title: Reducing extracellular pH sensitizes the acinar cell to secretagogue-induced pancreatitis responses in rats.
abstract: OBJECTIVE
  Protease activation within the pancreatic acinar cell is a key early event in acute pancreatitis and may require low pH intracellular compartments. Clinical studies suggest that acidosis may affect the risk for developing pancreatitis. We hypothesized that exposure to an acid load might sensitize the acinar cell to secretagogue-induced pancreatitis.
  
  
  METHODS
  Secretagogues (cerulein, carbachol, and bombesin) can induce protease activation in acinar cells at high (100 nmol/L, 1 mmol/L, and 10 micromol/L, respectively) but not at physiologically relevant concentrations. The effects of decreasing extracellular pH (pHe) in early secretagogue-induced pancreatitis (zymogen activation and injury) were examined in rats (1) in vitro with isolated acini and (2) in vivo with an acid challenge.
  
  
  RESULTS
  In acini, lowering pHe from 7.6 to 6.8 enhanced secretagogue-induced zymogen activation and injury, but did not affect secretion. For cerulein, this sensitization was seen over a range of concentrations (0.01-100.00 nmol/L). However, reduced pHe alone had no effect on zymogen activation, amylase secretion, or cell injury. We have reported that zymogen activation is mediated by the vacuolar ATPase (vATPase), a proton transporter. vATPase inhibition, using concanamycin (100 nmol/L), blocked the low pHe effects on zymogen activation. An acute acid load given in vivo enhanced cerulein-induced (50 microg/kg) trypsinogen activation and pancreatic edema.
  
  
  CONCLUSIONS
  These studies suggest that acid challenge sensitizes the pancreatic acinar cell to secretagogue-induced zymogen activation and injury and may increase the risk for the development and severity of acute pancreatitis.
authors.affiliation: Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Bhoomagoud
authors.forename: Thomas
authors.initials: T
authors.lastname: Jung
authors.forename: Jorunn
authors.initials: J
authors.lastname: Atladottir
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kolodecik
authors.forename: Christine
authors.initials: C
authors.lastname: Shugrue
authors.forename: Anamika
authors.initials: A
authors.lastname: Chaudhuri
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Thrower
authors.forename: Fred S
authors.initials: FS
authors.lastname: Gorelick
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000681:Amylases / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002108:Ceruletide / Q000494:pharmacology; D002918:Chymotrypsin / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D010179:Pancreas / Q000473:pathology*; D010195:Pancreatitis / Q000378:metabolism* / Q000473:pathology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014357:Trypsin / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D018942:Macrolides; D011422:Propionates; D019344:Lactic Acid; C036978:concanamycin A; D002108:Ceruletide; D002217:Carbachol; C514135:sodium propionate; D000681:Amylases; D002918:Chymotrypsin; D014357:Trypsin; D000251:Adenosine Triphosphatases