THE ROLE OF NITRIC OXIDE IN ACUTE LUNG INJURY

目的：本提案的目标是确定生物化学 一氧化氮（NO）影响氧化诱导肺的机制 损伤 假设：1. 我们假设NO可以在 通过增加cGMP，清除O2， 通过螯合铁减少铁介导的氧化剂产生，或 抑制血小板和多形核白细胞（PMN）粘附， activation. 2. 虽然NO通常起保护性生理作用， 作用，我们假设在失调的炎症事件中， NO水平的增加可增强或使肺易于氧化 通过抑制关键的含铁细胞内酶和通过 潜在地从NO和O2的相互作用产生OH。 研究：该项目将研究分子，生物化学和 活性氮中间体之间的生理相互作用， 活性氧中间体，强调这些相互作用如何可能 减轻或加重肺损伤。 第一个目标将决定 NO对离体肺及肺内氧化损伤的影响 内皮细胞 这些实验将扩展我们初步的 研究结果表明，在这些条件下，NO具有保护作用。 条件，并将重点研究潜在的机制。 的 第二个目标将研究分子和细胞调控， 肺血管内皮细胞和上皮细胞诱导型一氧化氮合酶 对炎症调节剂（TNF α、IFN γ和PDGF）的反应，以及 ARDS中存在的生理条件（缺氧和高氧） 患者 为此，我们还将建立以下关系： 诱导酶的改变。 NO的产生和对 氧化损伤 这些实验将检验这样一个假设， 诱导型高输出NO产生的激活引起代谢变化 在肺内皮和上皮细胞中， 氧化损伤 第三个目标是通过以下方式研究细胞机制： NO抑制PMN与内皮细胞的粘附和PMN的活化 对内皮细胞表达的信号分子作出反应。 的 第四个目标将确定脓毒症患者内源性NO产生的水平， 有ARDS风险的患者和ARDS患者。 意义：拟议的研究将提供更好的理解 一氧化氮在防止或促进 氧化性肺损伤 这是及时的，因为NO正在被推广为 ARDS患者的研究性治疗。

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.