THE ROLE OF NITRIC OXIDE IN ACUTE LUNG INJURY

目的：本方案的目的是确定生化指标。 一氧化氮影响氧化物性肺损伤的机制 受伤。 假设：1.我们假设NO在 增加cGMP，清除O2，减轻氧化性肺损伤 通过螯合铁来减少铁介导的氧化剂的生成，或者 抑制血小板和多形核白细胞(PMN)的黏附 激活。2.虽然一氧化氮通常起到保护生理的作用 角色，我们假设在失调的炎症事件中 NO水平的升高会增加或使肺易受氧化剂的影响 通过抑制关键含铁胞内酶和通过 潜在地从NO和O2的相互作用中产生OH。 研究计划：该项目将研究分子、生化和 活性氮中间体和活性氮中间体的生理相互作用 活性氧中间体，强调这些相互作用如何可能 改善或加重肺损伤。第一个目标将决定 一氧化氮在离体肺和肺组织氧化损伤中的作用 内皮细胞。这些实验将延长我们初步的 研究结果表明，在这些情况下，NO具有保护作用 条件，并将重点调查潜在的机制。这个 第二个目标将研究细胞和分子调控。 大鼠肺内皮细胞和上皮细胞诱导型一氧化氮合酶 对炎症调节剂(TNFa、IFNy和PDGF)的反应和 ARDS患者存在的生理状况(缺氧和高氧) 病人。在这一目标中，我们还将建立 诱导酶的变化。无生产和易感性 氧化损伤。这些实验将检验这一假设 可诱导的高产量NO产生的激活引起代谢变化 在肺内皮细胞和上皮细胞中，使它们容易发生 氧化损伤。第三个目的是研究细胞机制，通过 其中，NO抑制PMN与内皮细胞的黏附和PMN的激活 以响应内皮细胞表达的信号分子。这个 第四个目标将确定脓毒症患者内源性NO的产生水平 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 NO在预防或促进中可能扮演的相互冲突的角色 氧化性肺损伤。这是及时的，因为NO正在被宣传为 ARDS患者的探索性治疗。

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.