title: Sequential assessment of the intrahepatic expression of epidermal growth factor and transforming growth factor-beta1 in hepatofibrogenesis of a rat cirrhosis model.
abstract: Responses of the liver to chronic injury include inflammation, regeneration and fibrosis, which finally lead to cirrhosis. The cause of liver cirrhosis appears to be impaired proliferative capability of hepatocytes caused by continuous hepatic damage, and subsequent accumulation of extracellular matrix produced by hepatic stellate cells (HSCs). Epidermal growth factor (EGF) and transforming growth factor-beta1 (TGF-beta1) play a crucial role in hepatocyte proliferation and hepatofibrogenesis, respectively. However, sequential analyses of the intrahepatic expression of EGF and TGF-beta1 in the course of cirrhosis development have not been examined fully. In the present study, liver cirrhosis was produced in rats by intraperitoneal administration of dimethylnitrosamine (DMN), and intrahepatic mRNA expression levels of proliferating cell nuclear antigen (PCNA), EGF and TGF-beta1 were quantitatively estimated by a real-time reverse transcription-polymerase chain reaction method. Histological and semiquantitative densitometric examination of liver sections revealed that the accumulation of extracellular matrix components was increased according to the period of DMN treatment. Histological examination of liver sections of rats treated with DMN for 4 and 6 weeks revealed pre-cirrhosis and cirrhosis, respectively. Intrahepatic mRNA expression levels of PCNA and EGF correlated well. Expression levels of both molecules were increased significantly during the course of cirrhosis development, but decreased significantly at the time of complete cirrhosis manifestation. In contrast, intrahepatic TGF-beta1 expression was increased significantly according to the period of DMN treatment, and reached a peak at the time of cirrhosis manifestation. These results suggest that proliferative capability of hepatocytes was impaired by continuous liver damage due, in part, to the decrease of a hepatocyte mitogen EGF, and that increased intrahepatic TGF-beta1 activated HSCs to retrieve space lost by hepatocyte destruction, resulting in complete cirrhosis manifestation.
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. skuriyam@med.kagawa-u.ac.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
authors.forename: Fumi
authors.initials: F
authors.lastname: Yokoyama
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Inoue
authors.forename: Jitsuko
authors.initials: J
authors.lastname: Takano
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Ogawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Akihiro
authors.initials: A
authors.lastname: Deguchi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Himoto
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yoneyama
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Kurokohchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.forename: Naohito
authors.initials: N
authors.lastname: Uchida
authors.forename: Seishiro
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000235:genetics*; D005109:Extracellular Matrix / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor; D003094:Collagen; D004128:Dimethylnitrosamine