QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.109.151068v1 330/1/72    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Shaw, P. J. Articles by Roth, R. A. PubMed PubMed Citation Articles by Shaw, P. J. Articles by Roth, R. A.

TOXICOLOGY

Trovafloxacin Enhances the Inflammatory Response to a Gram-Negative or a Gram-Positive Bacterial Stimulus, Resulting in Neutrophil-Dependent Liver Injury in Mice

Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan

Trovafloxacin (TVX), a fluoroquinolone antibiotic, has been strongly linked with several cases of idiosyncratic hepatotoxicity in humans. Previous studies showed that a modest inflammatory stress induced by a Gram-negative bacterial stimulus [i.e., lipopolysaccharide (LPS)] rendered nontoxic doses of TVX hepatotoxic in mice. This study compared the interaction of TVX with Gram-negative and Gram-positive stimuli. Mice were given TVX 3 h before LPS (Gram-negative stimulus) or a peptidoglycan-lipoteichoic acid (PGN-LTA) mixture isolated from Staphylococcus aureus (Gram-positive stimulus). Administration of TVX, LPS, or PGN-LTA alone was nonhepatotoxic. However, TVX administration before PGN-LTA or LPS resulted in significant liver injury that occurred with similar time courses. TVX/PGN-LTA-induced hepatocellular necrosis was primarily localized to centrilobular regions, whereas that caused by TVX/LPS was predominantly midzonal. Administration of either LPS or PGN-LTA alone led to increased plasma concentrations of several cytokines and chemokines at a time near the onset of liver injury. TVX administration before LPS enhanced the concentrations of all of these cytokines, whereas TVX treatment before PGN-LTA increased all of the cytokines except tumor necrosis factor (TNF)- and interferon-. Liver injury was reduced in TVX/LPS- and TVX/PGN-LTA-treated mice given an antibody to CD18 and also in mice deficient in neutrophil [polymorphonuclear neutrophil (PMN)] elastase. Hepatic PMN accumulation and TNF- production after TVX/PGN-LTA-, but not after TVX/LPS-coexposure, was CD18-dependent. In summary, TVX significantly enhanced the murine inflammatory response to either a Gram-negative or a Gram-positive stimulus and caused hepatotoxicity that developed similarly and was dependent on PMN activation in mice but that differed in lesion location and cytokine profile.

Address correspondence to: Dr. Robert Roth, 221 Food Safety Bldg., Michigan State University, East Lansing, MI 48824. E-mail: rothr{at}msu.edu

This article has been cited by other articles:

				X. Deng, J. P. Luyendyk, P. E. Ganey, and R. A. Roth Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models Pharmacol. Rev., September 1, 2009; 61(3): 262 - 282. [Abstract] [Full Text] [PDF]