Nitric Oxide and the Beneficial effect of Lung Inflation

一氧化氮和肺充气的有益作用

• 批准号: 7157972
• 负责人: GEORGE J PYRGOS
• 金额: $ 5.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7157972
• 关键词: asthma; bronchoconstrictors; bronchodilators; bronchomotion; clinical research; cyclic GMP; cytoprotection; human subject; methacholine; nitric oxide; phosphodiesterase inhibitors; postdoctoral investigator; pulmonary respiration; respiratory disease /disorder therapy; respiratory disorder chemotherapy; respiratory hypersensitivity; respiratory pharmacology; rhinitis; smooth muscle; spirometry

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.

描述（由申请人提供）：气道高反应性（AHR）是哮喘的主要特征，似乎与深度吸气（Dl）对人体气道有益作用的缺陷有关。这一点很明显，因为没有Dl的健康人会对甲胆碱产生支气管收缩，这是很容易预防的，并且可以通过深度吸气、Dl诱导的支气管保护（BP）和支气管扩张（BD）来逆转。然而，哮喘患者完全没有血压，并根据疾病的严重程度有不同程度的双相障碍。一氧化氮是平滑肌生理学中受哮喘影响的重要介质。研究表明，NO对气道张力的调节在气道炎症或AHR遗传易感性的动物中效果较差。我们假设Dl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。我们建议开展研究以进一步确定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)通过磷酸二酯酶V抑制剂增加内在NO。2)在健康个体和哮喘个体中通过吸入外源性一氧化氮来评估dl诱导的血压变化。这将增加我们对Dl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。