Gracia-Sancho Jordi, Manicardi Nicolò, Ortega-Ribera Martí, Maeso-Díaz Raquel, Guixé-Muntet Sergi, Fernández-Iglesias Anabel, Hide Diana, García-Calderó Héctor, Boyer-Díaz Zoe, Contreras Patricia C, Spada Alfred, Bosch Jaime
Liver Vascular Biology Research Group Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute Barcelona Spain.
CIBEREHD Madrid Spain.
Hepatol Commun. 2019 Apr 22;3(7):987-1000. doi: 10.1002/hep4.1360. eCollection 2019 Jul.
In cirrhosis, liver microvascular dysfunction is a key factor increasing hepatic vascular resistance to portal blood flow, which leads to portal hypertension. De-regulated inflammatory and pro-apoptotic processes due to chronic injury play important roles in the dysfunction of liver sinusoidal cells. The present study aimed at characterizing the effects of the pan-caspase inhibitor emricasan on systemic and hepatic hemodynamics, hepatic cells phenotype, and underlying mechanisms in preclinical models of advanced chronic liver disease. We investigated the effects of 7-day emricasan on hepatic and systemic hemodynamics, liver function, hepatic microcirculatory function, inflammation, fibrosis, hepatic cells phenotype, and paracrine interactions in rats with advanced cirrhosis due to chronic CCl administration. The hepato-protective effects of emricasan were additionally investigated in cells isolated from human cirrhotic livers. Cirrhotic rats receiving emricasan showed significantly lower portal pressure than vehicle-treated animals with no changes in portal blood flow, indicating improved vascular resistance. Hemodynamic improvement was associated with significantly better liver function, reduced hepatic inflammation, improved phenotype of hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells and macrophages, and reduced fibrosis. experiments demonstrated that emricasan exerted its benefits directly improving hepatocytes' expression of specific markers and synthetic capacity, and ameliorated nonparenchymal cells through a paracrine mechanism mediated by small extracellular vesicles released by hepatocytes. : This study demonstrates that emricasan improves liver sinusoidal microvascular dysfunction in cirrhosis, which leads to marked amelioration in fibrosis, portal hypertension and liver function, and therefore encourages its clinical evaluation in the treatment of advanced chronic liver disease.
在肝硬化中，肝微血管功能障碍是增加肝脏对门静脉血流阻力的关键因素，进而导致门静脉高压。慢性损伤引起的炎症和促凋亡过程失调在肝窦细胞功能障碍中起重要作用。本研究旨在表征泛半胱天冬酶抑制剂恩杂鲁胺在晚期慢性肝病临床前模型中对全身和肝脏血流动力学、肝细胞表型及潜在机制的影响。我们研究了7天恩杂鲁胺对慢性四氯化碳给药所致晚期肝硬化大鼠的肝脏和全身血流动力学、肝功能、肝微循环功能、炎症、纤维化、肝细胞表型及旁分泌相互作用的影响。此外，还在从人肝硬化肝脏分离的细胞中研究了恩杂鲁胺的肝保护作用。接受恩杂鲁胺治疗的肝硬化大鼠门静脉压力明显低于接受载体治疗的动物，门静脉血流无变化，表明血管阻力得到改善。血流动力学改善与肝功能显著改善、肝脏炎症减轻、肝细胞、肝窦内皮细胞、肝星状细胞和巨噬细胞表型改善以及纤维化减轻有关。实验表明，恩杂鲁胺通过直接改善肝细胞特异性标志物的表达和合成能力发挥其益处，并通过肝细胞释放的小细胞外囊泡介导的旁分泌机制改善非实质细胞。本研究表明，恩杂鲁胺可改善肝硬化中的肝窦微血管功能障碍，从而显著改善纤维化、门静脉高压和肝功能，因此鼓励对其在晚期慢性肝病治疗中的临床评估。
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