Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany; Department of Immunology, Ophtalmology & ORL, Complutense University School of Medicine, Madrid, Spain; 12 de Octubre Health Research Institute (imas12), Madrid, Spain.
Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany; Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing Jiangsu, China.
J Hepatol. 2018 Dec;69(6):1326-1334. doi: 10.1016/j.jhep.2018.08.015. Epub 2018 Aug 23.
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.
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) or hepatocytes (Casp8), 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) 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.
Overexpression of activated caspase 3, CASP8 and RIPK3 was characteristic of liver explants from patients with primary biliary cholangitis. Twenty-eight days after BDL, Casp8mice 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.
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.
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.
半胱天冬酶 8（CASP8）是死亡受体介导的细胞凋亡中顶端起始的半胱天冬酶。最近有强有力的证据表明死亡受体信号通路与胆汁淤积之间存在联系。在此，我们研究了 CASP8 依赖性和非依赖性途径在实验性胆汁淤积中的作用。
对 28 例人类血清（n=28）和 4 期原发性胆汁性胆管炎患者活检组织的肝损伤进行了特征描述。同时，对肝实质细胞（Casp8）或肝细胞（Casp8）特异性缺失 Casp8 的小鼠以及 Ripk3 组成型缺失（Ripk3）的小鼠进行了胆总管结扎（BDL）手术，时间为 2 至 28 天。使用了 Casp8 或 Ripk3 的 floxed （Casp8）和 Ripk3 小鼠作为对照。此外，还使用了泛半胱天冬酶抑制剂 IDN-7314，并在原代分离的肝细胞中研究了细胞死亡机制。
原发性胆汁性胆管炎患者肝标本的特征是激活的半胱天冬酶 3、CASP8 和 RIPK3 的过度表达。BDL 后 28 天，Casp8 小鼠表现出坏死灶减少、血清转氨酶水平和凋亡减少，同时代偿性增殖和胆管反应减少。这些结果与炎症特征减少和肝纤维化改善相关。在 Ripk3 小鼠中也观察到类似的表型。IDN-7314 治疗降低了 CASP8 水平，但在肝细胞中不依赖于 CASP8 也未能预防 BDL 诱导的胆汁淤积。
这些发现表明，针对肝实质细胞（特别是胆管细胞）中 CASP8 的干预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会引发不良的副作用。
在肝实质细胞（特别是胆管细胞）中缺失半胱天冬酶 8（一种参与程序性细胞死亡的蛋白）可预防实验性胆汁淤积。因此，针对半胱天冬酶 8 的特定药理学干预可能是治疗临床阻塞性胆汁淤积的有效替代方法，而广泛的泛半胱天冬酶抑制剂可能会引发不良的副作用。
