Fibrin independent proinflammatory effects of tissuefactor in experimental crescentic glomerulonephritis

Abstract

Tissue factor initiated glomerular fibrin deposition is an important mediator of injury in crescentic glomerulonephritis. Recent data have suggested noncoagulant roles for tissue factor in inflammation. To test the hypothesis that in addition to its effects in initiating coagulation, tissue factor has proinflammatory effects in glomerulonephritis, rabbits given crescentic anti-glomerular basement membrane (GBM) antibody-induced glomerulonephritis were defibrinogenated with ancrod. One group of defibrinogenated rabbits was also given anti-tissue factor antibodies. Comparisons were made between these groups, as well as a third group that was neither defibrinogenated with ancrod nor given anti-tissue factor antibodies. Defibrinogenation alone abolished glomerular fibrin deposition, reduced crescent formation, and limited renal impairment (ancrod-treated, serum creatinine 274 +/- 37 micromol/L; untreated 415 +/- 51 micromol/L; P < 0.01). Tissue factor inhibition in defibrinogenated rabbits resulted in further protection of renal function (creatinine 140 +/- 19 micromol/L, P < 0.01) and reduced proteinuria (0.4 +/- 0.2g/day, untreated 2.6 +/- 0.4 g/day, P <0.01), which was significantly increased by defibrinogenation alone (ancrod-treated, 5.6 +/- 1.2 g/day). Anti-tissue factor antibodies (but not defibrinogenation alone) attenuated glomerular T-cell and macrophage recruitment, and major histocompatibility complex (MHC) class II expression. These results demonstrate important proinflammatory effects of tissue factor in crescentic glomerulonephritis that are fibrin independent and provide in vivo evidence for tissue factor's proinflammatory effects on MHC class II expression and leukocyte accumulation.