RT Journal Article
SR Electronic
T1 Coagulation-Mediated Hypoxia and Neutrophil-Dependent Hepatic Injury in Rats Given Lipopolysaccharide and Ranitidine
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1023
OP 1031
DO 10.1124/jpet.105.087981
VO 314
IS 3
A1 James P. Luyendyk
A1 Patrick J. Shaw
A1 Christopher D. Green
A1 Jane F. Maddox
A1 Patricia E. Ganey
A1 Robert A. Roth
YR 2005
UL http://jpet.aspetjournals.org/content/314/3/1023.abstract
AB Idiosyncrasy-like liver injury occurs in rats cotreated with nonhepatotoxic doses of ranitidine (RAN) and bacterial lipopolysaccharide (LPS). Hepatocellular oncotic necrosis is accompanied by neutrophil (PMN) accumulation and fibrin deposition in LPS/RAN-treated rats, but the contribution of PMNs to injury has not been shown. We tested the hypothesis that PMNs are critical mediators of LPS/RAN-induced liver injury and explored the potential for interaction between PMNs and hemostasis-induced hypoxia. Rats were given either LPS (44.4 × 106 endotoxin units/kg) or its vehicle and then RAN (30 mg/kg) or its vehicle 2 h later. They were killed 3 or 6 h after RAN treatment, and hepatocellular injury was estimated from serum alanine aminotransferase activity and liver histopathology. Plasma PMN chemokine concentration and the number of PMNs in liver increased after LPS treatment at 3 h and were not markedly altered by RAN cotreatment. Depletion of circulating PMNs attenuated hepatic PMN accumulation and liver injury and had no effect on coagulation system activation. Anticoagulation with heparin attenuated liver fibrin deposition and injury in LPS/RAN-treated rats; however, heparin had little effect on liver PMN accumulation or plasma chemokine concentration. Liver hypoxia occurred in LPS/RAN-cotreated rats and was significantly reduced by heparin. In vitro, hypoxia enhanced the killing of rat hepatocytes by PMN elastase and shortened its onset, indicating a synergistic interaction between PMNs and hypoxia. The results suggest that PMNs are involved in the hepatocellular injury caused by LPS/RAN-cotreatment and that hemostasis increases sensitivity to PMN-induced hepatocellular injury by causing liver hypoxia. The American Society for Pharmacology and Experimental Therapeutics