ToxSci Advance Access originally published online on April 14, 2004
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Toxicological Sciences 80, 203-213 (2004)
Toxicological Sciences vol. 80 no. 1 © Society of Toxicology 2004; all rights reserved.
Gene Expression Analysis Points to Hemostasis in Livers of Rats Cotreated with Lipopolysaccharide and Ranitidine
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Departments of * Pharmacology and Toxicology and Biochemistry and Molecular Biology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824; and Investigative Toxicology, Pharmacia Corporation, Kalamazoo, Michigan
Received February 26, 2004; accepted April 2, 2004
Studies in rats have demonstrated that modest underlying inflammation can precipitate idiosyncratic-like liver injury from the histamine 2-receptor antagonist, ranitidine (RAN). Coadministration to rats of nonhepatotoxic doses of RAN and the inflammagen, bacterial lipopolysaccharide (LPS), results in hepatocellular injury. We tested the hypothesis that hepatic gene expression changes could be distinguished among vehicle-, LPS-, RAN- and LPS/RAN-treated rats before the onset of significant liver injury in the LPS/RAN-treated rats (i.e., 3 h post-treatment). Rats were treated with LPS (44 x 106 EU/kg, iv) or its vehicle, then two hours later with RAN (30 mg/kg, iv) or its vehicle. They were killed 3 h after RAN treatment, and liver samples were taken for evaluation of liver injury and RNA isolation. Hepatic parenchymal cell injury, as estimated by increases in serum alanine aminotransferase (ALT) activity, was not significant at this time. Hierarchal clustering of gene expression data from Affymetrix U34A rat genome array grouped animals according to treatment. Relative to treatment with vehicle alone, treatment with RAN and/or LPS altered hepatic expression of numerous genes, including ones encoding products involved in inflammation, hypoxia, and cell death. Some were enhanced synergistically by LPS/RAN cotreatment. Real-time PCR confirmed robust changes in expression of B-cell translocation gene 2, early growth response-1, and plasminogen-activator inhibitor-1 (PAI-1) in cotreated rats. The increase in PAI-1 mRNA was reflected in an increase in serum PAI-1 protein concentration in LPS/RAN-treated rats. Consistent with the antifibrinolytic activity of PAI-1, significant fibrin deposition occurred only in livers of LPS/RAN-treated rats. The results suggest the possibility that expression of PAI-1 promotes fibrin deposition in liver sinusoids of LPS/RAN-treated rats and are consistent with the development of local ischemia and consequent tissue hypoxia.
Key Words: inflammation; ranitidine; liver; gene array; plasminogen activator inhibitor-1; hypoxia.
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