Nitric Oxide and the Beneficial effect of Lung Inflation

描述（由申请人提供）：气道高反应性（AHR）是哮喘的一个主要特征，似乎与深吸气（DI）对人体气道有益作用的缺陷有关。这变得明显，因为健康个体在不存在DI的情况下对乙酰甲胆碱产生支气管收缩，这是通过深吸气、DI诱导的支气管保护（BP）和支气管扩张（BD）容易预防和可逆的。然而，患有哮喘的个体完全缺乏BP，并且根据其疾病的严重程度而具有不同程度的BD。一氧化氮是一种在哮喘中受影响的平滑肌生理学中的重要介质。研究表明，通过NO调节气道张力在气道炎症或AHR遗传易感性的动物中效果较差。我们假设D1的缺陷有益作用是由一氧化氮调节气道张力的有效性降低引起的。我们建议进行研究，以进一步确定NO在气道平滑生理学中的作用，并检测两种方式的所谓缺陷，1）通过磷酸二酯酶V抑制剂增加内源性NO和2）通过吸入外源性递送一氧化氮，在健康个体以及哮喘个体中评估DI诱导的BP变化。这将增加我们对DI诱导BP机制的理解，增强我们对AHR机制的认识，并可能为哮喘提供新的治疗靶点。

DESCRIPTION (provided by applicant): Airways hyperresponsiveness (AHR) is a cardinal characteristic of asthma and appears to be related with defects in the beneficial effects of deep inspiration (Dl) on human airways. This becomes apparent because healthy individuals in the absence of Dl develop bronchoconstriction to methacholine which is easily preventable and reversible with deep inspirations, Dl-induced bronchoprotection (BP) and bronchodilation (BD). However individuals with asthma completely lack BP and have variable degrees of BD depending on the severity of their disease. An important mediator in smooth muscle physiology that is affected in asthma is nitric oxide. Studies suggest that modulation of airway tone by NO is less effective in animals with airway inflammation or the genetic predisposition to AHR. We hypothesize that the defective beneficial effects of Dl are caused by reduced effectiveness of nitric oxide to modulate airway tone. We propose to conduct studies to further define the role of NO in airway smooth physiology and detect the alleged defect in two fashions, 1) augmentation of the intrinsic NO by a phosphodiesterase V inhibitor.and 2) extrinsic delivery of nitric oxide by inhalation, in healthy individuals as well as in individuals with asthma for evaluation of changes in Dl-induced BP . This will increase our understanding of the mechanisms of Dl induced BP, enhance our knowledge of mechanisms of AHR and potentially provide new therapeutic targets for asthma.