Macrophage-induced glomerular fibrin deposition in experimental glomerulonephritis in the rabbit

Abstract

Glomerular fibrin deposition is important in the pathogenesis of renal failure and crescent formation in glomerulonephritis. The mechanisms of glomerular fibrin deposition are unknown. The current studies explored the role of macrophages in this process. Methods were developed for measuring glomerular fibrin deposition and glomerular procoagulant activity in a passive model of the autologous phase of antiglomerular basement membrane antibody-induced glomerulonephritis in rabbits. Significant fibrin deposition was observed to be associated with glomerular macrophage accumulation. Leukocyte ablation with mustine hydrochloride prevented both glomerular macrophage accumulation and fibrin deposition without affecting the coagulation system or the deposition of disease-inducing antibodies and complement. Repletion with mononuclear inflammatory cells produced significant fibrin deposition. To examine the role of tissue injury per se in glomerular fibrin deposition, a macrophage-independent model of glomerular injury (heterologous phase glomerulonephritis) was also studied. Although a similar degree of glomerular injury occurred, there was no significant fibrin deposition. This suggests that macrophages, rather than injury alone, are responsible for fibrin deposition. Lysates of isolated glomeruli containing macrophages demonstrated greatly enhanced procoagulant activity compared with lysates of glomeruli without macrophages. Thus macrophages appear to be directly responsible for glomerular fibrin deposition in antiglomerular basement membrane antibody-induced glomerulonephritis, and this appears to be due to their ability to express procoagulant activity rather than their propensity to cause glomerular injury.