Pathogenic mechanisms of acute pancreatitis

Current Opinion in Gastroenterology

Volumn 28, Issue 5, 2012, Pages 507-515

  Sah, Raghuwansh P ^a   Garg, Pramod ^a   Saluja, Ashok K ^a  

^a UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

acute pancreatitis; autodigestion; NFkB; trypsin

Indexed keywords

CALCIUM ION; HYDROLASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LYSOSOMAL MEMBRANE PROTEIN 2; LYSOSOME ENZYME; SNARE PROTEIN; TRYPSIN; TRYPSINOGEN; UNCLASSIFIED DRUG;

ACINAR CELL; ACUTE PANCREATITIS; AUTOLYSOSOME; AUTOPHAGY; CALCIUM SIGNALING; ENDOPLASMIC RETICULUM STRESS; ENZYME RELEASE; HUMAN; INFLAMMATION; INFLAMMATORY CELL; LYSOSOME; MITOCHONDRION; NONHUMAN; OXIDATIVE STRESS; PANCREAS SECRETION; PATHOGENESIS; REVIEW; SIGNAL TRANSDUCTION;

ACINAR CELLS; ANIMALS; AUTOPHAGY; CALCIUM; HUMANS; INFLAMMASOMES; MITOCHONDRIA; NF-KAPPA B; PANCREATITIS; TRYPSINOGEN;

EID: 84865521139     PISSN: 02671379     EISSN: 15317056     Source Type: Journal    
DOI: 10.1097/MOG.0b013e3283567f52     Document Type: Review

References (102)

1. Chiari H. About the digestion of the human pancreas (in German). ZeitschriftfürHeilkunde 1896; 17:69-96.
2. Saluja A, Hashimoto S, Saluja M, et al. Subcellular redistribution of lysosomal enzymes during caerulein-induced pancreatitis. Am J Physiol 1987; 253 (4 Pt 1):G508-G516.
3. Saluja AK, Bhagat L, Lee HS, et al. Secretagogue-induced digestive enzyme activation and cell injury in rat pancreatic acini. Am J Physiol 1999; 276 (4 Pt 1):G835-G842. (Pubitemid 29214095)
4. Lerch MM, Gorelick FS. Early trypsinogen activation in acute pancreatitis. Med Clin North Am 2000; 84:549-563; viii. (Pubitemid 30346151)
5. Saluja AK, Lerch MM, Phillips PA, Dudeja V. Why does pancreatic overstimulation cause pancreatitis? Annu Rev Physiol 2007; 69:249-269. (Pubitemid 46457643)
6. Gorelick FS, Thrower E. The acinar cell and early pancreatitis responses. Clin Gastroenterol Hepatol 2009; 7 (11 Suppl):S10-S14.
7. Sah RP, Saluja A. Molecular mechanisms of pancreatic injury. Curr Opin Gastroenterol 2011; 27:444-451.
8. 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; 141:2210-2217; e2.
9. Whitcomb DC, Lowe ME. Human pancreatic digestive enzymes. Dig Dis Sci 2007; 52:1-17.
10. Saluja A, Saluja M, Villa A, et al. Pancreatic duct obstruction in rabbits causes digestive zymogen and lysosomal enzyme colocalization. J Clin Invest 1989; 84:1260-1266. (Pubitemid 19247599)
11. Perides G, Laukkarinen JM, Vassileva G, Steer ML. Biliary acute pancreatitis in mice is mediated by the G-protein-coupled cell surface bile acid receptor Gpbar1. Gastroenterology 2010; 138:715-725.
12. Willemer S, Kloppel G, Kern HF, Adler G. Immunocytochemical and morphometric analysis of acinar zymogen granules in human acute pancreatitis. Virchows Arch A Pathol Anat Histopathol 1989; 415:115-123. (Pubitemid 19170559)
13. Ji B, Gaiser S, Chen X, et al. Intracellular trypsin induces pancreatic acinar cell death but not NF-kappaB activation. J Biol Chem 2009; 284:17488-17498.
14. Gaiser S, Daniluk J, Liu Y, et al. Intracellular activation of trypsinogen in transgenic mice induces acute but not chronic pancreatitis. Gut 2011; 60:1379-1388.
15. Sah RP, Saluja AK. Trypsinogen activation in acute and chronic pancreatitis: is it a prerequisite? Gut 2011; 60:1305-1307.
16. Van Acker GJ, Saluja AK, Bhagat L, et al. Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity. Am J Physiol Gastrointest Liver Physiol 2002; 283:G794-G800. (Pubitemid 34920370)
17. Van Acker GJ, Weiss E, Steer ML, Perides G. Cause-effect relationships between zymogen activation and other early events in secretagogue-induced acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2007; 292:G1738-G1746. (Pubitemid 47080596)
18. Halangk W, Lerch MM, Brandt-Nedelev B, et al. Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J Clin Invest 2000; 106:773-781.
19. Singh VP, Saluja AK, Bhagat L, et al. Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis. J Clin Invest 2001; 108:1387-1395.
20. Singh VP, Bren GD, Algeciras-Schimnich A, et al. Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis. Am J Physiol Gastrointest Liver Physiol 2009; 296:G1040-G1046.
21. Gukovsky I, Gukovskaya AS, Blinman TA, et al. Early NF-kappaB activation is associated with hormone-induced pancreatitis. Am J Physiol 1998; 275 (6 Pt 1):G1402-G1414.
22. Hietaranta AJ, Saluja AK, Bhagat L, et al. Relationship between NF-kappaB and trypsinogen activation in rat pancreas after supramaximal caerulein stimulation. Biochem Biophys Res Commun 2001; 280:388-395. (Pubitemid 32917525)
23. Han B, Ji B, Logsdon CD. CCK independently activates intracellular trypsinogen and NF-kappaB in rat pancreatic acinar cells. Am J Physiol Cell Physiol 2001; 280:C465-C472.
24. Tando Y, Algul H, Schneider G, et al. Induction of IkappaB-kinase by cholecystokinin is mediated by trypsinogen activation in rat pancreatic lobules. Digestion 2002; 66:237-245. (Pubitemid 36578774)
25. Rakonczay Z Jr, Hegyi P, Takacs T, et al. The role of NF-kappaB activation in the pathogenesis of acute pancreatitis. Gut 2008; 57:259-267. (Pubitemid 351158056)
26. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336:1066-1071. (Pubitemid 27163860)
27. Wong ET, Tergaonkar V. Roles of NF-kappaB in health and disease: mechanisms and therapeutic potential. Clin Sci (Lond) 2009; 116:451-465.
28. Baumann B, Wagner M, Aleksic T, et al. Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo. J Clin Invest 2007; 117:1502-1513. (Pubitemid 46871335)
29. Chen X, Ji B, Han B, et al. NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response. Gastroenterology 2002; 122:448-457. (Pubitemid 34116996)
30. Altavilla D, Famulari C, Passaniti M, et al. Attenuated cerulein-induced pancreatitis in nuclear factor-kappaB-deficient mice. Lab Invest 2003; 83:1723-1732. (Pubitemid 38018535)
31. Algul H, Treiber M, Lesina M, et al. Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis. J Clin Invest 2007; 117:1490-1501. (Pubitemid 46871334)
32. Treiber M, Neuhofer P, Anetsberger E, et al. Myeloid, but not pancreatic, RelA/p65 is required for fibrosis in a mouse model of chronic pancreatitis. Gastroenterology 2011; 141:1473-1485; 85e1-85e7.
33. Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 2009; 27:693-733.
34. Mazzon E, Impellizzeri D, Di Paola R, et al. Effects of mitogen-activated protein kinase signaling pathway inhibition on the development of ceruleininduced acute pancreatitis in mice. Pancreas 2012; 41:560-570.
35. Clemons AP, Holstein DM, Galli A, Saunders C. Cerulein-induced acute pancreatitis in the rat is significantly ameliorated by treatment with MEK1/2 inhibitors U0126 and PD98059. Pancreas 2002; 25:251-259.
36. Namkung W, Yoon JS, Kim KH, Lee MG. PAR2 exerts local protection against acute pancreatitis via modulation of MAP kinase and MAP kinase phosphatase signaling. Am J Physiol Gastrointest Liver Physiol 2008; 295:G886-G894.
37. Ju KD, Yu JH, Kim H, Kim KH. Role of mitogen-activated protein kinases, NFkappaB, and AP-1 on cerulein-induced IL-8 expression in pancreatic acinar cells. Ann N Y Acad Sci 2006; 1090:368-374. (Pubitemid 47092142)
38. Liu M, Shi L, Chen M, et al. Effects of c-Jun N-terminal kinase signaling pathway on severe acute pancreatitis-associated lung injury. Pancreas 2012; 41:358-366.
39. Yun SW, Bae GS, Kim MS, et al. Melittin inhibits cerulein-induced acute pancreatitis via inhibition of the JNK pathway. Int Immunopharmacol 2011; 11:2062-2072.
40. Chen P, Huang L, Zhang Y, et al. The antagonist of the JAK-1/STAT-1 signaling pathway improves the severity of cerulein-stimulated pancreatic injury via inhibition of NF-kappaB activity. Int J Mol Med 2011; 27:731-738.
41. Chen P, Huang L, Sun Y, Yuan Y. Upregulation of PIAS1 protects against sodium taurocholate-induced severe acute pancreatitis associated with acute lung injury. Cytokine 2011; 54:305-314.
42. Huang LY, Chen P, Xu LX, et al. Fractalkine upregulates inflammation through CX3CR1 and the Jak-Stat pathway in severe acute pancreatitis rat model. Inflammation 2012; 35:1023-1030.
43. Vaquero E, Gukovsky I, Zaninovic V, et al. Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis. Am J Physiol Gastrointest Liver Physiol 2001; 280:G1197-G1208.
44. Adcock IM. Transcription factors as activators of gene transcription: AP-1 and NF-kappa B. Monaldi Arch Chest Dis 1997; 52:178-186. (Pubitemid 27308290)
45. Tando Y, Algul H, Wagner M, et al. Caerulein-induced NF-kappaB/Rel activation requires both Ca2+ and protein kinase C as messengers. Am J Physiol 1999; 277 (3 Pt 1):G678-G686. (Pubitemid 29458242)
46. Yuan J, Liu Y, Tan T, et al. Protein kinase d regulates cell death pathways in experimental pancreatitis. Front Physiol 2012; 3:60.
47. Lee KP, Yuan JP, Hong JH, et al. An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs. FEBS Lett 2010; 584:2022-2027.
48. Liou J, Kim ML, Heo WD, et al. STIM is a Ca2+ sensor essential for Ca2+store- depletion-triggered Ca2+ influx. Curr Biol 2005; 15:1235-1241. (Pubitemid 40950523)
49. Wu MM, Buchanan J, Luik RM, Lewis RS. Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol 2006; 174:803-813. (Pubitemid 44373730)
50. Huang GN, Zeng W, Kim JY, et al. STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat Cell Biol 2006; 8:1003-1010. (Pubitemid 44314732)
51. Park CY, Hoover PJ, Mullins FM, et al. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 2009; 136:876-890.
52. Kim MS, Hong JH, Li Q, et al. Deletion of TRPC3 in mice reduces storeoperated Ca2+ influx and the severity of acute pancreatitis. Gastroenterology 2009; 137:1509-1517.
53. Kim MS, Lee KP, Yang D, et al. Genetic and pharmacologic inhibition of the Ca2+ influx channel TRPC3 protects secretory epithelia from Ca2+-dependent toxicity. Gastroenterology 2011; 140:2107-2115; 15e1-15e4.
54. Patel S, Muallem S. Acidic Ca(2+) stores come to the fore. Cell Calcium 2011; 50:109-112.
55. Patel S, Docampo R. Acidic calcium stores open for business: expanding the potential for intracellularCa2+signaling. TrendsCell Biol 2010; 20:277-286.
56. Petersen OH, Gerasimenko OV, Tepikin AV, Gerasimenko JV. Aberrant Ca(2+) signalling through acidic calcium stores in pancreatic acinar cells. Cell Calcium 2011; 50:193-199.
57. de Brito OM, Scorrano L. An intimate liaison: spatial organization of the endoplasmic reticulum-mitochondria relationship. EMBO J 2010; 29:2715-2723.
58. Hayashi T, Rizzuto R, Hajnoczky G, Su TP. MAM: more than just a housekeeper. Trends Cell Biol 2009; 19:81-88.
59. 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; 286:9136-9140.
60. Cancela JM, Van Coppenolle F, Galione A, et al. Transformation of local Ca2+ spikes to global Ca2+ transients: the combinatorial roles of multiple Ca2+ releasing messengers. EMBO J 2002; 21:909-919. (Pubitemid 34206164)
61. Patel S, Ramakrishnan L, Rahman T, et al. The endo-lysosomal system as an NAADP-sensitive acidic Ca(2+) store: role for the two-pore channels. Cell Calcium 2011; 50:157-167.
62. Straub SV, Giovannucci DR, Yule DI. Calcium wave propagation in pancreatic acinar cells: functional interaction of inositol 1,4,5-trisphosphate receptors, ryanodine receptors, and mitochondria. J Gen Physiol 2000; 116:547-560.
63. Petersen OH, Tepikin AV. Polarized calcium signaling in exocrine gland cells. Annu Rev Physiol 2008; 70:273-299. (Pubitemid 351738181)
64. Petersen OH. Ca2+ signalling and Ca2+-activated ion channels in exocrine acinar cells. Cell Calcium 2005; 38:171-200. (Pubitemid 41283258)
65. Mogami H, Nakano K, Tepikin AV, Petersen OH. Ca2+ flow via tunnels in polarized cells: recharging of apical Ca2+ stores by focal Ca2+ entry through basal membrane patch. Cell 1997; 88:49-55. (Pubitemid 27180330)
66. Gerasimenko OV, Gerasimenko JV, Rizzuto RR, et al. The distribution of the endoplasmic reticulum in living pancreatic acinar cells. Cell Calcium 2002; 32:261-268. (Pubitemid 36175749)
67. Gerasimenko JV, Flowerdew SE, Voronina SG, et al. Bile acids induce Ca2+ release from both the endoplasmic reticulum and acidic intracellular calcium stores through activation of inositol trisphosphate receptors and ryanodine receptors. J Biol Chem 2006; 281:40154-40163. (Pubitemid 46041820)
68. Gerasimenko JV, Lur G, Sherwood MW, et al. Pancreatic protease activation by alcohol metabolite depends on Ca2+ release via acid store IP3 receptors. Proc Natl Acad Sci U S A 2009; 106:10758-10763.
69. Gerasimenko JV, Sherwood M, Tepikin AV, et al. NAADP, cADPR and IP3 all release Ca2+ from the endoplasmic reticulum and an acidic store in the secretory granule area. J Cell Sci 2006; 119 (Pt 2):226-238. (Pubitemid 43210692)
70. Futatsugi A, Nakamura T, Yamada MK, et al. IP3 receptor types 2 and 3 mediate exocrine secretion underlying energy metabolism. Science 2005; 309:2232-2234. (Pubitemid 41396076)
71. Yule DI, Ernst SA, Ohnishi H, Wojcikiewicz RJ. Evidence that zymogen granules are not a physiologically relevant calcium pool. Defining the distribution of inositol 1,4,5-trisphosphate receptors in pancreatic acinar cells. J Biol Chem 1997; 272:9093-9098. (Pubitemid 27154912)
72. Muili KA, Ahmad M, Orabi AI, et al. Pharmacological and genetic inhibition of calcineurin protects against carbachol-induced pathological zymogen activation and acinar cell injury. Am J Physiol Gastrointest Liver Physiol 2012; 302:G898-G905.
73. Petersen OH, Gerasimenko OV, Gerasimenko JV. Pathobiology of acute pancreatitis: focus on intracellular calcium and calmodulin. F1000 Med Rep 2011; 3:15.
74. Gerasimenko JV, Lur G, Ferdek P, et al. Calmodulin protects against alcoholinduced pancreatic trypsinogen activation elicited via Ca2+ release through IP3 receptors. Proc Natl Acad Sci U S A 2011; 108:5873-5878.
75. Mukherjee R, Criddle DN, Gukovskaya A, et al. Mitochondrial injury in pancreatitis. Cell Calcium 2008; 44:14-23.
76. Gukovsky I, Pandol SJ, Mareninova OA, et al. Impaired autophagy and organellar dysfunction in pancreatitis. J Gastroenterol Hepatol 2012; 27 (Suppl 2):27-32.
77. Gukovsky I, Pandol SJ, Gukovskaya AS. Organellar dysfunction in the pathogenesis of pancreatitis. Antioxid Redox Signal 2011; 15:2699-2710.
78. Cardenas C, Miller RA, Smith I, et al. Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 2010; 142:270-283.
79. Pinton P, Giorgi C, Siviero R, et al. Calcium and apoptosis: ER-mitochondria Ca2+transfer in the control of apoptosis. Oncogene 2008; 27:6407-6418.
80. De Smedt H, Verkhratsky A, Muallem S. Ca(2+) signaling mechanisms of cell survival and cell death: an introduction. Cell Calcium 2011; 50:207-210.
81. Hashimoto D, Ohmuraya M, Hirota M, et al. Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells. J Cell Biol 2008; 181:1065-1072. (Pubitemid 351915482)
82. 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; 119:3340-3355.
83. 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; 286:8308-8324.
84. Lugea A, Waldron RT, French SW, Pandol SJ. Drinking and driving pancreatitis: links between endoplasmic reticulum stress and autophagy. Autophagy 2011; 7:783-785.
85. Decuypere JP, Bultynck G, Parys JB. A dual role for Ca(2+) in autophagy regulation. Cell Calcium 2011; 50:242-250.
86. Watanabe O, Baccino FM, Steer ML, Meldolesi J. Supramaximal caerulein stimulation and ultrastructure of rat pancreatic acinar cell: early morphological changes during development of experimental pancreatitis. Am J Physiol 1984; 246 (4 Pt 1):G457-G467. (Pubitemid 14143678)
87. Kloppel G, Dreyer T, Willemer S, et al. Human acute pancreatitis: its pathogenesis in the light of immunocytochemical and ultrastructural findings in acinar cells. Virchows Arch A Pathol Anat Histopathol 1986; 409:791-803. (Pubitemid 16044947)
88. Fortunato F, Burgers H, Bergmann F, et al. Impaired autolysosome formation correlates with Lamp-2 depletion: role of apoptosis, autophagy, and necrosis in pancreatitis. Gastroenterology 2009; 137:350-360; 60e1-60e5.
89. Cosen-Binker LI, Lam PP, Binker MG, Gaisano HY. Alcohol-induced protein kinase Calpha phosphorylation of Munc18c in carbachol-stimulated acini causes basolateral exocytosis. Gastroenterology 2007; 132:1527-1545. (Pubitemid 46627578)
90. Cosen-Binker LI, Lam PP, Binker MG, et al. Alcohol/cholecystokinin-evoked pancreatic acinar basolateral exocytosis is mediated by protein kinase C alpha phosphorylation of Munc18c. J Biol Chem 2007; 282:13047-13058. (Pubitemid 47100617)
91. Cosen-Binker LI, Binker MG, Wang CC, et al. VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis. J Clin Invest 2008; 118:2535-2551. (Pubitemid 351949781)
92. Gaisano HY, Gorelick FS. New insights into the mechanisms of pancreatitis. Gastroenterology 2009; 136:2040-2044.
93. Mashima H, Sato T, Horie Y, et al. Interferon regulatory factor-2 regulates exocytosis mechanisms mediated by SNAREs in pancreatic acinar cells. Gastroenterology 2011; 141:1102-1113; e1-e8.
94. Lugea A, Tischler D, Nguyen J, et al. Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage. Gastroenterology 2011; 140:987-997.
95. Escobar J, Pereda J, Lopez-Rodas G, Sastre J. Redox signaling and histone acetylation in acute pancreatitis. Free Radic Biol Med 2012; 52:819-837.
96. Escobar J, Pereda J, Arduini A, et al. Role of redox signaling, protein phosphatases and histone acetylation in the inflammatory cascade in acute pancreatitis. Therapeutic implications. Inflamm Allergy Drug Targets 2010; 9:97-108.
97. Escobar J, Pereda J, Arduini A, et al. Cross-talk between oxidative stress and pro-inflammatory cytokines in acute pancreatitis: a key role for protein phosphatases. Curr Pharm Des 2009; 15:3027-3042.
98. Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature 2012; 481:278-286.
99. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009; 27:229-265.
100. Piccinini AM, Midwood KS. DAMPening inflammation by modulating TLR signalling. Mediators Inflamm 2010; 2010. pii: 672395. [Epub 13 July 2010]
101. Leemans JC, Cassel SL, Sutterwala FS. Sensing damage by the NLRP3 inflammasome. Immunol Rev 2011; 243:152-162.
102. Hoque R, Sohail M, Malik A, et al. TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastroenterology 2011; 141:358-369.