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.
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