Antifibrogenic effect of a deletion variant of hepatocyte growth factor on liver fibrosis in rats.
Hepatic fibrosis, which may lead to cirrhosis, is associated with most chronic liver diseases. Current therapies for hepatic fibrosis are, however, generally ineffective. In this report we assessed the efficacy of the treatment of hepatic fibrosis with a naturally occurring deletion variant of hepatocyte growth factor (dHGF). The administration of dHGF increased liver weight and suppressed the increase of hepatic collagen content in rats treated with dimethylnitrosamine (DMN) to induce hepatic fibrosis. Furthermore, dHGF exerted its mitogenic and antifibrogenic activities even after the liver fibrosis had been established with DMN. Northern blot analysis showed that dHGF suppressed the increase of messenger RNA (mRNA) levels of procollagen alpha 2(I), alpha l(III), alpha 1(IV), transforming growth factor beta 1 (TGF-beta1), desmin (a marker of hepatic lipocytes), and alpha-smooth muscle (sm)-actin (a marker of activated hepatic lipocytes). In addition to suppressing the elevated TGF-beta1, mRNA level in hepatic fibrosis, dHGF had a potent ability to decrease TGF-beta1 mRNA level even in a normal liver. Immunohistochemical analysis revealed that desmin-positive cells and alpha-sm-actin-positive cells were increased in the hepatic fibrosis, whereas neither cells were seen in livers of DMN-treated rats given dHGF. We conclude that dHGF prevents and improves the DMN-induced hepatic fibrosis in rats by reducing mRNA levels of procollagens and TGF-beta1, by inhibiting an activation of hepatic lipocytes, and by stimulating liver regeneration. dHGF may be useful for and applicable to the treatment of fibrosis in chronic liver diseases.
Yasuda
H
H
Research Institute of Life Science, Snow Brand Milk Products, Co., Ltd., Tochigi, Japan.
Imai
E
E
Shiota
A
A
Fujise
N
N
Morinaga
T
T
Higashio
K
K
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D004128:Dimethylnitrosamine; D017353:Gene Deletion; D014644:Genetic Variation; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000494:pharmacology*; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000235:genetics
D000199:Actins; D003893:Desmin; D011347:Procollagen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D003094:Collagen; D004128:Dimethylnitrosamine