RENAL IMMUNE INJURY--NO/EICOSANOID INTERACTIONS

肾免疫损伤——无/二十烷酸相互作用

• 批准号: 2410085
• 负责人: Elias Lianos
• 金额: $ 16.23万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2410085
• 关键词: arachidonate; eicosanoid metabolism; eicosanoids; enzyme activity; fatty acid metabolism; gene targeting; genetically modified animals; kidney circulation; kidney disorder; laboratory mouse; nitric oxide; prostaglandin endoperoxide synthase; renal glomerulus; superoxides

DESCRIPTION (Adapted from Investigator's Abstract): The goal of these studies is to examine interactions between arachidonic acid pathways and nitric oxide pathways in renal immune injury. Previous studies by the Principal Investigator, as well as others, have demonstrated that in experimental models of renal immune injury, both of these pathways are activated and result in synthesis of proinflammatory eicosanoids and generation of nitric oxide in isolated glomeruli. Furthermore, there is evidence that infiltrating activated macrophages are a key site where both are generated. Eicosanoid species produced include both cyclooxygenase and 5-lipoxygenase metabolides. It is postulated that the vasoconstrictive eicosanoids produced may be important contributors to renal vasoconstriction and structural damage to the glomerulus. The Principal Investigator also postulates that nitric oxide may play a detrimental role in glomerular and inflammatory injury due to generation of peroxynitrite secondary to interactions of oxygen free radical species with nitric oxide, and hypothesizes that the induction of iNOS may have deleterious consequences due to this generation of nitric oxide in inflammatory renal injury. These studies are also motivated by evidence that nitric oxide may activate cyclooxygenase in vivo and in vitro. Therefore, the hypotheses are: 1) In glomerular immune-injury NO generated as a result of iNOS activation regulates synthesis of pro-inflammatory eicosanoids, and these eicosanoids modulate expression and activity of iNOS, and 2) In glomerular immune-injury, NO preserves renal hemodynamic function and activation of iNOS promotes glomerular cell injury. There are four specific aims in this proposal. The first specific aim will examine whether nitric oxide derived from iNOS activation by glomerular inflammatory injury will regulate cyclooxygenase activity and also whether there is an effect to activate lipoxygenase activity. The second specific aim will determine whether eicosanoids will modulate iNOS expression and generation of iNOS derived nitric oxide. The third specific aim will examine whether in glomerular immune-injury NO serves a beneficial function to preserve renal blood flow in glomerular filtration, and the fourth specific aim will determine whether in glomerular immune-injury NO may serve a harmful function via interaction of NO with superoxide in formation of peroxynitrite or similar oxidants. It is anticipated that the observations will provide new insights in the pathobiology of glomerulonephritis.

描述（改编自研究者摘要）：这些研究的目标 研究是检查花生四烯酸途径之间的相互作用， 肾免疫损伤中的一氧化氮途径 以前的研究， 主要研究者以及其他人已经证明， 肾免疫损伤的实验模型，这两种途径都是 激活并导致促炎性类二十烷酸的合成， 在离体肾小球中产生一氧化氮。 此外，还有 有证据表明，浸润的活化巨噬细胞是一个关键部位， 产生的。 所产生的类二十烷酸物质包括环氧合酶和聚环氧乙烷。 5-脂氧合酶代谢产物 据推测， 产生的类二十烷酸可能是肾血管收缩的重要因素 以及肾小球的结构性损伤 首席研究员还 假定一氧化氮可能在肾小球和肾小球疾病中起有害作用， 炎症损伤由于产生过氧亚硝酸继发于 氧自由基物质与一氧化氮的相互作用，以及 假设诱导型一氧化氮合酶的诱导可能会产生有害的后果， 这是由于在炎症性肾损伤中产生一氧化氮。 这些 研究还受到一氧化氮可能激活 环氧合酶在体内和体外。 因此，假设是：1）在 肾小球免疫损伤诱导型一氧化氮合酶激活产生NO 调节促炎类花生酸的合成，这些类花生酸 2）在肾小球中， 免疫损伤，NO保护肾血流动力学功能和激活 iNOS促进肾小球细胞损伤。 这有四个具体目标 提议 第一个具体目标是检查一氧化氮是否来源于 肾小球炎性损伤引起的iNOS激活将调节 环氧合酶活性以及是否有激活 脂氧合酶活性 第二个具体目标将决定是否 类花生酸将调节iNOS的表达和iNOS衍生物的产生。 一氧化氮 第三个具体目标是检查肾小球中是否存在 免疫损伤NO具有保护肾血流的有益功能 第四个具体目标将决定是否 在肾小球免疫损伤中，NO可能通过相互作用发挥有害作用 NO与超氧化物形成过氧亚硝酸盐或类似的氧化剂。 它 预计这些观测将为未来的研究提供新的见解。 肾小球肾炎的病理生物学