RENAL IMMUNE INJURY--NO/EICOSANOID INTERACTIONS

描述(改编自调查人员摘要)：这些目标 研究的目的是检查花生四烯酸途径和 肾免疫损伤中的一氧化氮途径。之前的研究由 首席调查员和其他人在#年证明了这一点 肾脏免疫损伤的实验模型，这两条途径都是 激活并导致合成促炎性二十烷类化合物和 离体肾小球中一氧化氮的生成。此外，还有 有证据表明，渗入激活的巨噬细胞是 都是生成的。产生的二十烷类化合物包括环氧合酶和 5-脂氧合酶代谢物。据推测，血管收缩 产生的二十烷类化合物可能是肾血管收缩的重要因素 以及肾小球的结构性损伤。首席调查员还 假设一氧化氮可能在肾小球和肾小球疾病中起有害作用 继发性过氧亚硝酸根生成引起的炎性损伤 氧自由基物种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具有有害后果 由于这一代一氧化氮在炎症性肾损伤中起作用。这些 研究也受到一氧化氮可能激活的证据的推动 体内和体外的环氧合酶。因此，假设是：1)在 INOS活化所致的肾小球免疫损伤 调节促炎二十烷类化合物的合成，而这些二十烷类化合物 调节iNOS的表达和活性；2)在肾小球中 免疫损伤，NO保护肾血流动力学功能和活化 INOS促进肾小球细胞损伤。这其中有四个具体目标 求婚。第一个具体目标将检查一氧化氮是否来自 由iNOS激活引起的肾小球炎症损伤将进行调节 环氧合酶活性以及是否有激活的效果 脂氧合酶活性。第二个具体目标将决定是否 二十碳二烯类化合物将调节iNOS的表达和iNOS衍生的生成 一氧化氮。第三个具体目标将检查在肾小球中 免疫损伤NO对肾血流量的保护作用 在肾小球滤过中，第四个特定目标将决定 在肾小球免疫损伤中，NO可能通过相互作用发挥有害作用 在过氧亚硝酸盐或类似氧化剂的形成过程中，NO与超氧化物发生反应。它 预计这些观察结果将为 肾小球肾炎的病理生物学。

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.