The role of the hemostatic system in murine liver injury induced by coexposure to lipopolysaccharide and trovafloxacin, a drug with idiosyncratic liability
The role of the hemostatic system in murine liver injury induced by coexposure to lipopolysaccharide and trovafloxacin, a drug with idiosyncratic liability
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DOI：
10.1016/j.taap.2009.01.018
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发表时间：
2009-05-01
影响因子：
3.8
通讯作者：
Roth, Robert A.
中科院分区：
文献类型：
--
作者：
Shaw, Patrick J.;Fullerton, Aaron M.;Roth, Robert A.
氟喹诺酮类抗生素曲瓦沙星（TVX）的使用在1999年受到严格限制，因为它与特异性肝毒性有关。先前，我们报道了无毒剂量的TVX与无毒剂量的脂多糖（LPS）相互作用，导致小鼠肝细胞损伤。左氧氟沙星（LVX）是一种与人类肝毒性无关的氟喹诺酮类药物，在用左氧氟沙星（LVX）治疗的小鼠中没有发现与LPS的相互作用。TVX/LPS共暴露引起血浆丙氨酸转氨酶（ALT）活性增加，早在LPS给药后4.5小时，并持续到15小时。我们研究了止血系统在TVX/LPS诱导的肝损伤中的作用。肝损伤开始时，同时暴露于TVX/LPS。但暴露于TVX、LVX、LPS或LVX/LPS均未引起血浆凝血酶-抗凝血酶二聚体浓度升高和血浆循环纤维蛋白原降低。lip处理可诱导血浆纤溶酶原激活物抑制剂-1 （PAI-1）浓度小幅升高，而TVX预处理可增强这一作用。TVX/LPS共暴露也导致肝纤维蛋白沉积。抗凝肝素治疗可减少TVX/ lps诱导的肝纤维蛋白沉积和肝损伤。经TVX/LPS处理的PAI-1（-/-）小鼠表现出与野生型小鼠相似的纤维蛋白沉积，但肝细胞损伤明显减轻。与TVX/ lps处理的对照组相比，PAI-1（-/-）小鼠的血浆中几种细胞因子浓度降低，而肝素处理的小鼠则没有。综上所述，TVX/ lps共暴露导致止血系统失衡，导致凝血酶激活升高，血浆PAI-1浓度升高，肝纤维蛋白沉积。凝血酶激活和PAI-1在TVX/ lps诱导的肝损伤的进展中都起关键作用，但通过不同的作用方式。(C) 2009爱思唯尔公司版权所有。
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. LIPS 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. (C) 2009 Elsevier Inc. All rights reserved.