The role of the hemostatic system in murine liver injury induced by coexposure to  lipopolysaccharide and trovafloxacin, a drug with idiosyncratic liability.
The use of the fluoroquinolone antibiotic trovafloxacin (TVX) was severely restricted in 1999 due to its association with idiosyncratic hepatotoxicity. Previously, we reported that a nontoxic dose of TVX interacts with a nontoxic dose of lipopolysaccharide (LPS) to cause robust hepatocellular injury in mice. This interaction with LPS was not seen in mice treated with levofloxacin (LVX), a fluoroquinolone not associated with hepatotoxicity in people. TVX/LPS-coexposure caused an increase in plasma alanine aminotransferase (ALT) activity as early as 4.5 h after LPS administration which progressed through 15 h.We examined the role of the hemostatic system in TVX/LPS-induced liver injury. At the onset of liver injury, coexposure to TVX/LPS, but not exposure to TVX, LVX, LPS or LVX/LPS, caused increased plasma concentration of thrombin-antithrombin dimers and decreased plasma circulating fibrinogen. LPS treatment induced a small increase in plasma plasminogen activator inhibitor-1 (PAI-1) concentration, and TVX pretreatment enhanced this effect. TVX/LPS coexposure also resulted in hepatic fibrin deposition. Anticoagulant heparin administration reduced TVX/LPS-induced hepatic fibrin deposition and liver injury. PAI-1-/- mice treated with TVX/LPS exhibited similar fibrin deposition to wild-type mice but had significantly reduced hepatocellular injury. PAI-1-/- mice, but not heparin-treated mice, had reduced plasma concentrations of several cytokines compared to TVX/LPS-treated controls. In summary, TVX/LPS-coexposure caused an imbalance in the hemostatic system, resulting in thrombin activation increased, plasma concentration of PAI-1 and hepatic fibrin deposition. Both thrombin activation and PAI-1 play critical roles in the progression of TVX/LPS-induced liver injury, but through different modes of action.
Department of Pharmacology & Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, East Lansing, MI 48824, USA. shawpatr@msu.edu
Patrick J
PJ
Shaw
Aaron M
AM
Fullerton
Michael A
MA
Scott
Patricia E
PE
Ganey
Robert A
RA
Roth
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D024841:Fluoroquinolones / Q000633:toxicity*; D006487:Hemostasis / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D009287:Naphthyridines / Q000633:toxicity*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology
D000925:Anticoagulants; D016207:Cytokines; D024841:Fluoroquinolones; D008070:Lipopolysaccharides; D009287:Naphthyridines; D017395:Plasminogen Activator Inhibitor 1; D006493:Heparin; C080163:trovafloxacin