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Pathophysiological mechanisms in acute pancreatitis: Current understanding

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Abstract

The precise mechanisms involved in the pathophysiology of acute pancreatitis (AP) are still far from clear. Several earlier studies have focused mainly on pancreatic enzyme activation as the key intracellular perturbation in the pancreatic acinar cells. For decades, the trypsin-centered hypothesis has remained the focus of the intra-acinar events in acute pancreatitis. Recent advances in basic science research have lead to the better understanding of various other mechanisms such as oxidative and endoplasmic stress, impaired autophagy, mitochondrial dysfunction, etc. in causing acinar cell injury. Despite all efforts, the clinical outcome of patients with AP has not changed significantly over the years. This suggests that the knowledge of the critical molecular pathways in the pathophysiology of AP is still limited. The mechanisms through which the acinar cell injury leads to local and systemic inflammation are not well understood. The role of inflammatory markers and immune system activation is an area of much relevance from the point of view of finding a target for therapeutic intervention. Some data are available from experimental animal models but not much is known in human pancreatitis. This review intends to highlight the current understanding in this area.

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References

  1. Isenmann R, Beger HG. Natural history of acute pancreatitis and the role of infection. Best Pract Res Clin Gastroenterol. 1999;13:291–301.

    Article  CAS  Google Scholar 

  2. Forsmark CE, Baillie J. AGA Institute technical review on acute pancreatitis. Gastroenterology. 2007;132:2022–44.

    Article  CAS  PubMed  Google Scholar 

  3. Chiari H. About the digestion of the human pancreas (in German). ZeitschriftfuHeilkunde. 1896;17:69–96.

    Google Scholar 

  4. Lerch MM, Gorelick FS. Early trypsinogen activation in acute pancreatitis. Med Clin North Am. 2000;84:549–63.

    Article  CAS  PubMed  Google Scholar 

  5. Saluja AK, Lerch MM, Phillips PA, Dudeja V. Why does pancreatic overstimulation cause pancreatitis? Annu Rev Physiol. 2007;69:249–69.

    Article  CAS  PubMed  Google Scholar 

  6. Cosen-Binker LI, Gaisano HY. Recent insights into the cellular mechanisms of acute pancreatitis. Can J Gastroenterol. 2007;21:19–24.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hashimoto D, Ohmuraya M, Hirota M, et al. Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells. J Cell Biol. 2008;181:1065–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sharma M, Banerjee D, Garg PK. Characterization of newer subgroups of fulminant and subfulminant pancreatitis associated with a high early mortality. Am J Gastroenterol. 2007;102:2688–95.

    Article  PubMed  Google Scholar 

  9. Gaiser S, Daniluk J, Liu Y, et al. Intracellular activation of trypsinogen in transgenic mice induces acute but not chronic pancreatitis. Gut. 2011;60:1379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dawra R, Sah RP, Dudeja V, et al. Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis. Gastroenterology. 2011;141:2210–7. e2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Criddle DN, Gerasimenko JV, Baumgartner HK, et al. Calcium signalling and pancreatic cell death: apoptosis or necrosis? Cell Death Differ. 2007;14:1285–94.

    Article  CAS  PubMed  Google Scholar 

  12. Petersen OH. Ca2+ induced pancreatic cell death: roles of the endoplasmic reticulum, zymogen granules, lysosomes and endosomes. J Gastroenterol Hepatol. 2008;23 Suppl 1:S31–6.

    Article  CAS  PubMed  Google Scholar 

  13. Sutton R, Criddle D, Raraty MG, Tepikin A, Neoptolemos JP, Petersen OH. Signal transduction, calcium and acute pancreatitis. Pancreatology. 2003;3:497–505.

  14. Husain SZ, Prasad P, Grant WM, Kolodecik TR, Nathanson MH, Gorelick FS. The ryanodine receptor mediates early zymogen activation in pancreatitis. Proc Natl Acad Sci U S A. 2005;102:14386–91.

  15. Cahalan MD. STIMulating store-operated Ca(2+) entry. Nat Cell Biol. 2009;11:669–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee KP, Yuan JP, Hong JH, So I, Worley PF, Muallem S. An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs. FEBS Lett. 2010;584:2022–27.

  17. Orabi AI, Shah AU, Ahmad MU, et al. Dantrolene mitigates caerulein-induced pancreatitis in vivo in mice. Am J Physiol Gastrointest Liver Physiol. 2010;299:G196–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim MS, Lee KP, Yang D, et al. Genetic and pharmacologic inhibitionof the Ca2+ influx channel TRPC3 protects secretory epithelia from Ca2+ dependent toxicity. Gastroenterology. 2011;140:2107–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Calcraft PJ, Ruas M, Pan Z, et al. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature. 2009;459:596–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ogunbayo OA, Zhu Y, Rossi D, et al. Cyclic adenosine diphosphate ribose activates ryanodine receptors, whereas NAADP activates two-pore domain channels. J Biol Chem. 2011;286:9136–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Voronina SG, Barrow SL, Simpson AW, et al. Dynamic changes in cytosolic and mitochondrial ATP levels in pancreatic acinar cells. Gastroenterology. 2010;138:1976–87.

    Article  CAS  PubMed  Google Scholar 

  22. Saluja AK, Donovan EA, Yamanaka K, Yamaguchi Y, Hofbauer B, Steer ML. Caerulein induced in vitro activation of trypsinogen in rat pancreatic aciniis mediated by cathepsin B. Gastroenterology. 1997;113:304–10.

  23. Meister T, Niehues R, Hahn D, et al. Missorting of cathepsin B into the secretory compartment of CI-MPR/IGFII-deficient mice does not induce spontaneous trypsinogen activation but leads to enhanced trypsin activity during experimental pancreatitis without affecting disease severity. J Physiol Pharmacol. 2010;61:565–75.

    CAS  PubMed  Google Scholar 

  24. Behrendorff N, Floetenmeyer M, Schwiening C, Thorn P. Protons released during pancreatic acinar cell secretion acidify the lumen and contribute to pancreatitis in mice. Gastroenterology. 2010;139:1711–20.

    Article  CAS  PubMed  Google Scholar 

  25. Waterford SD, Kolodecik TR, Thrower EC, Gorelick FS. Vacuolar ATPase regulates zymogen activation in pancreatic acini. J Biol Chem. 2005;280:5430–4.

    Article  CAS  PubMed  Google Scholar 

  26. Reed AM, Husain SZ, Thrower E, et al. Low extracellular pH induces damage in the pancreatic acinar cell by enhancing calcium signaling. J Biol Chem. 2010;286:1919–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Grasso D, Ropolo A, Lo Re A, et al. Zymophagy, a novel selective autophagy pathway mediated by VMP1-USP9x-p62, prevents pancreatic cell death. J Biol Chem. 2011;286:8308–24.

    Article  CAS  PubMed  Google Scholar 

  28. Mareninova OA, Hermann K, French SW, et al. Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis. J Clin Invest. 2009;119:3340–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Jacob TG, Vipin IS, Roy TS, Garg PK. Electron-microscopic evidence of mitochondriae containing macroautophagy in experimental acute pancreatitis: implications for cell death. Pancreatology. 2014;14:433–5.

    Article  Google Scholar 

  30. Sanfey H, Bulkley GB, Cameron JL. The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis. Ann Surg. 1984;200:405–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sweiry JH, Mann GE. Role of oxidative stress in the pathogenesis of acute pancreatitis. Scand J Gastroenterol Suppl. 1996;219:10–5.

    Article  CAS  PubMed  Google Scholar 

  32. Tsai K, Wang SS, Chen TS, et al. Oxidative stress: an important phenomenon with pathogenetic significance in the progression of acute pancreatitis. Gut. 1998;42:850–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chan YC, Leung PS. Angiotensin-II type 1 receptor-dependent nuclear factor-kβ activation mediated proinflammatory actions in a rat model of obstructive acute pancreatitis. J Pharmacol Exp Ther. 2007;323:10–8.

    Article  CAS  PubMed  Google Scholar 

  34. Escobar J, Pereda J, Lopez-Rodas G, Sastre J. Redox signaling and histone acetylation in acute pancreatitis. Free Radic Biol Med. 2012;52:819–37.

    Article  CAS  PubMed  Google Scholar 

  35. Ushio-Fukai M. Compartmentalization of redox signalling through NADPH oxidase-derived ROS. Antioxid Redox Signal. 2009;11:1289–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gukovskaya AS, Vaquero E, Zaninovic V, et al. Neutrophils and NADPH oxidase mediate intrapancreatic trypsin activation in murine experimental acute pancreatitis. Gastroenterology. 2002;122:974–84.

    Article  CAS  PubMed  Google Scholar 

  37. Booth DM, Murphy JA, Mukherjee R, et al. Reactive oxygen species induced by bile acid induce apoptosis and protect against necrosis in pancreatic acinar cells. Gastroenterology. 2011;140:2116–25.

    Article  CAS  PubMed  Google Scholar 

  38. Schoenberg MH, Buchler M, Gaspar M, et al. Oxygen free radicals in acute pancreatitis of the rat. Gut. 1990;31:1138–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Abu-Zidan FM, Bonham MJ, Windsor JA. Severity of acute pancreatitis: a multivariate analysis of oxidative stress markers and modified Glasgow criteria. Br J Surg. 2000;87:1019–23.

    Article  CAS  PubMed  Google Scholar 

  40. Jones DP. Redefining oxidative stress. Antioxid Redox Signal. 2006;8:1865–79.

    Article  CAS  PubMed  Google Scholar 

  41. Alsfasser G, Gock M, Herzog L, et al. Glutathione depletion with L-buthionine-(S, R)-sulfoximine demonstrates deleterious effects in acute pancreatitis of the rat. Dig Dis Sci. 2002;47:1793–9.

    Article  CAS  PubMed  Google Scholar 

  42. Neuschwander-Tetri BA, Ferrell LD, Sukhabote RJ, Grendell JH. Glutathione monoethyl ester ameliorates caerulein-induced pancreatitis in the mouse. J Clin Invest. 1992;89:109–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schulz HU, Niederau C, Klonowski-Stumpe H, Halangk W, Luthen R, Lippert H. Oxidative stress in acute pancreatitis. Hepatol Gastroenterol. 1999;46:2736–50.

  44. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP and ROS: a mitochondrial love-hate triangle. Am J Physiol-Cell Physiol. 2004;287:C817–33.

    Article  CAS  PubMed  Google Scholar 

  45. Pantano C, Reynaert NL, van der Vliet A, Janssen-Heininger YM. Redox-sensitive kinases of the nuclear factor-kappa β signalling pathway. Antioxid Redox Signal. 2006;8:1791–806.

    Article  CAS  PubMed  Google Scholar 

  46. Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappa β and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. 2006;291:L46–57.

    Article  CAS  PubMed  Google Scholar 

  47. Mukherjee R, Criddle DN, Gukovskaya A, Pandol S, Petersen OH, Sutton R. Mitochondrial injury in pancreatitis. Cell Calcium. 2008;44:14–23.

  48. de Brito OM, Scorrano L. An intimate liaison: spatial organization of the endoplasmic reticulum-mitochondria relationship. EMBO J. 2010;29:2715–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Cardenas C, Miller RA, Smith I, et al. Essential regulation of cell bioenergetics by constitutive Ins P3 receptor Ca2+ transfer to mitochondria. Cell. 2010;142:270–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pinton P, Giorgi C, Siviero R, ecchini E, Rizzuto R. Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene. 2008;27:6407–18.

  51. Szmola R, Sahin-Toth M. Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells. Gut. 2009;59:365–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Lugea A, Tischler D, Nguyen J, et al. Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage. Gastroenterology. 2011;140:987–97.

    Article  CAS  PubMed  Google Scholar 

  53. Malo A, Kruger B, Seyhun E, et al. Tauro ursodeoxycholic acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini. Am J Physiol Gastrointest Liver Physiol. 2010;299:G877–86.

    Article  CAS  PubMed  Google Scholar 

  54. Ye R, Mareninova OA, Barron E, et al. Grp78 heterozygosity regulates chaperone balance in exocrine pancreas with differential response to caerulein-induced acute pancreatitis. Am J Pathol. 2010;177:2827–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gukovsky I, Gukovskaya AS, Blinman TA, Zaninovic V, Pandol SJ. Early NF-kappaβ activation is associated with hormone-induced pancreatitis. Am J Physiol. 1998;275:G1402–14.

  56. Rakonczay Z Jr, Hegyi P, Takacs T, Saluja AK. The role of NF-kβ activation in the pathogenesis of acute pancreatitis. Gut. 2008;57:259–67.

    Article  CAS  PubMed  Google Scholar 

  57. Hietaranta AJ, Saluja AK, Bhagat L, Singh VP, Song AM, Steer ML. Relationship between NF-kappaβ and trypsinogen activation in rat pancreas after supra maximal caerulein stimulation. Biochem Biophys Res Commun. 2001;280:388–95.

  58. Barnes PJ, Karin M. Nuclear factor-kappa β: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997;336:1066–71.

    Article  CAS  PubMed  Google Scholar 

  59. Satoh A, Gukovskaya AS, Nieto JMC, et al. PKC-delta and epsilon regulate NF-kappaβ activation induced by cholecystokinin and TNF alpha in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol. 2004;287:G582–91.

    Article  CAS  PubMed  Google Scholar 

  60. Hietaranta AJ, Singh VP, Bhagat L, et al. Water immersion stress prevents caerulein-induced pancreatic acinar cell NF-kappa β activation by attenuating caerulein-induced intracellular Ca2+ changes. J Biol Chem. 2001;276:18742–7.

    Article  CAS  PubMed  Google Scholar 

  61. Gukovskaya AS, Mouria M, Gukovsky I, et al. Ethanol metabolism and transcription factor activation in pancreatic acinar cells in rats. Gastroenterology. 2002;122:106–18.

    Article  CAS  PubMed  Google Scholar 

  62. Bhatia M, Brady M, Shokuhi S, Christmas S, Neoptolemos JP, Slavin J. Inflammatory mediators in acute pancreatitis. J Pathol. 2000;190:117–25.

  63. Lin Y, Lin LJ, Jin Y, et al. Correlation between serum levels of high mobility group box-1 protein and pancreatitis: a meta-analysis. Biomed Res Int. 2015;2015:430185.

    PubMed  PubMed Central  Google Scholar 

  64. Wang W, Faubel S, Ljubanovic D, et al. Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice. Am J Physiol Renal Physiol. 2005;288:F997–1004.

    Article  CAS  PubMed  Google Scholar 

  65. Zhang XH, Zhu RM, Xu WA, Wan HJ, Lu H. Therapeutic effects of caspase-1 inhibitors on acute lung injury in experimental severe acute pancreatitis. World J Gastroenterol. 2007;13:623–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lampel M, Kern HF. Acute interstitial pancreatitis in the rat induced by excessive doses of a pancreatic secretagogue. Virchows Arch A Pathol Anat Histol. 1977;2:97–117.

    Article  Google Scholar 

  67. Grady T, Liang P, Ernst SA, Logsdon CD. Chemokine gene expression in rat pancreatic acinar cells is an early event associated with acute pancreatitis. Gastroenterology. 1997;6:1966–75.

    Article  Google Scholar 

  68. Demols A, Le Moine O, Desalle F, Quertinmont E, Van Laethem JL, Devière J. CD4+ T cells play an important role in acute experimental pancreatitis in mice. Gastroenterology. 2000;3:582–90.

  69. Pietruczuk M, Dabrowska MI, Wereszczynska-Siemiatkowska U, Dabrowski A. Alteration of peripheral blood lymphocyte subsets in acute pancreatitis. World J Gastroenterol. 2006;12:5344–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Telek G, Ducroc R, Scoazec JY, Pasquier C, Feldmann G, Roze C. Differential up-regulation of cellular adhesion molecules at the sites of oxidative stress in experimental acute pancreatitis. J Surg Res. 2001;1:56–67.

    Article  CAS  Google Scholar 

  71. Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C. JAM-1 is a ligand of the β2-integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002;2:151–8.

    Article  CAS  Google Scholar 

  72. Santoso S, Sachs UJ, Kroll H, et al. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med. 2002;5:679–91.

    Article  CAS  Google Scholar 

  73. Powell JJ, Siriwardena AK, Fearon KC, Ross JA. Endothelial derived selectins in the development of organ dysfunction in acute pancreatitis. Crit Care Med. 2001;3:567–72.

    Article  Google Scholar 

  74. Hartwig W, Werner J, Warshaw AL, et al. Membrane-bound ICAM-1 is up-regulated by trypsin and contributes to leukocyte migration in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2004;287:G1194–9.

    Article  CAS  PubMed  Google Scholar 

  75. Zhang XP, Wang L, Zhou YF. The pathogenic mechanism of severe acute pancreatitis complicated with renal injury: a review of current knowledge. Dig Dis Sci. 2008;53:297–306.

    Article  PubMed  Google Scholar 

  76. Bhatia M, Neoptolemos JP, Slavin J. Inflammatory mediators as therapeutic targets in acute pancreatitis. Curr Opin Investig Drugs. 2001;2:496–501.

    CAS  PubMed  Google Scholar 

  77. Dambrauskas Z, Giese N, Gulbinas A, et al. Different profiles of cytokine expression during mild and severe acute pancreatitis. World J Gastroenterol. 2010;16:1845–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sathyanarayan G, Garg PK, Prasad HK, Tandon RK. Elevated level of interleukin-6 predicts organ failure and severe disease in patients with acute pancreatitis. J Gastroenterol Hepatol. 2007;22:550–4.

    Article  CAS  PubMed  Google Scholar 

  79. Zhang H, Neuhöfer P, Song L, et al. IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. J Clin Invest. 2013;123:1019–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol. 2004;202:145–56.

    Article  CAS  PubMed  Google Scholar 

  81. Bhatia M, Wong FL, Cao Y, et al. Pathophysiology of acute pancreatitis. Pancreatology. 2005;5:132–44.

    Article  PubMed  Google Scholar 

  82. Norman JG, Fink GW, Franz MG. Acute pancreatitis induces intrapancreatic tumor necrosis factor gene expression. Arch Surg. 1995;130:966–70.

    Article  CAS  PubMed  Google Scholar 

  83. Fink GW, Norman JG. Specific changes in the pancreatic expression of the interleukin 1 family of genes during experimental acute pancreatitis. Cytokine. 1997;9:1023–7.

    Article  CAS  PubMed  Google Scholar 

  84. Suzuki S, Miyasaka K, Jimi A, Funakoshi A. Induction of acute pancreatitis by cerulein in human IL-6 gene transgenic mice. Pancreas. 2000;21:86–92.

    Article  CAS  PubMed  Google Scholar 

  85. Botoi G, Andercou A. Interleukin 17-prognostic marker of severe acute pancreatitis. Chirurgia (Bucur). 2009;104:431–8.

    CAS  Google Scholar 

  86. Perejaslov A, Chooklin S, Bihalskyy I. Implication of interleukin 18 and intercellular adhesion molecule (ICAM)-1 in acute pancreatitis. Hepatogastroenterology. 2008;55:1806–13.

    CAS  PubMed  Google Scholar 

  87. Calandra T, Echtenacher B, Le Roy D, et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med. 2000;6:164–70.

    Article  CAS  PubMed  Google Scholar 

  88. Rau B, Steinbach G, Gansauge F, Mayer JM, Grunert A, Beger HG. The potential role of procalcitonin and interleukin 8 in the prediction of infected necrosis in acute pancreatitis. Gut. 1997;41:832–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Shokuhi S, Bhatia M, Christmas S, Sutton R, Neoptolemos JP, Slavin J. Levels of the chemokines growth-related oncogene alpha and epithelial neutrophil-activating protein 78 are raised in patients with severe acute pancreatitis. Br J Surg. 2002;89:566–72.

    Article  CAS  PubMed  Google Scholar 

  90. Rau B, Baumgart K, Kruger CM, Schilling M, Beger HG. CC-chemokine activation in acute pancreatitis: enhanced release of monocyte chemoattractant protein-1 in patients with local and systemic complications. Intensive Care Med. 2003;29:622–9.

    Article  PubMed  Google Scholar 

  91. Gerard C, Frossard JL, Bhatia M, Saluja A, Lu B, Steer ML. Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. J Clin Invest. 1997;100:2022–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Konturek SJ, Dembinski A, Konturek PJ, Warzecha Z, Jaworek J, Gustaw P. Role of platelet activating factor in pathogenesis of acute pancreatitis in rats. Gut. 1992;33:1268–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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;95:4760–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bhatia M, Wong FL, Fu D, Lau HY, Moochhala SM, Moore PK. Role of hydrogen sulfide in acute pancreatitis and associated lung injury. FASEB J. 2005;19:623–5.

    CAS  PubMed  Google Scholar 

  95. Bhatia M, Saluja AK, Hofbauer B, Steer ML. Neutral endopeptidase (NEP) plays an anti-inflammatory role in acute pancreatitis and pancreatitis-associated lung injury. Pancreas. 1997;15:428.

    Google Scholar 

  96. Simovic MO, Bonham MJD, Abu-Zidan FM, Windsor JA. Anti-inflammatory cytokine response and clinical outcome in acute pancreatitis. Crit Care Med. 1999;27:2662–5.

    Article  CAS  PubMed  Google Scholar 

  97. Bhatia M, Singh VP, Frossard JL, Lee HS, Gerard C, Steer ML. Complement factor C5a exerts an anti-inflammatory effect in acute pancreatitis and associated lung injury. Am J Physiol Gastrointest Liver Physiol. 2001;280:G974–8.

    CAS  PubMed  Google Scholar 

  98. Cuthbertson CM, Christophi C. Disturbances of the microcirculation in acute pancreatitis. Br J Surg. 2006;93:518–30.

    Article  CAS  PubMed  Google Scholar 

  99. Pitkaranta P, Kivisaari L, Nordling S, Nuutinen P, Schroder T. Vascular changes of pancreatic ducts and vessels in acute necrotizing, and in chronic pancreatitis in humans. Int J Pancreatol. 1991;8:13–22.

    CAS  PubMed  Google Scholar 

  100. Foitzik T, Eibl G, Hotz HG, Faulhaber J, Kirchengast M, Buhr HJ. Endothelin receptor blockade in severe acute pancreatitis leads to systemic enhancement of microcirculation, stabilization of capillary permeability, and improved survival rates. Surgery. 2000;128:399–407.

    Article  CAS  PubMed  Google Scholar 

  101. Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med. 2007;35:1599–608.

    Article  PubMed  Google Scholar 

  102. Salomone T, Tosi P, Palareti G, et al. Coagulative disorders in human acute pancreatitis: role for the D-dimer. Pancreas. 2003;26:111–6.

    Article  CAS  PubMed  Google Scholar 

  103. Dixon B. The role of microvascular thrombosis in sepsis. Anaesth Intensive Care. 2004;32:619–29.

    CAS  PubMed  Google Scholar 

  104. Radenkovic D, Bajec D, Ivancevic N, et al. D-dimer in acute pancreatitis: a new approach for an early assessment of organ failure. Pancreas. 2009;38:655–60.

    Article  CAS  PubMed  Google Scholar 

  105. Bleeker WK, Agterberg J, Rigter G, Hack CE, Gool JV. Protective effect of antithrombin III in acute experimental pancreatitis in rats. Dig Dis Sci. 1992;37:280–5.

    Article  CAS  PubMed  Google Scholar 

  106. Hackert T, Werner J, Gebhard MM, Klar E. Effects of heparin in experimental models of acute pancreatitis and post-ERCP pancreatitis. Surgery. 2004;135:131–8.

    Article  PubMed  Google Scholar 

  107. Farrant GJ, Abu-Zidan FM, Liu X, Delahunt B, Zwi LJ, Windsor JA. The impact of intestinal ischaemia-reperfusion on caerulein induced edematous experimental pancreatitis. Eur Surg Res. 2003;35:395–400.

    Article  CAS  PubMed  Google Scholar 

  108. Juvonen PO, Tenhunen JJ, Heino AA, et al. Splanchnic tissue perfusion in acute experimental pancreatitis. Scand J Gastroenterol. 1999;34:308–14.

    Article  CAS  PubMed  Google Scholar 

  109. Flint RS, Windsor JA. The role of the intestine in the pathophysiology and management of severe acute pancreatitis. HPB (Oxford). 2003;5:69–85.

    Article  CAS  Google Scholar 

  110. Wu LM, Sankaran SJ, Plank LD, Windsor JA, Petrov MS. Meta-analysis of gut barrier dysfunction in patients with acute pancreatitis. Br J Surg. 2014;101:1644–56.

    Article  CAS  PubMed  Google Scholar 

  111. Ammori BJ. Role of the gut in the course of severe acute pancreatitis. Pancreas. 2003;26:122–9.

    Article  PubMed  Google Scholar 

  112. Fritz S, Hackert T, Hartwig W, et al. Bacterial translocation and infected pancreatic necrosis in acute necrotizing pancreatitis derives from small bowel rather than from colon. Am J Surg. 2010;200:111–7.

    Article  PubMed  Google Scholar 

  113. Garg PK, Khanna S, Bohidar NP, Kapil A, Tandon RK. Incidence, spectrum, and antibiotic sensitivity pattern of bacterial infections among patients with acute pancreatitis. J Gastroenterol Hepatol. 2001;16:1055–9.

    Article  CAS  PubMed  Google Scholar 

  114. Mentula P, Kylänpää ML, Kemppainen E, et al. Plasma anti-inflammatory cytokines and monocyte human leucocyte antigen-DR expression in patients with acute pancreatitis. Scand J Gastroenterol. 2004;39:178–87.

    Article  CAS  PubMed  Google Scholar 

  115. Beger HG, Bittner R, Block S, Buchler M. Bacterial contamination of pancreatic necrosis. A prospective clinical study. Gastroenterology. 1986;91:433–8.

    Article  CAS  PubMed  Google Scholar 

  116. Finfer SR, Vincent JL. Severe sepsis and septic shock. N Engl J Med. 2013;369:840–51.

    Article  CAS  Google Scholar 

  117. Mentula P, Kylänpää-Bäck ML, Kemppainen E, et al. Decreased HLA (human leucocyte antigen)-DR expression on peripheral blood monocytes predicts the development of organ failure in patients with acute pancreatitis. Clin Sci (Lond). 2003;105:409–17.

    Article  CAS  Google Scholar 

  118. Lindström O, Kylänpää ML, Mentula P, et al. Upregulated but insufficient generation of activated protein C is associated with development of multiorgan failure in severe acute pancreatitis. Crit Care. 2006;10:R16.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Gotzinger P, Sautner T, Kriwanek S, et al. Surgical treatment for severe acute pancreatitis: extent and surgical control of necrosis determine outcome. World J Surg. 2002;26:474–8.

    Article  PubMed  Google Scholar 

  120. Bai Y, Gao J, Zou DW, Li ZS. Prophylactic antibiotics cannot reduce infected pancreatic necrosis and mortality in acute necrotizing pancreatitis: evidence from a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2008;103:104–10.

    Article  PubMed  Google Scholar 

  121. Li JY, Yu T, Chen GC, et al. Enteral nutrition within 48 hours of admission improves clinical outcomes of acute pancreatitis by reducing complications: a meta-analysis. PLoS One. 2013;8, e64926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Goldberg RF, Austen WG Jr, Zhang X, et al. Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition. Proc Natl Acad Sci U S A. 2008;105:3551–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Premkumar R, Phillips AR, Petrov MS, Windsor JA. The clinical relevance of obesity in acute pancreatitis: targeted systematic reviews. Pancreatology. 2015;15:25–33.

    Article  PubMed  Google Scholar 

  124. Yashima Y, Isayama H, Tsujino T, et al. A large volume of visceral adipose tissue leads to severe acute pancreatitis. J Gastroenterol. 2011;46:1213–8.

    Article  PubMed  Google Scholar 

  125. Noel P, Patel K, Durgampudi C, et al. Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections. Gut. 2016;65:100–11.

    Article  CAS  PubMed  Google Scholar 

  126. Patel K, Trivedi RN, Durgampudi C, et al. Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation. Am J Pathol. 2015;185:808–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Balog A, Gyulai Z, Boros LG, et al. Polymorphism of the TNF-alpha, HSP70-2, and CD14 genes increases susceptibility to severe acute pancreatitis. Pancreas. 2005;30:e46–50.

    Article  PubMed  Google Scholar 

  128. Papachristou GI, Sass DA, Avula H, et al. Is the monocyte chemotactic protein-1 -2518 G allele a risk factor for severe acute pancreatitis? Clin Gastroenterol Hepatol. 2005;3:475–81.

    Article  CAS  PubMed  Google Scholar 

  129. Johnson CD, Kingsnorth AN, Imrie CW, et al. Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut. 2001;48:62–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371:651–9.

    Article  PubMed  Google Scholar 

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  1. Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India

    Pankaj Singh & Pramod Kumar Garg

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  1. Pankaj Singh
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  2. Pramod Kumar Garg
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Correspondence to Pramod Kumar Garg.

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Singh, P., Garg, P.K. Pathophysiological mechanisms in acute pancreatitis: Current understanding. Indian J Gastroenterol 35, 153–166 (2016). https://doi.org/10.1007/s12664-016-0647-y

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