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

Bile duct damage and/or loss is limited to a range of duct sizes in cholang iopathies. We tested the hypothesis that CCl4 damages only large ducts. CCl 4 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 numbe r 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 recep tor gene and secretin-induced cAMP response. Consistent with damage of larg e ducts, we detected cytochrome P-4502E1 (which CCl4 converts to its radica ls) only in large cholangiocytes. CCl4 induces selective apoptosis of large ducts associated with loss of large cholangiocyte proliferation and secret ion.