THE ROLE OF NITRIC OXIDE IN ACUTE LUNG INJURY

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OBJECTIVE: The goal of this proposal is to determine the biochemical mechanisms by which nitric oxide (NO) affects oxidant induced lung injury. HYPOTHESES: 1. We hypothesize that NO can play a pivotal role in reducing oxidant lung injury by increasing cGMP, scavenging O2, decreasing iron-mediated oxidant generation by chelating iron, or inhibiting platelet and polymorphonuclear leukocyte (PMN) adherence and activation. 2. Although NO generally plays a protective physiologic role, we hypothesize that during dysregulated inflammatory events increased levels of NO many augment or predispose the lung to oxidant injury by inhibiting key iron containing intracellular enzymes and by potentially generating OH from the interaction of NO and O2. RESEARCH PLAN: The project will investigate molecular, biochemical and physiologic interactions between reactive nitrogen intermediates and reactive oxygen intermediates, emphasizing how these interactions might ameliorate or augment lung injury. The first aim will determine the effect of NO on oxidant injury in the isolated lung and in pulmonary endothelial cells. These experiments will extend our preliminary findings, which indicate a protective effect of NO under these conditions, and will focus on investigating potential mechanisms. The second aim will investigate the molecular and cellular regulation of inducible NO synthase in lung endothelial and epithelial cells in response to inflammatory modulators (TNFa, IFNy, and PDGF) and physiological conditions (hypoxia and hyperoxia) present in ARDS patients. In this aim we will also establish the relationship between alterations in inducible enzyme. NO production and susceptibility to oxidant injury. These experiments will test the hypothesis that activation of inducible high output NO production cause metabolic changes in pulmonary endothelial and epithelial cells that predispose them to oxidant injury. The third aim investigates the cellular mechanisms by which NO inhibits PMN adhesion to endothelial cells and PMN activation in response to signaling molecules expressed by endothelial cells. The fourth aim will determine the level of endogenous NO production in septic patients, who are at risk for ARDS, and in patients with ARDS. SIGNIFICANCE: The proposed research will provide a better understanding of the conflicting roles that NO may play in preventing or promoting oxidant lung injury. This is timely since NO is being promoted as an investigational therapy in patients with ARDS.