Wang Xiaodong, Lu Yongke, Xie Bin, Cederbaum Arthur I
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Free Radic Biol Med. 2009 Sep 1;47(5):518-28. doi: 10.1016/j.freeradbiomed.2009.05.021. Epub 2009 May 27.
We have previously shown that treatment of mice with pyrazole or acute ethanol potentiated Fas agonistic Jo2 antibody-induced liver injury by a mechanism involving induction of CYP2E1 and elevated oxidative stress. The current study evaluated whether chronic alcohol feeding potentiates Fas-induced liver injury and whether CYP2E1 plays a role in any enhanced hepatotoxicity. Wild-type and CYP2E1 knockout mice were fed ethanol or isocaloric dextrose for 4 weeks followed by a single treatment with either saline or Jo2. Mice were killed 8 h after the Jo2 challenge. There were three- to five fold increases in transaminases and more extensive eosinophilic necrosis, hemorrhage, and infiltration of inflammatory cells in the central zone of the hepatic lobule in the ethanol-fed mice treated with Jo2 compared to the dextrose/Jo2- or ethanol/saline-treated mice. Liver injury was blunted in ethanol-fed CYP2E1 knockout mice treated with Jo2. The chronic ethanol feeding produced steatosis, elevation of CYP2E1, and oxidative stress in wild-type but not CYP2E1 knockout mice. These changes in wild-type mice fed ethanol were similar after saline or Jo2 treatment. The Jo2 treatment produced activation of JNK and P38 MAP kinase, increased activity of caspase-8 and -3, and lowered hepatic GSH levels in both the dextrose- and the alcohol-fed mice. JNK was activated at early times after Jo2 treatment in the ethanol-fed mice. Serum TNF-alpha levels were strikingly elevated in the wild-type ethanol/Jo2 group, which showed liver injury, compared to all the other groups, which did not show liver injury. Inhibition of JNK or P38 MAPK partially, but not completely, prevented the elevated liver injury in the wild-type ethanol/Jo2 mice. These results show that chronic ethanol feeding enhances Fas-induced liver injury by a mechanism associated with induction of CYP2E1, elevated serum TNF-alpha levels, and activation of MAPK.
我们之前已经表明，用吡唑或急性乙醇处理小鼠会通过一种涉及诱导CYP2E1和氧化应激升高的机制，增强Fas激动剂Jo2抗体诱导的肝损伤。本研究评估了长期饮酒是否会增强Fas诱导的肝损伤，以及CYP2E1是否在任何增强的肝毒性中发挥作用。野生型和CYP2E1基因敲除小鼠分别喂食乙醇或等热量的葡萄糖4周，随后单次注射生理盐水或Jo2。Jo2攻击8小时后处死小鼠。与葡萄糖/Jo2或乙醇/生理盐水处理的小鼠相比，用Jo2处理的乙醇喂养小鼠的转氨酶升高了三到五倍，肝小叶中央区出现更广泛的嗜酸性坏死、出血和炎症细胞浸润。用Jo2处理的乙醇喂养的CYP2E1基因敲除小鼠的肝损伤减轻。长期乙醇喂养在野生型小鼠而非CYP2E1基因敲除小鼠中产生了脂肪变性、CYP2E1升高和氧化应激。在生理盐水或Jo2处理后，野生型小鼠中这些由乙醇引起的变化是相似的。Jo2处理在葡萄糖喂养和乙醇喂养的小鼠中均导致JNK和P38丝裂原活化蛋白激酶的激活、半胱天冬酶-8和-3活性的增加以及肝脏谷胱甘肽水平的降低。在乙醇喂养的小鼠中，Jo2处理后早期JNK被激活。与所有未出现肝损伤的其他组相比，出现肝损伤的野生型乙醇/Jo2组血清肿瘤坏死因子-α水平显著升高。抑制JNK或P38丝裂原活化蛋白激酶部分但未完全阻止野生型乙醇/Jo2小鼠肝损伤的加剧。这些结果表明，长期乙醇喂养通过一种与诱导CYP2E1、血清肿瘤坏死因子-α水平升高和丝裂原活化蛋白激酶激活相关的机制增强Fas诱导的肝损伤。
