F2 − Isoprostanes are not just markers of oxidative stress

F2-isoprostanes are not just markers of oxidative stress. The discovery of F2-isoprostanes as specific and reliable markers of oxidative stress in vivo is briefly summarized. Isoprostanes are also agonists of important biological effects, such as the vasoconstriction of several microcircular districts. Since previous studies suggested a relation between oxidative stress and fibrosis and since aldehydic lipid peroxidation products have been suggested as possible mediators of liver fibrosis, in the present study we investigated whether collagen synthesis is induced by F2-isoprostanes, the most proximal products of lipid peroxidation. By contrast with aldehydes, F2-isoprostanes act through receptors able to elicit definite signal transduction pathways. In a rat model of carbon tetrachloride-induced hepatic fibrosis, plasma F2-isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content also increased. When hepatic stellate cells from normal liver were cultured up to activation (expression of α- smooth muscle-alpha actin) and then treated with F2-isoprostanes in the concentration range found in the in vivo studies (10-9 to 10-8M), a striking increase in DNA synthesis, in cell proliferation and in collagen synthesis was observed. Total collagen content was similarly increased. All these stimulatory effects were reversed by the specific antagonist of thromboxane A2 receptor, SQ 29 548, while the receptor agonist, also had a stimulatory effect. Moreover, F2-isoprostanes markedly increased the production of transforming growth factor-1 by U937 cells, considered a model of liver macrophages. The data provide evidence for the possibility that F2-isoprostanes generated by lipid peroxidation in hepatocytes mediate hepatic stellate cell proliferation and collagen hyperproduction seen in hepatic fibrosis.