*2.2. Liver Fibrogenesis: A Number of Di*ff*erent Cell Types Contributing to the Initiation and Progression of Fibrosis*

In the liver, viral infections (hepatitis), metabolic diseases, cholestasis, parasites, drugs, alcohol, genetic determinants, and a variety of environmental factors can lead to the initiation and progression of fibrogenesis. Like in many other organs, the pathogenic sequence begins with parenchymal cell destruction and inflammation. Hepatocytes, building 70–85% of the main parenchymal tissue, can metabolize, detoxify, and inactivate exogenous compounds. However, if the acute or chronic exposure to a toxicant is too high, the cellular phenotype of these cells becomes detrimentally altered. Cell necrosis occurs, causing many factors to leak out of injured cells, resulting in the activation of liver-resident macrophages, designated as Kupffer cells. In addition, the damaged tissue is infiltrated by various kinds of lymphocytes, which further increase the concentration of pro-inflammatory and pro-fibrotic mediators. In particular, the concentrations of TGF-β and PDGF increase. This, in turn, leads to the activation and propagation of HSCs that lose their quiescent phenotype and transdifferentiate into proliferative and extracellular matrix-producing MFBs [73]. In addition, portal fibroblasts, comprising a small population of the fibroblast cell lineage surrounding the portal vein to maintain the integrity of the portal tract, acquire a myofibroblast-like phenotype, start to proliferate, and synthesize extracellular

matrix. Moreover, mesenchymal progenitor cells and fibrocytes recruited from the bone marrow are other sources of cells contributing to the generation of excessive scar formation [73]. Also, liver sinusoidal endothelial cells (LSEC) forming the wall of the hepatic sinusoids lose their fenestrae during hepatic fibrosis and form a basement membrane, preventing the physiological bidirectional exchange of molecules between hepatocytes and hepatic blood sinusoids. This corroborates with a significant synthesis and release of soluble factors, such as TGF-β and PDGF, again triggering the fibrogenic response.

However, it should be mentioned that fibrogenesis is not a unidirectional path. Regression or even full resolution can be achieved by the withdrawal of the injurious agent and is regularly seen in patients undergoing successful causative treatment of their underlying disease [74].
