Modulation of Airway Reactivity with Chronic Mechanical Strain

描述（由申请人提供）：哮喘以慢性气道炎症、可逆性气道阻塞反复发作和气道高反应性为特征，最常由暴露于过敏原后ige介导的反应引发。严重、复发性哮喘患者也有气道重塑，气道平滑肌（ASM）增加，炎症细胞和胶原沉积增加。炎症和气道高反应性是过敏原诱导的炎症反应的关键组成部分，这是气道细胞和炎症细胞相互作用的结果，炎症细胞释放局部介质。尽管抗炎药和肾上腺素能支气管扩张剂仍然是慢性和急性支气管收缩发作的主要治疗方法，但仍需要新的治疗方法。在呼吸过程中施加在肺上的机械应变是气道反应的重要调节因子。本项目前期研究表明，持续气道正压（CPAP）在体内产生的慢性机械应变（CMS）显著降低了气道的体内反应性。从cpap治疗的动物身上分离出的肺和气道组织对支气管收缩剂的反应性也较低。CMS对气道反应性的抑制也发生在过敏原诱导的炎症中。在一项小型临床试验中，接受夜间CPAP治疗1周的成人哮喘患者气道反应性显著降低。虽然该项目的研究先前主要集中在CMS对气道收缩性的影响上，但令人兴奋的初步数据表明，CMS还抑制气道组织对炎症介质的合成反应。IL-13是哮喘气道炎症的关键介质，直接作用于ASM组织，导致嗜酸性粒细胞趋化剂eotaxin的合成和过度收缩。本课题研究表明，CMS作用于离体ASM组织可抑制IL-13诱导的eotaxin合成，CMS作用于小鼠肺内可抑制气道反应性，抑制ASM收缩性和IL-13激活信号分子的激活。这表明CMS是ASM收缩和合成功能的有效调节剂，并导致了新的假设，即慢性应变可能有效地抑制气道炎症和由此引起的气道重构。在拟开展的研究中，我们将采用分离气道组织和哮喘小鼠模型来评估ASM组织的炎症反应以及CMS调节其特性的分子机制。CPAP作为严重哮喘患儿气道高反应性和气道炎症抑制剂的疗效也将被确定。机械应变CPAP可能为哮喘患者的特应性炎症过程提供一种新的治疗方法，并且可能对患有严重哮喘的儿童特别有用，因为它可以减少与生长障碍等长期并发症相关的皮质类固醇的慢性使用。

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.