On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis.

Previous studies have suggested a possible involvement of free radical reactions in the pathogenesis of cholestatic liver injury as well as in the modulation of hepatic fibrogenesis. In this study we investigated whether lipid peroxidation is involved in the development of chronic liver damage induced by long-standing cholestasis. For this purpose we have used the rat model of bile duct ligation (BDL), which leads to liver fibrosis and cirrhosis. Using this model we observed that the development of chronic liver damage was associated with the onset of lipid peroxidation, as pointed out by detection of carbonyl compounds, 4-hydroxynonenal (HNE) and malondialdehyde (MDA), in BDL livers and of fluorescent adducts between MDA and serum proteins. Lipid peroxidation was a relatively late event (starting after 1-2 weeks of BDL) and was unrelated to the early development of liver necrosis and cholestasis (already evident after 72 h after BDL). A positive significant linear correlation between the kinetic of infiltration of neutrophils and of a monocyte/macrophage population in BDL livers and MDA and HNE generation in the same organs is presented, indicating a close link between lipid peroxidation and the activation of inflammatory cells. We also observed that a positive linear correlation exists between collagen deposition in these livers and hepatic production of MDA and HNE. This event, which is accompanied by an increase in the number of fat storing cells (FSC, the cells that produce collagen in fibrotic liver), suggests that lipid peroxidation in this model may contribute to stimulate collagen synthesis by proliferating FSC.