Hepatic and extrahepatic factors critical for liver injury during lipopolysaccharide exposure.
Bacterial endotoxin [lipopolysaccharide (LPS)] causes liver injury in vivo that is dependent on platelets, neutrophils [polymorphonuclear leukocytes (PMNs)], and several inflammatory mediators, including thrombin. We tested the hypothesis that thrombin contributes to LPS-induced hepatocellular injury through direct interactions with platelets and/or PMNs in vitro. Perfusion of isolated livers from LPS-treated rats with buffer containing thrombin resulted in a significant increase in alanine aminotransferase (ALT) activity in the perfusion medium, indicating hepatocellular damage. This effect was completely abolished by prior depletion of PMNs from the LPS-treated donor rats but not by depletion of platelets, suggesting interaction between thrombin and PMNs in the pathogenesis. Thrombin did not, however, enhance degranulation of rat PMNs in vitro, and it was not directly toxic to isolated rat hepatocytes in the presence of PMNs even after LPS exposure, suggesting that hepatocellular killing by the PMN-thrombin combination requires the intervention of an additional factor(s) within the liver. In livers from naive donors perfused with buffer containing PMNs and LPS, no injury occurred in the absence of thrombin. Addition of thrombin (10 nM) to the medium caused pronounced ALT release. These results indicate that thrombin and PMNs are sufficient extrahepatic requirements for LPS-induced hepatocellular damage in intact liver.
Moulin
F
F
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
Copple
B L
BL
Ganey
P E
PE
Roth
R A
RA
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury; D003571:Cytochalasin B / Q000494:pharmacology; D004926:Escherichia coli; D018836:Inflammation Mediators / Q000502:physiology; D007700:Kinetics; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D010976:Platelet Count; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D003571:Cytochalasin B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009195:Peroxidase; D000410:Alanine Transaminase; D013917:Thrombin