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The recovery of acute pancreatitis depends on the enzyme amount stored in zymogen granules at early stages

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Abstract

Little is known about the changes in pancreatic enzyme storage in acute pancreatitis. We have performed flow cytometric studies of zymogen granules from rats with acute pancreatitis induced by hyperstimulation with caerulein. A comparison was made with rats treated with hydrocortisone (10 mg/kg/day) over 7 days before inducing pancreatitis in order to find out whether the amount of enzymes stored in the pancreas plays a key role in the development of pancreatitis. The potentially therapeutic effect of L-364,718 (0.1 mg/kg/day, for 7 days), a CCK receptor antagonist, was assayed in the rats with caerulein-induced pancreatitis which had previously received the hydrocortisone treatment. A significant increase in the intragranular enzyme content was observed 5 h after hyperstimulation with caerulein. The highest values were reached in the rats previously treated with hydrocortisone. The greatest pancreatic enzyme load was parallel to the highest values in plasma amylase, edema and haematocrit observed. Acute pancreatitis was reversed seven days later. At this stage smaller granules appeared in the pancreas whose enzyme content was similar to that of controls when no treatment was applied after pancreatitis. In contrast, L-364,718 administration prevented the favourable evolution of pancreatitis since the antagonism exerted on CCK receptors induced a blockade of secretion of the large amounts of enzymes stored in the pancreas. Moreover, the enzyme content in zymogen granules was below normal values since the stimulatory CCK action on enzyme synthesis can be inhibited by L-364,718. Our results suggest that the efficiency of CCK antagonists, as potential therapy, would also depend on the load of enzymes in the pancreas when acute pancreatitis is produced.

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References

  1. Rail L, Pictet R, Githens S, Rutter WJ: Glucocorticoids modulate the in vitro development of the embryogenic rat pancreas. J Cell Biol 75: 398–409, 1977

    PubMed  Google Scholar 

  2. Garteman H, Zeitz M, Emde C, Stelzer M, Riecken EO: Three days continuous drainage of pancreatic juice in the cortisone-treated conscious rat: Analysis of enzyme activities and ultrastructural changes. Cell Tissue Res 242: 191–196, 1995

    Google Scholar 

  3. Manso MA, García-Montero AC, Rodríguez AI, Orfao A, De Dios I: Hydrocortisone induces an increase of amylase content in individual zymogen granules from rat pancreas. J Steroid Biochem Mol Biol 62: 439–448, 1997

    PubMed  Google Scholar 

  4. Manso MA, De Dios I, San Román JI, Martin M, López MA: Exocrine pancreatic response to CCK in rats after long-term hydrocortisone administration. Peptides 11: 237–242, 1990

    PubMed  Google Scholar 

  5. De Dios I, Manso MA: Effect of L-364,718 (CCK receptor antagonist) on exocrine pancreatic secretion of hydrocortisonetreated rats. Pancreas 9: 212–218, 1994

    PubMed  Google Scholar 

  6. Gomez G, Townsend CM, Green D, Rajaraman S, Uchida T, Thompson J: Involvement of cholecystokinin receptors in the adverse effect of glucocorticoids on diet-induced necrotizing pancreatitis. Surgery 105: 230–238, 1989

    PubMed  Google Scholar 

  7. Manso MA, Rebollo A, Pescador R, De Dios I: Action of CCK on CDE diet-induced acute pancreatitis in rats treated with hydrocortisone. Comp Biochem Physiol 111: 257–263, 1995

    Google Scholar 

  8. García-Montero AC, Manso MA, Rodríguez AI, De Dios I: Therapeutic and protective effect of subcutaneous injections of L-364,718 on caerulein-induced acute pancreatitis. Pancreas 9: 309–315, 1994

    PubMed  Google Scholar 

  9. Pescador R, Manso MA, Rebollo AJ, De Dios I: Effect of chronic administration of hydrocortisone on the induction and evolution of acute pancreatitis induced by cerulein. Pancreas 11: 165–172, 1995

    PubMed  Google Scholar 

  10. Majumdar APN, Nielsen H: Influence of glucocorticoids on prenatal development of the gut and pancreas in rats. Scand J Gastroenterol 20: 65–71, 1985

    PubMed  Google Scholar 

  11. Niederau C, Niederau M, Lüthen R, Strohmeyer G, Ferrell LD, Grendell JH: Pancreatic exocrine secretion in acute experimental pancreatitis. Gastroenterology 99: 1120–1127, 1990

    PubMed  Google Scholar 

  12. Saluja A, Saito I, Saluja M, Houlihan MJ, Powers RE, Meldolesi J, Steer M: In vivo rat pancreatic acinar cell function during supramaximal stimulation with caerulein. Am J Physiol 249: G702–G710, 1985

    PubMed  Google Scholar 

  13. Rao KN, Tuma J: Acute hemorrhagic pancreatic necrosis in mice. Intraparenchymal activation of zymogens and other enzyme changes in pancreas and serum. Gastroenterology 70: 720–726, 1976

    PubMed  Google Scholar 

  14. Schmidt J, Fernández-del-Castillo C, Rattner D, Lewandrowski K, Compton C, Warshow A: Trypsinogen-activation peptide in experimental rat pancreatitis: Prognostic implications and histopathologic correlates. Gastroenterology 103: 1009–1016, 1992

    PubMed  Google Scholar 

  15. Yamaguchi HT, Kimura K, Nawata H: Activation of proteases in caerulein-induced pancreatitis. Pancreas 4: 565–571, 1989

    PubMed  Google Scholar 

  16. De Dios I, Rodríguez A, García-Montero A, Orfao A, Manso MA: Enzyme changes in zymogen granules and in pancreatic secretion throughout long-term CCK treatment. Peptides 18: 101–110, 1997

    PubMed  Google Scholar 

  17. Tani S, Otsuki M, Itoh H, Fujii M, Nakamura T, Oka T, Baba S: Histologic and biochemical alterations in experimental acute pancreatitis induced by supramaximal caerulein stimulation. Int J Pancreatol 2: 337–348, 1987

    PubMed  Google Scholar 

  18. Otsuki M, Okabayashi Y, Ohki A, Suheiro I, Baba S: Dual effects of hydrocortisone on exocrine rat pancreas. Gastroenterology 93: 1398–1403, 1987

    PubMed  Google Scholar 

  19. Noelting G, Bernfeld P: Sur les enzimes amylolitiques. III. La alpha-amylase, dosage d'activité et contróle de l'absence de beta-amylase. Helv Chim Acta 31: 286–290, 1948

    Google Scholar 

  20. De Lisle RC, Schulz I, Tyrakowski T, Haase W, Hopfer U: Isolation of stable pancreatic zymogen granules. Am J Physiol 246: G411–G418, 1984

    PubMed  Google Scholar 

  21. De Dios I, Orfao A, García-Montero AC, Rodríguez A, Manso MA: Analysis of isolated zymogen granules from rat pancreas using flow cytometry. Anal Cell Pathol 9: 215–228, 1995

    PubMed  Google Scholar 

  22. Cabana CM, Nadeau D, Grondin G, Beaudoin A: Freeze-fracture study of the zymogen granule membrane of pancreas: Two novel types of intramembrane particles. Eur J Cell Biol 45: 246–255, 1987

    Google Scholar 

  23. Rodríguez AI, Manso MA, García-Montero AC, Orfao A, De Dios I: Long-term blockade of cholecystokinin (CCK): Effects of 1364,718 (a CCK receptor antagonist) on pancreatic enzyme storage and secretion. Pancreas 15: 314–322, 1997

    PubMed  Google Scholar 

  24. Kachel V, Fellner-Feldegg H, Menke E. In: M.R. Melamed, T. Lindmo, M.L. Mendelsohn (eds). Flow Cytometry and Sorting. J. Wiley & Liss, New York, 1990, pp 27–45

    Google Scholar 

  25. Salzman GC, Singham SB, Jonston RG, Bohren CF: In: M.R. Melamed, T. Lindmo, M.L. Mendelsohn (eds). Flow Cytometry and Sorting. J Wiley & Liss, New York, 1990, pp 81–107

    Google Scholar 

  26. Muirhead KA, Horan PK, Poste G: Flow cytometry: Present and future. Biotechnology 3: 337–358, 1985

    Google Scholar 

  27. Lampel M, Kern HF: Acute interstitial pancreatitis in the rat induced by excessive doses of a pancreatic secretagogue. Virchows Arch 373: 97–117, 1977

    Google Scholar 

  28. Scheele G, Adler G, Kern H: Exocytosis occurs at the lateral plasma membrane of the pancreatic acinar cell during supramaximal secretagogue stimulation. Gastroenterology 92: 345–353, 1987

    PubMed  Google Scholar 

  29. Saluja AK, Saluja M, Printz H, Zavertnik A, Sengupta A, Steer ML: Experimental pancreatitis is mediated by low-affinity cholecystokinin receptors that inhibit digestive enzyme secretion. Proc Natl Acad Sci USA 86: 8968–8971, 1989

    PubMed  Google Scholar 

  30. Manso MA, Orfao A, Tabernero MD, Vicente S, De Dios I: Changes in both the membrane and the enzyme content of individual zymogen granules are associated with sodium taurocholate-induced pancreatitis in rats. Clin Sci 94: 293–301, 1998

    PubMed  Google Scholar 

  31. Puccio F, Chariot J, Lehy T: Influence of hydrocortisone on the development of pancreas in suckling rats. Biol Neonatt 54: 35–44, 1998

    Google Scholar 

  32. Beaudoin AR, Grondin G, St-Jean P, Vachereau A, Cabana C, Grossman A: Steroids and the secretory function of the exocrine pancreas. Endocrinology 119: 2106–2117, 1986

    PubMed  Google Scholar 

  33. García-Montero AC, De Dios I, Rodríguez AI, Orfao A, Manso MA: Adrenalectomy induces a decrease in the light scatter properties and amylase content of isolated zymogen granules from rat pancreas as analyzed by flow cytometry. J Endocrinol 147: 431–440, 1995

    PubMed  Google Scholar 

  34. Mallory A, Kern F Jr: Drug-induced pancreatitis: A critical review. Gastroenterology 78: 813–820, 1980

    PubMed  Google Scholar 

  35. Steinberg WM, Lewis JH: Steroids-induced pancreatitis: Does it really exist? Gastroenterology 81: 799–808, 1981

    PubMed  Google Scholar 

  36. Logsdon CD: Glucocorticoids increase cholecystokinin receptors and amylase secretion in pancreatic acinar AR42J cells. J Biol Chem 261: 2096–2101, 1986

    PubMed  Google Scholar 

  37. Leonhardt U, Seidensticker F, Fussek M, Stöckmann F, Creutzfeldt W: Influence of the CCK-antagonist loxiglumide on bile-induced experimental pancreatitis. Int J Pancreatol 10: 73–80, 1991

    PubMed  Google Scholar 

  38. Tomita H, Miyasaka K, Jimi A, Mishima Y, Funakoshi A: Lack of effect of cholecystokinin receptor antagonist (CR 1505) on recovery of experimental pancreatitis after pancreatic duct occlusion in rats. Pancreas 9: 638–645, 1994

    PubMed  Google Scholar 

  39. Beaudoin AR, Grondin G, Filion M, Lord A: Secretagogues cause a preferential discharge of large size granules in rat pancreas. Can J Biochem Cell Biol 62: 1288–1292, 1984

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, University of Salamanca, 37007, Salamanca, Spain

    M.A. Manso, A.C. García-Montero & I. De Dios

  2. Flow Cytometry Service, University of Salamanca, 37007, Salamanca, Spain

    M.D. Tabernero & A. Orfao

Authors
  1. M.A. Manso
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  2. A.C. García-Montero
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  3. M.D. Tabernero
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  4. A. Orfao
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  5. I. De Dios
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Manso, M., García-Montero, A., Tabernero, M. et al. The recovery of acute pancreatitis depends on the enzyme amount stored in zymogen granules at early stages. Mol Cell Biochem 200, 35–41 (1999). https://doi.org/10.1023/A:1006920217206

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  • DOI: https://doi.org/10.1023/A:1006920217206

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