MOLECULAR AND CELLULAR ASPECTS OF IRON-INDUCED HEPATIC CIRRHOSIS IN RODENTS

Hepatic fibrosis and cirrhosis are common findings in humans with hemo chromatosis, In this study we investigated the molecular pathways of i ron-induced hepatic fibrosis and evaluated the anti-fibrogenic effect of vitamin E. Male gerbils were treated with iron-dextran and fed a st andard diet or a alpha-tocopherol enriched diet (250 mg/Kg diet), In g erbils on the standard diet at 6 wk after dosing with iron, in situ hy bridization analysis documented a dramatic increase of signal for coll agen mRNA around iron foci onto liver fat storing cells (FSC), as iden tified by immunocytochemistry with desmin antibody, After 4 mo, micron odular 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 [H-3]thymidine showed a mar ked proliferation of nonparenchymal cells, including FSC, In iron-dose d gerbils on the vitamin E-enriched diet for 4 mo, in spite of a sever e liver iron burden, a normal lobular architecture was found, with a d ramatic decrease of collagen mRNA accumulation and collagen deposition . At the molecular level, a total suppression of nonparenchymal cell p roliferation was appreciable, although expression of collagen and TGF beta mRNAs was still present into microscopic iron-filled nonparenchym al cell aggregates scattered throughout the hepatic lobule, In conclus ion, our study shows that anti-oxidant treatment during experimental h epatic fibrosis arrests fibrogenesis and completely prevents iron indu ced hepatic cirrhosis mainly through inhibition of nonparenchymal cell proliferation induced by iron.