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.
Shaw
Patrick J
PJ
Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824, USA.
Ganey
Patricia E
PE
Roth
Robert A
RA
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