Differential effects of pyrrolidine dithiocarbamate on TNF-α-mediated liver injury in two different models of fulminant hepatitis
Differential effects of pyrrolidine dithiocarbamate on TNF-α-mediated liver injury in two different models of fulminant hepatitis
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DOI：
10.1016/j.jhep.2007.10.014
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发表时间：
2008-03-01
影响因子：
25.7
通讯作者：
Xu, De-Xiang
中科院分区：
文献类型：
--
作者：
Lu, Jin-Wel;Wang, Hua;Xu, De-Xiang
背景/目的：吡咯烷二硫代氨基甲酸酯（PDTC）是核因子κ B（NF-κ B）激活的抑制剂。方法：采用卡介苗（BCG）感染小鼠，以脂多糖（LPS）（0.2mg/kg）诱导小鼠急性炎症性肝损伤模型，观察PDTC对LPS诱导的急性炎症性肝损伤的影响。小鼠腹腔注射D-氨基半乳糖（GalN，600 mg/kg）和脂多糖（LPS，20 μ g/kg）诱导凋亡性肝损伤模型。结果：PDTC预处理可减少炎症细胞浸润，抑制NF-κ B活化和肿瘤坏死因子α（TNF-α）表达，减少一氧化氮生成，减轻肝脏谷胱甘肽耗竭。相应地，PDTC降低血清丙氨酸氨基转移酶，改善肝坏死，并延长BCG/LPS模型中的存活时间。相反，PDTC加速死亡，加剧肝细胞凋亡的GalN/LPS模型，虽然它减少了一氧化氮的产生，衰减谷胱甘肽耗竭，并抑制TNF-α在liver.Conclusions的表达：PDTC保护小鼠aGalNst BCG/LPS诱导的炎症性肝损伤通过抑制NF-κ B介导的TNF-α的释放，而它似乎是有害的GalN/LPS诱导的凋亡性肝损伤。(C)2008年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Pyrrolidine dithiocarbamate (PDTC) is an inhibitor of nuclear factor kappa B (NF-kappa B) activation. The present study aimed to investigate the effects of PDTC on lipopolysaccharide (LPS)-induced liver injury in two different models of fulminant hepatitis.Methods: Mice infected with Bacillus Calmette Guerin (BCG) were challenged with LPS (0.2 mg/kg) to induce the model of inflammatory liver injury. Mice were injected with D-galactosamine (GalN, 600 mg/kg) and LPS (20 mu g/kg) to induce the model of apoptotic liver injury. In the treatment groups, mice were pre-treated with PDTC (100 mg/kg), initiated 24 h prior to LPS.Results: PDTC pretreatment reduced the infiltration of inflammatory cells, inhibited NF-kappa B activation and the expression of tumor necrosis factor alpha (TNF-alpha), attenuated nitric oxide production, and alleviated hepatic glutathione depletion. Correspondingly, PDTC reduced serum alanine aminotransferase, improved hepatic necrosis, and prolonged the survival in the BCG/LPS model. Conversely, PDTC accelerated death and aggravated liver apoptosis in the GalN/LPS model, although it reduced nitric oxide production, attenuated glutathione depletion, and inhibited the expression of TNF-alpha in liver.Conclusions: PDTC protects mice aGalNst BCG/LPS-induced inflammatory liver injury through the repression of NF-kappa B-mediated TNF-alpha release, while it seems to be detrimental in GalN/LPS-induced apoptotic liver damage. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.