F2-isoprostanes are not just markers of oxidative stress

F2-isoprostanes are not just markers of oxidative stress. The discovery of F2-isoprostanes (F2-IsoPs) as specific and reliable markers of oxidative stress in vivo is briefly summarized here. F2-IsoPs are also agonists of important biological effects, such as the vasoconstriction of renal glomerular arterioles, the retinal vessel, and the brain microcirculature. In addition to the F2-IsoPs, E2- and D2-IsoPs can be formed by rearrangement of H2-IsoP endoperoxides and can give rise to cyclopentenone IsoPs, which are very reactive α,β-unsaturated aldehydes. The same type of reactivity is also shown by acyclic γ-ketoaldehydes formed as products of the IsoP pathway. Because previous studies suggested a relation between oxidative stress and collagen hyperproduction, it was investigated whether collagen synthesis is induced by F2-IsoPs, the most proximal products of lipid peroxidation. In contrast to aldehydes, F2-IsoPs act through receptors able to elicit definite signal transduction pathways. In a rat model of carbon tetrachloride-induced hepatic fibrosis, plasma F2-IsoPs were markedly elevated for the entire experimental period; hepatic collagen content was also increased. When hepatic stellate cells from normal liver were cultured up to activation (expression of smooth muscle α-actin) and then treated with F2-IsoPs in the concentration range found in the in vivo studies (10− 9 to 10− 8 M), a striking increase in DNA synthesis, cell proliferation, and collagen synthesis was observed. Total collagen content was similarly increased. All these stimulatory effects were reversed by the specific antagonist of the thromboxane A2 receptor, SQ 29 548, whereas the receptor agonist, I-BOP, also had a stimulatory effect. Therefore F2-IsoPs generated by lipid peroxidation in hepatocytes may mediate hepatic stellate cell proliferation and collagen hyperproduction seen in hepatic fibrosis.