Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis
Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis
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DOI：
10.1016/j.jhep.2018.08.015
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发表时间：
2018-12-01
影响因子：
25.7
通讯作者：
Trautwein, Christian
中科院分区：
文献类型：
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作者：
Javier Cubero, Francisco;Peng, Jin;Trautwein, Christian
背景与目的：Caspase 8（CASP 8）是死亡受体介导的细胞凋亡的顶端启动子。最近出现了死亡受体信号通路和胆汁淤积之间联系的有力证据。在此，我们研究了CASP 8依赖和独立的途径在实验cholestasis.Methods的作用：肝损伤的特点是在一个队列的人血清（n = 28）和活组织检查，从IV期原发性胆管炎患者。平行地，在肝实质细胞（Casp 8（Delta hepa））或肝细胞（Casp 8（Delta hep））中具有Casp 8特异性缺失的小鼠，以及具有组成性Ripk 3（Ripk 3（-/-））缺失的小鼠，从2天至28天进行胆总管（BDL）的手术结扎。使用Floxed（Casp 8（fl/fl））和Ripk 3（+/+）小鼠作为对照。此外，泛caspase抑制剂IDN-7314的使用，并在原代分离的hepatocyte.Results细胞死亡机制进行了研究：活化的caspase 3，CASP 8和RIPK 3的过表达是原发性胆道胆管炎患者的肝外植体的特征。BDL后28天，Casp 8（Delta hepa）小鼠显示坏死灶、血清转氨酶水平和细胞凋亡沿着减少，代偿性增殖和小管反应减少。这些结果与降低的炎症特征和改善的肝纤维化相关。在Ripk 3（-/-）小鼠中观察到类似的表型。IDN-7314治疗可降低CASP 8水平，但未能预防BDL诱导的胆汁淤积，与肝细胞中的CASP 8无关。结论：这些发现表明，在肝实质细胞中-特别是在胆管细胞中-干预CASP 8可能是治疗阻塞性胆汁淤积的有益选择，而广泛的泛半胱天冬酶抑制可能引发不良副作用。肝实质细胞中半胱天冬酶8（一种参与细胞程序性死亡的蛋白质）的缺失可以防止实验性胆汁淤积。因此，针对caspase 8的特异性药物干预可能是临床上治疗阻塞性胆汁淤积的有效替代方案，而广泛的泛caspase抑制药物可能会引发不良副作用。(C)2018年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Caspase 8 (CASP8) is the apical initiator caspase in death receptor-mediated apoptosis. Strong evidence for a link between death receptor signaling pathways and cholestasis has recently emerged. Herein, we investigated the role of CASP8-dependent and independent pathways during experimental cholestasis.Methods: Liver injury was characterized in a cohort of human sera (n = 28) and biopsies from patients with stage IV primary biliary cholangitis. In parallel, mice with either specific deletion of Casp8 in liver parenchymal cells (Casp8(Delta hepa)) or hepatocytes (Casp8(Delta hep)), and mice with constitutive Ripk3 (Ripk3(-/-)) deletion, were subjected to surgical ligation of the common bile duct (BDL) from 2 to 28 days. Floxed (Casp8(fl/fl)) and Ripk3(+/+) mice were used as controls. Moreover, the pan-caspase inhibitor IDN-7314 was used, and cell death mechanisms were studied in primary isolated hepatocytes.Results: Overexpression of activated caspase 3, CASP8 and RIPK3 was characteristic of liver explants from patients with primary biliary cholangitis. Twenty-eight days after BDL, Casp8(Delta hepa) mice showed decreased necrotic foci, serum aminotransferase levels and apoptosis along with diminished compensatory proliferation and ductular reaction. These results correlated with a decreased inflammatory profile and ameliorated liver fibrogenesis. A similar phenotype was observed in Ripk3(-/-) mice. IDN-7314 treatment decreased CASP8 levels but failed to prevent BDL-induced cholestasis, independently of CASP8 in hepatocytes.Conclusion: These findings show that intervention against CASP8 in liver parenchymal cells - specifically in cholangiocytes - might be a beneficial option for treating obstructive cholestasis, while broad pan-caspase inhibition might trigger undesirable side effects.Lay summary: Loss of caspase 8 - a protein involved in programmed cell death - in liver parenchymal cells protects against experimental cholestasis. Therefore, specific pharmacological intervention against caspase 8 might be a valid alternative for the treatment of obstructive cholestasis in the clinic, whereas broad pan-caspase inhibiting drugs might trigger undesirable side effects. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.