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Mechanisms of hepatotoxic interaction of amiodarone with inflammatory stress---A model of idiosyncratic, drug-induced liver injury.

机译：胺碘酮与炎性应激的肝毒性相互作用机制-特发性药物性肝损伤模型

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摘要

Idiosyncratic, drug-induced liver injury is a type of adverse reaction that occurs in a small fraction of patients during drug therapy. Amiodarone (AMD) is a class III antiarrythmic drug that causes idiosyncratic hepatotoxicity in human patients. The mechanisms of AMD-induced hepatotoxicity are not understood, and inflammatory stress has been proposed to be one of the contributors to idiosyncratic, drug-induced hepatotoxicity. The inflammatory stress hypothesis is supported by the work presented in this thesis demonstrating that cotreatment with AMD and the inflammagen lipopolysaccharide (LPS) results in liver damage in rats.;The importance of several inflammatory factors was explored. AMD enhanced LPS-induced TNF production, coagulation system activation and fibrinolysis impairment. AMD/LPS cotreatment caused activation of neutrophils (PMNs) in the liver. Inhibition of TNF signaling, inhibition of activation of coagulation or inactivation of PMNs attenuated AMD/LPS-induced liver injury in rats, demonstrating the importance of each of these events to toxicity. The activation of PMNs in the liver after AMD/LPS cotreatment was dependent on the activation of coagulation system, suggesting interaction among these inflammatory pathways. TNF potentiated AMD-induced apoptotic cell death of Hepa1c1c7 cells, in which caspase activation and lipid peroxidation played important roles. These studies of the interaction between AMD and inflammatory responses in animals further our understanding of the mechanisms of AMD-induced idiosyncratic hepatotoxicity and provide potential targets for treatment or prevention of such reactions in human patients.
机译：异质性，药物诱发的肝损伤是一类不良反应，在药物治疗期间的一小部分患者中会发生。胺碘酮（AMD）是导致人类患者特发性肝毒性的III类抗心律失常药物。尚不了解AMD诱导的肝毒性的机制，并且已经提出炎症应激是特异的，药物诱导的肝毒性的促成因素之一。炎症应激假说得到了本文研究工作的支持，证明了与AMD和炎症原脂多糖（LPS）共同治疗可导致大鼠肝损伤。;探讨了几种炎症因子的重要性。 AMD增强了LPS诱导的TNF产生，凝血系统激活和纤维蛋白溶解障碍。 AMD / LPS共同治疗可引起肝脏中性粒细胞（PMN）的活化。 TNF信号的抑制，凝血激活或PMN失活的抑制减弱了大鼠的AMD / LPS诱导的肝损伤，证明了这些事件对毒性的重要性。在AMD / LPS共同治疗后，肝脏中PMN的激活取决于凝血系统的激活，表明这些炎症途径之间存在相互作用。 TNF增强了AMD诱导的Hepa1c1c7细胞凋亡，其中caspase激活和脂质过氧化起重要作用。这些关于AMD与动物炎症反应之间相互作用的研究进一步加深了我们对AMD诱发特发性肝毒性机制的理解，并为治疗或预防人类患者的此类反应提供了潜在的靶标。

著录项

  • 作者

    Lu, Jingtao.;

  • 作者单位

    Michigan State University.;

  • 授予单位 Michigan State University.;
  • 学科 Health Sciences Toxicology.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 196 p.
  • 总页数 196
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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