Alpini G, Glaser S S, Ueno Y, Rodgers R, Phinizy J L, Francis H, Baiocchi L, Holcomb L A, Caligiuri A, LeSage G D
Department of Internal Medicine, Scott & White Hospital and Texas A&M University Health Science Center College of Medicine, USA.
Gastroenterology. 1999 Jan;116(1):179-86. doi: 10.1016/s0016-5085(99)70242-8.
BACKGROUND & AIMS: We have shown that taurocholate (TC) and taurolithocholate (TLC) interact in vitro with normal cholangiocytes, increasing DNA synthesis, secretin receptor (SR) gene expression, and adenosine 3',5'-cyclic monophosphate (cAMP) synthesis. To further extend these in vitro studies, we tested the hypothesis that bile acids (BAs) directly stimulate cholangiocyte proliferation and secretion in vivo.
After feeding with TC or TLC (1% for 1-4 weeks), we assessed the following in vivo: (1) ductal proliferation by both morphometry and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and measurement of [3H]thymidine incorporation; and (2) the effect of secretin on bile secretion and bicarbonate secretion in vivo. Genetic expression of H3-histone and SR and intracellular cAMP levels were measured in isolated cholangiocytes.
After BA feeding, there was an increased number of PCNA-positive cholangiocytes and an increased number of ducts compared with control rats. [3H]Thymidine incorporation, absent in control cholangiocytes, was increased in cholangiocytes from BA-fed rats. In BA-fed rats, there was increased SR gene expression (approximately 2.5-fold) and secretin-induced cAMP levels (approximately 3.0-fold) in cholangiocytes, which was associated with de novo secretin-stimulated bile flow and bicarbonate secretion.
These data indicate that elevated BA levels stimulate ductal secretion and cholangiocyte proliferation.
我们已经证明，牛磺胆酸盐（TC）和牛磺石胆酸盐（TLC）在体外与正常胆管细胞相互作用，可增加DNA合成、促胰液素受体（SR）基因表达以及3',5'-环磷酸腺苷（cAMP）合成。为了进一步扩展这些体外研究，我们检验了胆汁酸（BAs）在体内直接刺激胆管细胞增殖和分泌的假说。
用TC或TLC喂食（1%，持续1 - 4周）后，我们在体内评估以下指标：（1）通过形态学测量以及针对增殖细胞核抗原（PCNA）的免疫组织化学和[3H]胸腺嘧啶核苷掺入量测量来评估导管增殖；（2）促胰液素对体内胆汁分泌和碳酸氢盐分泌的影响。在分离的胆管细胞中测量H3组蛋白和SR的基因表达以及细胞内cAMP水平。
与对照大鼠相比，喂食胆汁酸后，PCNA阳性胆管细胞数量增加，导管数量增多。对照胆管细胞中不存在的[3H]胸腺嘧啶核苷掺入，在喂食胆汁酸的大鼠的胆管细胞中增加。在喂食胆汁酸的大鼠中，胆管细胞中SR基因表达增加（约2.5倍），促胰液素诱导的cAMP水平增加（约3.0倍），这与促胰液素刺激的胆汁流量和碳酸氢盐分泌的重新出现相关。
这些数据表明，升高的胆汁酸水平刺激导管分泌和胆管细胞增殖。
