Liver fibrosis: from the bench to clinical targets

Progressive liver fibrosis is the main cause of organ failure in chronic liver diseases of any aetiology. Fibrosis develops with different spatial patterns and is a consequence of different prevalent mechanisms according to the diverse causes of parenchymal damage. Indeed, fibrosis, observed as a consequence of chronic viral infection is initially concentrated within and around the portal tract, while fibrosis secondary to toxic/metabolic damage is located mainly in the centrolobular areas. In addition, it is increasingly evident that different cell types are involved in the deposition of fibrillar extracellular matrix during active hepatic fibrogenesis: hepatic stellate cells are mainly involved when hepatocellular damage is limited or concentrated within the liver lobule, whereas portal myofibroblasts and fibroblasts provide a predominant contribution when the damage is located in the proximity of the portal tracts. In the later stages of evolution (septal fibrosis) it is likely that all extracellular matrix-producing cells contribute to fibrogenesis. Recruitment and activation of extracellular matrix-producing cells to the site of tissue damage can be due to different major mechanisms: (1) Chronic activation of the tissue repair process. In this case, as a consequence of the reiterated damage, accumulation of fibrillar extracellular matrix reflects the impossibility of an effective remodelling and regeneration. (2) Effect of oxidative stress products, including reactive oxygen intermediates and reactive aldehydes. These products, whose concentration become critical in toxic/metabolic liver injury, are able to induce the synthesis of fibrillar extracellular matrix even in the absence of significant hepatocyte damage and inflammation. (3) Derangement of normal the epithelial/mesenchymal interaction. This typically occurs in all conditions characterised by cholangiocyte damage/proliferation, where a consensual proliferation of extracellular matrix-producing cells and progressive fibrogenesis is commonly observed. A major advancement towards the understanding of the molecular mechanisms of fibrogenesis is derived from a consistent number of in vitro studies investigating the biological role of growth factors/cytokines and other soluble factors and their intracellular signalling pathways. The relevance of these factors has been confirmed by studies performed on animal models and by studies performed on pathological human liver. Along these lines, the elucidation of a consistent number of cellular and molecular mechanisms responsible for the progression of liver fibrosis has provided sound basis for the development of pharmacological strategies able to modulate this important pathophysiological process. Finally, there are several clinically relevant issues that need re-evaluation and/or further investigation, and in particular: (1) the need of an accurate and effective monitoring of the fibrotic progression of chronic liver diseases and of the effectiveness of the currently proposed treatments; (2) the identification of general or individual factors potentially relevant for a faster progression of the disease. (C) 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.