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1 Department of Internal
Medicine, 2 Division of Research
and Education and 4 Medical
Physiology and 6 Department of
Psychiatry and Behavioral Science,
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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