GROWTH-RELATED GENE-EXPRESSION IN EARLY CHOLESTATIC LIVER-INJURY

Background. Extrahepatic biliary obstruction initiates cholestasis, bi le duct proliferation, periportal fibrosis, and, eventually, lethal bi liary cirrhosis. Little is known about the genetic regulation of the c ellular proliferation and differentiation that begins with the onset o f bile duct obstruction. To focus this and future gene expression stud ies, we sought to determine the time frame for growth-related gene exp ression and questioned whether the in vivo expression of the protoonco genes H-ras and c-myc was altered after bile duct obstruction. Methods . Female Fisher rats underwent ligation and division of the common bil e duct or sham laparotomy. Results. After obstruction, serum bilirubin and gamma-glutamyl transpeptidase rose to 24% and 30%, respectively, of maximum levels by 10 days after ligation. Morphologic evidence of p roliferation of bile duct epithelial cells was first evident after 3 d ays. After hybridization to c-DNA probes, densitometry for H-ras and b eta-actin revealed an immediate and parallel increase in steady-state levels of expression after 24 hours of cholestasis. Levels of c-myc me ssenger RNA were elevated during the first 3 days of cholestasis; howe ver, at 7 and 10 days c-myc expression was depressed 16% and 60%, resp ectively. Conclusions. These profiles of expression show an oncogene r esponse induced by early cholestasis. These data showed that elevation s in H-ras and c-myc steady-state expression accompany the proliferati ve response of bile duct epithelial cells. Decreased levels of c-myc a fter initial elevation infer that ductal proliferation may continue in dependently of its steady-state expression, a response usually seen in vitro rather than in in vivo proliferation.