title: Trypsin reduces pancreatic ductal bicarbonate secretion by inhibiting CFTR Cl⁻ channels and luminal anion exchangers.
abstract: OBJECTIVE
  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 Ca(2+) 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 Ca(2+) 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-2-dependent 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.
authors: First Department of Medicine, University of Szeged, Szeged, Hungary.
authors: Petra
authors: P
authors: Pallagi
authors: Viktória
authors: V
authors: Venglovecz
authors: Zoltán
authors: Z
authors: Rakonczay
authors: Katalin
authors: K
authors: Borka
authors: Anna
authors: A
authors: Korompay
authors: Béla
authors: B
authors: Ozsvári
authors: Linda
authors: L
authors: Judák
authors: Miklós
authors: M
authors: Sahin-Tóth
authors: Andrea
authors: A
authors: Geisz
authors: Andrea
authors: A
authors: Schnúr
authors: József
authors: J
authors: Maléth
authors: Tamás
authors: T
authors: Takács
authors: Mike A
authors: MA
authors: Gray
authors: Barry E
authors: BE
authors: Argent
authors: Julia
authors: J
authors: Mayerle
authors: Markus M
authors: MM
authors: Lerch
authors: Tibor
authors: T
authors: Wittmann
authors: Péter
authors: P
authors: Hegyi
mesh_terms: D000818:Animals; D000837:Anion Exchange Resins / Q000378:metabolism; D001639:Bicarbonates / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism*; D050500:Pancreatitis, Chronic / Q000201:enzymology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014357:Trypsin / Q000502:physiology*; D014362:Trypsinogen / Q000378:metabolism
chemical_list: D000837:Anion Exchange Resins; D001639:Bicarbonates; D044464:Receptor, PAR-2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014362:Trypsinogen; D014357:Trypsin