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Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;8(3):402–409. doi: 10.1111/j.1582-4934.2004.tb00330.x

Apoptosis of pancreatic acinar cells in acute pancreatitis: is it good or bad?

M Bhatia 1,
PMCID: PMC6740226  PMID: 15491516

Abstract

Acute pancreatitis is a disease of variable severity in which some patients experience mild, self‐limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. The events that regulate the severity of acute pancreatitis are, for the most part, unknown. Several recent studies have suggested that the acinar cell response to injury may be an important determinant of disease severity. In these studies, mild acute pancreatitis was found to be associated with extensive apoptotic acinar cell death while severe acute pancreatitis was found to involve extensive acinar cell necrosis but very little acinar cell apoptosis. These observations have led to the hypothesis that apoptosis might be a favorable response to acinar cell and that interventions which favor induction of apoptotic, as opposed to necrotic, acinar cell death might reduce the severity of an attack of acute pancreatitis. This review aims to discuss our current understanding of the contribution of acinar cell apoptosis to the severity of acute pancreatitis.

Keywords: apoptosis, necrosis, inflammation, pancreatitis

References

  • 1. Bhatia M., Wong F.L., Cao Y., Lau H.Y., Huang J., Puneet P., Chevali L., Pathophysiology of acute pancreatitis, Pancreatology. (in press), 2004. [DOI] [PubMed]
  • 2. Bhatia M., Brady M., Shokuhi S., Christmas S., Neoptolemos J.P., Slavin J., Inflammatory mediators in acute pancreatitis, J. Pathol., 190: 117–125, 2000. [DOI] [PubMed] [Google Scholar]
  • 3. Bhatia M., Neoptolemos J.P., Slavin J., Inflammatory mediators as therapeutic targets in acute pancreatitis, Curr. Opin. Investig. Drugs, 2: 496–501, 2001. [PubMed] [Google Scholar]
  • 4. Bhatia M., Novel therapeutic targets for acute pancreatitis and associated multiple organ dysfunction syndrome, Curr. Drug Targets - Infl. Allergy, 1: 343–351, 2002. [DOI] [PubMed] [Google Scholar]
  • 5. Bhatia M., Apoptosis versus Necrosis in Acute Pancreatitis, Am. J. Physiol., 286 G189–196, 2004. [DOI] [PubMed] [Google Scholar]
  • 6. Bhatia M., Saluja A.K., Hofbauer B., Lee H.S., Frossard J.L., Castagliuolo I., Wang C.C., Gerard N., Pothoulakis C., Steer M.L. Role of NK1 receptor in the development of acute pancreatitis and pancreatitis‐associated lung injury. Proc Natl Acad Sci USA. 95: 4760–4765, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Bhatia M., Saluja A.K., Hofbauer B., Lee H.S., Frossard J.L., Steer M.L., The effects of neutrophil depletion on a completely non‐invasive model of acute pancreatitis‐associated lung injury, Int. J. Pancreatol., 24: 77–83, 1998. [DOI] [PubMed] [Google Scholar]
  • 8. Bhatia M., Zagorski J., Brady M., Christmas S., Campbell F., Neoptolemos J.P., Slavin J., Treatment with neutralising antibody against cytokine‐induced neutrophil chemoattractant protects rats against acute pancreatitisassociated lung injury, Gut, 47: 838–844, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Bhatia M., Brady M., Kang Y.K., Costello E., Newton D.J., Christmas S., Neoptolemos J.P., Slavin J., MCP‐1 but not CINC synthesis is increased in rat pancreatic acini in response to caerulein hyperstimulation, Am. J. Physiol., 282:G77–G85, 2002. [DOI] [PubMed] [Google Scholar]
  • 10. Bhatia M., Slavin J., Cao Y., Basbaum A.I., Neoptolemos J., Preprotachykinin‐A gene deletion protects mice against acute pancreatitis and associated lung injury, Am. J. Physiol., 284:G830–G836, 2003. [DOI] [PubMed] [Google Scholar]
  • 11. Bhatia M., Saluja A.K., Lee H.S., Frossard J.L., Gerard C., Steer M.L., Complement factor C5a exerts an anti‐inflammatory effect in acute pancreatitis and associated lung injury, Amer. J. Physiol., 280:G974–G978, 2001. [DOI] [PubMed] [Google Scholar]
  • 12. Bhatia M., Proudfoot, A.E.I. , Wells T.N.C., Christmas S., Neoptolemos J.P., Slavin J., Treatment with Met‐RANTES reduces lung injury in caerulein induced pancreatitis in mice, Br. J. Surg., 90: 698–704, 2003. [DOI] [PubMed] [Google Scholar]
  • 13. Horvitz H.R., Shaham S., Hengartner M.O., The genetics of programmed cell death in the nematode Caenorhabditis elegans, Cold Spring Harb. Symp. Quant. Biol., 59: 377–385, 1994. [DOI] [PubMed] [Google Scholar]
  • 14. Thornberry N.A., Lazebnik Y., Caspases: enemies within. Science 281: 1312–1316, 1998. [DOI] [PubMed] [Google Scholar]
  • 15. Tibbetts M.D., Zheng L., Lenardo M.J., The death effector domain protein family: regulators of cellular homeostasis, Nat. Immunol., 4: 404–409, 2003. [DOI] [PubMed] [Google Scholar]
  • 16. Wang X., The expanding role of mitochondria in apoptosis, Genes Dev., 15: 2922–2933, 2001. [PubMed] [Google Scholar]
  • 17. Johnstone R.J., Ruefli A.A., Lowe S.W., Apoptosis: a link between cancer genetics and chemotherapy, Cell, 108: 153–164, 2002. [DOI] [PubMed] [Google Scholar]
  • 18. Wyllie A.H., Death from inside out: an overview, Philos. Trans. R. Soc. Lond. B. Biol. Sci., 345: 237–241, 1994. [DOI] [PubMed] [Google Scholar]
  • 19. Adrain C., Martin S.J., The mitochondrial apoptosome: a killer unleashed by the cytochrome seas, Trends Biochem. Sci., 26: 390–397, 2001. [DOI] [PubMed] [Google Scholar]
  • 20. Nicholson D.W, Thornberry N.A., Apoptosis: life and death decisions, Science, 299: 214–215, 2003. [DOI] [PubMed] [Google Scholar]
  • 21. Korsmeyer S.J., Regulators of cell death, Trends Genet., 11: 101–105, 1995. [DOI] [PubMed] [Google Scholar]
  • 22. Joza N., Kroemer G., Penninger J.M., Genetic analysis of the mammalian cell death machinery, Trends Genet, 18: 142–149, 2002. [DOI] [PubMed] [Google Scholar]
  • 23. Huang D.C., Strasser A., BH3‐only proteins‐essential initiators of apoptotic cell death, Cell, 103: 839–842, 2000. [DOI] [PubMed] [Google Scholar]
  • 24. Kloppel G., Maillet B., Pathology of acute and chronic pancreatitis, Pancreas, 8: 659–670, 1993. [DOI] [PubMed] [Google Scholar]
  • 25. Nevalainen T.J, Aho H.J., Standards of morphological evaluation and histological grading in experimental acute pancreatitis, Eur. J. Surg. Res., 24(Suppl): 14–23, 1992. [DOI] [PubMed] [Google Scholar]
  • 26. Walker N.I., Ultrastructure of rat pancreas after experimental duct ligation. I. The role of apoptosis and interepithelial macrophages in acinar cell deletion, Am. J. Pathol., 126: 439–541, 1987. [PMC free article] [PubMed] [Google Scholar]
  • 27. Walker N.I., Winterford C.M., Kerr J.F.R., Ultrastructure of rat pancreas after experimental duct ligation. II. Duct and stromal cell proliferation, differentiation, and deletion, Pancreas, 7: 420–434, 1992. [DOI] [PubMed] [Google Scholar]
  • 28. Gukovskaya A.S., Perkins P., Zaninovic V., Sandoval D., Rutherford R., Fitzsimmons T., Pandol S.J., Poucell‐Hatton S., Mechanisms of cell death after pancreatic duct obstruction in the opossum and the rat. Gastroenterology, 110: 875–884, 1996. [DOI] [PubMed] [Google Scholar]
  • 29. Kaiser A.M., Saluja A.K., Sengupta A., Saluja M., Steer M.L., Relationship between severity, necrosis, and apoptosis in five models of experimental acute pancreatitis, Am. J. Physiol., 269 C1295–1304, 1995. [DOI] [PubMed] [Google Scholar]
  • 30. Beil M., Leser J., Lutz M.P., Gukovskaya A., Seufferlein T., Lynch G., Pandol S.J., Adler G., Caspase 8‐mediated cleavage of plectin precedes F‐actin breakdown in acinar cells during pancreatitis, Am. J. Physiol. Gastrointest. Liver Physiol., 282:G450–G460, 2002. [DOI] [PubMed] [Google Scholar]
  • 31. Song J.Y., Lim J.W., Kim H., Morio T., Kim K.H., Oxidative stress induces nuclear loss of DNA repair proteins Ku70 and Ku80 and apoptosis in pancreatic acinar AR42J cells, J. Biol. Chem., 278: 36676–36687, 2003. [DOI] [PubMed] [Google Scholar]
  • 32. Gukovskaya A.S., Gukovsky I., Jung Y., Mouria M., Pandol S.J. Cholecystokinin induces caspase activation and mitochondrial dysfunction in pancreatic acinar cells. Roles in cell injury processes of pancreatitis, J. Biol. Chem., 277: 22595–604, 2002. [DOI] [PubMed] [Google Scholar]
  • 33. Gomez G., Lee H.M., He Q., Englander E.W., Uchida T., Greeley G.H. Jr., Acute pancreatitis signals activation of apoptosis‐associated and survival genes in mice, Exp. Biol. Med., 226: 692–700, 2001. [DOI] [PubMed] [Google Scholar]
  • 34. Tomasini R., Samir A.A., Vaccaro M.I., Pebusque M.J., Dagorn J.C., Iovanna J.L., Dusetti N.J., Molecular and functional characterization of the stress‐induced protein (SIP) gene and its two transcripts generated by alternative splicing. SIP induced by stress and promotes cell death, J. Biol. Chem., 276: 44185–44192, 2001. [DOI] [PubMed] [Google Scholar]
  • 35. Yuan Y., Gong Z., Lou K., Tu S., Di Z., Xu J., Effects and mechanisms of somatostatin analogs on apoptosis of pancreatic acinar cells in acute pancreatitis in mice, J. Gastroenterol. Hepatol., 16: 683–688, 2001. [DOI] [PubMed] [Google Scholar]
  • 36. Gukovsky I., Gukovskaya A.S., Blinman T.A., Zaninovic V., Pandol S.J., Early NF‐kappaB activation is associated with hormone‐induced pancreatitis, Am. J. Physiol., 275:G1402–G1414, 1998. [DOI] [PubMed] [Google Scholar]
  • 37. Fujimoto K., Hosotani R., Doi R., Wada M., Lee J.U., Koshiba T., Miyamoto Y., Imamura M., Role of neutrophils in cerulein‐induced pancreatitis in rats: possible involvement of apoptosis, Digestion, 58: 421–430, 1997. [DOI] [PubMed] [Google Scholar]
  • 38. Rau B., Paszkowski A., Esber S., Gansauge F., Poch B., Beger H.G., Moller P., Anti‐ICAM‐1 antibody modulates late onset of acinar cell apoptosis and early necrosis in taurocholate‐induced experimental acute pancreatitis, Pancreas, 23: 80–88, 2001. [DOI] [PubMed] [Google Scholar]
  • 39. Gukovskaya A.S., Gukovsky I., Zaninovic V., Song M., Sandoval D., Gukovsky S., Pandol S.J., Pancreatic acinar cells produce, release, and respond to tumor necrosis factoralpha. Role in regulating cell death and pancreatitis, J. Clin. Invest., 100: 1853–1862, b1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Monks T.J., Hanzlik R.P., Cohen G.M., Ross D., Graham D.G., Quinone chemistry and toxicity, Toxicol. Appl. Pharmacol., 112: 2–16, 1992. [DOI] [PubMed] [Google Scholar]
  • 41. Gerasimenko J.V., Gerasimenko O.V., Palejwala A., Tepikin A.V., Petersen O.H., Watson A.J., Menadione‐induced apoptosis: roles of cytosolic Ca2+ elevations and the mitochondrial permeability transition pore, J. Cell. Sci., 115: 485–497, 2002. [DOI] [PubMed] [Google Scholar]
  • 42. Niedoborski T.E., Klein B.P., Wallig M.A., Rapid isolation and purification of 1‐cyano‐2‐hydroxy‐3‐butene (crambene) from Crambe abyssinica seed meal using immiscible solvent extraction and high‐performance liquid chromatography, J. Agric. Food Chem., 49: 3594–3599, 2001. [DOI] [PubMed] [Google Scholar]
  • 43. Wallig M.A., Kingston S., Staack R., Jefferey E.H., Induction of rat pancreatic glutathione S‐transferase and quinone reductase activities by a mixture of glucosinolate breakdown derivatives found in Brussels sprouts, Food Chem Toxicol., 36: 365–373, 1998. [DOI] [PubMed] [Google Scholar]
  • 44. Jarrell V.L., Epps D., Wallig M.A., Jeffery E.H., Antiproliferative effects of crambene, a nitrile common in cruciferous vegetables, FASEB J., 13:A918, 1999. (Abstract). [Google Scholar]
  • 45. Bhatia M., Wallig M.A., Hofbauer B., Lee H.S., Frossard J.L., Steer M.L., Saluja A.K., Induction of apoptosis in pancreatic acinar cells reduces the severity of acute pancreatitis, Biochem. Biophys. Res. Commun., 246: 476–483, 1998. [DOI] [PubMed] [Google Scholar]
  • 46. Bhatia M., Wallig M.A., 1‐Cyano‐2‐hydroxy‐3‐butene: A plant nitrile that induces apoptosis in pancreatic acinar cells and reduces the severity of acute pancreatitis In ‘Novel Compounds from Natural Products in the New Millennium: Potential and Challenges' (World Scientific Publishing Co; ). 2004; pp 92–99. [Google Scholar]
  • 47. Frossard J.L., Rubbia‐Brandt L., Wallig M.A., Benathan M., Ott T., Morel P., Hadengue A., Suter S., Willecke K., Chanson M., Severe acute pancreatitis and reduced acinar cell apoptosis in the exocrine pancreas of mice deficient for the Cx32 gene, Gastroenterology, 124: 481–493, 2003. [DOI] [PubMed] [Google Scholar]
  • 48. Hahm K.B., Kim J.H., You B.M., Kim Y.S., Cho S.W., Yim H., Ahn B.O., Kim W.B., Induction of apoptosis with an extract of Artemisia asiatica attenuates the severity of ceruleininduced pancreatitis in rats, Pancreas, 17: 153–157, 1998. [DOI] [PubMed] [Google Scholar]

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