Su Tung-Hung, Kao Jia-Horng, Liu Chun-Jen
Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te Street, Taipei 10002, Taiwan.
Int J Mol Sci. 2014 Jun 12;15(6):10578-604. doi: 10.3390/ijms150610578.
Hepatic fibrosis is a wound-healing response to various chronic stimuli, including viral hepatitis B or C infection. Activated myofibroblasts, predominantly derived from the hepatic stellate cells (HSCs), regulate the balance between matrix metalloproteinases and their tissue inhibitors to maintain extracellular matrix homeostasis. Transforming growth factor-β and platelet-derived growth factor are classic profibrogenic signals that activate HSC proliferation. In addition, proinflammatory cytokines and chemokines coordinate macrophages, T cells, NK/NKT cells, and liver sinusoidal endothelial cells in complex fibrogenic and regression processes. In addition, fibrogenesis involves angiogenesis, metabolic reprogramming, autophagy, microRNA, and epigenetic regulations. Hepatic inflammation is the driving force behind liver fibrosis; however, host single nucleotide polymorphisms and viral factors, including the genotype, viral load, viral mutation, and viral proteins, have been associated with fibrosis progression. Eliminating the underlying etiology is the most crucial antifibrotic therapy. Growing evidence has indicated that persistent viral suppression with antiviral therapy can result in fibrosis regression, reduced liver disease progression, decreased hepatocellular carcinoma, and improved chances of survival. Preclinical studies and clinical trials are currently examining several investigational agents that target key fibrogenic pathways; the results are promising and shed light on this debilitating illness.
肝纤维化是对各种慢性刺激（包括乙型或丙型肝炎病毒感染）的一种伤口愈合反应。活化的肌成纤维细胞主要来源于肝星状细胞（HSC），它们调节基质金属蛋白酶及其组织抑制剂之间的平衡，以维持细胞外基质的稳态。转化生长因子-β和血小板衍生生长因子是激活HSC增殖的经典促纤维化信号。此外，促炎细胞因子和趋化因子在复杂的纤维化和消退过程中协调巨噬细胞、T细胞、NK/NKT细胞和肝窦内皮细胞。此外，纤维化形成涉及血管生成、代谢重编程、自噬、微小RNA和表观遗传调控。肝脏炎症是肝纤维化背后的驱动力；然而，宿主单核苷酸多态性和病毒因素，包括基因型、病毒载量、病毒突变和病毒蛋白，都与纤维化进展有关。消除潜在病因是最关键的抗纤维化治疗方法。越来越多的证据表明，抗病毒治疗持续抑制病毒可导致纤维化消退、减少肝病进展、降低肝细胞癌发生率并提高生存几率。临床前研究和临床试验目前正在研究几种针对关键纤维化途径的研究性药物；结果令人鼓舞，并为这种使人衰弱的疾病带来了希望。
