The role of tumor necrosis factor alpha in lipopolysaccharide/ranitidine-Induced inflammatory liver injury
The role of tumor necrosis factor alpha in lipopolysaccharide/ranitidine-Induced inflammatory liver injury
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DOI：
10.1093/toxsci/kfm209
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发表时间：
2007-11-01
影响因子：
3.8
通讯作者：
Roth, Robert A.
中科院分区：
文献类型：
--
作者：
Tukov, Francis F.;Luyendyk, James P.;Roth, Robert A.
暴露于无毒剂量的细菌脂多糖（LPS）会增加组胺-2（H2）受体拮抗剂雷尼替丁（RAN）的肝毒性。由于与LPS相关的一些病理生理效应是通过炎症介质如肿瘤坏死因子α（TNF）的表达和释放介导的，因此本研究旨在深入了解TNF在LPS/RAN肝毒性中的作用。为了确定RAN是否在接近肝损伤开始时影响LPS诱导的TNF释放，雄性Sprague-Dawley大鼠用2.5 × 10（6）内毒素单位（EU）/kg LPS或其盐水载体（iv）处理，2小时后用30 mg/kg RAN或无菌磷酸盐缓冲盐水载体（iv）处理。LPS给药引起循环TNF浓度增加。RAN共治疗增强了LPS诱导的TNF增加肝细胞损伤的发病前，法莫替丁，一种H2受体拮抗剂没有特异性的责任，没有产生的效果。对血清白细胞介素（IL）-1 β、IL-6和IL-10观察到类似的影响。为了确定TNF是否在LPS/RAN诱导的肝毒性中起因果作用，大鼠被给予戊乙茶碱（PTX; 100 mg/kg，iv）以抑制TNF的合成或依那西普（Etan; 8 mg/kg，sc）以阻碍TNF到达细胞受体的能力，然后用LPS和RAN处理它们。评估肝细胞损伤、炎症介质释放、肝中性粒细胞（PMN）蓄积以及凝血和纤溶生物标志物。在LPS/RAN联合治疗的动物中，PTX或Etan预处理导致肝损伤减轻，TNF、IL-1 β、IL-6、巨噬细胞炎性蛋白-2和凝血/纤溶生物标志物的循环浓度降低。PTX和Etan预处理均未改变肝脏PMN蓄积。这些结果表明，TNF有助于LPS/RAN诱导的肝损伤，通过增强炎症细胞因子的产生和止血。
Exposure to a nontoxic dose of bacterial lipopolysaccharide (LPS) increases the hepatotoxicity of the histamine-2 (H2) receptor antagonist, ranitidine (RAN). Because some of the pathophysiologic effects associated with LPS are mediated through the expression and release of inflammatory mediators such as tumor necrosis factor alpha (TNF), this study was designed to gain insights into the role of TNF in LPS/RAN hepatotoxicity. To determine whether RAN affects LPS-induced TNF release at a time near the onset of liver injury, male Sprague-Dawley rats were treated with 2.5 x 10(6) endotoxin units (EU)/kg LPS or its saline vehicle (iv) and 2 h later with either 30 mg/kg RAN or sterile phosphate-buffered saline vehicle (iv). LPS administration caused an increase in circulating TNF concentration. RAN cotreatment enhanced the LPS-induced TNF increase before the onset of hepatocellular injury, an effect that was not produced by famotidine, a H2-receptor antagonist without idiosyncrasy liability. Similar effects were observed for serum interleukin (IL)-1beta, IL-6, and IL-10. To determine if TNF plays a causal role in LPS/RAN-induced hepatotoxicity, rats were given either pentoxifylline (PTX; 100 mg/kg, iv) to inhibit the synthesis of TNF or etanercept (Etan; 8 mg/kg, sc) to impede the ability of TNF to reach cellular receptors, and then they were treated with LPS and RAN. Hepatocellular injury, the release of inflammatory mediators, hepatic neutrophil (PMN) accumulation, and biomarkers of coagulation and fibrinolysis were assessed. Pretreatment with either PTX or Etan resulted in the attenuation of liver injury and diminished circulating concentrations of TNF, IL-1 beta, IL-6, macrophage inflammatory protein-2, and coagulation/fibrinolysis biomarkers in LPS/RAN-cotreated animals. Neither PTX nor Etan pretreatments altered hepatic PMN accumulation. These results suggest that TNF contributes to LPS/RAN-induced liver injury by enhancing inflammatory cytokine production and hemostasis.