Glomerular disease is a major cause of renal failure in man. For this reason, the mediators of glomerular injury have been the target of extensive research. Examination of the roles of vasoactive peptides, catecholamines, the complement cascade, Hageman factor-related systems, oxygen metabolites, cyclooxygenase products, and other mediators of injury has led to the realization that impairment of glomerular filtration and permselectivity function is the end-result of highly complex interactions among these various systems. Despite much controversy regarding the contribution of each of the mediators involved, consensus exists as to the central role of the polymorphonuclear leukocyte and cells of macrophage/monocyte origin in initiating and perpetuating glomerular dysfunction. This finding has generated interest in the biologically active compounds released during the activation of these cells, including the cyclooxygenase and lipoxygenase (LO) products of arachidonic acid.
The aim of the proposed studies is to attempt a definition of roles of LO products of arachidonic acid in mediating the impairment of glomerular perfusion, filtration, and permselectivity functions seen in selected, clinically relevant models of experimental glomerular injury. The experimental approach involves: (1) Examining, through glomerular micropuncture and dextran clearance techniques, the glomerular responses to exogenously administered sulfidopeptide leukotrienes (LTC4, D4, and E4) and the 15-LO products, lipoxins A and B. (2) Defining the roles of these compounds in mediating glomerular dysfunction in nephrotoxic serum and endotoxin-induced glomerular injury, through measurement of their endogenous generation rates and selective antagonism of their physiologic actions. (3) Assessing the capacity of glomerular cell subpopulations to generate these compounds upon appropriate stimulation. The presence of LO activity within the glomerulus, the identification of LT receptors on isolated glomeruli, and the demonstration by us and others of potent effects of LO products on glomerular and mesangial cell function under physiologic and pathophysiologic conditions, render the investigation of their glomerular effects potentially rewarding.
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