Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis
Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis
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DOI：
10.1016/j.jhep.2010.03.016
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发表时间：
2010-09-01
影响因子：
25.7
通讯作者：
Goldin, Robert D.
中科院分区：
文献类型：
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作者：
Anstee, Quentin M.;Concas, Danilo;Goldin, Robert D.
背景与目的：非酒精性脂肪性肝病是一种进行性疾病，包括脂肪变性、脂肪性肝炎和肝硬化。半胱天冬酶激活介导细胞凋亡和炎症反应。研究表明NASH中细胞凋亡活性增加，尽管其病理生理学重要性尚不确定。我们试图确定不可逆的泛半胱天冬酶抑制的影响，在小鼠模型建立脂肪变性（高脂饮食，HFD）和脂肪性肝炎（蛋氨酸胆碱缺乏饮食，MCD）。方法：在一个研究组中，雄性C3 H/HeN小鼠喂食HFD;在其他的，Db/Db小鼠喂食MCD。一旦确立疾病，将动物随机分配至接受半胱天冬酶抑制剂（VX-166）、TPGS/PEG溶媒或无其他治疗，直至研究结束。检测生化和组织学指标以确定NASH活性和组织氧化应激。凋亡活性和细胞周转率进行了评估，半胱天冬酶切割CK-18和PCNA.Results染色：MCD和HFD显着增加细胞凋亡，这是减少VX-166治疗。VX-166没有减少脂肪变性，但减少了组织学炎症、血清ALT水平和氧化应激，特别是在MCD模型中。TPGS/PEG车辆也表现出一定的抗炎activity.Conclusions：在这两种模型中，VX-166抑制细胞凋亡，减少组织炎症浸润，虽然有一个更温和的影响，对其他指标的肝损伤。此外，TPGS/PEG载体还表现出一定的抗炎活性，可能是通过维生素E的抗氧化作用和肠道植物群/粘膜相互作用的变化。这些数据表明，半胱天冬酶抑制可能是一种有效的治疗方法，然而，进一步的研究，以评估更有选择性的半胱天冬酶抑制的长期价值是值得的。(C)2010年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Non-alcoholic fatty liver disease is a progressive condition comprising steatosis, steatohepatitis, and cirrhosis. Caspase activation mediates apoptosis and the inflammatory response. Studies demonstrate increased apoptotic activity in NASH although its pathophysiological importance is uncertain. We sought to determine the effects of irreversible pan-caspase inhibition in murine models of established steatosis (high fat diet, HFD) and steatohepatitis (methionine-choline deficient diet, MCD).Methods: In one study arm, male C3H/HeN mice were fed HFD; in the other, Db/Db mice were fed MCD. Once disease was established, animals were randomised to receive caspase inhibitor (VX-166), TPGS/PEG vehicle or no additional therapy until the end of the study. Biochemical and histological indices were examined to determine NASH activity and tissue oxidative stress. Apoptotic activity and cell turnover were assessed immunohistochemically by staining for caspase-cleaved CK-18 and PCNA.Results: MCD and HFD significantly increased apoptosis, which was reduced by VX-166 treatment. VX-166 did not reduce steatosis but reduced histological inflammation, serum ALT levels, and oxidative stress, particularly in the MCD model. TPGS/PEG vehicle also exhibited some anti-inflammatory activity.Conclusions: In both models, VX-166 inhibited apoptosis and reduced histological inflammatory infiltrate although there was a more modest impact on other indices of liver injury. In addition, TPGS/PEG vehicle also exhibited some anti-inflammatory activity, likely through the antioxidant effects of vitamin E and changes in gut flora/mucosal interactions. These data suggest that caspase inhibition may represent a valid therapeutic approach; however, further studies to assess the long-term value of more selective caspase inhibition are merited. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.