Hepatic resection in cirrhotic patients is associated with impaired liver regeneration and poor clinical outcome. Because experimental
cirrhosis is associated with hepatic cell
hypoxia, we herein investigated whether
hypoxia might alter the mechanisms of liver regeneration in the cirrhotic liver.
Cirrhosis was induced by
diethylnitrosamine in rats. Immunohistochemistry was performed to assess hepatocellular
hypoxia and proliferation 24 hours after a two-thirds partial
hepatectomy (PH) in cirrhotic and control rats. Cultured hepatocytes and myofibroblastic hepatic stellate cells were submitted to
hypoxia using anaerobic jars.
Hepatocyte growth factor (HGF) and c-Met expressions were determined by
reverse transcriptase-polymerase chain reaction, Northern blot, and Western blot. In control rats,
hypoxia was restricted to perivenular hepatocytes, and PH induced a marked increase in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression remained unchanged. In cirrhotic rats,
hypoxia was detected virtually in all of the hepatocytes, and PH induced no significant change in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression was decreased as compared to normal livers. In vitro, the expression of HGF in myofibroblastic hepatic stellate cells and of c-Met in hepatocytes underwent a dramatic decrease under
hypoxia. Our results suggest that hepatocellular
hypoxia causes inhibition of HGF (and of c-Met)-mediated proliferation and thereby might contribute to liver regeneration failure in cirrhotic liver.