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ToxSci Advance Access published online on August 13, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm209
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Role of Tumor Necrosis Factor alpha in Lipopolysaccharide/Ranitidine-induced Inflammatory Liver Injury.

Francis F. Tukov, James P. Luyendyk, Patricia E. Ganey and Robert A. Roth

Center for Integrative Toxicology and the Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824

(Corresponding author), Phone: 517-353-9841, FAX: 517-432-2310, Email: rothr{at}msu.edu

Received March 20, 2007; revision received July 26, 2007; accepted July 26, 2007


  Abstract

Exposure to a nontoxic dose of bacterial lipopolysaccharide (LPS) increases the hepatotoxicity of the H2-receptor antagonist, ranitidine (RAN). Because some of the pathophysiologic effects associated with LPS are mediated through the expression and release of inflammatory mediators such as tumor necrosis factor alpha (TNF), this study was designed to gain insight into the role of TNF in LPS/RAN hepatotoxicity. To determine whether RAN affects LPS-induced TNF release at a time near the onset of liver injury, male, Sprague-Dawley rats were treated with 2.5 x 106 endotoxin units (EU)/kg LPS or its saline vehicle (iv), and 2 h later with either 30 mg/kg RAN or sterile phosphate-buffered saline vehicle (iv). LPS administration caused an increase in circulating TNF concentration. RAN cotreatment enhanced the LPS-induced TNF increase before the onset of hepatocellular injury, an effect that was not produced by famotidine, a H2-receptor antagonist without idiosyncrasy liability. Similar effects were observed for serum interleukin (IL)-1beta, IL-6 and IL-10. To determine if TNF plays a causal role in LPS/RAN-induced hepatotoxicity, rats were given either pentoxifylline (100 mg PTX/kg, iv) to inhibit the synthesis of TNF, or etanercept (8 mg Etan/kg, sc) to impede the ability of TNF to reach cellular receptors, and then they were treated with LPS and RAN. Hepatocellular injury, the release of inflammatory mediators, hepatic neutrophil (PMN) accumulation and biomarkers of coagulation and fibrinolysis were assessed. Pretreatment with either PTX or Etan resulted in the attenuation of liver injury and diminished circulating concentrations of TNF, IL-1ß, IL-6, macrophage inflammatory protein-2 (MIP-2) and coagulation/fibrinolysis biomarkers in LPS/RAN-cotreated animals. Neither PTX nor Etan pretreatments altered hepatic PMN accumulation. These results suggest that TNF contributes to LPS/RAN-induced liver injury by enhancing inflammatory cytokine production and hemostasis.

Key Words: tumor necrosis factor alpha; inflammation; liver injury; lipopolysaccharide; ranitidine; adverse drug reactions; coagulation; hemostasis; hepatotoxicity.


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