HEPATIC STELLATE CELLS ARE NOT SUBJECTED TO OXIDANT STRESS DURING IRON-INDUCED FIBROGENESIS IN RODENTS

Oxidant stress plays a key role in hepatic fibrogenesis. This study wa s undertaken to assess whether, during iron overload-associated liver fibrosis in vivo, oxidant stress occurs in hepatic stellate cells (HSC ) during active fibrogenesis. Gerbils were treated with iron-dextran, and, after hepatic fibrosis developed, livers were subjected to variou s combination of in situ hybridization and immunocytochemistry analyse s. In iron-treated animals, no specific accumulation of ferritin prote in was found in collagen mRNA-expressing cells. Moreover, the activity of the iron regulatory protein, the main sensor of cellular iron stat us, was unchanged in HSC from iron-treated animals. Although a signifi cant amount of malondialdehyde-protein adducts was detected in gerbil liver during fibrogenesis, accumulation of these lipid peroxidation by -products was restricted to iron-laden cells adjacent to activated HSC . In cultured gerbil HSC, iron, aldehydes, and other pro-oxidants were able to enhance the expression of an oxidant stress-responsive gene, heme oxygenase (HO), with no change in collagen mRNA accumulation. In keeping with these findings, we found that, in vivo, activation of HO gene was present in iron-filled nonparenchymal cell aggregates, but ab sent in HSC. In conclusion, the data indicate that during iron overloa d-associated fibrogenesis, HSC are not directly subjected to oxidant s tress, but are likely to be activated by paracrine signals arising in neighboring cells.