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Research ArticleTOXICOLOGY

Tumor Necrosis Factorα Is a Proximal Mediator of Synergistic Hepatotoxicity from Trovafloxacin/Lipopolysaccharide Coexposure

Patrick J. Shaw, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics January 2009, 328 (1) 62-68; DOI: https://doi.org/10.1124/jpet.108.143792
Patrick J. Shaw
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Patricia E. Ganey
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Robert A. Roth
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Abstract

The use of trovafloxacin (TVX), a fluoroquinolone antibiotic, was severely restricted because of an association of TVX therapy with idiosyncratic hepatotoxicity in patients. The mechanisms underlying idiosyncratic toxicity are unknown; however, one hypothesis is that an inflammatory stress can render an individual sensitive to the drug. Previously, we reported that treatment of mice with TVX and lipopolysaccharide (LPS) induced tumor necrosis factor (TNF) α-dependent liver injury, whereas TVX or LPS treatment alone was nontoxic. The goal of this study was to elucidate the role of TNFα in TVX/LPS-induced liver injury. TNF receptor (TNFR) 1 p55-/- and TNFR2 (p75-/-) mice were protected from hepatotoxicity caused by TVX/LPS coexposure, suggesting that TVX/LPS-induced liver injury requires both TNF receptors. TNFα inhibition using etanercept significantly reduced the TVX/LPS-induced increases in the plasma concentrations of several cytokines around the time of onset of liver injury. However, despite the reduction in chemokines, etanercept treatment did not affect the TVX/LPS-induced hepatic accumulation of neutrophils. In addition, etanercept treatment attenuated TVX/LPS induction of plasminogen activator inhibitor-1, and this was associated with a reduction in hepatic fibrin deposition. Mice treated with TVX and a nontoxic dose of TNFα also developed liver injury. In summary, TNFα acts through p55 and p75 receptors to precipitate an innocuous inflammatory cascade. TVX enhances this cascade, converting it into one that results in hepatocellular injury.

Footnotes

  • This study was supported by National Institutes of Health [Grant DK061315] and by National Institute of Environmental Health Sciences [Training Grant GM075685].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.143792.

  • ABBREVIATIONS: IADR, idiosyncratic adverse drug reaction; TVX, trovafloxacin; LPS, lipopolysaccharide; TNF, tumor necrosis factor; p55, TNF receptor 1; p75, TNF receptor 2; NF, nuclear factor; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; VEGF, vascular endothelial growth factor; MIP, macrophage inflammatory protein; KC, keratinocyte chemoattractant; PMN, neutrophil; TAT, thrombin/antithrombin III; PAI, plasminogen activator inhibitor; Veh, vehicle.

    • Received July 21, 2008.
    • Accepted September 25, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticleTOXICOLOGY

Tumor Necrosis Factorα Is a Proximal Mediator of Synergistic Hepatotoxicity from Trovafloxacin/Lipopolysaccharide Coexposure

Patrick J. Shaw, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics January 1, 2009, 328 (1) 62-68; DOI: https://doi.org/10.1124/jpet.108.143792

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Research ArticleTOXICOLOGY

Tumor Necrosis Factorα Is a Proximal Mediator of Synergistic Hepatotoxicity from Trovafloxacin/Lipopolysaccharide Coexposure

Patrick J. Shaw, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics January 1, 2009, 328 (1) 62-68; DOI: https://doi.org/10.1124/jpet.108.143792
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