Liver fibrosis is associated with major alterations in both the quantity and composition of ECM (34). In advanced stages, the liver contains approximately 6 times more ECM than normal, including collagens (I, III, and IV), fibronectin, undulin, elastin, laminin, hyaluronan, and proteoglycans. Accumulation of ECM results from both increased synthesis and decreased degradation (35). Decreased activity of ECM-removing MMPs is mainly due to an overexpression of their specific inhibitors (TIMPs).
Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-β1, angiotensin II, and leptin.
Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins
In the normal liver, HSCs reside in the space of Disse and are the major storage sites of vitamin A. Following chronic injury, HSCs activate or transdifferentiate into myofibroblast-like cells, acquiring contractile, proinflammatory, and fibrogenic properties (37, 38) (Figure (Figure2A).2A). Activated HSCs migrate and accumulate at the sites of tissue repair, secreting large amounts of ECM and regulating ECM degradation.
As fibrotic liver diseases advance, disease progression from collagen bands to bridging fibrosis to frank cirrhosis occurs.
The relative importance of each cell type in liver fibrogenesis may depend on the origin of the liver injury. While HSCs are the main fibrogenic cell type in pericentral areas, portal myofibroblasts may predominate when liver injury occurs around portal tracts.
Damaged hepatocytes release ROS and fibrogenic mediators and induce the recruitment of white blood cells by inflammatory cells. Apoptosis of damaged hepatocytes stimulates the fibrogenic actions of liver myofibroblasts
lymphocytes or polymorphonuclear cells, activate HSCs to secrete collagen
Activated HSCs secrete inflammatory chemokines, express cell adhesion molecules, and modulate the activation of lymphocytes (53). Therefore, a vicious circle in which inflammatory and fibrogenic cells stimulate each other is likely to occur
Kupffer cells are resident macrophages that play a major role in liver inflammation by releasing ROS and cytokines
Finally, changes in the composition of the ECM can directly stimulate fibrogenesis. Type IV collagen, fibrinogen, and urokinase type plasminogen activator stimulate resident HSCs by activating latent cytokines such as TGF-β1
Collagen synthesis in HSCs is regulated at the transcriptional and posttranscriptional levels