Progressive accumulation of fibrillar extracellular matrix (ECM) in the liver is the consequence of reiterated liver tissue damage due to infective (mostly hepatitis B and C viruses), toxic/drug-induced, metabolic and autoimmune causes, and the relative chronic activation of the wound-healing reaction. The process may result in clinically evident liver cirrhosis and hepatic failure. Although cirrhosis is the common result of progressive fibrogenesis, there are distinct patterns of fibrotic development related to the underlying disorders causing the fibrosis. These different patterns of fibrogenic evolution are related to different factors and particularly: (1) the topographic localization of tissue damage, (2) the relative concentration of profibrogenic factors and (3) the prevalent profibrogenic mechanism(s). The mechanisms responsible for the fibrogenic evolution of chronic liver diseases can be summarized in three main groups: chronic activation of the wound-healing reaction, oxidative stress-related molecular mechanisms, and the derangement of the so-called ‘epithelial-mesenchymal' interaction leading to the generation of reactive cholangiocytes and peribiliary fibrosis. Most of the knowledge on the cell and molecular biology of hepatic fibrosis derives from in vitro studies employing culture of activated hepatic stellate cells isolated from rat, mouse or human liver. It is now evident that other ECM-producing cells, i.e. fibroblasts and myofibroblasts of the portal tract and circulating ‘fibrocytes', are likely to contribute to liver fibrosis. More recently, the attention is progressively shifting to the profibrotic microenvironment of the liver with increasing interest for the role of immune cells and specific subsets of macrophages regulating the progression or the regression of fibrosis, the role of intestinal microbiota and the influence of tissue stiffness. Other major areas of development include the role of tissue hypoxia and the establishment of an anaerobic proinflammatory environment and the influence of epigenetic modification in conditioning the progression of fibrosis.

Keywords:
Cirrhosis, Fibrosis, Liver, Hepatic stellate cells, Myofibroblasts
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