Trypsin reduces pancreatic ductal bicarbonate secretion by inhibiting CFTR Cl- channels and luminal anion exchangers

Petra Pallagi, Viktória Venglovecz, Zoltán Rakonczay, Katalin Borka, Anna Korompay, Béla Zsvári, Linda Judák, Miklós Sahintóth, Andrea Geisz, Andrea Schnr, József Maléth, Tamás Takács, Mike A. Gray, Barry E. Argent, Julia Mayerle, Markus M. Lerch, Tibor Wittmann, Péter Hegyi

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42 Citations (Scopus)

Abstract

Background & Aims: The effects of trypsin on pancreatic ductal epithelial cells (PDECs) vary among species and depend on the localization of proteinase-activated receptor 2 (PAR-2). We compared PAR-2 localization in human and guinea-pig PDECs, and used isolated guinea pig ducts to study the effects of trypsin and a PAR-2 agonist on bicarbonate secretion. Methods: 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). Functionally, guinea pig PDECs were studied by microperfusion of isolated ducts, measurements of intracellular pH and intracellular Ca2+ concentration, and patch clamp analysis. The effect of pH on trypsinogen autoactivation was assessed using recombinant human cationic trypsinogen. Results: PAR-2 localized to the apical membrane of human and guinea pig PDECs. Trypsin increased intracellular Ca2+ concentration and intracellular pH 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 markedly reduced. Conclusions: Trypsin reduces pancreatic ductal bicarbonate secretion via PAR-2dependent inhibition of the apical anion exchanger and the CFTR Cl- channel. This could contribute to the development of chronic pancreatitis by decreasing luminal pH and promoting premature activation of trypsinogen in the pancreatic ducts.

Original languageEnglish
Pages (from-to)2228-2239.e6
JournalGastroenterology
Volume141
Issue number6
DOIs
Publication statusPublished - Dec 2011

Keywords

  • Acinar Cells
  • Animal Model
  • Ductal Epithelium
  • Pancreatic Enzymes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Pallagi, P., Venglovecz, V., Rakonczay, Z., Borka, K., Korompay, A., Zsvári, B., Judák, L., Sahintóth, M., Geisz, A., Schnr, A., Maléth, J., Takács, T., Gray, M. A., Argent, B. E., Mayerle, J., Lerch, M. M., Wittmann, T., & Hegyi, P. (2011). Trypsin reduces pancreatic ductal bicarbonate secretion by inhibiting CFTR Cl- channels and luminal anion exchangers. Gastroenterology, 141(6), 2228-2239.e6. https://doi.org/10.1053/j.gastro.2011.08.039