Natural history of liver fibrosis

The liver extracellular matrix Liver fibrosis is the result of the accumulation of extracellular matrix components (ECM) with subsequent destruction of liver architecture and liver cell dysfunction. ECM is a complex network composed of three main groups of macromolecules: the collagens, the adhesive glycoproteins and the proteoglycans (1). Among the most abundant proteins are those of the collagen family (mainly type I, III, IV, V, VI and XVIII in the liver). From a histopathological point of view, these different collagen isotypes form either interstitial or fibrillar collagens (collagen type I, III and V) or basement membranes (type IV collagen). Among the glycoprotein family, most important are laminin (an other major constituent of basement membranes) and fibronectin. These molecules serve not only as a scaffold for epithelial liver cells but also have specific functions according to their modular architectures. Fibronectin is involved in cell attachment, differentiation and migration through its different domains, each involved in interaction with specific ECM component. Proteoglycans, the third major group of ECM molecules are composed of a protein backbone linked to sulfated polydisaccharides (glycosaminoglycans). They are located in the interstitium or in cell membrane, either transmembranous or pericellular. Liver ECM is also rich in cytokines, growth factors, or serum macromolecules that are sequestrated into ECM through specific interactions with various components, mainly proteoglycans and adhesive glycoproteins. Transforming growth factor-ß (TGF-ß), a major growth factor involved in fibrogenesis is bound to ECM in an inactive form. Under certain circumstances, these molecules can be activated and serve as a local reservoir of active molecules. Hepatic stellate cells (HSC) are the major cellular source of EOM molecules (2). They are located in the Disse’s space. In the normal liver, the function of HSO is to store vitamin A. Under various stimuli (disruption of cell-cell or cell-matrix contacts, growth factors such as TGF-ß, reactive oxygen species, lipid peroxidation products, acetaldehyde), these cell undergo phenotypical transformation to transitional cells with a myofibroblast phenotype. In this condition, HSC produce a large amount of the different EOM components. Endothelial cells but also fibroblasts of the portal tract are also involved in ECM production. It is now feasible to isolate and grow HSC in vitro. This approach makes it possible to study in detail the multiple molecules involved in HSCactivation as well as their signal transduction pathways. With this model, it has been showed that TGF-ß is the major fibrogenic molecule inducing transcription of most of the EOM molecule-associated genes (collagen, fibronectin, laminin) and that platelet-derived growth factor (PDGF) is the major mitogenic molecule for HSC. Other cytokines and growth factors such as fibroblast growth factor-2 (FGF-2), interleukin-10 (IL-10) and interferon-gamma are also involved in the regulation of these genes as well as in HSC proliferation. These studies have also allowed for the development arid the study of antifibrogenic agents which have also been tested on different experimental models of liver fibrosis. Antioxidants, antisense or soluble receptors of growth factors are being tested, some of them with promising results.