Asthma is a chronic disease characterized by airway inflammation, reversible airway obstruction and airways hyperresponsiveness (AHR). Levels of the endogenous bronchodilator S-nitrosoglutathione (GSNO) are reduced in the airways of asthmatics, and recently, a GSNO-metabolizing enzyme (GSNO reductase; GSNOR) has been identified as a potential modifier of AHR in human asthma. In the lungs of allergen- challenged mice, we observe upregulation of GSNOR and decreased S-nitrosothiols (SNOs), concomitant with increased AHR. We hypothesize that GSNO supplementation via GSNOR inhibition may provide a new avenue for asthma therapy, and in preliminary studies, we have found in mice that inhalation of a small-molecule GSNOR inhibitor (GSNORi) abrogates airway inflammation and protects from allergen-induced AHR.
Our specific aims are to: 1) Identify the specific source(s), and levels, of NOS2 that are required for the effects of acute GSNORi administration; 2) Evaluate the therapeutic and potential toxic effects of chronic GSNO/GSNORi versus inhaled corticosteroid (ICS) therapy in a chronic model of HDM challenge; and 3) Identify targets of GSNOR inhibition in primary human airway epithelial cells. Completion of these specific aims will critically advance our understanding of the potential impact and limitations of GSNO- based therapies as acute and chronic treatments for asthma.
Asthma is a chronic disease, which is increasing in prevalence in many regions around the world. It affects an estimated 300 million people worldwide and imposes a considerable health care burden in the United States on both individuals afflicted with the disease and on society. Dysregulated S-nitrosothiol metabolism has been implicated in the pathogenesis of asthma. However, the molecular mechanisms linking S-nitrosthiols and asthma are not well understood. This proposal will use primary epithelial cell culture and mouse models of allergic asthma to understand how GSNO/GSNOR-based therapies may be applied to the treatment of asthma and to identify potential target proteins and pathways that are responsible for the anti- inflammatory and bronchodilatory effects of GSNO.
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