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-naphthylisothiocyanate (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 large cholangiocytes by proliferating cellular nuclear antigen immunoblots and measurement of cAMP levels. Apoptosis and reactive oxygen species (ROS) levels were also assessed. ANIT feeding increased small and large cholangiocyte proliferation and apoptosis. Cessation of ANIT feeding was associated with 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 injury results in enhanced proliferation and apoptosis in small and large cholangiocytes. The mechanism of ANIT-induced apoptosis may be due to ROS generation induced directly by ANIT. Our model has implications for understanding the pathophysiology of cholangiopathies (characterized by the coexistence of cholangiocyte apoptosis and proliferation).
Lesage
G
G
Department of Internal Medicine, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76504, USA.
Glaser
S
S
Ueno
Y
Y
Alvaro
D
D
Baiocchi
L
L
Kanno
N
N
Phinizy
J L
JL
Francis
H
H
Alpini
G
G
D015058:1-Naphthylisothiocyanate; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009929:Organ Size; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D018809:Proliferating Cell Nuclear Antigen; D017382:Reactive Oxygen Species; D015058:1-Naphthylisothiocyanate; D000242:Cyclic AMP