THE THROMBIN INHIBITOR, HIRUDIN, ATTENUATES LIPOPOLYSACCHARIDE-INDUCED LIVER-INJURY IN THE RAT

The administration of gram-negative bacterial lipopolysaccharide (LPS) to rats results in hepatic parenchymal cell injury within 6 hr. The c oagulation system is critical to the pathogenesis, but previously repo rted results suggested that its critical role is independent of insolu ble clot formation and that thrombin may be a key mediator of liver in jury. To test the hypothesis that thrombin is involved in LPS-induced liver injury, animals were treated with the selective thrombin inhibit or, hirudin. The hirudin treatment regimen effectively inhibited throm bin, as evidenced by prolonged activated partial thromboplastin time a nd by maintenance of plasma fibrinogen concentrations in LPS-treated r ats. Treatment with hirudin prevented LPS-induced liver injury, assess ed by plasma alanine aminotransferase activity and histological eviden ce of hepatocellular necrosis. Previous studies have shown that LPS ex posure results in the accumulation of neutrophils and platelets within the liver and that both of these cell types are critical for the deve lopment of LPS-induced liver injury. Hirudin attenuated in part the de crease in blood platelet concentration that accompanied LPS administra tion, but did not alter hepatic platelet or neutrophil accumulation. T hese results support the hypothesis that thrombin is required for hepa tic injury from LPS exposure, but that it does not act by promoting th e accumulation of platelets or neutrophils within the liver.