The role of the hemostatic system in murine liver injury induced by coexposure to lipopolysaccharide and trovafloxacin, a drug with idiosyncratic liability
| Autor: | Aaron M. Fullerton, Patricia E. Ganey, Michael A. Scott, Patrick J. Shaw, Robert A. Roth |
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| Rok vydání: | 2009 |
| Předmět: |
Lipopolysaccharides
Lipopolysaccharide Inflammation Pharmacology Toxicology Fibrinogen Fibrin chemistry.chemical_compound Mice Thrombin Plasminogen Activator Inhibitor 1 medicine Animals Naphthyridines Antibacterial agent Liver injury Mice Knockout Hemostasis biology business.industry Heparin Anticoagulants medicine.disease chemistry Liver Toxicity Immunology biology.protein Cytokines lipids (amino acids peptides and proteins) medicine.symptom business medicine.drug Fluoroquinolones |
| Zdroj: | Toxicology and applied pharmacology. 236(3) |
| ISSN: | 1096-0333 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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