title: Protons released during pancreatic acinar cell secretion acidify the lumen and contribute to pancreatitis in mice.
abstract: OBJECTIVE
  Secretory granules are acidic; cell secretion will therefore lead to extracellular acidification. We propose that during secretion, protons co-released with proteins from secretory granules of pancreatic acinar cells acidify the restricted extracellular space of the pancreatic lumen to regulate normal physiological and pathophysiological functions in this organ
  
  
  METHODS
  Extracellular changes in pH were quantified in real time using 2-photon microscopy analysis of pancreatic tissue fragments from mouse models of acute pancreatitis (mice given physiological concentrations [10 -20 pM] of cholecystokinin or high concentrations of [100 nM] cerulein). The effects of extracellular changes in pH on cell behavior and structures were measured.
  
  
  RESULTS
  With physiological stimulation, secretory granule fusion (exocytosis) caused acidification of the pancreatic lumen. Acidifications specifically affected intracellular calcium responses and accelerated the rate of recovery from agonist-evoked calcium signals. Protons therefore appear to function as negative-feedback, extracellular messengers during coupling of cell stimuli with secretion. At high concentrations of cerulein, large increases in secretory activity were associated with extreme, prolonged acidification of the luminal space. These pathological changes in pH led to disruption of intercellular junctional coupling, measured by movement of occludin and E-cadherin.
  
  
  CONCLUSIONS
  By measuring changes in extracellular pH in pancreas of mice, we observed that luminal acidification resulted from exocytosis of zymogen granules from acinar cells. This process is part of normal organ function but could contribute to the tissue damage in cases of acute pancreatitis.
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Behrendorff
authors.forename: Matthias
authors.initials: M
authors.lastname: Floetenmeyer
authors.forename: Christof
authors.initials: C
authors.lastname: Schwiening
authors.forename: Peter
authors.initials: P
authors.lastname: Thorn
mesh_terms: D000818:Animals; D002108:Ceruletide / Q000494:pharmacology; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D045604:Extracellular Fluid / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism* / Q000473:pathology; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002756:Cholagogues and Choleretics; D002108:Ceruletide; D002766:Cholecystokinin