Bacterial- and Viral-Induced Inflammation Increases Sensitivity to Acetaminophen Hepatotoxicity

Abstract

Acetaminophen (APAP)-induced hepatotoxicity accounts for nearly half of acute liver failure cases in the United States. The doses that produce hepatotoxicity vary considerably and many risk factors have been proposed, including liver inflammation from viral hepatitis. Interestingly, inflammatory stress from another stimulus, bacterial endotoxin (lipopolysaccharide, LPS), renders the liver more sensitive to hepatotoxicity from numerous xenobiotic agents. The purpose of these studies was to test the hypothesis that inflammation induced by LPS or infection with reovirus increases sensitivity to APAP-induced liver injury. For LPS-induced inflammation, C57BL/6J mice were treated with either saline or LPS (44 × 10⁶ EU/kg, ip) 2 h before treatment with APAP (100–400 mg/kg, ip) or saline. No elevation in serum alanine aminotransferase (ALT) activity was observed in mice that received vehicle or LPS alone. LPS co-treatment produced a leftward shift of the dose-response curve for APAP-induced hepatotoxicity and led to significantly greater tumor necrosis factor-α (TNF) production than APAP alone. Reovirus serotype 1 (10⁸ PFU, iv) induced inflammation in Balb/c mice as evidenced by increases in hepatic mRNAs for macrophage inhibitory protein-2, interleukin-6, and TNF. Co-administration of reovirus and APAP at doses of 450 and 700 mg/kg (2 h after reovirus) led to increases in serum ALT activity, whereas neither reovirus nor APAP alone produced liver injury. Consistent with the increases in serum ALT activity, histopathologic examination revealed centrilobular necrosis with marked neutrophilic accumulation only in livers of mice treated with LPS/APAP or with reovirus/APAP. The results suggest that normally noninjurious doses of APAP are rendered hepatotoxic by modest inflammation, whether bacterial or viral in origin.

Acknowledgments

This study was supported by a Strategic Research Grant from the Michigan State University Foundation and by National Institutes of Health grants DK061315 and GM075865. E. Sparkenbaugh was supported by NIEHS Training Grant T32ES007255. We thank Eleni Beli for technical assistance and the Laboratory of Experimental Pathology, Michigan State University, for help with microscopy, and Jack A. Hinson (University of Arkansas, Little Rock, AR) for his generous gift of antiserum to NAPQI adducts.