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Acute Pancreatitis: Mechanisms of Cell Injury — Genetics

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Pancreatic Disease

Abstract

Acute pancreatitis was defined at the Symposium of Marseilles as an acute condition typically presenting with abdominal pain and usually associated with elevated pancreatic enzymes in blood or urine, due to inflammatory disease of the pancreas. This clinically based definition remains useful for diagnosing and treating most cases of acute pancreatitis. However, it also reflects the limits in identifying and understanding the molecular and cellular pathophysiologic mechanisms that underlie this common disorder. Acute pancreatitis encompasses a variety of processes. The acute injury within the pancreas appears to develop rapidly, and the inciting factors may resolve before diagnosis and therapeutic interventions can be initiated. The injury results in an acute inflammatory response that may itself worsen the injury, causing significant local and systemic complications. Investigative efforts directed toward understanding and limiting the subsequent inflammatory reaction provide some hope of improving the outcome of more severe cases, if instituted early in the disease process. However, research directed at understanding the early molecular mechanisms initiating acute pancreatitis, and developing effective preventive strategies may be equally important.

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References

  1. Arias AE, Boldicke T, Bendayan M (1993) Absence of trypsinogen auto activation and immunolocalization of pancreatic secretory trypsin inhibitor in acinar cells in vitro. In Vitro Cell Dev Biol 29:221–227

    Article  Google Scholar 

  2. Banerjee A, Galloway S, Kingsnorth A (1994) Experimental models of acute pancreatitis. Br J Surg 81:1096–1103

    Article  PubMed  CAS  Google Scholar 

  3. Bartness M, Duerr RH, Ford MA, et al (1998) Potential linkage of a pancreatitis associated gene on chromosome 12. Pancreas 17:426

    Google Scholar 

  4. Bernard C (1856) Leçons de physiologie experimentale, vol 2. Bailleire, Paris, pp 278

    Google Scholar 

  5. Blackstone M, Whitcomb DC (1998) Premature trypsin activation in hereditary pancreatitis. Gastroenterology 115:796–799

    Article  PubMed  CAS  Google Scholar 

  6. Brunzell JD, Miller NE, Alaupovic P, et al (1983) Familial chylomicronemia due to a circulating inhibitor of lipoprotein lipase activity. J Lipid Res 24:12–19

    PubMed  CAS  Google Scholar 

  7. Carey MC, Fitzgerald O (1968) Hyperparathyroidism associated with chronic pancreatitis in a family. Gut 9:700–703

    Article  PubMed  CAS  Google Scholar 

  8. Cavallini G, Tittobello A, Frulloni L, Masci E, Mariana A, Di Francesco V (1996) Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography. N Engl J Med 335:919–923

    Article  PubMed  CAS  Google Scholar 

  9. Collins JE, Brenton DP (1990) Pancreatitis and homocystinuria. J Inherit Metab Dis 13:232–233

    Article  PubMed  CAS  Google Scholar 

  10. Colomb E, Figarella C (1979) Comparative studies on the mechanism of activation of the two human trypsinogens. Biochim Biophys Acta 571:343–351

    PubMed  CAS  Google Scholar 

  11. Colomb E, Figarella C, Guy O (1979) The two human trypsinogens. Evidence of complex formation with basic pancreatic trypsin inhibitor-proteolytic activity. Biochim Biophys Acta 570:397–405

    PubMed  CAS  Google Scholar 

  12. Colomb E, Guy O, Deprez P, Michel R, Figarella C (1978) The two human trypsinogens: catalytic properties of the corresponding trypsins. Biochim Biophys Acta 525:186–193

    PubMed  CAS  Google Scholar 

  13. Comfort M, Steinberg A (1952) Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology 21:54–63

    PubMed  CAS  Google Scholar 

  14. Cox DW, Breckenridge WC, Little JA (1978) Inheritance of apolipoprotein C-II deficiency with hypertriglyceridemia and pancreatitis. N Engl J Med 299:1421–1424

    Article  PubMed  CAS  Google Scholar 

  15. Dartsch H, Kleene R, Kern HF (1998) In vitro condensation-sorting of enzyme proteins isolated from rat pancreatic acinar cells. Eur J Cell Biol 75:211–222

    PubMed  CAS  Google Scholar 

  16. Dasouki M, Cogan J, Summar M, et al (1998) Heterogeneity in hereditary pancreatitis. Am J Med Genet 77:47–53

    Article  PubMed  CAS  Google Scholar 

  17. Ferec C, Raguenes O, Bignon JD, Georgelin T, Lebodic L (1997) Hereditary pancreatitis gene (in French). M S Med Sci 13:246–249

    Google Scholar 

  18. Figarella C, Amouric M, Guy-Crotte O (1984) Proteolysis of human trypsinogen. I. Pathogenic implications in chronic pancreatitis. Biochem Biophys Res Commun 118:154–161

    Article  PubMed  CAS  Google Scholar 

  19. Figarella C, Miszczuk-Jamska B, Barrett AJ (1988) Possible lysosomal activation of pancreatic zymogens. Activation of both human trypsinogens by cathepsin B and spontaneous acid activation of human trypsinogen 1. Biol Chem Hoppe-Seylers 369[Suppl]: 293–298

    CAS  Google Scholar 

  20. Frick TW, Fernandez, del CC, Bimmler D, Warshaw AL (1997) Elevated calcium and activation of trypsinogen in rat pancreatic acini. Gut 41:339–343

    Article  PubMed  CAS  Google Scholar 

  21. Gorry M, Gabbaizadeh D, Furey W, et al (1997) Multiple mutations in the cationic trypsinogen gene are associated with hereditary pancreatitis. Gastroenterology 113:1063–1068

    Article  PubMed  CAS  Google Scholar 

  22. Grady T, Saluja A, Kaiser A, Steer M (1996) Edema and intrapancreatic trypsinogen activation precede glutathione depletion during cerulein pancreatitis. Am J Physiol 271:G20–G26

    PubMed  CAS  Google Scholar 

  23. Grady T, Otani T, Mah’moud M, Rhee S, Learch MM, Gorelick FS (1998) Zymogen proteolysis within the pancreatic acinar cell is associated with cellular injury. Am J Physiol 275:G1010–G1017

    PubMed  CAS  Google Scholar 

  24. Greenbaum LM, Hirshkowitz A, Shoichet I (1959) The activation of trypsinogen by ca-thepsin B. J Biol Chem 234:2885–2890

    PubMed  CAS  Google Scholar 

  25. Gress TM, Micha AE, Lacher U, Adler G (1997) Hereditary pancreatitis, caused by mutations in the cationic trypsinogen gene (in German). Dtsch Med Wochenschr 122:1461–1465

    Article  PubMed  CAS  Google Scholar 

  26. Gress TM, Micha AE, Lacher U, Adler G (1998) Diagnosis of a “hereditary pancreatitis” by the detection of a mutation in the cationic trypsinogen gene (in German). Dtsch Med Wochenschr 123:453–456

    Article  PubMed  CAS  Google Scholar 

  27. Hofbauer B, Daluja A, Learch M, et al (1998) Intra-acinar cell activation of trypsinogen during cerulein-induced pancreatitis in rats. Am J Physiol 275:G352–G362

    PubMed  CAS  Google Scholar 

  28. Hubbard S, Eisenmenger F, Thornton J (1994) Modeling studies of the change in conformation required for cleavage of limited proteolytic sites. Protein Sci 3:757–768

    Article  PubMed  CAS  Google Scholar 

  29. Hubbard S, Eisenmenger F, Thornton J (1994) Limited proteolysis sites modeling, Hubbard. kin 3.5 (2PTC, 1TGN, 5RSA). Protein Sci [serial online] 3:URL: http://prosci.org/Kinemage/, Filename: Hubbard.kin 3.5

    Google Scholar 

  30. Klumperman J, Kuliawat R, Griffith JM, Geuze HJ, Arvan P (1998) Mannose 6-phosphate receptors are sorted from immature secretory granules via adaptor protein AP-1, clathrin, and syntaxin 6-positive vesicles. J Cell Biol 141:359–371

    Article  PubMed  CAS  Google Scholar 

  31. Kruger B, Lerch MM, Tessenow W (1998) Direct detection of premature protease activation in living pancreatic acinar cells. Lab Invest 78:763–764

    PubMed  CAS  Google Scholar 

  32. Kurth T, Teich N, Kistner S, Mossner J, Keim V (1998) Expression of the N21I-mutation of human cationic trypsinogen in a yeast system. Digestion 59:243 (abstr)

    Google Scholar 

  33. Le Bodic L, Bignon JD, Raguenes O, et al (1996) The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum Mol Genet 5:549–554

    Article  PubMed  Google Scholar 

  34. Leach SD, Moldin IM, Sheele GA, Gorelick FS (1991) Intracellular activation of digestive enzymes in rat pancreatic acini: stimulation by high dose of cholecystokinin. J Clin Invest 87:362–366

    Article  PubMed  CAS  Google Scholar 

  35. Lerch M, Adler G (1994) Experimental models of acute pancreatitis. Int J Pancreatol 15:159–170

    PubMed  CAS  Google Scholar 

  36. Mithofer K, Fernandez-Del Castillo C, Frick TW, Lewandrowski KB, Rattner DW, Warshaw AL (1995) Acute hypercalcemia causes acute pancreatitis and ectopic trypsinogen activation in the rat [see comments]. Gastroenterology 109:239–246

    Article  PubMed  CAS  Google Scholar 

  37. Mithofer K, Fernandez-Del Castillo C, Rattner DW, Warshaw AL (1998) Subcellular kinetics of early trypsinogen activation in acute rodent pancreatitis. Am J Physiol 274:G71–G79

    PubMed  CAS  Google Scholar 

  38. Nagasaki Y, Koizumi M, Shimosegawa T, et al (1997) Trypsinogen gene mutation in Japanese patients with juvenile or familial pancreatitis. Pancreas 15:447

    Google Scholar 

  39. Nishimori I, Adachi K, Kamakura M, et al (1997) Cationic trypsinogen gene mutation in hereditary pancreatitis. Pancreas 14:448

    Google Scholar 

  40. Otani T, Chepilko S, Grendell J, Gorelick F (1998) Co-distribution of trypsinogen activation peptide and the granule membrane protein, GRAMP-92, in rat cerulein-induced pancreatitis. Am J Physiol 275:G999–G1009

    PubMed  CAS  Google Scholar 

  41. Pandya A, Blanton SH, Landa B, et al (1996) Linkage studies in a large kindred with hereditary pancreatitis confirms mapping of the gene to a 16-cm region on 7q. Genomics 38:227–230

    Article  PubMed  CAS  Google Scholar 

  42. Perrault J (1994) Hereditary pancreatitis. Gastroenterol Clin North Am 23:743–752

    PubMed  CAS  Google Scholar 

  43. Rao K, Tuma J, Lombardi B (1976) Acute hemorrhagic pancreatic necrosis in mice. Intraparenchymal activation of zymogens, and other enzyme changes in pancreas and serum. Gastroenterology 70:720–726

    PubMed  CAS  Google Scholar 

  44. Richardson D (1996) MAGE. Protein Science Kinemages. Available on URL:http://prosci.org/Kinemage/, gopher://gopher.prosci.uci/11/kinemage: The Protein Society, 1992–1996

    Google Scholar 

  45. Rinderknecht H (1986) Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanims against inappropriate activation. Dig Dis Sci 31:314–321

    Article  PubMed  CAS  Google Scholar 

  46. Rinderknecht H (1993) Pancreatic secretory enzymes. In: Go VLW, DiMagno EP, Gardner JD, Lebenthal E, Reber HA, Scheele GA (eds) The pancreas: biology, pathobiology, and disease. Raven, New York, pp 219–251

    Google Scholar 

  47. Rinderknecht H, Adham NF, Renner IG, Carmack C (1988) A possible zymogen self-destruct mechanism preventing pancreatic autodigestion. Int J Pancreatol 3:33–44

    PubMed  CAS  Google Scholar 

  48. Saluga AK, Donovan EA, Yamanaka K, Yamaguchi Y, Hofbauer B, Steer ML (1997) Cerulein-induced in vitro activation of trypsinogen in rat pancreatic acini is mediated by cathepsin B. Gastroenterology 113:304–310

    Article  Google Scholar 

  49. Sibert JR (1978) Hereditary pancreatitis in England and Wales. J Med Genet 15:189–201

    Article  PubMed  CAS  Google Scholar 

  50. Steer ML (1992) How and where does acute pancreatitis begin? Arch Surg 127:1350–1353

    PubMed  CAS  Google Scholar 

  51. Steer ML, Meldolesi J, Figarella C (1984) Pancreatitis. The role of lysosomes. Dig Dis Sci 29:934–938

    Article  PubMed  CAS  Google Scholar 

  52. Steinberg W, Schlesselman S (1987) Treatment of acute pancreatitis: comparison of animal and human studies. Gastroenterology 93:1420–1427

    PubMed  CAS  Google Scholar 

  53. Ward JB, Petersen OH, Jenkins SA, Sutton R (1995) Is an elevated concentration of acinar cytosolic free ionised calcium the trigger for acute pancreatitis? (review) [42 refs]. Lancet 346:1016–1019

    Article  PubMed  CAS  Google Scholar 

  54. Whitcomb DC, Gorry MC, Preston RA, et al (1996) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14:141–145

    Article  PubMed  CAS  Google Scholar 

  55. Whitcomb DC, Preston RA, Aston CE, et al (1996) A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 110:1975–1980

    Article  PubMed  CAS  Google Scholar 

  56. Whitcomb DC, Ulrich II CD (1999) Hereditary pancreatitis: new insights, new directions. In: Neoptolemus JP (ed) Balliere’s clinical gastroenterology: acute pancreatitis. Blackwell Scientific, Oxford (in press)

    Google Scholar 

  57. Wilson DE, Hata A, Kwong LK, et al (1993) Mutations in exon 3 of the lipoprotein lipase gene segregating in a family with hypertriglyceridemia, pancreatitis, and non-insulin-dependent diabetes. J Clin Invest 92:203–211

    Article  PubMed  CAS  Google Scholar 

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© 1999 Springer-Verlag Berlin Heidelberg

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Whitcomb, D.C. (1999). Acute Pancreatitis: Mechanisms of Cell Injury — Genetics. In: Pancreatic Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60068-5_1

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  • DOI: https://doi.org/10.1007/978-3-642-60068-5_1

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-65357-8

  • Online ISBN: 978-3-642-60068-5

  • eBook Packages: Springer Book Archive

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