Trypsin reduces pancreatic ductal bicarbonate secretion by inhibiting CFTR Cl⁻ channels and luminal anion exchangers.
Trypsin reduces pancreatic ductal bicarbonate secretion by inhibiting CFTR Cl⁻ channels and luminal anion exchangers.
复制标题
DOI：
10.1053/j.gastro.2011.08.039
复制
发表时间：
2011-12
期刊：
影响因子：
29.4
通讯作者：
Hegyi P
中科院分区：
文献类型：
--
作者：
Pallagi P;Venglovecz V;Rakonczay Z Jr;Borka K;Korompay A;Ozsvári B;Judák L;Sahin-Tóth M;Geisz A;Schnúr A;Maléth J;Takács T;Gray MA;Argent BE;Mayerle J;Lerch MM;Wittmann T;Hegyi P
胰蛋白酶对胰腺导管上皮细胞（PDEC）的影响因物种而异，并取决于蛋白酶激活受体-2（PAR-2）的定位。在人和豚鼠PDEC中，Biclycerin分泌相似;我们比较了其在这些细胞类型和离体豚鼠导管中的定位，以研究胰蛋白酶和PAR-2激动剂对该过程的影响。PAR-2的定位进行了分析，通过免疫组织化学在豚鼠和人类胰腺组织样本（15例慢性胰腺炎和15例无胰腺疾病）。通过离体豚鼠肺导管微灌注、细胞内pH（pHi）和Ca ~（2+）浓度[Ca ~（2+）]i的测定以及膜片钳分析，研究了豚鼠PDEC的功能。使用重组人阳离子胰蛋白酶原评估pH对胰蛋白酶原自激活的影响。PAR-2定位于人和豚鼠PDEC的顶膜。胰蛋白酶增加[Ca ~（2+）]i和pHi，并通过腔阴离子交换器和囊性纤维化跨膜传导调节器（CFTR）Cl-通道抑制重碳酸盐的分泌。当pH从8.5降低到6.0时，人阳离子胰蛋白酶原的自活化加速。PAR-2表达强烈下调，在转录和蛋白质水平，在导管慢性胰腺炎患者，与导管内胰蛋白酶活性增加一致。重要的是，在PAR-2敲除小鼠中，胰蛋白酶的作用是PAR-2依赖性的。胰蛋白酶通过PAR-2依赖性抑制顶端阴离子交换器和CFTR Cl-通道减少胰腺导管碳酸氢盐分泌。这可能有助于慢性胰腺炎的发展，降低管腔pH值并促进胰管中胰蛋白酶原的过早激活。
The effects of trypsin on pancreatic ductal epithelial cells (PDEC) vary among species and depend on localization of proteinase-activated receptor-2 (PAR-2). Bicarbonate secretion is similar in human and guinea pig PDEC; we compared its localization in these cell types and isolated guinea pig ducts to study the effects of trypsin and a PAR-2 agonist on this process. PAR-2 localization was analyzed by immunohistochemistry in guinea pig and human pancreatic tissue samples (from 15 patients with chronic pancreatitis and 15 without pancreatic disease). Functions of guinea pig PDEC were studied by microperfusion of isolated ducts, measurements of intracellular pH (pHi) and Ca2+ concentration [Ca2+]i, and patch clamp analysis. The effect of pH on trypsinogen autoactivation was assessed using recombinant human cationic trypsinogen. PAR-2 localized to the apical membrane of human and guinea pig PDEC. Trypsin increased [Ca2+]i and pHi, and inhibited secretion of bicarbonate by the luminal anion exchanger and the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Autoactivation of human cationic trypsinogen accelerated when the pH was reduced from 8.5 to 6.0. PAR-2 expression was strongly down-regulated, at transcriptional and protein levels, in the ducts of patients with chronic pancreatitis, consistent with increased activity of intraductal trypsin. Importantly, in PAR-2 knockout mice, the effects of trypsin were PAR-2 dependent. Trypsin reduces pancreatic ductal bicarbonate secretion via PAR-2–dependent inhibition of the apical anion exchanger and the CFTR Cl- channel. This could contribute to the development of chronic pancreatitis, decreasing luminal pH and promoting premature activation of trypsinogen in the pancreatic ducts.
登录
查看更多内容
影响因子：
9.8
作者：
Cavestro, Giulia Martina;Zuppardo, Raffaella Alessia;Di Mario, Francesco
通讯作者：
Di Mario, Francesco
影响因子：
5.5
作者：
Ishiguro, H;Naruse, X;Steward, MC
通讯作者：
Steward, MC
影响因子：
24.5
作者：
FEDAIL, SS;HARVEY, RF;READ, AE
通讯作者：
READ, AE
影响因子：
3.8
作者：
Ishiguro, H;Steward, MC;Naruse, S
通讯作者：
Naruse, S
影响因子：
5.5
作者：
Ishiguro, H;Steward, MC;Case, RM
通讯作者：
Case, RM