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Hepatic stellate cells as key target in liver fibrosis
Advanced Drug Delivery Reviews ( IF 16.1 ) Pub Date : 2017-05-12 , DOI: 10.1016/j.addr.2017.05.007
Takaaki Higashi 1 , Scott L Friedman 2 , Yujin Hoshida 2
Affiliation  

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.



中文翻译:

肝星状细胞是肝纤维化的关键靶标

由慢性病毒和代谢紊乱引起的进行性肝纤维化每年通过肝硬化的发展导致超过 100 万人死亡,尽管迄今为止尚未批准抗纤维化治疗。肝星状细胞的转分化(或“激活”)是分泌基质蛋白的肌成纤维细胞的主要细胞来源,肌成纤维细胞是肝纤维发生的主要驱动力。来自受损上皮细胞、纤维化组织微环境、免疫和全身代谢失调、肠道生态失调和肝炎病毒产物的旁分泌信号可直接或间接诱导星状细胞活化。失调的细胞内信号、表观遗传变化和细胞应激反应代表了通过诱导回复到失活状态、细胞衰老、细胞凋亡、使星状细胞失活的候选靶点,和/或被免疫细胞清除。细胞类型和靶点特异性药理学干预以治疗性诱导失活将实现更有效和毒性更小的精确抗纤维化疗法。

更新日期:2017-05-12
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