In humans, S-nitrosoglutathione (GSNO), an endogenous bronchodilator, is depleted in the airway of asthmatics. GSNO reductase (GSNOR), an enzyme widely expressed across tissues including lung, regulates levels of lung GSNO levels. Wild-type mice develop increased GSNOR activity and decreased lung S-nitrosothiol (SNO) concentration following allergen challenge and suffer from increased airway hypersensitivity. In contrast, mice with a genetic deletion of GSNOR have increased lung SNO levels after allergen challenge and are protected from airway hyperreactivity. GSNOR deficient mice also have lower basal bronchial tone than normal animals and do not desensitize after repeated stimulation with (2 agonist therapy suggesting that endogenous SNOs regulate smooth muscle tone. These results provide genetic evidence in mice that dynamic SNO turnover is a critical mechanism of NO function in health and disease. In this grant application, we will test the hypothesis that depletion of the endogenous bronchodilator, GSNO, from the airway increases airway hyperresponsiveness to methacholine and decreases response to inhaled (2 agonists in human asthma. We will first determine if GSNOR activity is increased in human asthma and correlates with airway SNO expression (Aim 1). We will next determine if GSNOR activity predicts responsiveness to inhaled ((2 agonist therapy and if the presence of polymorphisms of GSNOR predicts enzyme activity, airway SNO concentration, and response to (2 agonists in asthmatic as compared to control subjects (Aim 2). Finally, we plan to determine whether repletion of SNO in subjects with mild asthma confers protection against methacholine induced bronchoconstriction and desensitization to an inhaled (2 agonist (Aim 3). This proposal will further our understanding of GSNOR and SNOs in asthma, how they function as homeostatic agents in asthma, and how repletion of SNO provides a novel therapeutic target.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-RES-C (02))
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Noel, Patricia
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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