Fibrogenic effects of isoprostanes on hepatic stellate cells are mediated by TP receptor

isoprostanes (IsoPs) proved to be mediators of important biological effects and would act through the activation of receptors analogous to those for thromboxane A2 (TP receptors) In a previous work, we provided evidence that IsoPs, generated during carbon tetrachloride-induced hepatic fibrosis, mediate cell proliferation and collagen hyperproduction in hepatic stellate cells (HSC). These effects seem to be mediated by a modified form of isoprostane receptor, homologous to the classic TxA2 binding site, as suggested by binding studies. Moreover, western blotting and immunocytochemistry analysis revealed the expression of TP in HSC both on plasma membranes and within the cells. Further experiments, carried out to clarify the signal transduction pathways, showed that 8-epi-PGF2induced in HSC an increase of Ins(1,4,5)P3. In addition, the treatment of HSC with IsoPs activated ERK1/2, p38 MAPK and cyclin D1. Since these pathways are involved in cell proliferation and collagen gene expression, it is likely that the fibrogenic effects induced by 8-epi-PGF2 in HSC are mediated by these signalling transduction pathways.