Friedman Scott L
Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
Nat Clin Pract Gastroenterol Hepatol. 2004 Dec;1(2):98-105. doi: 10.1038/ncpgasthep0055.
Hepatic fibrosis, or scarring of the liver, is emerging as a treatable complication of advanced liver disease, following significant progress in understanding its underlying mechanisms. Efforts have focused on the hepatic stellate cell, as these cells can undergo 'activation' into proliferative and fibrogenic myofibroblast-like cells during liver injury. Stimuli driving stellate cell activation include hepatocellular necrosis due to oxidant stress, apoptosis, and soluble growth factors. Specific lymphocyte subsets can also stimulate fibrogenesis. A cascade of signaling and transcriptional events in stellate cells underlies the fibrogenic response to liver injury, with each step in the cascade being a potential target for antifibrotic therapy. Disease-specific fibrogenic mechanisms have also been uncovered: in hepatitis C, this may include direct stimulation of stellate cell activation by viral infection; in nonalcoholic steatohepatitis, elevated levels of leptin and increased leptin signaling by stellate cells increase fibrogenesis. Determinants of fibrosis progression include both environmental and genetic factors, with ongoing efforts to define specific polymorphisms correlating with fibrosis progression rates. Human studies now indicate that fibrosis and even cirrhosis could be reversible, especially if the underlying disease is eradicated. A key challenge is to establish noninvasive means of assessing fibrosis stage and progression using either serum tests and/or imaging. In addition, endpoints of antifibrotic clinical trials need to be established so that reliable evidence of benefit can be identified. We are on the cusp of a new era in which antifibrotic therapies could become important in treating chronic fibrosing liver disease.
肝纤维化，即肝脏瘢痕化，随着对其潜在机制的理解取得重大进展，正逐渐成为晚期肝病可治疗的并发症。研究工作主要集中在肝星状细胞上，因为这些细胞在肝损伤过程中可“激活”成为增殖性和纤维化的肌成纤维细胞样细胞。驱动星状细胞激活的刺激因素包括氧化应激、凋亡导致的肝细胞坏死以及可溶性生长因子。特定的淋巴细胞亚群也可刺激纤维化形成。星状细胞中的一系列信号传导和转录事件构成了对肝损伤的纤维化反应基础，该级联反应的每一步都是抗纤维化治疗的潜在靶点。特定疾病的纤维化机制也已被揭示：在丙型肝炎中，这可能包括病毒感染直接刺激星状细胞激活；在非酒精性脂肪性肝炎中，瘦素水平升高以及星状细胞中瘦素信号增加会促进纤维化形成。纤维化进展的决定因素包括环境和遗传因素，目前正在努力确定与纤维化进展速率相关的特定基因多态性。现在的人体研究表明，纤维化甚至肝硬化可能是可逆的，尤其是在潜在疾病被根除的情况下。一个关键挑战是利用血清检测和/或影像学建立评估纤维化阶段和进展的非侵入性方法。此外，需要确定抗纤维化临床试验终点，以便能够识别出可靠的获益证据。我们正处于一个新时代的开端，抗纤维化疗法可能在治疗慢性纤维化肝病中发挥重要作用。
