Li D, Friedman S L
Department of Medicine and Liver Diseases, Mount Sinai School of Medicine, New York 10029-6574, USA.
J Gastroenterol Hepatol. 1999 Jul;14(7):618-33. doi: 10.1046/j.1440-1746.1999.01928.x.
Hepatic fibrosis is a wound-healing response to chronic liver injury, which if persistent leads to cirrhosis and liver failure. Exciting progress has been made in understanding the mechanisms of hepatic fibrosis. Major advances include: (i) characterization of the components of extracellular matrix (ECM) in normal and fibrotic liver; (ii) identification of hepatic stellate cells as the primary source of ECM in liver fibrosis; (iii) elucidation of key cytokines, their cellular sources, modes of regulation, and signalling pathways involved in liver fibrogenesis; (iv) characterization of key matrix proteases and their inhibitors; (v) identification of apoptotic mediators in stellate cells and exploration of their roles during the resolution of liver injury. These advances have helped delineate a more comprehensive picture of liver fibrosis in which the central event is the activation of stellate cells, a transformation from quiescent vitamin A-rich cells to proliferative, fibrogenic and contractile myofibroblasts. The progress in understanding fibrogenic mechanisms brings the development of effective therapies closer to reality. In the future, targeting of stellate cells and fibrogenic mediators will be a mainstay of antifibrotic therapy. Points of therapeutic intervention may include: (i) removing the injurious stimuli; (ii) suppressing hepatic inflammation; (iii) down-regulating stellate cell activation; and (iv) promoting matrix degradation. The future prospects for effective antifibrotic treatment are more promising than ever for the millions of patients with chronic liver disease worldwide.
肝纤维化是对慢性肝损伤的一种伤口愈合反应，若持续存在会导致肝硬化和肝衰竭。在理解肝纤维化机制方面已取得了令人兴奋的进展。主要进展包括：（i）对正常和纤维化肝脏中细胞外基质（ECM）成分的表征；（ii）确定肝星状细胞是肝纤维化中ECM的主要来源；（iii）阐明关键细胞因子、它们的细胞来源、调节模式以及参与肝纤维化形成的信号通路；（iv）对关键基质蛋白酶及其抑制剂的表征；（v）确定星状细胞中的凋亡介质并探索它们在肝损伤消退过程中的作用。这些进展有助于勾勒出一幅更全面的肝纤维化图景，其中核心事件是星状细胞的激活，即从富含维生素A的静止细胞转变为增殖、纤维化和收缩性的肌成纤维细胞。在理解纤维化机制方面的进展使有效治疗方法的开发更接近现实。未来，靶向星状细胞和纤维化介质将成为抗纤维化治疗的主要手段。治疗干预点可能包括：（i）去除有害刺激；（ii）抑制肝脏炎症；（iii）下调星状细胞激活；（iv）促进基质降解。对于全球数百万慢性肝病患者而言，有效抗纤维化治疗的未来前景比以往任何时候都更有希望。
