Gastroenterology
Volume 137, Issue 3 , Pages 1083-1092 , September 2009

Reducing Extracellular pH Sensitizes the Acinar Cell to Secretagogue-Induced Pancreatitis Responses in Rats

  • Madhavi Bhoomagoud

      Affiliations

    • Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    • ,
  • Thomas Jung

      Affiliations

    • Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    • ,
  • Jorunn Atladottir

      Affiliations

    • Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
    • ,
  • Thomas R. Kolodecik

      Affiliations

    • Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    • ,
  • Christine Shugrue

      Affiliations

    • Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    • ,
  • Anamika Chaudhuri

      Affiliations

    • Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    • ,
  • Edwin C. Thrower

      Affiliations

    • Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    • ,
  • Fred S. Gorelick

      Affiliations

    • Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    • Department of Veterans Affairs Connecticut Healthcare, West Haven, Connecticut
    • Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut
    • Corresponding Author InformationReprint requests Address requests for reprints to: Fred Gorelick, MD, Room # D 226, Bldg. 4, VA Medical Center 950 Campbell Avenue West Haven, Connecticut 06516

References 

  1. Leach SD, Modlin IM, Scheele GA, et al. Intracellular activation of digestive zymogens in rat pancreatic acini (Stimulation by high doses of cholecystokinin). J Clin Invest. 1991;87:362–366
  2. Saluja A, Saito I, Saluja M, et al. In vivo rat pancreatic acinar cell function during supramaximal stimulation with caerulein. Am J Physiol Gastrointest Liver Physiol. 1985;249:G702–G710
  3. Niederau CGJ. Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment. J Clin Invest. 1988;81:229–236
  4. Kukor Z, Mayerle J, Kruger B, et al. Presence of cathepsin B in the human pancreatic secretory pathway and its role in trypsinogen activation during hereditary pancreatitis. J Biol Chem. 2002;277:21389–21396
  5. Guillaumes S, Blanco I, Villanueva A, et al. Chloroquine stabilizes pancreatic lysosomes and improves survival of mice with diet-induced acute pancreatitis. Pancreas. 1997;14:262–266
  6. Leach SD, Bilchik AJ, Karapetian O, et al. Influence of chloroquine on diet-induced pancreatitis. Pancreas. 1993;8:64–69
  7. Waterford SD, Kolodecik TR, Thrower EC, et al. Vacuolar ATPase regulates zymogen activation in pancreatic acini. J Biol Chem. 2005;280:5430–5434
  8. Lu Z, Karne S, Kolodecik T, et al. Alcohols enhance caerulein-induced zymogen activation in rat pancreatic acini. Am J Physiol. 2002;282:G501–G507
  9. Chaudhuri A, Kolodecik TR, Gorelick FS. Effects of increased intracellular cAMP on carbachol-stimulated zymogen activation, secretion, and injury in the pancreatic acinar cell. Am J Physiol Gastrointest Liver Physiol. 2005;288:G235–G243
  10. Unwin R, Capasso G, Giebisch G. Potassium and sodium transport along the loop of Henle: effects of altered dietary potassium intake. Kidney Int. 1994;46:1092–1099
  11. Saluja AK, Saluja M, Printz H, et al. Experimental pancreatitis is mediated by low-affinity cholecystokinin receptors that inhibit digestive enzyme secretion. Proc Natl Acad Sci U S A. 1989;86:8968–8971
  12. Bhagat L, Singh VP, Hietaranta AJ, et al. Heat shock protein 70 prevents secretagogue-induced cell injury in the pancreas by preventing intracellular trypsinogen activation. J Clin Invest. 2000;106:81–89
  13. Carter KJ, Rutledge PL, Steer ML, et al. Secretagogue-induced changes in intracellular pH and amylase release in mouse pancreatic acini. Am J Physiol Gastrointest Liver Physiol. 1987;253:G690–G696
  14. Grady T, Mah'moud M, Otani T, et al. Zymogen proteolysis within the pancreatic acinar cell is associated with cellular injury. Am J Physiol. 1998;275:G1010–G1017
  15. Frick TW, Fernandez-del-Castillo C, Bimmler D, et al. Elevated calcium and activation of trypsinogen in rat pancreatic acini. Gut. 1997;41:339–343
  16. Morihata H, Kawawaki J, Okina M, et al. Early and late activation of the voltage-gated proton channel during lactic acidosis through pH-dependent and -independent mechanisms. Pflügers Arch. 2007;455:829–838
  17. Ludwig MG, Vanek M, Guerini D, et al. Proton-sensing G-protein-coupled receptors. Nature. 2003;425:93–98
  18. Spitzer KW, Ershler PR, Skolnick RL, et al. Generation of intracellular pH gradients in single cardiac myocytes with a microperfusion system. Am J Physiol. 2000;278:H1371–H1382
  19. Katz M, Carangelo R, Miller LJ, et al. Effect of ethanol on cholecystokinin-stimulated zymogen conversion in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol. 1996;270:G171–G175
  20. Otani T, Matsukura A, Takamoto T, et al. Effects of pancreatic duct ligation on pancreatic response to bombesin. Am J Physiol Gastrointest Liver Physiol. 2006;290:G633–G639
  21. Nair S, Yadav D, Pitchumoni CS. Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA. Am J Gastroenterol. 2000;95:2795–2800
  22. Kishnani PS, Van Hove JL, Shoffner JS, et al. Acute pancreatitis in an infant with lactic acidosis and a mutation at nucleotide 3243 in the mitochondrial DNA tRNALeu(UUR) gene. Eur J Pediatr. 1996;155:898–903
  23. Patel V, Hedayati SS. Lactic acidosis in an HIV-infected patient receiving highly active antiretroviral therapy. Nat Clin Pract Nephrol. 2006;2:109–114
  24. Takeda K, Mikami Y, Fukuyama S, et al. Pancreatic ischemia associated with vasospasm in the early phase of human acute necrotizing pancreatitis. Pancreas. 2005;30:40–49
  25. Reber HA, Karanjia ND, Alvarez C, et al. Pancreatic blood flow in cats with chronic pancreatitis. Gastroenterology. 1992;103:652–659
  26. Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol. 2004;286:R686–R692
  27. Wagner CA, Finberg KE, Breton S, et al. Renal vacuolar H+-ATPase. Physiol Rev. 2004;84:1263–1314
  28. Bond S, Forgac M. The Ras/cAMP/protein kinase a pathway regulates glucose-dependent assembly of the vacuolar (H+)-ATPase in yeast. J Biol Chem. 2008;283:36513–36521
  29. Presig P. The acid-activated signaling pathway: starting with Pyk2 and ending with increased NHE3 activity. Kidney Int. 2007;72:1324–1329
  30. Unno N, Menconi MJ, Smith M, et al. Hyperpermeability of intestinal epithelial monolayers is induced by NO: effect of low extracellular pH. Am J Physiol. 1997;272:G923–G934
  31. Kellum J, Song M, Li J. Science review: extracellular acidosis and the immune response: clinical and physiologic implications. Crit Care. 2004;8:331–336
  32. Bhatia M, Saluja AK, Hofbauer B, et al. Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. Proc Natl Acad Sci U S A. 1998;95:4760–4765
  33. Hegde A. Neurogenic inflammation in acute pancreatitis. J Pancreas. 2005;5:417–421
  34. Noble MD, Romac J, Vigna SR, et al. A pH-sensitive, neurogenic pathway mediates disease severity in a model of post-ERCP pancreatitis. Gut. 2008;57:1566–1571

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by grants from the NIH NRSA to MB (DK80582); NIH T32 award to TJ (DK07017): Veterans Administration Merit Award to FG; and NIH R01 (DK54021) to FG.

PII: S0016-5085(09)00773-2

doi: 10.1053/j.gastro.2009.05.041

Gastroenterology
Volume 137, Issue 3 , Pages 1083-1092 , September 2009

Article Tools

* Image Usage & Resolution