F2-Isoprostanes and hepatic fibrosis

In CCl4 induced hepatotoxicity, besides steatonecrosis, fibrosis also develops which evolves to cirrhosis. Such fibrosis may be linked to oxidative stress. In fact, lipid peroxidation induced in vitro in hepatic stellate cells (HSC, the major source of matrix proteins) or the treatment of the latter with 4-hydroxynonenal or malonaldehyde stimulates expression of procollagen gene and synthesis of TGFbeta1. F2-isoprostanes (F2-Iso) are considered the most reliable markers of oxidative stress and are also mediators of important biological effects. Since aldehydic lipid peroxidation products seem to induce collagen expression, we have investigated whether analogue effects are induced by F2-Iso, which present receptors able to elicit definite signal transduction pathways. In a rat model of chronic CCl4 intoxication leading to fibrosis, plasma F2-Iso were elevated for the entire experimental period. HSC from normal liver were cultured up to activation and then treated for 48 h with F2-Iso in the range of the concentrations found in the in vivo studies (10-8 to 10-9M). F2-Iso induced marked increase in cell proliferation as well as increase in collagen synthesis. Total collagen content was similarly increased. Therefore, F2-Iso generated by lipid peroxidation in hepatocytes may mediate the HSC proliferation and collagen hyperproduction seen in hepatic fibrosis.