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 was 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 various combination of in situ hybridization and immunocytochemistry analyses. In iron-treated animals, no specific accumulation of ferritin protein was found in collagen mRNA-expressing cells. Moreover, the activity of the iron regulatory protein, the main sensor of cellular iron status, was unchanged in HSC from iron-treated animals. Although a significant 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 absent in HSC. In conclusion, the data indicate that during iron overload-associated fibrogenesis, HSC are not directly subjected to oxidant stress, but are likely to be activated by paracrine signals arising in neighboring cells.
Montosi
G
G
Department of Internal Medicine, University of Modena, Italy.
Garuti
C
C
Martinelli
S
S
Pietrangelo
A
A
D000818:Animals; D002478:Cells, Cultured; D005849:Gerbillinae; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000378:metabolism* / Q000473:pathology*; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D018384:Oxidative Stress
D007501:Iron