ROLE OF ESSENTIAL FATTY ACID IN GLOMERULONEPHRITIS

必需脂肪酸在肾小球肾炎中的作用

• 批准号: 3236878
• 负责人: JAMES B LEFKOWITH
• 金额: $ 9.42万
• 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 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3236878
• 关键词: arachidonate; chemotaxis; endotoxins; fatty acid biosynthesis; fatty acid metabolism; glomerulonephritis; inflammation; kidney disorder; leukotrienes; macrophage; membrane lipids; nitrogen mustard; prostaglandins; radioimmunoassay; radiotracer; tissue /cell culture

Macrophages play an important pathogenic role in immune- mediated glomerulonephritis. These cells are known to be capable of synthesizing a number of biologically active metabolites of arachidonic acid and to be able to influence the proliferation of resident glomerular mesangial cells. Essential fatty acid deficiency (which leads to a lack of arachidonate and an accumulation of the abnormal fatty acid 20:3(n-9)) has been shown to prevent the inflammatory cell infiltrate and glomerular damage in immune-mediated glomerulonephritis. Therefore, the central hypothesis of the proposed project is that arachidonate and its metabolites play a critical role in initiating and perpetuating the injury in glomerulonephritis. To test this hypothesis the changes in glomerular arachidonate metabolism that occur in nephritis will be determined. Immunologic agents (such as nitrogen mustard, radiation, glucan, and endotoxin) will be used to elucidate the relationship between the inflammatory cell infiltrate in nephritis and the observed changes in glomerular arachidonate metabolism. Essential fatty acid deficiency will be utilized to help determine the role of arachidonate and its metabolites in attracting leukocytes into the glomerulus and in the functional deficits of nephritis. The cellular and biochemical mechanisms underlying the changes in glomerular arachidonate metabolism in nephritis will be investigated by determining the effects of macrophages on mesangial cell arachidonate metabolism and proliferation in culture. Pharmacologic manipulations (inhibition of cyclooxygenase of lipoxygenase) will be utilized to establish the role of arachidonate metabolism in the functional deficits of glomerulonephritis. The goal of the proposed study is to develop pharmacologic and/or dietary strategies to prevent the tissue injury and renal dysfunction in glomerulonephritis which avoid the toxicity of present therapeutic modalities. Additionally, understanding the mechamisms by which inflammatory cells interact with resident tissue cells and produce changes in tissue metabolism and function may elucidate the pathogenesis of other inflammatory conditions.

巨噬细胞在免疫系统中发挥着重要的致病作用 介导的肾小球肾炎。 已知这些细胞能够 合成多种具有生物活性的代谢物 花生四烯酸并能够影响增殖 常驻肾小球系膜细胞。 必需脂肪酸 缺乏症（导致花生四烯酸缺乏和 已显示异常脂肪酸 20:3(n-9)) 的积累 防止炎性细胞浸润及肾小球 免疫介导的肾小球肾炎的损害。 因此， 该项目的中心假设是花生四烯酸 及其代谢物在启动和 使肾小球肾炎的损伤永久化。 为了测试这个 假设肾小球花生四烯酸代谢的变化 肾炎发生的情况将被确定。 免疫剂 （如氮芥、辐射、葡聚糖和内毒素）会 用于阐明炎症之间的关系 肾炎细胞浸润和肾小球观察到的变化 花生四烯酸代谢。 必需脂肪酸缺乏会 用于帮助确定花生四烯酸及其作用 吸引白细胞进入肾小球的代谢物 肾炎的功能缺陷。 细胞和生化 肾小球花生四烯酸变化的机制 肾炎的代谢将通过确定 巨噬细胞对系膜细胞花生四烯酸的影响 文化中的新陈代谢和增殖。 药理作用 操作（抑制环氧合酶或脂氧合酶）将 用于确定花生四烯酸代谢在 肾小球肾炎的功能缺陷。 的目标 拟议的研究是为了开发药理学和/或饮食 预防组织损伤和肾功能障碍的策略 避免现有治疗方法毒性的肾小球肾炎 方式。 此外，了解其机制 炎症细胞与常驻组织细胞相互作用并产生 组织代谢和功能的变化可以阐明 其他炎症性疾病的发病机制。