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Dimethylnitrosamine-Induced Liver Cirrhosis and Expression of Hepatocyte Growth Factor (HGF), its Receptor c-Met, and the Transforming Growth Factor (TGF)- β 1 in Sprague-Dawley Rats

Other Title
백서에서 Dimethylnitrosamine에 의한 간경화의 유도와 간세포성장인자, 수용체인 c-Met, 그리고 형질전환인자-베타 1의 발현에 관한 연구
김, 욱환; 이, 재호; 진, 윤미; 조, 혜성; 박, 혜리; 정, 민권; 곽, 연식; 한, 상욱; 왕, 희정; 이, 건욱; 김, 명욱
Taehan Oekwa Hakhoe, 55(4):453-468, 1998
Journal Title
Taehan Oekwa Hakhoe; 대한외과학회지
Background: Liver fibrosis and cirrhosis are the ultimate histologic consequences of

chronic liver damage. Efforts have been made to Study the mechanisms of cirrhosis and

to discover effective therapeutic strategies. However, to date, no animal model

reproduces the disease in man. The purpose of this work is to establish a model of

DMN-induced liver cirrhosis for treatment of liver cirrhosis, to understand the basic

characteristics of DMN-induced liver cirrhosis, and to confirm the expression of HGF,

its receptor c-Met, and TGF-β 1 in Sprague-Dawley rats.

Methods: Five-week-old male Sprague-Dawley rats (n=56) were used for this study.

Liver cirrhosis was induced in the rats by using DMN (1 ㎖/㎏ body weight, i.p.) given

3 consecutive days a week for 6 week. Changes in the portal vein pressure were

measured by a venous catheter during the duration of the DMN-treatment. The levels

of serum albumin, bilirubin, and ammonia were determined in a clinical laboratory by

routive methods. Pieces of the median lobe were cut and fixed in 10% buffered neutral

formalin, embedded in paraffin, and stained by hematoxylin-eosin (H&E) &

masson-trichrome (M&T). Changes in the extracellular matrix were measured by image

analysis and hydroxyproline content. Immunohistochemical staining of α-smooth muscle

actin was performed to confirm the activation of hepatic stellate cells. Northern blot

analyses were performed to confirm the expression of HGF and TGF-β 1 and westers

blotting was performed c-Met, HGF receptor.

Results: Pressures in the portal vein were significantly increased during the

DMN-treatment time (p<0.05). Biochemical parameters were significantly correlated with

the progression of liver cirrhosis. H&E staining of 4-week DMN-treated rats

demonstrated fibrous tissue bridging between the periportal and the pericentral areas

with gradual widening of fibrous bands. Both the extracellular matrix measured by

image analysis of the M&T staining and the hydroxyproline content rose continuously

throughout the 6 weeks of DMN treatment. A-smooth muscle actin was observed in the

stellate cells of DMN-treated rats. The northern blot analyses showed that the

expression of HGF mRNA decreased with the progression of DMN-induced liver

cirrhosis but that of TGF-β 1 mRNA did not. The western blot analyses showed that

the expression of the c-Met receptor protein increased continuously, but the expression

of HGF mRNA a decreased.

Conclusion: The model of cirrhosis induced by chronic, discontinuous treatment with a

low dose of DMN in rats was simple and predictable and displayed many of the

features of human cirrhosis. The decrease in the expression of HGF mRNA may be

responsible for the reduced hepatocyte regeneration in liver cirrhosis. The expression of

the c-Met protein was related with the decreased expression of HGF. The exact

significance of TGF-β 1 was not determined in this study.
Liver cirrhosisDimethylnitrosamineStellate cellHGFc-MetTGF-β1
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Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
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