Nitric Oxide and the Beneficial effect of Lung Inflation

描述(由申请人提供)：呼吸道高反应性(AHR)是哮喘的一个基本特征，似乎与深吸气(DL)对人类呼吸道有益效果的缺陷有关。这一点变得很明显，因为健康人在缺乏DL的情况下会对乙酰甲胆碱产生支气管缩窄，这是很容易预防和可逆的，具有深刻的灵感、DL诱导的支气管壁保护(BP)和支气管壁扩张(BD)。然而，哮喘患者完全没有血压，并根据疾病的严重程度而有不同程度的BD。在哮喘中受影响的一种重要的平滑肌生理学介质是一氧化氮。研究表明，在患有呼吸道炎症或AHR遗传易感性的动物中，NO对气道张力的调节效果较差。我们假设，丹参的不良有益作用是由于一氧化氮调节气道张力的有效性降低所致。我们建议进行研究，以进一步确定NO在气道平滑生理中的作用，并通过两种方式检测所谓的缺陷：1)磷酸二酯酶V抑制剂增加内在NO；2)吸入外源性一氧化氮，在健康人和哮喘患者中评价DL诱导的血压变化。这将增加我们对DL诱发BP的机制的了解，增强我们对AHR机制的认识，并有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.