Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents.
Hepatic fibrosis and cirrhosis are common findings in humans with hemochromatosis. In this study we investigated the molecular pathways of iron-induced hepatic fibrosis and evaluated the anti-fibrogenic effect of vitamin E. Male gerbils were treated with iron-dextran and fed a standard diet or a alpha-tocopherol enriched diet (250 mg/Kg diet). In gerbils on the standard diet at 6 wk after dosing with iron, in situ hybridization analysis documented a dramatic increase of signal for collagen mRNA around iron foci onto liver fat storing cells (FSC), as identified by immunocytochemistry with desmin antibody. After 4 mo, micronodular cirrhosis developed in these animals, with nonparenchymal cells surrounding hepatocyte nodules and expressing high level of TGF beta mRNA. In this group, in vivo labeling with [3H]-thymidine showed a marked proliferation of nonparenchymal cells, including FSC. In iron-dosed gerbils on the vitamin E-enriched diet for 4 mo, in spite of a severe liver iron burden, a normal lobular architecture was found, with a dramatic decrease of collagen mRNA accumulation and collagen deposition. At the molecular level, a total suppression of nonparenchymal cell proliferation was appreciable, although expression of collagen and TGF beta mRNAs was still present into microscopic iron-filled nonparenchymal cell aggregates scattered throughout the hepatic lobule. In conclusion, our study shows that anti-oxidant treatment during experimental hepatic fibrosis arrests fibrogenesis and completely prevents iron induced hepatic cirrhosis mainly through inhibition of nonparenchymal cell proliferation induced by iron.
Pietrangelo
A
A
Department of Internal Medicine, University of Modena, Italy.
Gualdi
R
R
Casalgrandi
G
G
Montosi
G
G
Ventura
E
E
D000818:Animals; D002455:Cell Division; D003094:Collagen / Q000032:analysis / Q000235:genetics; D005527:Food, Fortified; D005849:Gerbillinae; D017403:In Situ Hybridization; D007501:Iron / Q000032:analysis / Q000633:toxicity*; D008099:Liver / Q000737:chemistry; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D012333:RNA, Messenger / Q000302:isolation & purification; D000637:Transaminases / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics; D014810:Vitamin E / Q000032:analysis / Q000627:therapeutic use*
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014810:Vitamin E; D008315:Malondialdehyde; D003094:Collagen; D007501:Iron; D000637:Transaminases