SEQUENTIAL INCREASES IN THE INTRAHEPATIC EXPRESSION OF EPIDERMAL GROWTH-FACTOR, BASIC FIBROBLAST GROWTH-FACTOR, AND TRANSFORMING-GROWTH-FACTOR-BETA IN A BILE-DUCT LIGATED RAT MODEL OF CIRRHOSIS

Chronic hepatic regeneration constitutes an important part of the cirr hotic process. The factors regulating chronic hepatic regeneration how ever, remain unclear. We therefore analyzed the intrahepatic messenger RNA (mRNA) expression of growth factors (epidermal growth factor [EGF ], basic fibroblast growth factor [bFGF], hepatocyte growth factor [HG F], transforming growth factor [TGF]-alpha, and TGF-beta) at progressi ve time points (postoperative days 2, 7, 14, and 21) in a rat bile duc t-ligated (BDL) model of cirrhosis versus sham controls. Intrahepatic growth factor mRNA expression was quantitatively assessed by polymeras e chain reaction (PCR) using a dot-blot hybridization technique. Cirrh osis was associated with statistically significant (P < .05) progressi ve increases in the intrahepatic mRNA expression of bFGF (80-fold), EG F (25-fold), and TGF-beta (fourfold) in BDL animals versus controls. F urthermore, immunohistochemistry of hepatic sections showed a progress ive up-regulation of bFGF protein in areas of bile duct proliferation. These areas also showed a dramatic increase in the number of hepatic stellate cells (HSC). In contrast, the intrahepatic expression of hepa tocyte growth factor (HGF) mRNA was only significantly increased at po stoperative days 7 and 14 in BDL animals before returning to control l evels as cirrhosis developed There were no significant differences fou nd at any timepoint in the expression of TGF-alpha in BDL animals vers us controls. In conclusion, the development of cirrhosis in this BDL r at model was associated with a progressive increase in the intrahepati c expression of EGF, bFGF, and TGF-beta. Early increased expression of HGF was not maintained in established cirrhosis. The findings suggest that these growth factors may play important roles in the pathogenesi s of chronic hepatic regeneration in cirrhosis.