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Reducing extracellular pH sensitizes the acinar cell to secretagogue-induced pancreatitis responses in rats
- Publication Year :
- 2009
-
Abstract
- Background & Aims 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 μmol/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 μg/kg) trypsinogen activation and pancreatic edema. Conclusion 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.
- Subjects :
- Male
medicine.medical_specialty
Intracellular pH
In Vitro Techniques
digestive system
Article
Rats, Sprague-Dawley
Internal medicine
medicine
Acinar cell
Animals
Chymotrypsin
Trypsin
Lactic Acid
Enzyme Inhibitors
Trypsinogen activation
Pancreas
Ceruletide
Adenosine Triphosphatases
Enzyme Precursors
Hepatology
Chemistry
Gastroenterology
Hydrogen-Ion Concentration
medicine.disease
Rats
Enzyme Activation
Endocrinology
Pancreatitis
Zymogen activation
Amylases
Carbachol
Secretagogue
Macrolides
Propionates
Intracellular
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....c8791d8e4265d057d37426b5a9f9cb8e