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During the last few years, considerable progress has been made in the dissection of cellular and molecular mechanisms of hepatic fibrogenesis. The disease, initiated by hepatocellular damage and perpetuated by inflammatory reactions, results not only in an overall increase in extracellular matrix (ECM) but also in molecular and histological rearrangement of virtually all matrix molecules including collagens, structural glycoproteins, proteoglycans and hyaluronan. These alterations of ECM cause severe clinical (e.g. hemodynamic) complications and further metabolic changes in the whole organ. Perisinusoidal fat (retinoid)-storing cells have been identified as the (precursor) cell type mainly responsible for matrix production in the diseased liver. However, these cells have to be activated, i.e. stimulated to proliferate, to transform phenotypically to myofibroblasts and to express matrix genes before full competency for fibrogenesis is reached. Multiple cell interactions with Kupffer cells, platelets, endothelial cells and hepatocytes mediated by various cytokines and growth factors (e.g. TGF-beta 1, TGF-alpha, PDGF, FGF, IGF-1) are involved in the mechanism of fat-storing cell activation which is the common and central pathogenetic mechanism in fibrogenesis. A three-step cascade model of fat-storing cell activation is proposed, which offers target mechanisms for possible anti-fibrotic interventions.
Gressner et al. (Thu,) studied this question.