ROLE AND MANIPULATION OF LIPID MEDIATORS IN NEPHRITIS

脂质介质在肾炎中的作用和调控

• 批准号: 3236880
• 负责人: JAMES B LEFKOWITH
• 金额: $ 16.79万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-15 至 1994-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3236880
• 关键词: arachidonate; autoimmune disorder; cellular immunity; chemoattractants; chemotaxis; dietary supplements; enzyme inhibitors; essential fatty acids; fatty acid biosynthesis; fatty acid metabolism; glomerulonephritis; high performance liquid chromatography; immunopharmacology; inflammation; kidney function; laboratory mouse; laboratory rat; leukotrienes; luminescence; macrophage; membrane lipids; nutrition related tag; platelet activating factor; prostaglandins; radiotracer; receptor mediated endocytosis; renal glomerulus; tissue /cell culture

Immune-mediated glomerulonephritis is characterized by an invasion of macrophages into the glomerulus, and enhancement in glomerular lipid mediator production, and renal dysfunction. Evidence suggests that macrophages and lipid mediators are critical components of the renal in jury. Essential fatty acid (EFA) deficiency, which leads to a decrease in arachidonate and its replacement with the abnormal fatty acid, 20:3(n-9), has proven to be a uniquely valuable tool to probe the role of macrophages, attenuates the changes in glomerular lipid mediator production, and prevents the renal dysfunction. In consequence, it is hypothesized that lipid mediators play a crucial role in glomerulonephritis, mediating the influx of macrophages and the consequent renal functional alterations. The protective effect of EFA deficiency is conjectured to result from an interference with macrophage elicitation and an inhibition of lipid mediator production. Specific goals of the project are thus to determine the synthesis and cellular source within glomerulonephritis and how their elaboration is affected by EFA deficiency. Studies will also address whether EFA deficiency affects macrophage functional responses relevant to inflammation such as chemotaxis, adherence or activation. Ongoing efforts to isolate the mediator responsible for macrophage elicitation in glomerulonephritis will be continued. Immunologic and pharmacologic agents will be used to dissect out the role of both resident and elicited glomerular macrophages in the observed metabolic and functional alterations. Attempts will be made to develop dietary and/or pharmacologic strategies to reproduce the salutary effects of EFA deficiency in glomerulonephritis. Experiments will also address the underlying cellular and biochemical mechanisms of the changes in glomerular lipid mediator production in nephritis. The ultimate aim of the project is to develop strategies to treat glomerulonephritis that avoid the toxicity of current therapy (i.e non-specific immunosuppression). Because glomerulonephritis can also be thought of as a general paradigm for immunoinflammatory disorders, it is hoped that the results derived from this study will be applicable to other disorders such as autoimmune diabetes, myocardial infarction, or rheumatoid arthritis.

免疫介导的肾小球肾炎的特征是侵袭性肾小球肾炎 巨噬细胞进入肾小球，肾小球脂质增强 介质的产生和肾功能障碍。 有证据表明 巨噬细胞和脂质介质是肾脏的重要组成部分 陪审团。 必需脂肪酸（EFA）缺乏，导致 花生四烯酸及其用异常脂肪酸的替代物，20:3(n-9)， 已被证明是探索巨噬细胞作用的独特有价值的工具， 减弱肾小球脂质介质产生的变化，并且 预防肾功能障碍。 因此，假设 脂质介质在肾小球肾炎中起着至关重要的作用，介导 巨噬细胞的涌入以及随后的肾功能改变。 这 据推测，EFA 缺乏的保护作用是由于 干扰巨噬细胞激发和抑制脂质 中介生产。 因此，该项目的具体目标是确定 肾小球肾炎的合成和细胞来源及其如何 阐述受到全民教育缺乏的影响。 研究还将解决 EFA缺乏是否会影响巨噬细胞的功能反应 炎症，例如趋化性、粘附性或激活性。 持续努力 分离负责巨噬细胞诱导的介质 肾小球肾炎将继续。 免疫学和药理学制剂 将用于剖析驻留者和引出者的角色 观察肾小球巨噬细胞的代谢和功能 变更。 将尝试开发饮食和/或药物 重现全民教育缺乏的有益影响的策略 肾小球肾炎。 实验还将解决潜在的细胞 肾小球脂质介质变化及生化机制 肾炎的产生。 该项目的最终目标是开发 避免当前药物毒性的治疗肾小球肾炎的策略 治疗（即非特异性免疫抑制）。 因为肾小球肾炎 也可以被认为是免疫炎症的一般范例 疾病，希望这项研究的结果能够 适用于其他疾病，如自身免疫性糖尿病、心肌病 梗塞或类风湿性关节炎。