NOVEL INFLAMMATORY MEDIATORS IN GLOMERULONEPHRITIS

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The proposed research has the following objectives: 1) Establishment of experimental models of glomerular immune injury in the rat, representative of the various forms of human immunologically mediated glomerulopathies. 2) Characterization in isolated immunologically injured glomeruli of the biosynthetic mechanisms of three classes of "novel" inflammatory mediators: a) arachidonate cyclo-oxygenation products (prostaglandins and thromboxanes; b) arachidonate lipoxygenation products (monohydroxy-eicosatetraenoic acids and leukotrienes) and c) platelet-activating factor (PAF-acether). 3) Correlation between glomerular biosynthesis of arachidonate metabolites (eicosanoids) and PAF-acether and pertubations in renal hemdynamics and in glomerular permeability to protein in experimental glomerulonephritis. These objective are directly related to the mechanism of glomerular injury in glomerulonephritis since they aim at exploring biochemical events which are triggered by the interaction of immune reactants within the glomerulus and are responsible for the release of pro-inflammatory mediators. The mediators to be studied are potent vasoactive compounds (prostaglandins and thromboxanes), induce chemotaxis (monohydroxylated fatty acids and leukotrienes) and increase vascular permeability (leukotrienes, PAF-acether). Identification of their synthetic profiles during the evolution of glomerulonephritis could, therefore, allow specific pharmacologic manipulations in order to beneficially modify their effects. The experimental approach will employ: 1) Immunopathologic methods in order to establish three key models of experimental glomerulonephritis: antiglomerular basement membrane disease, membranous glomerulonephritis and serum sickness glomerulonephritis. 2) Biochemical methods (chromatograhic analyses and radioimmunoassay) for the characterization and quantification of glomerular prostaglandins, thromboxanes, monohydroxy-eicosatetraenoic acids, leukotrienes and PAF-acether. 3) Physiological methods (whole kidney clearance and urine protein analyses) to characterize pertubations in renal hemodynamics (glomerular filtration rate and renal plasma flow) and in glomerular permeability to protein. It is anticipated that the information accrued from the proposed studies will provide new insights into the pathophysiology and pathobiochemistry of glomerulonephritis.