The decrease in total collagen fibers in the liver by hepatocyte growth factor after formation of cirrhosis induced by thioacetamide.
Liver cirrhosis is an inveterate disease accompanying fibrosis, hepatocyte damage, and liver dysfunction. In this study, the therapeutic effects of recombinant human hepatocyte growth factor (rhHGF) on liver cirrhosis were examined in rats administered thioacetamide (TAA). Repeated administration of TAA for 10 weeks to rats induced liver cirrhosis with collagen nodes and pseudo-lobe generation, a condition that was pathologically similar to that in humans. Administration of rhHGF after the formation of liver cirrhosis markedly decreased the incidence of pathological fibrosis and the degree of fibrosis as measured by a computed image analysis system. Continuous administration of rhHGF by infusion pump was more effective than bolus administration. Northern blotting analysis showed that rhHGF reduced mRNA levels of procollagen alpha2(I), alpha1(IV), and transforming growth factor-beta1 (TGF-beta1) that were stimulated in the TAA-treated liver. The labeling index of hepatocytes increased following administration of rhHGF in this model. These observations suggest that the pathological recession of liver fibrosis is the result of the reduction of TGF-beta1 and collagen synthesis and, in part, of the stimulation of mitosis of hepatocytes directly by rhHGF and indirectly by TGF-beta1 reduction in the cirrhotic liver. These results demonstrate the usefulness of rhHGF as a therapeutic agent in liver cirrhosis.
Sato
M
M
Pharmaceuticals Laboratory I, Mitsubishi Chemical Corp., Yokohama Research Center, Yokohama, Japan. maki@rc.m-kagaku.co.jp
Kakubari
M
M
Kawamura
M
M
Sugimoto
J
J
Matsumoto
K
K
Ishii
T
T
D000818:Animals; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D017228:Hepatocyte Growth Factor / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide; D016212:Transforming Growth Factor beta / Q000378:metabolism
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D013853:Thioacetamide; D017228:Hepatocyte Growth Factor; D003094:Collagen