The coagulation system, but not circulating fibrinogen, contributes to liver injury in rats exposed to lipopolysaccharide from gram-negative bacteria

JA Hewett and RA Roth

Department of Pharmacology and Toxicology, Michigan State University, E. Lansing.

Evidence suggests that components of the coagulation system contribute to the pathogenesis of liver injury after exposure to lipopolysaccharide (LPS) from gram-negative bacteria. Although the mechanism by which the coagulation system mediates liver injury remains unknown, it has been proposed that the conversion of fibrinogen to insoluble fibrin and consequent deposition in liver microvasculature may contribute to the development of liver injury. The purpose of this study was to test the hypothesis that the coagulation system contributes to LPS hepatotoxicity by a mechanism which is dependent on circulating fibrinogen. A marked reduction in plasma fibrinogen concentration occurred in rats after LPS exposure. The decrease in circulating fibrinogen, which marked activation of the coagulation cascade: 1) occurred at doses of LPS that caused liver injury; 2) was temporally associated with the onset of liver injury; and 3) was attenuated by pretreatment with heparin or warfarin under conditions which afforded protection against liver injury. Pretreatment with either pentoxifylline or antiserum to tumor necrosis factor-alpha, both of which protect against LPS hepatotoxicity, also attenuated the LPS- induced decrease in circulating fibrinogen. Polymorphonuclear leukocyte (neutrophil) depletion protected against liver injury after administration of either a small (2 mg/kg) or a large (8 mg/kg) dose of LPS and attenuated the decrease in circulating fibrinogen albeit to a lesser degree after the larger LPS dose. Depletion of circulating fibrinogen with ancrod did not afford protection against LPS hepatotoxicity. These results suggest that the coagulation system contributes to the pathogenesis of LPS-induced liver injury, but it does so by a mechanism which is independent of circulating fibrinogen.

Volume 272, Issue 1, pp. 53-62, 01/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics

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