RELATIONSHIPS BETWEEN PROSTANOIDS AND CELLULAR INJURY

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Our goal is to characterize the role of lipid mediators in the processes of cellular injury and death. We have demonstrated arachidonic acid (AA) involvement in circulatory shock, hypoxia, burn injury, and complement-mediated (C') lung injury. We have also observed complement-mediated stimulation of eicosanoid formation in cultured cells. Furthermore, short-term C' treatment can augment long-term eicosanoid formation in response to appropriate stimuli. The aims are to characterized the mechanisms by which C' directly stimulates AA metabolism in isolated endothelial cells, b) characterize the nature of the C' interaction with endothelial cells which results in the long-term augmentation of eicosanoid release, and c) carry out studies in a model of endotoxemia to determine whether complement- mediated augmentation of eicosanoid production is of physiologic significance. Specific studies include assessment of the pattern, magnitude, and time course of AA metabolite formation by cultured bovine and human endothelial cells in response to C', investigation of the role of calcium in the complement-mediated activation process, characterization of the membrane phospholipid sources of the AA utilized, and characterization of the role of phospholipases A and C in the stimulation process. Additional studies will include determinations of the stimulus specificity of the long-term complement-mediated augmentation of eicosanoid formation, the time course of this sensitization, whether the pattern of eicosanoid production after C' pretreatment differs from that in normal cells, and the long-term changes in membrane phospholipid AA content which may accompany C' pretreatment. Studies related to the functional importance of this phenomenon will involve experiments carried out in the isolated perfused liver, heart, and vascular ring preparations to determine functional changes which result from endotoxemia in animals which are either C' replete or depleted. The above studies will characterize the biochemical mechanisms by which C' activation can lead to enhanced eicosanoid production and will elucidate the physiologic effect of this phenomenon during a period of global injury. The data obtained will be of value in the understanding therapeutic approaches to the management of clinical disorders which are characterized by C' activation including septicemia, hemodialysis-induced lung injury, burn injury, glomerulonephritis, and various autoimmune diseases.