title: Tumor necrosis factor alpha is a proximal mediator of synergistic hepatotoxicity from trovafloxacin/lipopolysaccharide coexposure.
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) alpha-dependent liver injury, whereas TVX or LPS treatment alone was nontoxic. The goal of this study was to elucidate the role of TNFalpha 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. TNFalpha 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 TNFalpha also developed liver injury. In summary, TNFalpha 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.
authors.affiliation: Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity; D016207:Cytokines / Q000097:blood; D024841:Fluoroquinolones / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009287:Naphthyridines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D054390:Receptors, CCR2 / Q000097:blood; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000502:physiology; D053319:Tumor Necrosis Factor Decoy Receptors / Q000172:deficiency / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000890:Anti-Infective Agents; D016207:Cytokines; D024841:Fluoroquinolones; D008070:Lipopolysaccharides; D009287:Naphthyridines; D054390:Receptors, CCR2; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C069521:recombinant human tumor necrosis factor-binding protein-1; C080163:trovafloxacin