An introduction to oxidative stress enlightening the spreading of interest in lipid peroxidation in the 60's and in the identification of cytotoxic
aldehydes originating from it is given. The discovery of
F2-isoprostanes as specific markers of oxidative stress is described.
Isoprostanes are also agonists of important
biological effects. Since a relationship between oxidative stress and
collagen hyperproduction has been previously suggested, and since lipid peroxidation products (
aldehydes) have been proposed as possible mediators of
liver fibrosis, we investigated whether
collagen synthesis is induced by
F2-isoprostanes, which can possess receptors for signal transduction pathways. In a rat model of
carbon tetrachloride-induced hepatic
fibrosis, plasma
isoprostanes were markedly elevated for the entire experimental period and hepatic
collagen content was also increased. Moreover, when hepatic stellate cells (HSC) isolated from normal livers were cultured up to activation and then treated with
F2-isoprostanes (8-epi-PGF2alpha) in the concentration range found in the in vivo studies (10(-9) to 10(-8) M), a striking increase in
DNA synthesis, in cell proliferation and in
collagen synthesis was observed.
F2-isoprostanes also increased the production of
transforming growth factor-beta1 by U937 cells, assumed as a model of Kupffer cells or liver macrophages. The hypothesis that
F2-isoprostanes generated by lipid peroxidation in hepatocytes mediate HSC proliferation and
collagen hyperproduction, seen in this experimental hepatic
fibrosis, was reinforced by the demonstration, by using immunoblot analysis, that
isoprostane receptors identical or analogous to those for
thromboxane A2 (TxA2r) are present in HSC. Immunocytochemical studies showed the major localization of TxA2r in the perinuclear site and its colocalization with alpha-smooth muscle actin.