ACUTE EFFECTS OF BILE-ACIDS ON THE PANCREATIC DUCT EPITHELIUM IN-VITRO

Background. Acute pancreatitis is associated with passage of gallstone s, although the mechanism(s) linking the two processes remains undefin ed, Bile reflux into the pancreatic duct could play a role but the exp erimental conditions often employed to induce pancreatitis rarely deve lop clinically, Here we examined whether low concentrations of bile af fect ductal electrophysiology as an indirect measure of ductal epithel ial integrity and function in vitro. Methods. The main duct was dissec ted out of freshly harvested bovine pancreata, cut into 1- x 2-cm sect ions, placed in tissue culture for 48-72 h, then placed in Ussing cham bers. Changes in tissue resistance (R-t) and short-circuit current (I- sc) were monitored, The responses to forskolin and bile (taurodeoxycho lic acid, TDCA) were examined separately and together. Results. Forsko lin (10 mu M) produced a decrease in the I-sc without a significant ch ange in R-t, suggesting a secretory response, followed by a return to baseline. TDCA caused a similarly reversible decrease in the I-sc at l ow doses, but a persistent drop at higher concentrations, A concurrent drop in R-t was noted at all TDCA concentrations, the duration of whi ch correlated with dosage and degree of histological damage, Prior exp osure to low (0.5 mM) doses of TDCA significantly blunted the response to subsequent forskolin challenge. Conclusions. Acute exposure to TDC A in vitro causes epithelial damage at levels lower than those normall y used to induce experimental pancreatitis. At the lower concentration s, R-t returns to baseline rapidly, suggesting recovery (restitution) from epithelial damage but with a persistent loss of the response to f orskolin, Reflux of minute amounts of bile into the pancreatic duct co uld play a significant role in the pathogenesis of gallstone pancreati tis by uncoupling the normal stimulus-secretion apparatus of the ducta l system and breaking down the epithelial barrier. (C) 1998 Academic P ress.