Trovafloxacin Enhances the Inflammatory Response to a Gram-Negative or a Gram-Positive Bacterial Stimulus, Resulting in Neutrophil-Dependent Liver Injury in Mice
Trovafloxacin Enhances the Inflammatory Response to a Gram-Negative or a Gram-Positive Bacterial Stimulus, Resulting in Neutrophil-Dependent Liver Injury in Mice
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DOI：
10.1124/jpet.109.151068
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Roth, Robert A.
中科院分区：
文献类型：
--
作者：
Shaw, Patrick J.;Ganey, Patricia E.;Roth, Robert A.
曲伐他汀（TVX）是一种氟喹诺酮类抗生素，与几例人类特异质肝毒性病例密切相关。先前的研究表明，由革兰氏阴性细菌刺激诱导的适度炎症应激[即，脂多糖（LPS）]使无毒剂量的TVX在小鼠中具有肝毒性。本研究比较了TVX与革兰氏阴性和阳性刺激的相互作用。在LPS（革兰氏阴性刺激）或从金黄色葡萄球菌分离的肽聚糖-脂磷壁酸（PGN-LTA）混合物（革兰氏阳性刺激）之前3小时给予小鼠TVX。TVX、LPS或PGN-LTA单独给药无肝毒性。然而，在PGN-LTA或LPS之前给予TVX导致以相似的时间过程发生的显著肝损伤。TVX/PGN-LTA诱导的肝细胞坏死主要位于小叶中心区，而TVX/LPS引起的肝细胞坏死主要位于中带区。单独施用LPS或PGN-LTA导致在接近肝损伤发作时几种细胞因子和趋化因子的血浆浓度增加。LPS前TVX给药增强了所有这些细胞因子的浓度，而PGN-LTA前TVX治疗增加了除肿瘤坏死因子（TNF）-α和干扰素-α外的所有细胞因子。在给予CD 18抗体的TVX/LPS和TVX/PGN-LTA处理的小鼠中，以及在中性粒细胞弹性蛋白酶缺乏的小鼠中，肝损伤减少。TVX/PGN-LTA-暴露后肝脏PMN蓄积和TNF-α产生是CD 18依赖性的，而TVX/LPS-共暴露后则不是。总之，TVX显着增强了小鼠的炎症反应，无论是革兰氏阴性或革兰氏阳性刺激，并导致肝毒性，发展相似，并依赖于小鼠的PMN激活，但不同的病变部位和细胞因子谱。
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-alpha. 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.