ToxSci Advance Access originally published online on August 13, 2007
Toxicological Sciences 2007 100(1):267-280; doi:10.1093/toxsci/kfm209
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The Role of Tumor Necrosis Factor Alpha in Lipopolysaccharide/Ranitidine-Induced Inflammatory Liver Injury
,1
* Center for Integrative Toxicology
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824
1 To whom correspondence should be addressed at Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, 221 Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824. Fax: (517) 432-2310. E-mail: rothr{at}msu.edu.
Received March 20, 2007; accepted July 26, 2007
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Abstract |
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Exposure to a nontoxic dose of bacterial lipopolysaccharide (LPS) increases the hepatotoxicity of the histamine-2 (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 insights 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 (PTX; 100 mg/kg, iv) to inhibit the synthesis of TNF or etanercept (Etan; 8 mg/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, 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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  X. Deng, J. Lu, L. D. Lehman-McKeeman, E. Malle, D. L. Crandall, P. E. Ganey, and R. A. Roth p38 Mitogen-Activated Protein Kinase-Dependent Tumor Necrosis Factor-{alpha}-Converting Enzyme Is Important for Liver Injury in Hepatotoxic Interaction between Lipopolysaccharide and Ranitidine J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 144 - 152. [Abstract] [Full Text] [PDF]
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