Alvarez C, Fasano A, Bass B L
Surgical Service, Baltimore VAMC, Maryland 21201, USA.
J Surg Res. 1998 Jan;74(1):43-6. doi: 10.1006/jsre.1997.5202.
Acute pancreatitis is associated with passage of gallstones, although the mechanism(s) linking the two processes remains undefined. Bile reflux into the pancreatic duct could play a role but the experimental conditions often employed to induce pancreatitis rarely develop clinically. Here we examined whether low concentrations of bile affect ductal electrophysiology as an indirect measure of ductal epithelial integrity and function in vitro.
The main duct was dissected out of freshly harvested bovine pancreata, cut into 1- x 2-cm sections, placed in tissue culture for 48-72 h, then placed in Ussing chambers. Changes in tissue resistance (Rt) and short-circuit current (Isc) were monitored. The responses to forskolin and bile (taurodeoxycholic acid, TDCA) were examined separately and together.
Forskolin (10 microM) produced a decrease in the Isc without a significant change in Rt, suggesting a secretory response, followed by a return to baseline. TDCA caused a similarly reversible decrease in the Isc at low doses, but a persistent drop at higher concentrations. A concurrent drop in Rt was noted at all TDCA concentrations, the duration of which correlated with dosage and degree of histological damage. Prior exposure to low (0.5 mM) doses of TDCA significantly blunted the response to subsequent forskolin challenge.
Acute exposure to TDCA in vitro causes epithelial damage at levels lower than those normally used to induce experimental pancreatitis. At the lower concentrations, Rt returns to baseline rapidly, suggesting recovery (restitution) from epithelial damage but with a persistent loss of the response to forskolin. Reflux of minute amounts of bile into the pancreatic duct could play a significant role in the pathogenesis of gallstone pancreatitis by uncoupling the normal stimulus-secretion apparatus of the ductal system and breaking down the epithelial barrier.
急性胰腺炎与胆结石的排出有关，尽管连接这两个过程的机制尚不清楚。胆汁反流至胰管可能起一定作用，但常用于诱发胰腺炎的实验条件在临床上很少出现。在此，我们研究了低浓度胆汁是否会影响导管电生理，以此作为体外导管上皮完整性和功能的间接指标。
从新鲜采集的牛胰腺中分离出主胰管，切成1×2厘米的片段，置于组织培养中48 - 72小时，然后放入尤斯灌流小室。监测组织电阻（Rt）和短路电流（Isc）的变化。分别及联合检测对福斯高林和胆汁（牛磺脱氧胆酸，TDCA）的反应。
福斯高林（10微摩尔）使Isc降低，而Rt无显著变化，提示有分泌反应，随后恢复至基线水平。低剂量TDCA使Isc出现类似的可逆性降低，但高浓度时则持续下降。在所有TDCA浓度下均观察到Rt同时下降，其持续时间与剂量及组织学损伤程度相关。预先暴露于低剂量（0.5毫摩尔）的TDCA显著减弱了随后对福斯高林刺激的反应。
体外急性暴露于TDCA会在低于通常用于诱发实验性胰腺炎的水平时导致上皮损伤。在较低浓度时，Rt迅速恢复至基线水平，提示上皮损伤得以恢复（修复），但对福斯高林的反应持续丧失。微量胆汁反流至胰管可能通过使导管系统的正常刺激 - 分泌机制解偶联并破坏上皮屏障，在胆石性胰腺炎的发病机制中起重要作用。
