Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.

Abstract

To establish the role of the biliary epithelium in bile formation, we studied several aspects of biliary physiology in control rats and in rats with ductular cell hyperplasia induced by a 14-d extrahepatic biliary obstruction. Under steady-state conditions, spontaneous bile flow was far greater in obstructed rats (266.6±51.9 Mli/min per kg) than in controls (85.6±10.6 d1/ min per kg), while excretion of 3-hydroxy bile acids was the same in the two groups. Infusion of 10 clinical units (CU)/kg per h secretin produced a minimal choleretic effect in controls (+3.8±1.9 ,l/min per kg) but a massive increase in bile flow in the obstructed animals (+127.8±34.9 ,l/min per kg). Secretin choleresis was associated with an increase in bicarbonate biliary concentration and with a decline in 1'4C]mannitol bile-toplasma ratio, although solute biliary clearance significantly increased. Conversely, administration of taurocholate (5 ,umol/min per kg) produced the same biliary effects in control rats and in rats with proliferated biliary ductules. In the obstructed animals, the biliary tree volume measured during taurocholate choleresis (67.4±15.8 .I/g liver) was significantly greater than that determined during the increase in bile flow induced by secretin (39.5±10.4 ,l/g liver). These studies indicate that, in the rat, the proliferated bile ductules/ducts spontaneously secrete bile and are the site of secretin choleresis. Furthermore, because the proliferated cells expressed phenotypic traits of bile ductular cells, our results suggest that whereas under normal conditions the biliary ductules/ducts in the rat seem to contribute little to bile formation, secretion of water and electrolytes is a property of biliary epithelial cells.

Secretin activation of the apical Na+‐dependent bile acid transporter is associated with cholehepatic shunting in rats†

“…Yet, it is unlikely the increases in bicarbonate alone account for the TC-induced hypercholeresis following secretin. The maximum expected increase in ductal bile flow for each bicarbonate anion secreted (8.5 L bile flow for each Eq bicarbonate in BDL rats 12 ) is considerably less than that the extra bile flow for each bicarbonate anion secreted (15.7 L bile flow for each Eq bicarbonate) when TC was administrated following secretin in this study. Our recent studies show tauroursodeoxycholate increases biliary bicarbonate greater in BDL than compared with normal control rats, thus tauroursodeoxycholate is likely increasing bicarbonate secretion by a ductal mechanism.…”

“…Considering biliary dead space in BDL rats is 1070 L, 12 TC transit from canalicular membrane to the end of bile fistula is 10 minutes. Thus the transit time from blood to canalicular membrane would be around 5 minutes during the control period and 10 minutes during the period following secretin pretreatment.…”

“…Until biliary physiology studies were done in BDL rats, bile duct contribution to overall bile formation in rodents remained unrecognized. 12 Thus, the lack of evidence does not exclude the presence of cholehepatic shunting in normal rats; rather, the absence may be due to the limits of the current in vivo models of bile duct function.…”

“…To study bile ductal secretion in vivo, we employed the 1-week bile duct ligation rat model, which we have previously established as a model of cholangiocyte hyperplasia and secretin-stimulated ductal bile secretion. 12 The common bile duct was cannulated with PE-50 tubing and the end sealed with heat. After 1 week of obstruction, the end of the tubing was exteriorized and the tip cut off to allow for bile collections.…”

Acute Carbon Tetrachloride Feeding Selectively Damages Large, But Not Small, Cholangiocytes From Normal Rat Liver

“…Cholangiocytes play a key role in the modification of bile of canalicular origin by a series of spontaneous and hormoneregulated processes. 2,[5][6][7][8][9][10][11] For example, secretin enhances ductal secretory activity by interaction with specific receptors on cholangiocytes, 12 resulting in an increase in intracellular adenosine 3Ј,5Ј-monophosphate (cAMP) levels. [5][6][7]9,13,14 Increased cAMP levels induce the opening of Cl Ϫ channels and activation of the Cl Ϫ /HCO 3 Ϫ exchanger activity, which results in the secretin-induced bicarbonate-rich choleresis in vivo.…”