Hepatic fibrosis is the result of the wound-healing response of the liver to repeated injury (1
) (Figure ). After an acute liver injury (e.g., viral hepatitis), parenchymal cells regenerate and replace the necrotic or apoptotic cells. This process is associated with an inflammatory response and a limited deposition of ECM. If the hepatic injury persists, then eventually the liver regeneration fails, and hepatocytes are substituted with abundant ECM, including fibrillar collagen. The distribution of this fibrous material depends on the origin of the liver injury. In chronic viral hepatitis and chronic cholestatic disorders, the fibrotic tissue is initially located around portal tracts, while in alcohol-induced liver disease, it locates in pericentral and perisinusoidal areas (33
). As fibrotic liver diseases advance, disease progression from collagen bands to bridging fibrosis to frank cirrhosis occurs.
Figure 1 Changes in the hepatic architecture (A) associated with advanced hepatic fibrosis (B). Following chronic liver injury, inflammatory lymphocytes infiltrate the hepatic parenchyma. Some hepatocytes undergo apoptosis, and Kupffer cells activate, releasing (more ...)
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).
HSCs are the main ECM-producing cells in the injured liver (36
). 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
) (Figure A). Activated HSCs migrate and accumulate at the sites of tissue repair, secreting large amounts of ECM and regulating ECM degradation. PDGF, mainly produced by Kupffer cells, is the predominant mitogen for activated HSCs. Collagen synthesis in HSCs is regulated at the transcriptional and posttranscriptional levels (39
). Increased collagen mRNA stability mediates the increased collagen synthesis in activated HSCs. In these cells, posttranscriptional regulation of collagen is governed by sequences in the 3′ untranslated region via the RNA-binding protein αCP2 as well as a stem-loop structure in the 5′ end of collagen mRNA (40
). Interestingly, HSCs express a number of neuroendocrine markers (e.g., reelin, nestin, neurotrophins, synaptophysin, and glial-fibrillary acidic protein) and bear receptors for neurotransmitters (8
). Quiescent HSCs express markers that are characteristic of adipocytes (PPARγ, SREBP-1c, and leptin), while activated HSCs express myogenic markers (α smooth muscle actin, c-myb, and myocyte enhancer factor–2).
Figure 2 Expression of collagen α1(I) in a model of cholestasis-induced liver fibrosis. Transgenic mice with green fluorescence protein reporter gene under the direction of the collagen α1(I) promoter/enhancers were subjected to bile duct ligation (more ...)
Hepatic cell types other than HSCs may also have fibrogenic potential. Myofibroblasts derived from small portal vessels proliferate around biliary tracts in cholestasis-induced liver fibrosis to initiate collagen deposition (43
) (Figure B). HSCs and portal myofibroblasts differ in specific cell markers and response to apoptotic stimuli (45
). Culture of CD34+
hematopoietic stem cells with various growth factors has been shown to generate HSCs and myofibroblasts of bone marrow origin that infiltrate human livers undergoing tissue remodeling (15
). These data suggest that cells originating in bone marrow can be a source of fibrogenic cells in the injured liver. Other potential sources of fibrogenic cells (i.e., epithelial-mesenchymal transition and circulating fibrocytes) have not been demonstrated in the liver (47
). 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.
A complex interplay among different hepatic cell types takes place during hepatic fibrogenesis (Figure ) (49
). Hepatocytes are targets for most hepatotoxic agents, including hepatitis viruses, alcohol metabolites, and bile acids (50
). 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 (51
). Inflammatory cells, either lymphocytes or polymorphonuclear cells, activate HSCs to secrete collagen (52
). 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 (54
). Fibrosis is influenced by different T helper subsets, the Th2 response being associated with more active fibrogenesis (55
). Kupffer cells are resident macrophages that play a major role in liver inflammation by releasing ROS and cytokines (56
). In chronic cholestatic disorders (i.e., primary biliary cirrhosis [PBC] and primary sclerosis cholangitis), epithelial cells stimulate the accumulated portal myofibroblasts to initiate collagen deposition around damaged bile ducts (43
). 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 (58
). Fibrillar collagens can bind and stimulate HSCs via discoidin domain receptor DDR2 and integrins. Moreover, the altered ECM can serve as a reservoir for growth factors and MMPs (59
Figure 3 Cellular mechanisms of liver fibrosis. Different types of hepatotoxic agents produce mediators that induce inflammatory actions in hepatic cell types. Damaged hepatocytes and biliary cells release inflammatory cytokines and soluble factors that activate (more ...)