Increased iron deposition in rat liver fibrosis induced by a high-dose injection of dimethylnitrosamine.
Using a developed rat model of hepatic necrosis and subsequent fibrosis induced by a high-dose intraperitoneal injection of dimethylnitrosamine (DMN), we studied iron deposition and expression of transforming growth factor-beta(1) (TGF-beta(1)) during the development of persistent liver fibrosis. Rats were sacrificed at several timepoints from 6 h to 10 months post-injection and the livers were examined for iron content and distribution, and for expression of alpha-smooth muscle actin, ED-1, TGF-beta(1), and collagen (alpha(2))I. Morphologic evidence of acute submassive hemorrhagic necrosis peaked at 36 h; on day 3 the residual parenchyma contained activated hepatic stellate cells (HSCs) and necrotic areas contained numerous macrophages; and on day 5, necrotic tissues and erythrocytes had been phagocytosed and macrophages contained abundant iron deposits. From days 7 to 10, iron-laden macrophages and activated HSCs (myofibroblasts) populated the fibrous septa in parallel. From week 2 to month 10, closely arranged macrophages and myofibroblasts were found in central-to-central bridging fibrotic tissue. TGF-beta(1) was strongly detected in both macrophages and HSCs during development of liver fibrosis. Our data suggest that increased iron deposition may be involved in the initiation and perpetuation of rat liver fibrosis. Iron-laden macrophages may influence HSCs through the action of TGF-beta(1) in DMN-induced liver fibrosis.
Guo
Limei
L
Department of Pathology, School of Medicine, Kochi University, Kochi, Japan. guolimei@bjmu.edu.cn <guolimei@bjmu.edu.cn>
Enzan
Hideaki
H
Hayashi
Yoshihiro
Y
Miyazaki
Eriko
E
Jin
Yulan
Y
Toi
Makoto
M
Kuroda
Naoto
N
Hiroi
Makoto
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D024042:Collagen Type I / Q000235:genetics; D004128:Dimethylnitrosamine / Q000008:administration & dosage*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D007501:Iron / Q000032:analysis / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000473:pathology / Q000648:ultrastructure; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013054:Spectrophotometry, Atomic; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D000199:Actins; D024042:Collagen Type I; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D007501:Iron; D004128:Dimethylnitrosamine