Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
Adv Drug Deliv Rev. 2017 Nov 1;121:27-42. doi: 10.1016/j.addr.2017.05.007. Epub 2017 May 12.
Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or "activation") of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.
慢性病毒和代谢紊乱引起的进行性肝纤维化导致每年有超过 100 万人死于肝硬化，但迄今为止尚无批准的抗纤维化疗法。肝星状细胞的转分化（或“激活”）是分泌细胞外基质蛋白的肌成纤维细胞的主要细胞来源，是肝纤维化发生的主要驱动因素。受损的上皮细胞、纤维组织微环境、免疫和全身代谢失调、肠道菌群失调以及肝炎病毒产物的旁分泌信号可以直接或间接诱导星状细胞激活。细胞内信号失调、表观遗传改变和细胞应激反应是通过诱导静止状态的恢复、细胞衰老、细胞凋亡和/或免疫细胞清除来使星状细胞失活的候选靶点。针对特定细胞类型和靶标的药理学干预可以通过诱导失活来进行更有效的、毒性更小的精准抗纤维化治疗。
