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 coagulation system is critical to the pathogenesis, but previously reported results suggested that its critical role is independent of insoluble clot formation and that thrombin may be a key mediator of liver injury. To test the hypothesis that thrombin is involved in LPS-induced liver injury, animals were treated with the selective thrombin inhibitor, hirudin. The hirudin treatment regimen effectively inhibited thrombin, as evidenced by prolonged activated partial thromboplastin time and by maintenance of plasma fibrinogen concentrations in LPS-treated rats. Treatment with hirudin prevented LPS-induced liver injury, assessed by plasma alanine aminotransferase activity and histological evidence of hepatocellular necrosis. Previous studies have shown that LPS exposure results in the accumulation of neutrophils and platelets within the liver and that both of these cell types are critical for the development of LPS-induced liver injury. Hirudin attenuated in part the decrease in blood platelet concentration that accompanied LPS administration, but did not alter hepatic platelet or neutrophil accumulation. These results support the hypothesis that thrombin is required for hepatic injury from LPS exposure, but that it does not act by promoting the accumulation of platelets or neutrophils within the liver.
Pearson
J M
JM
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, USA.
Schultze
A E
AE
Schwartz
K A
KA
Scott
M A
MA
Davis
J M
JM
Roth
R A
RA
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006629:Hirudins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000293:injuries*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006629:Hirudins; D008070:Lipopolysaccharides