Molecular mechanisms of hepatic fibrosis in chronic liver diseases

Hepatic fibrosis is characterized by the disruption of normal liver architecture due to proliferation of hepatic myofibroblasts, and excess of extracellular matrix (ECM) deposition. The final stage of liver diseases, cirrhosis, is common across the spectrum of chronic hepatitis such as viral hepatitis, alcoholic and non-alcoholic hepatitis, and autoimmune hepatitis. Although several molecular mechanisms involved in fibrogenesis are common in all etiologies, some of them may differ for certain aspects. A key feature of hepatic fibrosis is the activation and proliferation of hepatic stellate cells (HSCs) that become able to produce extracellular matrix ECM components. The altered ratio between ECM deposition and matrix turnover contributes to fibrogenesis with the risk of progression of liver disease. Fibrogenesis enhances an inflammatory process contributing to the activation of immune cells that reach the site of injury releasing pro-inflammatory cytokines. Moreover, other cells contribute to the activation of HSCs, for example Kupffer cells (KCs) (resident macrophages), endothelial cells and hepatocytes. In this review we summarize molecular mechanisms of hepatic fibrogenesis in the setting of the main chronic liver diseases (CLD) (alcoholic hepatitis, viral hepatitis and non-alcoholic steatohepatitis) focusing on the emerging issues involved in the onset and progression of liver damage.