung strategies. Airway pressure release ventilation (APRV) and high-frequency oscillatory ventilation (HFOV) are 2 different open-lung strategies that have been proposed to treat refractory hypoxemic respiratory failure while preventing ventilator-induced lung injury. APRV provides increased airway pressure as a potential recruitment mechanism and allows spontaneous breathing, with the potential benefits of decreased sedation, shorter duration of mechanical ventilation, and improvement in cardiac performance. HFOV delivers very small tidal volumes, to prevent volutrauma, at a constant (relatively high) mean airway pressure, thus avoiding atelectrauma. Despite their theoretical benefits, the utility of APRV and HFOV remains unproven and controversial for the routine treatment of ARDS in adult patients. This review is focused on the theoretical and practical aspects of APRV and HFOV, provides an overview of the current evidence, and addresses their possible use in the treatment of ARDS. PMID:26405188

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

    PubMed

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

    2009-01-01

    Moringaceae, which belongs to the Moringa oleifera Lam. family, is a well-known herb used in Asian medicine as an antiallergic drug. In the present study, the efficacy of the n-butanol extract of the seeds of the plant (MONB) is examined against ovalbumin-induced airway inflammation in guinea pigs. The test drugs (MONB or dexamethasone) are administered orally prior to challenge with aerosolized 0.5% ovalbumin. During the experimental period, bronchoconstriction tests are performed, and lung function parameters are measured. The blood and bronchoalveolar lavage fluid are collected to assess cellular content, and serum is used for cytokine (tumor necrosis factor-alpha, interleukin-4, and interleukin-6) assays. Histamine assays of lung tissue are performed using lung tissue homogenate. The results suggest that in ovalbumin-sensitized model control animals, tidal volume is decreased, respiration rate is increased, and both the total and differential cell counts in blood and bronchoalveolar lavage fluid are increased significantly compared with nonsensitized controls. MONB treatment shows improvement in all parameters except bronchoalveolar lavage tumor necrosis factor-alpha and interleukin-4. Moreover, MONB treatment demonstrates protection against acetylcholine-induced bronchoconstriction and airway inflammation. These results indicate that MONB has an inhibitory effect on airway inflammation. Thus, MONB possesses an antiasthmatic property through modulation of the relationship between Th1/Th2 cytokine imbalances. PMID:19966143

  17. Relationship between gene responses and symptoms induced by Rice grassy stunt virus

    PubMed Central

    Satoh, Kouji; Yoneyama, Kaori; Kondoh, Hiroaki; Shimizu, Takumi; Sasaya, Takahide; Choi, Il-Ryong; Yoneyama, Koichi; Omura, Toshihiro; Kikuchi, Shoshi

    2013-01-01

    Rice grassy stunt virus (RGSV) is a serious threat to rice production in Southeast Asia. RGSV is a member of the genus Tenuivirus, and it induces leaf yellowing, stunting, and excess tillering on rice plants. Here we examined gene responses of rice to RGSV infection to gain insight into the gene responses which might be associated with the disease symptoms. The results indicated that (1) many genes related to cell wall synthesis and chlorophyll synthesis were predominantly suppressed by RGSV infection; (2) RGSV infection induced genes associated with tillering process; (3) RGSV activated genes involved in inactivation of gibberellic acid and indole-3-acetic acid; and (4) the genes for strigolactone signaling were suppressed by RGSV. These results suggest that these gene responses to RGSV infection account for the excess tillering specific to RGSV infection as well as other symptoms by RGSV, such as stunting and leaf chlorosis. PMID:24151491

  18. Influence of influenza A infection on capsaicin-induced responses in murine airways.

    PubMed

    Taylor, Samuel J; Mann, Tracy S; Henry, Peter J

    2012-02-01

    The principal aim of the study was to determine the influence of influenza A virus infection on capsaicin-induced relaxation responses in mouse isolated tracheal segments and clarify the underlying mechanisms. Anesthetized mice were intranasally inoculated with influenza A/PR-8/34 virus (VIRUS) or vehicle (SHAM), and 4 days later tracheal segments were harvested for isometric tension recording and biochemical and histologic analyses. Capsaicin induced dose-dependent relaxation responses in carbachol-contracted SHAM trachea (e.g., 10 μM capsaicin produced 66 ± 4% relaxation; n = 11), which were significantly inhibited by capsazepine [transient receptor potential vanilloid type 1 (TRPV1) antagonist], (2S,3S)-3-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-2-phenylpiperidine hydrochloride (L-733,060) [neurokinin 1 (NK₁) receptor antagonist], indomethacin [cyclooxygenase (COX) inhibitor], and the combination of 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) and 7-[5α-([1S,1α(Z)-biphenyl]-4-ylmethoxy)-2β-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, calcium salt, hydrate (AH23848) [E-prostanoid (EP)₂ and EP₄ receptor antagonists, respectively], indicating that capsaicin-induced relaxation involved the TRPV1-mediated release of substance P (SP), activation of epithelial NK₁ receptors, and production of COX products capable of activating relaxant EP₂/EP₄ receptors. Consistent with this postulate, capsaicin-induced relaxation was associated with the significant release of SP and prostaglandin E₂ (PGE₂) from mouse tracheal segments. As expected, influenza A virus infection was associated with widespread disruption of the tracheal epithelium. Tracheal segments from VIRUS mice responded weakly to capsaicin (7 ± 3% relaxation) and were 25-fold less responsive to SP than tracheas from SHAM mice. In contrast, relaxation responses to exogenous PGE₂ and the β-adrenoceptor agonist isoprenaline were not inhibited in VIRUS trachea. Virus infection

  19. Reversible Control by Vitamin D of Granulocytes and Bacteria in the Lungs of Mice: An Ovalbumin-Induced Model of Allergic Airway Disease

    PubMed Central

    Gorman, Shelley; Weeden, Clare E.; Tan, Daryl H. W.; Scott, Naomi M.; Hart, Julie; Foong, Rachel E.; Mok, Danny; Stephens, Nahiid; Zosky, Graeme; Hart, Prue H.

    2013-01-01

    Vitamin D may be essential for restricting the development and severity of allergic diseases and asthma, but a direct causal link between vitamin D deficiency and asthma has yet to be established. We have developed a ‘low dose’ model of allergic airway disease induced by intraperitoneal injection with ovalbumin (1 µg) and aluminium hydroxide (0.2 mg) in which characteristics of atopic asthma are recapitulated, including airway hyperresponsiveness, antigen-specific immunoglobulin type-E and lung inflammation. We assessed the effects of vitamin D deficiency throughout life (from conception until adulthood) on the severity of ovalbumin-induced allergic airway disease in vitamin D-replete and -deficient BALB/c mice using this model. Vitamin D had protective effects such that deficiency significantly enhanced eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male but not female mice. Vitamin D also suppressed the proliferation and T helper cell type-2 cytokine-secreting capacity of airway-draining lymph node cells from both male and female mice. Supplementation of initially vitamin D-deficient mice with vitamin D for four weeks returned serum 25-hydroxyvitamin D to levels observed in initially vitamin D-replete mice, and also suppressed eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male mice. Using generic 16 S rRNA primers, increased bacterial levels were detected in the lungs of initially vitamin D-deficient male mice, which were also reduced by vitamin D supplementation. These results indicate that vitamin D controls granulocyte levels in the bronchoalveolar lavage fluid in an allergen-sensitive manner, and may contribute towards the severity of asthma in a gender-specific fashion through regulation of respiratory bacteria. PMID:23826346

  20. Beta-carotene promotes the development of NNK-induced small airway-derived lung adenocarcinoma

    PubMed Central

    Al-Wadei, Hussein A. N.; Schuller, Hildegard M.

    2009-01-01

    Aim Beta-carotene has shown cancer preventive effects in preclinical studies while increasing lung cancer mortality in clinical trials. We have shown that β-carotene stimulates cAMP signaling in vitro. Here, we have tested the hypothesis that beta-carotene promotes the development of pulmonary adenocarcinoma (PAC) in vivo via cAMP signaling. Methods: PAC was induced in hamsters with the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) followed by β-carotene for 1.5 years. Incidence, multiplicity and size of lung tumors were recorded and phosphorylated CREB and ERK1/2 in tumour cells determined by Western blots. Cyclic AMP in blood cells was analysed by immunoassays, retinoids in serum and lungs by HPLC. Results: beta-carotene increased lung tumor multiplicity, lung tumour size, blood cell cAMP, serum and lung levels of retinoids and induced p-CREB and p-ERK1/2 in lung tumours. Conclusions:Our data suggest that beta-carotene promotes the development of PAC via increased cAMP signaling. PMID:19254833

  1. 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

    Ibba, Salome' V; Ghonim, Mohamed A; Pyakurel, Kusma; Lammi, Matthew R; Mishra, Anil; Boulares, A Hamid

    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

  2. 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

  3. GnRH-agonist induced depressive and anxiety symptoms during in vitro fertilization-embryo transfer cycles.

    PubMed

    Bloch, Miki; Azem, Foad; Aharonov, Inbar; Ben Avi, Irit; Yagil, Yaron; Schreiber, Shaul; Amit, Ami; Weizman, Abraham

    2011-01-01

    To determine whether the use of a GnRH agonist inducing a hypogonadic state during IVF-ET cycles induces negative mood symptoms, we conducted a prospective randomized study in 108 women comparing two different controlled ovarian stimulation protocols. A significant phase effect was observed for depression and anxiety symptoms during IVF-ET cycles reflecting an increase in symptoms between the hypogonadal phase and the peak in gonadotropin stimulation; however, the hypogonadal phase induced by the GnRH agonist was not associated with a significant increase in any of the studied mood parameters. PMID:20801439

  4. Prediction of Symptom Change in Placebo Versus No-Treatment Group in Experimentally Induced Motion Sickness.

    PubMed

    Horing, Bjoern; Weimer, Katja; Muth, Eric R; Enck, Paul

    2015-09-01

    The long-standing question of who responds to placebo and who does not is of great theoretical and clinical relevance and has received increasing attention in recent years. We therefore performed a post hoc analysis of one of our previously published studies on placebo responses (PRs). In the analysis, fourteen potential predictors for the PR on experimentally induced motion sickness in 32 healthy volunteers were explored using moderated multiple regression. Generalized self-efficacy, generalized self, internal locus of control and cognitive flexibility were significantly associated with symptom improvement in the placebo group, as compared to the untreated control group. Notably, the directions of the associations were such that the "unfavorable" side of the constructs (e.g. low self-efficacy) predicted a higher PR. Instead, the "favorable" side predicted symptom improvement in the control group. Results fit well with prior research into psychological influences on motion sickness. Although PRs in motion sickness are not well established, it is suggested to include the identified constructs in future research involving motion sickness-related symptoms such as nausea and vertigo. Concerning PRs in general, the results may have implications for clinical as well as experimental research on other symptoms and disorders, such as pain or depression. PMID:25912825

  5. IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung

    PubMed Central

    Beamer, Celine A.; Girtsman, Teri A.; Seaver, Benjamin P.; Finsaas, Krissy J.; Migliaccio, Christopher T.; Perry, Victoria K.; Rottman, James B.; Smith, Dirk E.; Holian, Andrij

    2014-01-01

    Allergic asthma is a chronic inflammatory disorder of the airway associated with bronchial obstruction, airway hyper-reactivity (AHR), and mucus production. The epithelium may direct and propagate asthmatic-like responses. Central to this theory is the observation that viruses, air pollution, and allergens promote epithelial damage and trigger the generation of IL-25, IL-33, and TSLP via innate pathways such as TLRs and purinergic receptors. Similarly, engineered nanomaterials promote a Th2-associated pathophysiology. In this study, we tested the hypothesis that instillation of multi-walled carbon nanotubes (MWCNT) impair pulmonary function in C57Bl/6 mice due to the development of IL-33-dependent Th2-associated inflammation. MWCNT exposure resulted in elevated levels of IL-33 in the lavage fluid (likely originating from airway epithelial cells), enhanced AHR, eosinophil recruitment, and production of Th2-associated cytokines and chemokines. Moreover, these events were dependent on IL-13 signaling and the IL-33/ST2 axis, but independent of T and B cells. Finally, MWCNT exposure resulted in the recruitment of innate lymphoid cells. Collectively, our data suggest that MWCNT induce epithelial damage that results in release of IL-33, which in turn promotes innate lymphoid cell recruitment and the development of IL-13-dependent inflammatory response. PMID:22686327

  6. Brd4 Is Essential for IL-1β-Induced Inflammation in Human Airway Epithelial Cells

    PubMed Central

    Khan, Younis M.; Kirkham, Paul; Barnes, Peter J.; Adcock, Ian M.

    2014-01-01

    Background Chronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-κB). Histone acetylation plays a critical role in chronic inflammation and bromodomain and extra terminal (BET) proteins act as “readers” of acetylated histones. Therefore, we examined the role of BET proteins in particular Brd2 and Brd4 and their inhibitors (JQ1 and PFI-1) in oxidative stress- enhanced inflammation in human bronchial epithelial cells. Methods Human primary epithelial (NHBE) cells and BEAS-2B cell lines were stimulated with IL-1β (inflammatory stimulus) in the presence or absence of H2O2 (oxidative stress) and the effect of pre-treatment with bromodomain inhibitors (JQ1 and PFI-1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to the native IL-8 and IL-6 promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated. Result H2O2 enhanced IL1β-induced IL-6 and CXCL8 expression in NHBE and BEAS-2B cells whereas H2O2 alone did not have any affect. H3 acetylation at the IL-6 and IL-8 promoters was associated with recruitment of p65 and Brd4 proteins. Although p65 acetylation was increased this was not directly targeted by Brd4. The BET inhibitors JQ1 and PFI-1 significantly reduced IL-6 and CXCL8 expression whereas no effect was seen with the inactive enantiomer JQ1(-). Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ1 also inhibited p65 and Brd4 recruitment to the IL-6 and IL-8 promoters. Conclusion Oxidative stress enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by Brd4 inhibition. Brd4 plays an important role in

  7. Determination of the Minimal Clinically Important Difference Scores for the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Scale in Two Populations of Patients With Cystic Fibrosis and Chronic Pseudomonas aeruginosa Airway Infection

    PubMed Central

    Quittner, Alexandra L.; Modi, Avani C.; Wainwright, Claire; Otto, Kelly; Kirihara, Jean; Montgomery, A. Bruce

    2009-01-01

    Background: The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a validated patient-reported outcome (PRO) containing both generic scales and scales specific to cystic fibrosis (CF). The minimal clinically important difference (MCID) score for a PRO corresponds to the smallest clinically relevant change a patient can detect. MCID scores for the CFQ-R respiratory symptom (CFQ-R-Respiratory) scale were determined using data from two 28 day, open-label, tobramycin inhalation solution (TIS) studies in patients with CF and chronic Pseudomonas aeruginosa airway infection. At study enrollment, patients in the study 1-exacerbation had symptoms indicative of pulmonary exacerbation (n = 84; < 14 years of age, 31 patients; ≥ 14 years of age, 53 patients); patients in study 2-stable had stable respiratory symptoms (n = 140; < 14 years of age, 14 patients; ≥ 14 years, 126 patients). Methods: The anchor-based method utilized a global rating-of-change questionnaire (GRCQ) that assessed patients' perceptions of change in their respiratory symptoms after TIS treatment. The mean change from baseline CFQ-R-Respiratory scores were mapped onto the GRCQ to estimate the MCID. The two distribution-based methods were as follows: (1) 0.5 SD of mean change in CFQ-R-Respiratory scores (baseline to end of TIS treatment); and (2) 1 SEM for baseline CFQ-R-Respiratory scores. Triangulation of these three estimates defined the MCIDs. Results: MCID scores were larger for patients in study 1-exacerbation (8.5 points) than for those in study 2-stable (4.0 points), likely reflecting differences in patient disease status (exacerbation/stable) between these studies. Conclusions: Patient benefit from new and current CF therapies can be evaluated using changes in CFQ-R-Respiratory scores. Using the MCID provides a systematic way to interpret these changes, and facilitates the identification of CF treatments that improve both symptoms and physiologic variables, potentially leading to better treatment

  8. Increased airway glucose increases airway bacterial load in hyperglycaemia

    PubMed Central

    Gill, Simren K.; Hui, Kailyn; Farne, Hugo; Garnett, James P.; Baines, Deborah L.; Moore, Luke S.P.; Holmes, Alison H.; Filloux, Alain; Tregoning, John S.

    2016-01-01

    Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection. We hypothesize that increased airway glucose caused by hyperglycaemia leads to increased bacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisation is significantly more likely when blood glucose is high. We engineered mutants in genes affecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa, strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented with glucose as the sole carbon source. The effect of glucose on growth in vivo was tested using streptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose. Bacterial burden in hyperglycaemic animals was greater than control animals when infected with wild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reduced both airway glucose and bacterial load. These data support airway glucose as a critical determinant of increased bacterial load during diabetes. PMID:27273266

  9. Increased airway glucose increases airway bacterial load in hyperglycaemia.

    PubMed

    Gill, Simren K; Hui, Kailyn; Farne, Hugo; Garnett, James P; Baines, Deborah L; Moore, Luke S P; Holmes, Alison H; Filloux, Alain; Tregoning, John S

    2016-01-01

    Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection. We hypothesize that increased airway glucose caused by hyperglycaemia leads to increased bacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisation is significantly more likely when blood glucose is high. We engineered mutants in genes affecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa, strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented with glucose as the sole carbon source. The effect of glucose on growth in vivo was tested using streptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose. Bacterial burden in hyperglycaemic animals was greater than control animals when infected with wild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reduced both airway glucose and bacterial load. These data support airway glucose as a critical determinant of increased bacterial load during diabetes. PMID:27273266

  10. Effects of age on muscarinic agonist-induced contraction an IP accumulation in airway smooth muscle

    SciTech Connect

    Wills-Karp, M. )

    1991-01-01

    The effects of age on carbachol-stimulated force development and ({sup 3}H)inositol phosphate production was studied in tracheal rings from guinea pigs aged 1 month and 25 months of age. The pD{sub 2} for the contractile response to carbachol was significantly reduced in tracheal tissues from old animals as compared to that of the young tissues, respectively. In contrast, inositol phosphate formation was not altered with increasing age when stimulated by carbachol or NaF, a direct activator of G proteins. Carbachol-induced inositol phosphate accumulation was inhibited by treatment with 1{mu}g/ml pertussis toxin, suggesting that IP1 accumulation is coupled to a pertussis-toxin-sensitive protein. The pD{sub 2} values for contraction were significantly different from the pD{sub 2} values for IP1 accumulation, in both young and old tissues, respectively. These data suggest that IP1 accumulation is not responsible for the decreased contractile ability in tracheal smooth muscle during aging.

  11. CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response

    PubMed Central

    CHEN, HUILONG; XU, XIANGQIN; TENG, JIEMING; CHENG, SHENG; BUNJHOO, HANSVIN; CAO, YONG; LIU, JIN; XIE, JUNGANG; WANG, CONGYI; XU, YONGJIAN; XIONG, WEINING

    2016-01-01

    Accumulating evidence suggests that chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor chemokine (C-X-C motif) receptor 4 (CXCR4) may contribute to the pathogenesis of allergic asthma. However, the underlying molecular mechanisms remain to be fully understood. T-helper 17 cells (Th17) and T-cytotoxic 17 cells (Tc17) have been implicated in the development of several allergic disorders, including asthma. The present study aimed to explore the association between CXCL12 signaling and Th17/Tc17 cells in the development of asthma. Ovalbumin (OVA)-sensitized BALB/c mice were treated with AMD3100, a specific CXCR4 antagonist, prior to OVA challenge. Following the final allergen (OVA) challenge, airway responsiveness to methacholine, influx of inflammatory cells to the airway, and cytokine levels in the bronchoalveolar lavage fluids (BALF) and lung homogenate were assessed. Interleukin (IL)-17-expressing CD3+CD8− lymphocytes (Th17 cells) and IL-17+CD3+CD8+ lymphocytes (Tc17 cells) isolated from lung tissue samples were detected by flow cytometry. The results of the present study demonstrated that administration of AMD3100 significantly decreased airway responsiveness to methacholine, attenuated the influx of inflammatory cells to the airway and reduced the levels of IL-4, IL-5 and IL-13 in the BALF. Furthermore, AMD3100 significantly reduced the increased number of lung Th17 and Tc17 cells as well as the levels of IL-17 in the lung homogenate induced by OVA challenge. In conclusion, the CXCR4 inhibitor suppresses the asthmatic response, which is associated with attenuation of the Th17 and Tc17 cell immune response. PMID:27168818

  12. Dermatophagoides pteronyssinus group 2 allergen bound to 8-OH modified adenine reduces the Th2-mediated airway inflammation without inducing a Th17 response and autoimmunity.

    PubMed

    Pratesi, Sara; Nencini, Francesca; Filì, Lucia; Occhiato, Ernesto G; Romagnani, Sergio; Parronchi, Paola; Maggi, Enrico; Vultaggio, Alessandra

    2016-09-01

    8-OH modified adenine bound to Dermatophagoides pteronyssinus group 2 (nDer p2-Conj), a novel allergen-TLR7 agonist conjugate, improves murine airway inflammation in priming and therapeutic settings, however no data are known on the activity of this construct on Th17 cells. The aim of the study was to evaluate if nDer p2-Conj elicited in vivo Th17 cells and Th17-driven autoimmune responses, by using both short- and long-term priming and therapeutic protocols in a nDer p2-driven model of murine airway inflammation. The conjugate induced the in vitro production of cytokines favouring the Th17 polarization by bone marrow-derived dendritic cells. In short-term protocols, the priming or treatment with the conjugate ameliorated the airway inflammation by shifting Th2 allergen-specific cells into T cells producing IFN-γ, IL-10, but not IL-17A. Similar results were found in long-term protocol where the conjugate down-regulated airway inflammation without any evidence of autoimmune response and B cell compartment expansion. nDer p2-Conj also failed to shorten the spontaneous onset of diabetes on conjugates-primed NOD/LtJ mice. We found that neutrophils in BALF, ROR-γt and IL-17A expression in lungs were increased in conjugate-treated IL-10KO mice. These data emphasize the role of conjugate-driven IL-10 production, which can regulate the activity of memory Th17 cells and prevent the onset of autoimmune response. PMID:27475304

  13. Wogonin, a plant flavone from Scutellariae radix, attenuated ovalbumin-induced airway inflammation in mouse model of asthma via the suppression of IL-4/STAT6 signaling.

    PubMed

    Ryu, Eun Kyung; Kim, Tae-Hyun; Jang, Eun Jeong; Choi, Yoon Suk; Kim, Seon Tae; Hahm, Ki Baik; Lee, Ho-Jae

    2015-09-01

    Bronchial asthma is a chronic inflammatory disease of the airways characterized by a marked infiltration of eosinophils at the site of inflammation. Eotaxins are potent chemoattractants for eosinophils and play important roles in pathogenesis of asthma. In the course of screening for eotaxin-3 inhibitors, we found that wogonin showed potent inhibitory activity of interleukin-4 (IL-4)-induced eotaxin-3 expression in BEAS-2B cells. In this study, we examined the effects of wogonin on IL-4/STAT6 signaling pathway and biological implication in a mouse model of asthma. Wogonin inhibited IL-4-induced activation and nuclear translocation of STAT6 which plays a key role in either the transcription of STAT6-response genes or Th2 cytokine-mediated inflammation. Oral administration of wogonin significantly reduced activation of STAT6 in the lung and the expression of eotaxin and RANTES in bronchoalveolar lavage fluids. Histological examination of lung tissue demonstrated that wogonin significantly inhibited allergen-induced eosinophilic inflammation. Administration of wogonin reduced the total IgE and ovalbumin-specific IgE levels compared with the ovalbumin-challenged group. All of these data demonstrated that wogonin could alleviate airway inflammation through inhibition of STAT6 activation induced by Th2 cytokines. Our finding implicates a potential therapeutic value of wogonin in the treatment of asthma through regulation of IL-4/STAT6 signaling pathway. PMID:26388667

  14. Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction

    PubMed Central

    Leppert, Wojciech

    2015-01-01

    Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD

  15. Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury.

    PubMed

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

    2015-05-01

    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 Ca(2+), and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca(2+), 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 Ca(2+) channels of airway smooth muscle cells, increasing their contractility and thus causing AHR. PMID:25747964

  16. 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

  17. Ozone-induced inflammation in the lower airways of human subjects

    SciTech Connect

    Koren, H.S.; Devlin, R.B.; Graham, D.E.; Mann, R.; McGee, M.P.; Horstman, D.H.; Kozumbo, W.J.; Becker, S.; House, D.E.; McDonnell, W.F.

    1989-02-01

    Although ozone (O3) has been shown to induce inflammation in the lungs of animals, very little is known about its inflammatory effects on humans. In this study, 11 healthy nonsmoking men, 18 to 35 yr of age (mean, 25.4 +/- 3.5), were exposed once to 0.4 ppm O3 and once to filtered air for 2 h with intermittent exercise. Eighteen hours later, bronchoalveolar lavage (BAL) was performed and the cells and fluid were analyzed for various indicators of inflammation. There was an 8.2-fold increase in the percentage of polymorphonuclear leukocytes (PMN) in the total cell population, and a small but significant decrease in the percentage of macrophages after exposure to O3. Immunoreactive neutrophil elastase often associated with inflammation and lung damage increased by 3.8-fold in the fluid while its activity increased 20.6-fold in the lavaged cells. A 2-fold increase in the levels of protein, albumin, and IgG suggested increased vascular permeability of the lung. Several biochemical markers that could act as chemotactic or regulatory factors in an inflammatory response were examined in the BAL fluid (BALF). The level of complement fragment C3 alpha was increased by 1.7-fold. The chemotactic leukotriene B4 was unchanged while prostaglandin E2 increased 2-fold. In contrast, three enzyme systems of phagocytes with potentially damaging effects on tissues and microbes, namely, NADPH-oxidase and the lysosomal enzymes acid phosphatase and beta-glucuronidase, were increased neither in the lavaged fluid nor cells. In addition, the amounts of fibrogenic-related molecules were assessed in BALF.

  18. Clinical Correlates of Co-occurring Psychiatric and Autism Spectrum Disorder (ASD) Symptom-Induced Impairment in Children with ASD.

    PubMed

    Gadow, Kenneth D; Perlman, Greg; Ramdhany, Lianne; de Ruiter, Janneke

    2016-01-01

    Although psychiatric symptom severity and impairment are overlapping but nevertheless distinct illness parameters, little research has examined whether variables found to be associated with the severity are also correlated with symptom-induced impairment. Parents and teachers completed ratings of symptom-induced impairment for DSM-IV-referenced syndromes, and parents completed a background questionnaire for a consecutively referred sample of primarily male (81%) 6-to-12 year olds with autism spectrum disorder (ASD) (N = 221). Some clinical correlates (e.g., IQ < 70, maternal level of education, pregnancy complications, current use of psychotropic medication, season of birth) were associated with impairment for several disorders, whereas others were correlated with only a few syndromes (e.g., gender, co-morbid medical conditions) or were not related to impairment in any disorder (e.g., family psychopathology). There was little convergence in findings for parents' versus teachers' ratings. Some clinical correlates (e.g., season of birth, current psychotropic medication, maternal education) were unique predictors of three or more disorders. Pregnancy complications were uniquely associated with social anxiety and schizoid personality symptom-induced impairment. IQ was a unique predictor of schizophrenia, ASD, oppositional defiant disorder symptom-induced impairment. Children whose mothers had relatively fewer years of education had greater odds for symptom-induced impairment in social anxiety, depression, aggression, and mania and greater number of impairing conditions. Season of birth was the most robust correlate of symptom-induced impairment as rated by teachers but not by parents. Children born in fall evidenced higher rates of co-occurring psychiatric and ASD symptom-induced impairment and total number of impairing conditions. Many variables previously linked with symptom severity are also correlated with impairment. PMID:25640910

  19. Recent insights into the relationship between airway inflammation and asthma.

    PubMed

    Siva, R; Berry, M; Pavord, I D

    2003-01-01

    There have been important recent advances in our understanding of the relationship between eosinophilic airway inflammation and airway dysfunction. Observational studies have shown that eosinophilic airway inflammation is not always present in asthma nor is it an exclusive feature of asthma. Its presence seems to be more closely linked to the presence of corticosteroid responsive airways disease and the occurrence of severe exacerbations than the presence of symptoms or the extent of airway dysfunction--indeed recent evidence suggests that in asthma these features may be more closely linked to the site of localisation of mast cells in the airway wall. One implication of this new understanding of the significance of eosinophilic airway inflammation is that it predicts that measuring airway inflammation might provide information that it is not readily available from a more traditional clinical assessment, and that patients might do better if this information is available. Recent studies support this view, showing a marked reduction in asthma exacerbation in patients with moderate to severe disease who are managed with reference to markers of airway inflammation as well as symptoms and simple tests of airway function. The development of new agents that have the potential to modulate specific aspects of airway inflammation, together with refinements in non-invasive techniques to assess the efficacy of these agents offers the prospect of further refining our understanding of the role of this aspect of the inflammatory response in asthma and other airway diseases. PMID:15148839

  20. Resistin-Like Molecule–α Regulates IL-13–Induced Chemokine Production but Not Allergen-Induced Airway Responses

    PubMed Central

    Munitz, Ariel; Cole, Eric T.; Karo-Atar, Danielle; Finkelman, Fred D.

    2012-01-01

    Resistin-like molecule α (Relm-α) is one of the most up-regulated gene products in allergen- and parasite-associated Th2 responses. Localized to alternatively activated macrophages, Relm-α was shown to exert an anti-inflammatory effect in parasite-induced Th2 responses, but its role in experimental asthma remains unexplored. Here, we analyzed the cellular source, the IL-4 receptors required to stimulate Relm-α production, and the role of Relm-α after experimental asthma induction by IL-4, IL-13, or multiple experimental regimes, including ovalbumin and Aspergillus fumigatus immunization. We demonstrate that Relm-α was secreted into the airway lumen, dependent on both the IL-13 receptor–α1 chain and likely the Type I IL-4 receptor, and differentially localized to epithelial cells and myeloid cells, depending on the specific cytokine or aeroallergen trigger. Studies performed with Retnla gene–targeted mice demonstrate that Relm-α was largely redundant in terms of inducing the infiltration of Th2 cytokines, mucus, and inflammatory cells into the lung. These results mirror the dispensable role that other alternatively activated macrophage products (such as arginase 1) have in allergen-induced experimental asthma and contrast with their role in the setting of parasitic infections. Taken together, our findings demonstrate the distinct utilization of IL-4/IL-13 receptors for the induction of Relm-α in the lungs. The differential regulation of Relm-α expression is likely determined by the relative expression levels of IL-4, IL-13, and their corresponding receptors, which are differentially expressed by divergent cells (i.e., epithelial cells and macrophages.) Finally, we identify a largely redundant functional role for Relm-α in acute experimental models of allergen-associated Th2 immune responses. PMID:22246861

  1. Relationship between airway reactivity induced by methacholine or ultrasonically nebulized distilled cold water and BAL fluid cellular constituents in patients with sulfur mustard gas-induced asthma.

    PubMed

    Emad, Ali; Emad, Yasaman

    2007-01-01

    The objective of this article was to evaluate the relationship between the bronchial reactivity to methacholine and distilled cold water and inflammatory bronchial alveolar lavage (BAL) cells in mustard gas-induced asthma. This was a randomized, crossover clinical study set in a university hospital. The patients were 17 veterans with mustard gas-induced asthma and 17 normal veterans as a control group. Inhalation challenges with ultrasonically nebulized distilled water and methacholine and BAL via bronchoscopy and were performed in all patients and subjects. All patients did sustain a 20% fall in FEV(1) after methacholine, whereas two of them did not with distilled cold water. The patients were sensitive to distilled cold water with a median PD20 of 8.44 +/- 6.55 mL and sensitive to methacholine with the median PC20 of 4.88 +/- 4.22 mg/mL. Significant correlation was found between PC20 of methacholine and PD20 of distilled cold water (r = -0.74, p = 0.005). The proportion of BAL macrophages was significantly lower in patients with asthma than in the control group (p = 0.001). The proportions of lymphocytes and neutrophils were similar in the two groups. The percentage of eosinophils was higher in BAL fluid from the asthmatics compared with that in BAL fluid from the control group (p < 0.001). The percentage of the BAL eosinophils significantly correlated with both PC20 of methacholine (r = - 0.58, p = 0.01) and PD20 of distilled cold water (r = -0.81, p = 0.002). No relationship between PC20 of methacholine or PD20 of distilled cold water was found for other inflammatory BAL cells. This study showed that in patients with mustard gas-induced asthma, the degree of airway responsiveness to both methacholine and distilled water was associated with the percentage of BAL eosinophils. PMID:17894540

  2. Alcohol-induced respiratory symptoms are common in patients with aspirin exacerbated respiratory disease

    PubMed Central

    Cardet, Juan Carlos; White, Andrew A.; Barrett, Nora A.; Feldweg, Anna M.; Wickner, Paige G.; Savage, Jessica; Bhattacharyya, Neil; Laidlaw, Tanya M.

    2014-01-01

    Background A large percentage of patients with aspirin exacerbated respiratory disease (AERD) report the development of alcohol-induced respiratory reactions, but the true prevalence of respiratory reactions caused by alcoholic beverages in these patients was not known. Objective We sought to evaluate the incidence and characteristics of alcohol-induced respiratory reactions in patients with AERD. Methods A questionnaire designed to assess alcohol-induced respiratory symptoms was administered to patients at Brigham and Women’s Hospital and Scripps Clinic. At least 50 patients were recruited into each of four clinical groups: 1) patients with aspirin challenge-confirmed AERD, 2) aspirin-tolerant asthmatics (ATA), 3) aspirin-tolerant patients with chronic rhinosinusitis (CRS), and 4) healthy controls. Two-tailed Fisher’s exact test with Bonferroni corrections were used to compare the prevalence of respiratory symptoms between AERD and other groups, with P≤0.017 considered significant. Results The prevalence of alcohol-induced upper (rhinorrhea/nasal congestion) respiratory reactions in patients with AERD was 75%, compared to 33% in ATA, 30% in CRS, and 14% in healthy controls (P<0.001 for all comparisons). The prevalence of alcohol-induced lower (wheezing/dyspnea) respiratory reactions in AERD was 51%, compared to 20% in ATA, and 0% in both CRS and healthy controls (P<0.001 for all comparisons). These reactions were generally not specific to one type of alcohol and often occurred after ingestion of only a few sips of alcohol. Conclusion Alcohol ingestion causes respiratory reactions in the majority of patients with AERD and clinicians should be aware that these alcohol-induced reactions are significantly more common in AERD than in aspirin-tolerant controls. PMID:24607050

  3. Apoptosis and the Airway Epithelium

    PubMed Central

    White, Steven R.

    2011-01-01

    The airway epithelium functions as a barrier and front line of host defense in the lung. Apoptosis or programmed cell death can be elicited in the epithelium as a response to viral infection, exposure to allergen or to environmental toxins, or to drugs. While apoptosis can be induced via activation of death receptors on the cell surface or by disruption of mitochondrial polarity, epithelial cells compared to inflammatory cells are more resistant to apoptotic stimuli. This paper focuses on the response of airway epithelium to apoptosis in the normal state, apoptosis as a potential regulator of the number and types of epithelial cells in the airway, and the contribution of epithelial cell apoptosis in important airways diseases. PMID:22203854

  4. United airway disease: current perspectives

    PubMed Central

    Giavina-Bianchi, Pedro; Aun, Marcelo Vivolo; Takejima, Priscila; Kalil, Jorge; Agondi, Rosana Câmara

    2016-01-01

    Upper and lower airways are considered a unified morphological and functional unit, and the connection existing between them has been observed for many years, both in health and in disease. There is strong epidemiologic, pathophysiologic, and clinical evidence supporting an integrated view of rhinitis and asthma: united airway disease in the present review. The term “united airway disease” is opportune, because rhinitis and asthma are chronic inflammatory diseases of the upper and lower airways, which can be induced by allergic or nonallergic reproducible mechanisms, and present several phenotypes. Management of rhinitis and asthma must be jointly carried out, leading to better control of both diseases, and the lessons of the Allergic Rhinitis and Its Impact on Asthma initiative cannot be forgotten. PMID:27257389

  5. Effect of nedocromil sodium on airway sensory nerves.

    PubMed

    Barnes, P J

    1993-07-01

    There is increasing evidence that the sensory nerves of the airway play a role in the asthmatic response. Nerve endings are exposed by the epithelial shedding that occurs with asthma. They may become sensitized and activated by inflammatory mediators and may release neuropeptides that then spread and amplify the inflammatory process in the airways. Nedocromil sodium may prevent the sensory nerves from becoming sensitized and inhibit their activation. This possibility is suggested because nedocromil is highly effective against several indirect challenges that involve sensory nerve stimulation. Nedocromil sodium was able to inhibit the bronchoconstriction induced in patients with asthma by exposure to bradykinin, sulfur dioxide, metabisulfite, and ultrasonically nebulized water. Cough, which is a prominent symptom of asthma, is believed to be a result of sensory nerve activation. In several long-term clinical studies, nedocromil sodium reduces the severity of cough among patients with asthma. Studies are needed to define how nedocromil sodium acts on the sensory nerves. PMID:8393025

  6. Role of signal transducer and activator of transcription 1 in murine allergen-induced airway remodeling and exacerbation by carbon nanotubes.

    PubMed

    Thompson, Elizabeth A; Sayers, Brian C; Glista-Baker, Ellen E; Shipkowski, Kelly A; Ihrie, Mark D; Duke, Katherine S; Taylor, Alexia J; Bonner, James C

    2015-11-01

    Asthma is characterized by a T helper type 2 phenotype and by chronic allergen-induced airway inflammation (AAI). Environmental exposure to air pollution ultrafine particles (i.e., nanoparticles) exacerbates AAI, and a concern is possible exacerbation posed by engineered nanoparticles generated by emerging nanotechnologies. Signal transducer and activator of transcription (STAT) 1 is a transcription factor that maintains T helper type 1 cell development. However, the role of STAT1 in regulating AAI or exacerbation by nanoparticles has not been explored. In this study, mice with whole-body knockout of the Stat1 gene (Stat1(-/-)) or wild-type (WT) mice were sensitized to ovalbumin (OVA) allergen and then exposed to multiwalled carbon nanotubes (MWCNTs) by oropharygneal aspiration. In Stat1(-/-) and WT mice, OVA increased eosinophils in bronchoalveolar lavage fluid, whereas MWCNTs increased neutrophils. Interestingly, OVA sensitization prevented MWCNT-induced neutrophilia and caused only eosinophilic inflammation. Stat1(-/-) mice displayed increased IL-13 in bronchoalveolar lavage fluid at 1 day compared with WT mice after treatment with OVA or OVA and MWCNTs. At 21 days, the lungs of OVA-sensitized Stat1(-/-) mice displayed increased eosinophilia, goblet cell hyperplasia, airway fibrosis, and subepithelial apoptosis. MWCNTs further increased OVA-induced goblet cell hyperplasia, airway fibrosis, and apoptosis in Stat1(-/-) mice at 21 days. These changes corresponded to increased levels of profibrogenic mediators (transforming growth factor-β1, TNF-α, osteopontin) but decreased IL-10 in Stat1(-/-) mice. Finally, fibroblasts isolated from the lungs of Stat1(-/-) mice produced significantly more collagen mRNA and protein in response to transforming growth factor-β1 compared with WT lung fibroblasts. Our results support a protective role for STAT1 in chronic AAI and exacerbation of