Low molecular weight heparin prevents hepatic fibrogenesis caused by carbon tetrachloride in the rat.
OBJECTIVE
In this study, we investigated the effect of dalteparin sodium, a low molecular weight (LMW)-heparin, on hepatic fibrogenesis caused by chronic carbon tetrachloride (CCl4) administration in the rat.


METHODS
Female Wistar rats were given a single, or repeated intraperitoneal injections of CCl4 (1ml/kg, twice per week) and dalteparin (50IU/kg, daily) for 7 weeks.


RESULTS
Dalteparin did not prevent acute CCl4-induced hepatic necrosis and elevation in serum aminotransferases levels; however, proliferating cell nuclear antigen (PCNA)-positive hepatocytes were dramatically increased 24h after simultaneous administration of CCl4 and dalteparin. Interestingly, serum hepatocyte growth factor (HGF) levels 12h after injection of CCl4 were almost doubled when dalteparin was given simultaneously. Hepatic fibrosis following 7-week CCl4 treatment was markedly ameliorated by daily co-administration of dalteparin. Indeed, dalteparin largely inhibited CCl4-induction of smooth muscle alpha-actin expression, alpha1(I)procollagen and transforming growth factor (TGF)-beta1 mRNA levels in the liver. Further, dalteparin blunted platelet-derived growth factor (PDGF)-induced increases in 5-bromo-2'deoxyuridine (BrdU) uptake in 3-day cultured hepatic stellate cells (HSCs) in a dose-dependent manner.


CONCLUSIONS
Dalteparin enhances hepatic regeneration and minimizes hepatic fibrogenesis caused by chronic CCl4 treatment. The mechanism underlying these effects most likely involves both up-regulation of HGF and inhibition of HSC proliferation.
Abe
Wataru
W
Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Ikejima
Kenichi
K
Lang
Tie
T
Okumura
Kyoko
K
Enomoto
Nobuyuki
N
Kitamura
Tsuneo
T
Takei
Yoshiyuki
Y
Sato
Nobuhiro
N
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D017985:Dalteparin / Q000008:administration & dosage*; D005260:Female; D005355:Fibrosis; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage*; D017228:Hepatocyte Growth Factor / Q000097:blood; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008115:Liver Regeneration / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D000199:Actins; D002251:Carbon Tetrachloride; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D017985:Dalteparin; D006495:Heparin, Low-Molecular-Weight; D017228:Hepatocyte Growth Factor; D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C498862:Acta2 protein, rat