Epidermal growth factor is decreased in liver of rats with biliary cirrhosis but does not act as paracrine growth factor immediately after hepatectomy

Abstract

Background/Aims: Epidermal growth factor, a potent mitogen for hepatocytes and cholangiocytes, is thought to act as an immediate-early gene after partial hepatectomy. Since regeneration is impaired in cirrhosis, we explored the expression of epidermal growth factor in cirrhotic rat liver immediately after partial hepatectomy.Methods: Cirrhosis was induced by bile duct ligation (n=21); sham-operated animals served as controls (n=21). Twenty-five days after initial surgery animals were subjected to 70% partial hepatectomy or sham operation; the liver was sampled before surgery and 20, 40 and 90 min thereafter. Epidermal growth factor mRNA levels were assessed by quantitative reverse transcription polymerase chain reaction. Protein expression was estimated by immunohistochemistry using a polyclonal antibody against epidermal growth factor.Results: Before hepatectomy, epidermal growth factor mRNA averaged 70.3±39.9 pgμg of total RNA in controls; this was markedly decreased to 21.9±12.7 pg/μg RNA in bile duct ligation (p<0.01). Epidermal growth factor mRNA did not increase after partial hepatectomy in either group, with the exception of sham-operated controls. Immunohistochemistry revealed that partial hepatectomy had no effect on epidermal growth factor expression. Hepatocytes showed uniformly cytosolic epidermal growth factor in controls, while in bile duct ligation immunostaining was faint or absent. Cholangiocytes exhibited a strong cytosolic staining in all experimental groups.Conclusions: The present study shows that epidermal growth factor is reduced in the cirrhotic liver. This could contribute to the loss of parenchymal liver tissue observed in cirrhosis. The lack of up-regulation after PH sheds doubt on the role of epidermal growth factor as an immediate-early gene in hepatic regeneration. Further, we demonstrate that epidermal growth factor accumulates in cholangiocytes. This observation is strong evidence for involvement of the mitogen epidermal growth factor in the proliferation of bile ducts during cirrhogenesis.