Regression of cholangiocyte proliferation after cessation of ANIT feeding is coupled with increased apoptosis

Cholangiocyte proliferation and loss through apoptosis occur in cholestatic liver diseases. Our aim was to determine the mechanisms of apoptosis in an animal model of ductal hyperplasia. Rats were fed alpha -naphthylisothiocy anate (ANIT) for 2 wk and subsequently fed normal chow for 1, 2, and 4 wk. Proliferation was assessed in sections by morphometry and in small and larg e cholangiocytes by proliferating cellular nuclear antigen immunoblots and measurement of cAMP levels. Apoptosis and reactive oxygen species (ROS) lev els were also assessed. ANIT feeding increased small and large cholangiocyt e proliferation and apoptosis. Cessation of ANIT feeding was associated wit h decreased proliferation and a further increase in apoptosis in small and large cholangiocytes. Cholangiocytes from ANIT-fed rats or exposed to ANIT in vitro showed increased apoptosis and ROS generation. ANIT-induced duct i njury results in enhanced proliferation and apoptosis in small and large ch olangiocytes. The mechanism of ANIT-induced apoptosis may be due to ROS gen eration induced directly by ANIT. Our model has implications for understand ing the pathophysiology of cholangiopathies (characterized by the coexisten ce of cholangiocyte apoptosis and proliferation).