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.