Oxidative stress is important in the pathogenesis of liver injury induced by sulindac and lipopolysaccharide cotreatment.
Oxidative stress is important in the pathogenesis of liver injury induced by sulindac and lipopolysaccharide cotreatment.
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DOI：
10.1016/j.tox.2010.03.015
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发表时间：
2010-06-04
期刊：
影响因子：
4.5
通讯作者：
Ganey, Patricia E.
中科院分区：
文献类型：
--
作者：
Zou, Wei;Roth, Robert A.;Younis, Husam S.;Burgoon, Lyle D.;Ganey, Patricia E.
关键词：
在所有非甾体抗炎药中，舒林酸（SLD）与人类特异性肝毒性的发生率最高。先前，通过与非肝毒性剂量的LPS共同治疗大鼠，建立了sld诱导的特异性肝毒性动物模型。肿瘤坏死因子- α (TNF)在其发病机制中起着至关重要的作用。本研究进一步探讨SLD/LPS共处理诱导肝损伤的机制。氧化应激产物蛋白羰基在SLD/ lps共处理大鼠肝脏线粒体中升高。分析肝损伤前大鼠肝脏基因表达结果表明，SLD/LPS共处理可选择性调节氧化应激相关基因。用艾布selen或二甲亚砜抗氧化处理可减轻SLD/ lps诱导的肝损伤。在体外进一步研究氧化应激的作用。SLD的毒性代谢物SLD硫化物在HepG2细胞中增强了tnf诱导的细胞毒性和caspase 3/7活性。SLD硫化物还增加了二氯荧光素的荧光，提示活性氧（ROS）的产生。过氧化氢和TNF共处理HepG2细胞比单独处理产生更大的细胞毒性。抗氧化剂tempol或pancaspase抑制剂Z-VAD-FMK均可降低SLD硫化物/TNF共暴露诱导的细胞死亡和caspase 3/7活性。这些结果表明，SLD/LPS处理引起大鼠肝脏氧化应激，提示ROS在SLD/LPS诱导的肝损伤中起重要作用。此外，ROS通过激活caspase 3/7参与SLD和TNF的细胞毒性相互作用。
Among all the nonsteroidal anti-inflammatory drugs, sulindac (SLD) is associated with the greatest incidence of idiosyncratic hepatotoxicity in humans. Previously, an animal model of SLD-induced idiosyncratic hepatotoxicity was developed by cotreating rats with a nonhepatotoxic dose of LPS. Tumor necrosis factor-alpha (TNF) was found to be critically important to the pathogenesis. In this study, the mechanism of liver injury induced by SLD/LPS cotreatment was further explored. Protein carbonyls, products of oxidative stress, were elevated in liver mitochondria of SLD/LPS-cotreated rats. The results of analyzing gene expression in livers of rats before the onset of liver injury indicated that genes associated with oxidative stress were selectively regulated by SLD/LPS cotreatment. Antioxidant treatment with either ebselen or dimethyl sulfoxide attenuated SLD/LPS-induced liver injury. The role of oxidative stress was further investigated in vitro. SLD sulfide, the toxic metabolite of SLD, enhanced TNF-induced cytotoxicity and caspase 3/7 activity in HepG2 cells. SLD sulfide also increased dichlorofluorescein fluorescence, suggesting generation of reactive oxygen species (ROS). Hydrogen peroxide and TNF cotreatment of HepG2 cells caused greater cytotoxicity than either treatment alone. Either antioxidant tempol or a pancaspase inhibitor Z-VAD-FMK decreased cell death as well as caspase 3/7 activity induced by SLD sulfide/TNF coexposure. These results indicate that SLD/LPS treatment causes oxidative stress in livers of rats and suggest that ROS are important in SLD/LPS-induced liver injury in vivo. Furthermore, ROS contribute to the cytotoxic interaction of SLD and TNF by activating caspase 3/7.
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影响因子：
1.1
作者：
Eckel, J E;Gennings, C;Zacharewski, T R
通讯作者：
Zacharewski, T R
影响因子：
29.4
作者：
TARAZI, EM;HARTER, JG;EATON, RA
通讯作者：
EATON, RA
DOI：
10.1152/ajpgi.00422.2005
发表时间：
2006-04-01
影响因子：
4.5
作者：
Schwabe, RF;Brenner, DA
通讯作者：
Brenner, DA
影响因子：
5.3
作者：
Han, Yong Hwan;Kim, Suhn Hee;Park, Woo Hyun
通讯作者：
Park, Woo Hyun
影响因子：
4.8
作者：
Wang, Yongjun;Singh, Rajat;Czaja, Mark J.
通讯作者：
Czaja, Mark J.