Department of Hepatology & Gastroenterology, St Mary's Hospital Campus, Imperial College London, UK.
J Hepatol. 2010 Sep;53(3):542-50. doi: 10.1016/j.jhep.2010.03.016. Epub 2010 May 26.
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).
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.
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.
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.
非酒精性脂肪性肝病是一种进展性疾病，包括脂肪变性、脂肪性肝炎和肝硬化。半胱天冬酶的激活介导细胞凋亡和炎症反应。研究表明，NASH 中凋亡活性增加，但其病理生理重要性尚不确定。我们旨在确定不可逆的全半胱天冬酶抑制剂在建立的脂肪变性（高脂肪饮食，HFD）和脂肪性肝炎（蛋氨酸-胆碱缺乏饮食，MCD）的小鼠模型中的作用。
在一个研究臂中，雄性 C3H/HeN 小鼠喂食 HFD；在另一个研究臂中，Db/Db 小鼠喂食 MCD。一旦疾病确立，动物被随机分配接受半胱天冬酶抑制剂（VX-166）、TPGS/PEG 载体或不接受额外治疗，直到研究结束。通过检测丙氨酸转氨酶水平和组织氧化应激，检测生化和组织学指标来确定 NASH 活动和组织氧化应激。通过染色半胱天冬酶切割的 CK-18 和 PCNA 来评估免疫组织化学中的凋亡活性和细胞更新。
MCD 和 HFD 显著增加了凋亡，而 VX-166 治疗减少了凋亡。VX-166 并没有减少脂肪变性，但减少了组织炎症、血清 ALT 水平和氧化应激，特别是在 MCD 模型中。TPGS/PEG 载体也表现出一些抗炎活性。
在两种模型中，VX-166 抑制了凋亡并减少了组织炎症浸润，尽管对其他肝损伤指标的影响较小。此外，TPGS/PEG 载体也表现出一些抗炎活性，可能是通过维生素 E 的抗氧化作用和肠道菌群/黏膜相互作用的改变。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，进一步评估更选择性半胱天冬酶抑制的长期价值的研究是值得的。
