MECHANISMS OF DISEASE PREVENTION OF N-3 FATTY ACIDS

本研究的目的是了解 细胞膜磷脂组成的改变 膜可以影响细胞和组织对损伤的反应。 磷脂的组成将通过富集而改变 具有长链多不饱和n-3或n-6脂肪酸（PUFA）。 已经表明，n-3 PUFA保护冠状动脉 疾病的人和对实验性心脏缺血和 动物的大脑 它们还能防止遗传性 模拟狼疮性肾炎的小鼠自身免疫性肾炎 这些PUFAs在保护人体免受缺氧 肾系膜细胞损伤及炎症性增生 将在体外细胞系统中进行检查。 保护作用，即 可能是由于改变了类花生酸的生产从n-3 前体，二十碳五烯酸，以及可能的直接 富集磷脂产生的膜效应 主要是二十碳五烯酸和二十二碳六烯酸， 考察 直接的膜效应将包括： 膜结合酶活性和抗 富含n-3脂肪酸的膜的磷脂酶A-2; 线粒体呼吸和对Ca 2+敏感性的改变 以及心脏和肾脏细胞的氧自由基损伤。 动物喂食n-3脂肪酸含量高的食物。 的响应 培养的肾小球系膜细胞富含n-3脂肪酸， 促有丝分裂因子、血小板衍生生长因子和血小板 参与细胞炎症的活化因子 答案将被确定。 具体假设： 将测试保护机制。 我们在这些模型系统中的发现应该与 增加对缺血性和炎性损伤的了解 并帮助设计预防性干预措施， 治疗这些普遍存在的疾病， 死亡和残疾的风险。

The object of this study is to learn the mechanisms by which alterations of membrane phospholipid composition of cell membranes can affect the response of cells and tissues to injury. The composition of phospholipids will be modified by enrichment with long chain, polyunsaturated n-3 or n-6 fatty acids (PUFAs). It has been shown that n-3 PUFAs protect against coronary artery disease in man and against experimental ischemia of heart and brain in animals. They also are protective against a hereditary antoimmune nephritis in mice which mimics lupus erythematosis in man. The effect of these PUFAs in protection against anoxic injury and the inflammatory proliferation of renal mesangial cells will be examined in in vitro cell systems. Protective effects, that may be attributed to altered eicosanoid production from the n-3 precursor, eicosapentaenoic acid, as well as to possible direct membrane effects produced by enriched phospholipid content primarily of eicosapentaenoic and docosahexaenoic acids, will be examined. The direct membrane effects will include: changes in membrane bound enzyme activities and resistance to phospholipase A-2 of membranes enriched with n-3 fatty acids; alterations in mitochondrial respiration and susceptibility to Ca2+ and oxygen free radical injury from heart and kidney cells of animals fed diets high in n-3 fatty acid content. The response of cultured mesangial cells enriched in n-3 fatty acids to potent mitogenic factors, platelet derived growth factor and platelet activating factor that participate in the cellular inflammatory response will be determined. Specific hypotheses regarding mechanisms of protection will be tested. Our findings in these model systems should be relevant to increasing understanding of ischemic and inflammatory injuries and in helping to design interventions that are preventive or therapeutic for these ubiquitous diseases which are major causes of death and disability in our society.