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Am J Physiol Gastrointest Liver Physiol 276: G1289-G1301, 1999;
0193-1857/99 $5.00
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Vol. 276, Issue 5, G1289-G1301, May 1999

Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver

Gene D. LeSage1, Shannon S. Glaser2, Luca Marucci3, Antonio Benedetti3, Jo Lynne Phinizy2, Rebecca Rodgers4, Alessandra Caligiuri1, Emanuela Papa1, Ziga Tretjak1, Anne-Marie Jezequel5, Leigh A. Holcomb6, and Gianfranco Alpini1,4,7

1 Department of Internal Medicine, 2 Division of Research and Education and 4 Medical Physiology and 6 Department of Psychiatry and Behavioral Science, Scott & White Hospital and The Texas A&M University System Health Science Center College of Medicine and 7 Central Texas Veterans Health Care System, Temple, Texas 76504; and 3 Department of Gastroenterology, and 5 Institute of Experimental Pathology, University of Ancona, Ancona, Italy 60020

Bile duct damage and/or loss is limited to a range of duct sizes in cholangiopathies. We tested the hypothesis that CCl4 damages only large ducts. CCl4 or mineral oil was given to bile duct-ligated (BDL) rats, and 1, 2, and 7 days later small and large cholangiocytes were purified and evaluated for apoptosis, proliferation, and secretion. In situ, we measured apoptosis by morphometric and TUNEL analysis and the number of small and large ducts by morphometry. Two days after CCl4 administration, we found an increased number of small ducts and reduced number of large ducts. In vitro apoptosis was observed only in large cholangiocytes, and this was accompanied by loss of proliferation and secretion in large cholangiocytes and loss of choleretic effect of secretin. Small cholangiocytes de novo express the secretin receptor gene and secretin-induced cAMP response. Consistent with damage of large ducts, we detected cytochrome P-4502E1 (which CCl4 converts to its radicals) only in large cholangiocytes. CCl4 induces selective apoptosis of large ducts associated with loss of large cholangiocyte proliferation and secretion.

intrahepatic biliary tree; morphometry; proliferation; secretin receptor; adenosine 3',5'-cyclic monophosphate; bile secretion


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