Modulation of Airway Reactivity with Chronic Mechanical Strain

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DESCRIPTION (provided by applicant): Asthma, which is characterized by chronic airway inflammation, repeated episodes of reversible airway obstruction and airway hyper-reactivity, is most often initiated by IgE-mediated responses following exposure to allergens. Patients with severe, recurrent asthma also have airway remodeling with increased airway smooth muscle (ASM), increased inflammatory cells and collagen deposition. Inflammation and airway hyperresponsiveness are key components of the allergen-induced inflammatory response, which results from the interaction of airway cells and inflammatory cells that release local mediators. Although anti-inflammatory agents and �-adrenergic bronchodilators remain the primary treatment for chronic and acute episodes of bronchoconstriction, there is a great need for new therapeutic approaches. Mechanical strain imposed on the lungs during breathing is an important modulator of airway responsiveness in vivo. Previous studies from this project have shown that chronic mechanical strain (CMS) produced in vivo by imposing continuous positive airway pressure (CPAP) dramatically reduces airway reactivity in vivo. Lungs and airway tissues isolated from the CPAP-treated animals also exhibit lower responsiveness to bronchoconstrictors. This suppression of airway responsiveness by CMS also occurs in the presence of allergen induced inflammation. A small clinical trial was also performed in which adults with asthma treated with nocturnal CPAP for 1 week showed a significant reduction in airway reactivity. Whereas studies from this project have previously focused on the effects of CMS on airway contractility, exciting preliminary data suggest that CMS also suppresses synthetic responses of the airway tissues to inflammatory mediators. IL-13, a key mediator of airway inflammation in asthma, acts directly on ASM tissues to cause the synthesis of the eosinophil chemoattractant, eotaxin, and hypercontractility. Studies from this project showed that the imposition of CMS on isolated ASM tissues suppressed the IL-13 induced eotaxin synthesis and that CMS imposed on the lungs of mice in vivo suppressed airway responsiveness, and inhibited ASM contractility and the activation of IL-13 activated signaling molecules. This suggests that CMS is a potent modulator of both contractile and synthetic functions of ASM and led to the novel hypothesis that chronic strain may be effective as an inhibitor of airway inflammation and the resultant airway remodelling. In the proposed studies, isolated airway tissues and mouse models of asthma will be used to evaluate the inflammatory responses of ASM tissues and the molecular mechanisms by which CMS modulates their properties. The efficacy of CPAP as an inhibitor of airway hyperreactivity and airway inflammation in children with severe asthma will also be determined. Mechanical strain with CPAP may provide a novel therapy for asthma patients with atopic inflammatory processes, and may be particularly useful in children with severe asthma, as it could reduce the chronic use of corticosteroids, which are associated with long term complications such as growth impairment.