Neutrophil-cytokine interactions in a rat model of sulindac-induced idiosyncratic liver injury.
Neutrophil-cytokine interactions in a rat model of sulindac-induced idiosyncratic liver injury.
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DOI：
10.1016/j.tox.2011.10.005
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发表时间：
2011-12-18
期刊：
影响因子：
4.5
通讯作者：
Ganey PE
中科院分区：
文献类型：
--
作者：
Zou W;Roth RA;Younis HS;Malle E;Ganey PE
以往的研究表明，脂多糖（LPS）与非甾体抗炎药舒林酸（SLD）相互作用可导致大鼠肝损伤。本研究进一步探讨了SLD/LPS诱导肝损伤的机制。SLD/LPS联合治疗组大鼠肝脏中多形核中性粒细胞（PMNs）的蓄积明显高于单纯SLD或LPS治疗组。此外，PMN激活发生在SLD/LPS共处理的大鼠肝脏中。对中性粒细胞及其释放的蛋白酶在肝毒性中起关键作用的假设进行了检验。SLD/LPS诱导的肝损伤通过预先耗尽PMN或用PMN蛋白酶抑制剂eglin C治疗而减弱。以往的研究表明，肿瘤坏死因子-α（TNF-α）和止血系统在SLD/LPS诱导的肝损伤的发病机制中起重要作用。TNF和纤溶酶原激活物抑制剂-1（派-1）可通过影响PMN活化和纤维蛋白沉积而导致肝毒性。因此，在SLD/LPS诱导的肝损伤模型中，检测了TNF和派-1在PMN活化和纤维蛋白沉积中的作用。中和TNF或抑制派-1可减弱PMN活化。TNF对派-1的产生或纤维蛋白沉积没有影响。相比之下，派-1促进了SLD/LPS处理大鼠肝脏中的纤维蛋白沉积。综上所述，PMN、TNF和派-1参与了SLD/LPS共处理诱导的肝损伤。TNF和派-1独立地促进PMN活化，这在肝损伤的发病机制中至关重要。此外，派-1通过促进纤维蛋白沉积而促进肝损伤。
Previous studies indicated that lipopolysaccharide (LPS) interacts with the nonsteroidal anti-inflammatory drug sulindac (SLD) to produce liver injury in rats. In the present study, the mechanism of SLD/LPS-induced liver injury was further investigated. Accumulation of polymorphonuclear neutrophils (PMNs) in the liver was greater in SLD/LPS-cotreated rats compared to those treated with SLD or LPS alone. In addition, PMN activation occurred specifically in livers of rats cotreated with SLD/LPS. The hypothesis that PMNs and proteases released from them play critical roles in the hepatotoxicity was tested. SLD/LPS-induced liver injury was attenuated by prior depletion of PMNs or by treatment with the PMN protease inhibitor, eglin C. Previous studies suggested that tumor necrosis factor-α (TNF) and the hemostatic system play critical roles in the pathogenesis of liver injury induced by SLD/LPS. TNF and plasminogen activator inhibitor-1 (PAI-1) can contribute to hepatotoxicity by affecting PMN activation and fibrin deposition. Therefore, the role of TNF and PAI-1 in PMN activation and fibrin deposition in the SLD/LPS-induced liver injury model was tested. Neutralization of TNF or inhibition of PAI-1 attenuated PMN activation. TNF had no effect on PAI-1 production or fibrin deposition. In contrast, PAI-1 contributed to fibrin deposition in livers of rats treated with SLD/LPS. In summary, PMNs, TNF and PAI-1 contribute to the liver injury induced by SLD/LPS cotreatment. TNF and PAI-1 independently contributed to PMN activation, which is critical to the pathogenesis of liver injury. Moreover, PAI-1 contributed to liver injury by promoting fibrin deposition.
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DOI：
10.1124/jpet.107.122069
发表时间：
2007-08
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Deng X;Luyendyk JP;Zou W;Lu J;Malle E;Ganey PE;Roth RA
通讯作者：
Roth RA
影响因子：
5.1
作者：
BARANES, D;MATZNER, J;RAZIN, E
通讯作者：
RAZIN, E
DOI：
10.1124/jpet.109.151068
发表时间：
2009-07-01
影响因子：
3.5
作者：
Shaw, Patrick J.;Ganey, Patricia E.;Roth, Robert A.
通讯作者：
Roth, Robert A.
影响因子：
3.1
作者：
LIU, P;MCGUIRE, GM;JAESCHKE, H
通讯作者：
JAESCHKE, H
DOI：
10.1152/ajpgi.00141.2005
发表时间：
2005-10-01
影响因子：
4.5
作者：
Hasegawa, T;Malle, E;Jaeschke, H
通讯作者：
Jaeschke, H