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

Author:

Lesage Gene1,Glaser Shannon2,Ueno Yoshiyuki3,Alvaro Domenico4,Baiocchi Leonardo5,Kanno Noriatsu5,Phinizy Jo Lynne2,Francis Heather2,Alpini Gianfranco156

Affiliation:

1. Departments of Internal Medicine and

2. Division of Research and Education, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine and

3. Third Department of Internal Medicine, Tohoku University School of Medicine, Aobaku, Sendai, Japan 980-8574; and

4. Division of Gastroenterology, University of Rome, La Sapienza, Rome, Italy 00100

5. Medical Physiology,

6. Central Texas Veterans Health Care System, Temple, Texas 76504;

Abstract

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 α-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).

Publisher

American Physiological Society

Subject

Physiology (medical),Gastroenterology,Hepatology,Physiology

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