Modulation of Airway Reactivity with Chronic Mechanical Strain

描述(申请人提供)：哮喘的特征是慢性呼吸道炎症、反复发作的可逆性呼吸道阻塞和呼吸道高反应性，最常见的是暴露于变应原后由IgE介导的反应。反复发作的重度哮喘患者也有气道重塑，表现为气道平滑肌(ASM)增多、炎性细胞增多和胶原沉积。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，炎症反应是呼吸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。虽然抗炎药和�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，但非常需要新的治疗方法。呼吸过程中施加在肺上的机械应变是体内呼吸道反应性的重要调节因素。该项目以前的研究表明，通过施加持续气道正压(CPAP)而在体内产生的慢性机械应变(CMS)显著降低了体内的气道反应性。从经CPAP处理的动物身上分离出的肺和呼吸道组织对支气管收缩药的反应性也较低。CMS对呼吸道反应性的抑制也发生在过敏原诱导的炎症存在时。还进行了一项小型临床试验，成人哮喘患者接受夜间CPAP治疗1周后，呼吸道反应性显著降低。虽然该项目的研究以前主要集中在CMS对呼吸道收缩的影响上，但令人兴奋的初步数据表明，CMS还抑制了呼吸道组织对炎症介质的合成反应。IL-13是哮喘呼吸道炎症的关键介质，直接作用于ASM组织，导致嗜酸性粒细胞趋化因子、嗜酸性粒细胞趋化因子和高收缩能力的合成。本项目的研究表明，施加在分离的ASM组织上的CMS抑制IL-13诱导的嗜酸性粒细胞合成，在体小鼠肺上施加CMS抑制气道反应性，并抑制ASM的收缩和IL-13激活的信号分子的激活。这表明CMS是ASM收缩和合成功能的有效调节器，并导致了新的假说，即慢性应激可能是一种有效的抑制气道炎症和由此产生的气道重塑的药物。在拟议的研究中，将使用分离的呼吸道组织和哮喘小鼠模型来评估ASM组织的炎症反应和CMS调节其特性的分子机制。此外，还将确定CPAP作为严重哮喘儿童的气道高反应性和气道炎症的抑制药的有效性。机械张力CPAP可能为有特应性炎症过程的哮喘患者提供一种新的治疗方法，并可能对患有严重哮喘的儿童特别有用，因为它可以减少皮质类固醇的长期使用，后者与生长障碍等长期并发症有关。

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.