Nitric Oxide and the Beneficial effect of Lung Inflation

Johns Hopkins University, Baltimore MD

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Abstract

[unreadable] 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. [unreadable] [unreadable] [unreadable]