RECEPTOR ANTAGONIST OF PLATELET-ACTIVATING-FACTOR INHIBITS INFLAMMATORY INJURY INDUCED BY INSITU FORMATION OF IMMUNE-COMPLEXES IN RENAL GLOMERULI AND IN THE SKIN

Abstract

Experiments were designed to test the effect of a receptor antagonist of platelet activating factor (PAF), SR163072, on inflammatory injury induced by in situ formation of immune complexes in two vascular districts of the rat that have different structural and hemodynamic characteristics: unilateral glomerulonephritis induced by perfusion of the left kidney of preimmunized animals with cationic human IgG, and passive reversed Arthus reaction in the skin. Three days after perfusion of left kidneys of rats not treated with SR163072 (group I) were greatly enlarged, and pale and severe exudative and proliferative lesions were present in glomeruli. Granular deposits of human IgG, rat IgG, and rat C3 were seen by immunofluorescence microscopy, and subepithelial electron-dense deposits were visualized by electron microscopy. The right kidneys were consistently normal. The animals were severely proteinuric and had increased levels of PAF in the circulation. In contrast, rats treated with SR163072 (group II) and studied at the same interval of time developed only mild, focal glomerulonephritis in the perfused kidneys. By immunofluorescence microscopy the glomerular deposits of human IgG and rat IgG were similar in quantity and distribution to those observed in rats of group I. Despite the fact that SR163072 did not influence the level or the activity of the rat serum complement system, the deposits of C3 were less abundant and more focal. As in animals of group I, electron-dense deposits were present at the epithelial side of the glomerular basement membrane. Proteinuria was slight, and levels of circulating PAF were not significantly increased. These effects cannot be ascribed to interference of SR163072 with antigen "implantation," antibody binding, or local hemodynamic conditions, because (1) the amounts of glomerular human and rat IgG were the same in treated and untreated rats; (2) SR163072 did not decrease the glomerular filtration rate; and (3) SR163072 prevented the increase in vascular permeability and the exudative lesions in passive Arthus reaction in the skin, a model less affected by hemodynamic changes than glomerulonephritis. The beneficial effect of SR163072 indicates that PAF is an important mediator of the inflammatory process generated either in glomeruli or in the skin by in situ immune complex formation.