After partial hepatectomy, the increase in secretin-induced ductal bile secretion observed during bile duct renewal results from proliferation of remaining cholangiocytes.

We have shown that agonist-regulated ductal secretion is limited to large cholangiocytes. To directly study cholangiocyte heterogeneity along the length of the normal biliary tree, we defined the genetic and functional expression of agonist-induced ductal secretion in intrahepatic bile duct units (IBDU) of different sizes. Small IBDU (< 15-microns diam) were separated from large IBDU (> or = 15-microns diam), and then ducts of different sizes were characterized by morphometric analysis, gene expression, secretin-induced adenosine 3',5'-cyclic monophosphate (cAMP) synthesis, and secretion by change in luminal size in response to agonists. IBDU diameters ranged from 11 to 65 microns. Secretin increased ductal secretion solely in large IBDU. Forskolin induced a modest increase in ductal secretion in small IBDU but markedly increased ductal secretion in large IBDU. Secretion increased Cl-/HCO3- exchanger activity and cAMP levels in large but not small IBDU. Secretin receptor and Cl-/HCO3 exchanger mRNAs were detected only in large IBDU. We propose that agonist-induced ductal secretion occurs in large (> or = 15-microns diam) but not small (< 15-microns diam) intrahepatic ducts.

The aim of this study was to develop a model of selective duct damage restricted to hormone-responsive segments corresponding to the ducts damaged in primary biliary cirrhosis (PBC). Carbon tetrachloride (CCl 4 ) was fed by gavage to rats, and 2, 7, 14, and 28 days later, small and large cholangiocytes were isolated. Apoptosis was determined in situ by morphology and in purified cholangiocytes by assessment of nuclear fragmentation by 4,6-diamidino-2-phenylindole (DAPI) staining. Cholangiocyte proliferation was evaluated in situ by morphometry of liver sections stained for cytokeratin-19 (CK-19) and by proliferating cellular nuclear antigen (PCNA) staining in liver sections and in purified cholangiocytes by PCNA gene expression.

We assessed the effect of gastrin on ductal secretion in normal and bile duct-ligated (BDL) rats. The effect of gastrin on ductal secretion was examined in the presence of proglumide, a specific antagonist for gastrin receptor (GR). We isolated pure cholangiocytes from normal and BDL rats and assessed gastrin effects on secretin receptor (SR) gene expression and intracellular adenosine 3′,5′-cyclic monophosphate (cAMP) levels. We examined the presence of GR mRNA in cholangiocytes by reverse transcription polymerase chain reaction (RT-PCR). In normal or BDL rats, gastrin produced no changes in spontaneous bile secretion. Simultaneous infusion of gastrin inhibited secretin-induced choleresis and bicarbonate output in BDL rats. In the presence of proglumide gastrin did not inhibit secretin-induced choleresis in BDL rats. Gastrin decreased in cholangiocytes from BDL rats 1) SR gene expression and 2) secretin-induced cAMP levels. With the use of RT-PCR, GR mRNA was detected in cholangiocytes. Similar to what is shown for secretin and somatostatin, we propose that the opposing effects of secretin and gastrin on cholangiocyte secretory activity regulate ductal secretion in rats.

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