Trovafloxacin enhances the inflammatory response to a Gram-negative or a Gram-positive bacterial stimulus, resulting in neutrophil-dependent liver injury in mice.
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)-alpha and interferon-gamma. 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-alpha 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.
Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824, USA.
Patrick J
PJ
Shaw
Patricia E
PE
Ganey
Robert A
RA
Roth
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000382:microbiology* / Q000473:pathology*; D024841:Fluoroquinolones / Q000633:toxicity*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000472:pathogenicity*; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000472:pathogenicity*; D018836:Inflammation Mediators / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009287:Naphthyridines / Q000633:toxicity*; D009504:Neutrophils / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology*
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D018836:Inflammation Mediators; D009287:Naphthyridines; C080163:trovafloxacin