Acknowledgments
Funding: VPS was supported by DK092460, DK100358 (NIH) and the PR151612 by the department of Army
(DOA). PKG received funding from Indian Council of Medical Research for pancreatitis related research projects.
Biography
References:
1. Xiao AY, Tan ML, Wu LM, et al. Global incidence and mortality of pancreatic diseases: a systematic
review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol
Hepatol 2016;1:45–55. [PubMed: 28404111]
2. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis--2012: revision of the
Atlanta classification and definitions by international consensus. Gut 2013;62:102–11. [PubMed:
23100216]
3. Garg PK, Madan K, Pande GK, et al. Association of extent and infection of pancreatic necrosis with
organ failure and death in acute necrotizing pancreatitis. Clin Gastroenterol Hepatol 2005;3:159–66.
[PubMed: 15704050]
4. Johnson CD, Abu-Hilal M. Persistent organ failure during the first week as a marker of fatal
outcome in acute pancreatitis. Gut 2004;53:1340–4. [PubMed: 15306596]
5. Mofidi R, Duff MD, Wigmore SJ, et al. Association between early systemic inflammatory response,
severity of multiorgan dysfunction and death in acute pancreatitis. The British journal of surgery
2006;93:738–44. [PubMed: 16671062]
6. Shen HN, Lu CL. Incidence, resource use, and outcome of acute pancreatitis with/without intensive
care: a nationwide population-based study in Taiwan. Pancreas 2011;40:10–5. [PubMed: 20938365]
7. Hamada S, Masamune A, Kikuta K, et al. Nationwide epidemiological survey of acute pancreatitis
in Japan. Pancreas 2014;43:1244–8. [PubMed: 25084001]
8. Kamal A, Sinha A, Hutfless SM, et al. Hospital admission volume does not impact the in-hospital
mortality of acute pancreatitis. HPB (Oxford) 2017;19:21–28. [PubMed: 27887788]
9. Padhan RK, Jain S, Agarwal S, et al. Primary and Secondary Organ Failures Cause Mortality
Differentially in Acute Pancreatitis and Should be Distinguished. Pancreas 2018;47:302–307.
[PubMed: 29401171]
10. Schepers NJ, Bakker OJ, Besselink MG, et al. Impact of characteristics of organ failure and
infected necrosis on mortality in necrotising pancreatitis. Gut 2018.
Garg and Singh
Page 13
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
11. Lowenfels AB, Maisonneuve P, Sullivan T. The changing character of acute pancreatitis:
epidemiology, etiology, and prognosis. Curr Gastroenterol Rep 2009;11:97–103. [PubMed:
19281696]
12. Carvalho JR, Fernandes SR, Santos P, et al. Acute pancreatitis in the elderly: a cause for increased
concern? Eur J Gastroenterol Hepatol 2018;30:337–341. [PubMed: 29189393]
13. Sternby H, Bolado F, Canaval-Zuleta HJ, et al. Determinants of Severity in Acute Pancreatitis: A
Nation-wide Multicenter Prospective Cohort Study. Ann Surg 2018.
14. Krishna SG, Hinton A, Oza V, et al. Morbid Obesity Is Associated With Adverse Clinical
Outcomes in Acute Pancreatitis: A Propensity-Matched Study. Am J Gastroenterol
2015;110:1608–19. [PubMed: 26482857]
15. Yoon SB, Choi MH, Lee IS, et al. Impact of body fat and muscle distribution on severity of acute
pancreatitis. Pancreatology 2017;17:188–193. [PubMed: 28190685]
16. Navina S, Acharya C, DeLany JP, et al. Lipotoxicity causes multisystem organ failure and
exacerbates acute pancreatitis in obesity. Sci Transl Med 2011;3:107ra110.
17. 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. [PubMed: 25500204]
18. Nawaz H, Koutroumpakis E, Easler J, et al. Elevated serum triglycerides are independently
associated with persistent organ failure in acute pancreatitis. Am J Gastroenterol 2015;110:1497–
503. [PubMed: 26323188]
19. Isenmann R, Rau B, Beger HG. Early severe acute pancreatitis: characteristics of a new subgroup.
Pancreas 2001;22:274–8. [PubMed: 11291929]
20. Tenner S, Sica G, Hughes M, et al. Relationship of necrosis to organ failure in severe acute
pancreatitis. Gastroenterology 1997;113:899–903. [PubMed: 9287982]
21. Lankisch PG, Pflichthofer D, Lehnick D. No strict correlation between necrosis and organ failure
in acute pancreatitis. Pancreas 2000;20:319–22. [PubMed: 10766460]
22. Isenmann R, Rau B, Beger HG. Bacterial infection and extent of necrosis are determinants of organ
failure in patients with acute necrotizing pancreatitis. Br J Surg 1999;86:1020–4. [PubMed:
10460637]
23. Singh P, Garg PK. Pathophysiological mechanisms in acute pancreatitis: Current understanding.
Indian J Gastroenterol 2016;35:153–66. [PubMed: 27206712]
24. Mole DJ, McClymont KL, Lau S, et al. Discrepancy between the extent of pancreatic necrosis and
multiple organ failure score in severe acute pancreatitis. World J Surg 2009;33:2427–32. [PubMed:
19641951]
25. Sah RP, Garg P, Saluja AK. Pathogenic mechanisms of acute pancreatitis. Curr Opin Gastroenterol
2012;28:507–15. [PubMed: 22885948]
26. de-Madaria E, Martinez J, Sempere L, et al. Cytokine genotypes in acute pancreatitis: association
with etiology, severity, and cytokine levels in blood. Pancreas 2008;37:295–301. [PubMed:
18815552]
27. Bishehsari F, Sharma A, Stello K, et al. TNF-alpha gene (TNFA) variants increase risk for multi-
organ dysfunction syndrome (MODS) in acute pancreatitis. Pancreatology 2012;12:113–8.
[PubMed: 22487520]
28. Yang Z, Qi X, Wu Q, et al. Lack of association between TNF-alpha gene promoter polymorphisms
and pancreatitis: a meta-analysis. Gene 2012;503:229–34. [PubMed: 22579868]
29. Chen WC, Nie JS. Genetic polymorphism of MCP-1-2518, IL-8-251 and susceptibility to acute
pancreatitis: a pilot study in population of Suzhou, China. World J Gastroenterol 2008;14:5744–8.
[PubMed: 18837094]
30. 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. [PubMed:
15880317]
31. 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. [PubMed: 17662103]
Garg and Singh
Page 14
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
32. Wig JD, Bharathy KG, Kochhar R, et al. Correlates of organ failure in severe acute pancreatitis.
JOP 2009;10:271–5. [PubMed: 19454818]
33. Mole DJ, Olabi B, Robinson V, et al. Incidence of individual organ dysfunction in fatal acute
pancreatitis: analysis of 1024 death records. HPB (Oxford) 2009;11:166–70. [PubMed: 19590643]
34. Chandra S, Murali A, Bansal R, et al. The Bedside Index for Severity in Acute Pancreatitis: a
systematic review of prospective studies to determine predictive performance. J Community Hosp
Intern Med Perspect 2017;7:208–213. [PubMed: 29046745]
35. Wu BU, Johannes RS, Sun X, et al. The early prediction of mortality in acute pancreatitis: a large
population-based study. Gut 2008;57:1698–703. [PubMed: 18519429]
36. Parniczky A, Kui B, Szentesi A, et al. Prospective, Multicentre, Nationwide Clinical Data from 600
Cases of Acute Pancreatitis. PLoS One 2016;11:e0165309. [PubMed: 27798670]
37. Sathyanarayan G, Garg PK, Prasad H, et al. Elevated level of interleukin-6 predicts organ failure
and severe disease in patients with acute pancreatitis. J Gastroenterol Hepatol 2007;22:550–4.
[PubMed: 17376050]
38. Mofidi R, Duff MD, Wigmore SJ, et al. Association between early systemic inflammatory
response, severity of multiorgan dysfunction and death in acute pancreatitis. Br J Surg
2006;93:738–44. [PubMed: 16671062]
39. Singh VK, Wu BU, Bollen TL, et al. Early systemic inflammatory response syndrome is associated
with severe acute pancreatitis. Clin Gastroenterol Hepatol 2009;7:1247–51. [PubMed: 19686869]
40. Jain S, Midha S, Mahapatra SJ, et al. Interleukin-6 significantly improves predictive value of
systemic inflammatory response syndrome for predicting severe acute pancreatitis. Pancreatology
2018.
41. Garret C, Peron M, Reignier J, et al. Risk factors and outcomes of infected pancreatic necrosis:
Retrospective cohort of 148 patients admitted to the ICU for acute pancreatitis. United European
Gastroenterol J 2018;6:910–918.
42. Thandassery RB, Yadav TD, Dutta U, et al. Hypotension in the first week of acute pancreatitis and
APACHE II score predict development of infected pancreatic necrosis. Dig Dis Sci 2015;60:537–
42. [PubMed: 24623313]
43. Petrov MS, Shanbhag S, Chakraborty M, et al. Organ failure and infection of pancreatic necrosis as
determinants of mortality in patients with acute pancreatitis. Gastroenterology 2010;139:813–20.
[PubMed: 20540942]
44. Deng LH, Xue P, Xia Q, et al. Effect of admission hypertriglyceridemia on the episodes of severe
acute pancreatitis. World J Gastroenterol 2008;14:4558–61. [PubMed: 18680239]
45. Lloret Linares C, Pelletier AL, Czernichow S, et al. Acute pancreatitis in a cohort of 129 patients
referred for severe hypertriglyceridemia. Pancreas 2008;37:13–2. [PubMed: 18580438]
46. Wang Y, Sternfeld L, Yang F, et al. Enhanced susceptibility to pancreatitis in severe
hypertriglyceridaemic lipoprotein lipase-deficient mice and agonist-like function of pancreatic
lipase in pancreatic cells. Gut 2009;58:422–30. [PubMed: 18936103]
47. 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 2014.
48. 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. The American journal of pathology 2015;185:808–19. [PubMed: 25579844]
49. Durgampudi C, Noel P, Patel K, et al. Acute Lipotoxicity Regulates Severity of Biliary Acute
Pancreatitis without Affecting Its Initiation. The American journal of pathology 2014;184:1773–
84. [PubMed: 24854864]
50. Song AM, Bhagat L, Singh VP, et al. Inhibition of cyclooxygenase-2 ameliorates the severity of
pancreatitis and associated lung injury. Am J Physiol Gastrointest Liver Physiol 2002;283:G1166–
74. [PubMed: 12381531]
51. Hofbauer B, Saluja AK, Bhatia M, et al. Effect of recombinant platelet-activating factor
acetylhydrolase on two models of experimental acute pancreatitis. Gastroenterology
1998;115:1238–47. [PubMed: 9797380]
Garg and Singh
Page 15
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
52. Bhatia M, Saluja AK, Hofbauer B, et al. The effects of neutrophil depletion on a completely
noninvasive model of acute pancreatitis-associated lung injury. Int J Pancreatol 1998;24:77–83.
[PubMed: 9816540]
53. Navina S, Acharya C, DeLany JP, et al. Lipotoxicity causes multisystem organ failure and
exacerbates acute pancreatitis in obesity. Science translational medicine 2011;3:107ra110.
54. Matthay MA, Zemans RL. The acute respiratory distress syndrome: pathogenesis and treatment.
Annu Rev Pathol 2011;6:147–63. [PubMed: 20936936]
55. Wu BU, Johannes RS, Sun X, et al. Early changes in blood urea nitrogen predict mortality in acute
pancreatitis. Gastroenterology 2009;137:129–35. [PubMed: 19344722]
56. Geokas MC, Rinderknecht H, Brodrick JW, et al. Studies on the ascites fluid of acute pancreatitis
in man. Am J Dig Dis 1978;23:182–8. [PubMed: 623083]
57. Buchler M, Malfertheiner P, Uhl W, et al. [Gabexate mesilate in the therapy of acute pancreatitis.
Multicenter study of tolerance of a high intravenous dose (4 g/day)]. Medizinische Klinik
1988;83:320–4, 352. [PubMed: 3135470]
58. Berling R, Borgstrom A, Ohlsson K. Peritoneal lavage with aprotinin in patients with severe acute
pancreatitis. Effects on plasma and peritoneal levels of trypsin and leukocyte proteases and their
major inhibitors. Int J Pancreatol 1998;24:9–17. [PubMed: 9746884]
59. Renner IG, Rinderknecht H, Douglas AP. Profiles of pure pancreatic secretions in patients with
acute pancreatitis: the possible role of proteolytic enzymes in pathogenesis. Gastroenterology
1978;75:1090–8. [PubMed: 710862]
60. Chiari H Ueber Selbstverdauung des menschlichen Pankreas. Zeitschrift für Heilkunde
1896;17:69–96.
61. Jobling JW, Petersen W, Eggstein AA. Serum Ferments and Antiferment during Trypsin Shock :
Studies on Ferment Action. Xxii. J Exp Med 1915;22:141–53. [PubMed: 19867906]
62. Tagnon HJ. The Nature of the Mechanism of the Shock Produced by the Injection of Trypsin and
Thrombin. J Clin Invest 1945;24:1–10. [PubMed: 16695179]
63. 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. [PubMed: 19436232]
64. Easler J, Muddana V, Furlan A, et al. Portosplenomesenteric venous thrombosis in patients with
acute pancreatitis is associated with pancreatic necrosis and usually has a benign course. Clin
Gastroenterol Hepatol 2014;12:854–62. [PubMed: 24161350]
65. Hartwig W, Werner J, Jimenez RE, et al. Trypsin and activation of circulating trypsinogen
contribute to pancreatitis-associated lung injury. Am J Physiol 1999;277:G1008–16. [PubMed:
10564107]
66. Singh VP, Bhagat L, Navina S, et al. Protease-activated receptor-2 protects against pancreatitis by
stimulating exocrine secretion. Gut 2007;56:958–64. [PubMed: 17114298]
67. Namkung W, Han W, Luo X, et al. Protease-activated receptor 2 exerts local protection and
mediates some systemic complications in acute pancreatitis. Gastroenterology 2004;126:1844–59.
[PubMed: 15188179]
68. Andriulli A, Caruso N, Quitadamo M, et al. Antisecretory vs. antiproteasic drugs in the prevention
of post-ERCP pancreatitis: the evidence-based medicine derived from a meta-analysis study. JOP :
Journal of the pancreas 2003;4:41–8. [PubMed: 12555015]
69. Andriulli A, Leandro G, Clemente R, et al. Meta-analysis of somatostatin, octreotide and gabexate
mesilate in the therapy of acute pancreatitis. Alimentary pharmacology & therapeutics
1998;12:237–45. [PubMed: 9570258]
70. Asang E [Changes in the therapy of inflammatory diseases of the pancreas. A report on 1 year of
therapy and prophylaxis with the kallikrein- and trypsin inactivator trasylol (Bayer)]. Langenbecks
Arch Klin Chir Ver Dtsch Z Chir 1960;293:645–70. [PubMed: 13794633]
71. Buchler M, Malfertheiner P, Uhl W, et al. Gabexate mesilate in human acute pancreatitis. German
Pancreatitis Study Group. Gastroenterology 1993;104:1165–70. [PubMed: 8462805]
72. Chen HM, Chen JC, Hwang TL, et al. Prospective and randomized study of gabexate mesilate for
the treatment of severe acute pancreatitis with organ dysfunction. Hepato-gastroenterology
2000;47:1147–50. [PubMed: 11020900]
Garg and Singh
Page 16
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
73. Park KT, Kang DH, Choi CW, et al. Is high-dose nafamostat mesilate effective for the prevention
of post-ERCP pancreatitis, especially in high-risk patients? Pancreas 2011;40:1215–9. [PubMed:
21775918]
74. Seta T, Noguchi Y, Shimada T, et al. Treatment of acute pancreatitis with protease inhibitors: a
meta-analysis. Eur J Gastroenterol Hepatol 2004;16:1287–93. [PubMed: 15618834]
75. Trapnell JE, Rigby CC, Talbot CH, et al. Proceedings: Aprotinin in the treatment of acute
pancreatitis. Gut 1973;14:828.
76. Trapnell JE, Rigby CC, Talbot CH, et al. A controlled trial of Trasylol in the treatment of acute
pancreatitis. The British journal of surgery 1974;61:177–82. [PubMed: 4595174]
77. Trapnell JE, Talbot CH, Capper WM. Trasylol in acute pancreatitis. The American journal of
digestive diseases 1967;12:409–12. [PubMed: 5336018]
78. Rebours V, Boutron-Ruault MC, Jooste V, et al. Mortality rate and risk factors in patients with
hereditary pancreatitis: uni- and multidimensional analyses. The American journal of
gastroenterology 2009;104:2312–7. [PubMed: 19550412]
79. Nakae Y, Hayakawa T, Kondo T, et al. Serum alpha 2-macroglobulin-trypsin complex and early
recognition of severe acute pancreatitis after endoscopic retrograde pancreatography. J
Gastroenterol Hepatol 1994;9:272–6. [PubMed: 7519897]
80. McMahon MJ, Bowen M, Mayer AD, et al. Relation of alpha 2-macroglobulin and other
antiproteases to the clinical features of acute pancreatitis. Am J Surg 1984;147:164–70. [PubMed:
6197893]
81. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the
use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee.
American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644–
55. [PubMed: 1303622]
82. Keck T, Balcom JHt, Fernandez-del Castillo C, et al. Matrix metalloproteinase-9 promotes
neutrophil migration and alveolar capillary leakage in pancreatitis-associated lung injury in the rat.
Gastroenterology 2002;122:188–201. [PubMed: 11781293]
83. Inoue S, Nakao A, Kishimoto W, et al. Anti-neutrophil antibody attenuates the severity of acute
lung injury in rats with experimental acute pancreatitis. Arch Surg 1995;130:93–8. [PubMed:
7802585]
84. Telek G, Ducroc R, Scoazec JY, et al. Differential upregulation of cellular adhesion molecules at
the sites of oxidative stress in experimental acute pancreatitis. J Surg Res 2001;96:56–67.
[PubMed: 11180997]
85. Powell JJ, Siriwardena AK, Fearon KC, et al. Endothelial-derived selectins in the development of
organ dysfunction in acute pancreatitis. Crit Care Med 2001;29:567–72. [PubMed: 11373422]
86. Wetterholm E, Linders J, Merza M, et al. Platelet-derived CXCL4 regulates neutrophil infiltration
and tissue damage in severe acute pancreatitis. Transl Res 2016;176:105–18. [PubMed: 27183218]
87. Lira SA. Genetic approaches to study chemokine function. Journal of leukocyte biology
1996;59:45–52. [PubMed: 8558066]
88. Mehrad B, Wiekowski M, Morrison BE, et al. Transient lung-specific expression of the chemokine
KC improves outcome in invasive aspergillosis. American journal of respiratory and critical care
medicine 2002;166:1263–8. [PubMed: 12403697]
89. Tsai WC, Strieter RM, Wilkowski JM, et al. Lung-specific transgenic expression of KC enhances
resistance to Klebsiella pneumoniae in mice. Journal of immunology 1998;161:2435–40.
90. Cryz SJ Jr., Furer E, Germanier R. Simple model for the study of Pseudomonas aeruginosa
infections in leukopenic mice. Infect Immun 1983;39:1067–71. [PubMed: 6404816]
91. Uchida K, Yamamoto Y, Klein TW, et al. Granulocyte-colony stimulating factor facilitates the
restoration of resistance to opportunistic fungi in leukopenic mice. J Med Vet Mycol 1992;30:293–
300. [PubMed: 1279154]
92. Wang E, Simard M, Ouellet N, et al. Pathogenesis of pneumococcal pneumonia in
cyclophosphamide-induced leukopenia in mice. Infect Immun 2002;70:4226–38. [PubMed:
12117931]
Garg and Singh
Page 17
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
93. Merza M, Hartman H, Rahman M, et al. Neutrophil Extracellular Traps Induce Trypsin Activation,
Inflammation, and Tissue Damage in Mice With Severe Acute Pancreatitis. Gastroenterology
2015;149:1920–1931 e8. [PubMed: 26302488]
94. Leppkes M, Maueroder C, Hirth S, et al. Externalized decondensed neutrophil chromatin occludes
pancreatic ducts and drives pancreatitis. Nat Commun 2016;7:10973. [PubMed: 26964500]
95. Bicker KL, Thompson PR. The protein arginine deiminases: Structure, function, inhibition, and
disease. Biopolymers 2013;99:155–63. [PubMed: 23175390]
96. Wang Y, Li M, Stadler S, et al. Histone hypercitrullination mediates chromatin decondensation and
neutrophil extracellular trap formation. J Cell Biol 2009;184:205–13. [PubMed: 19153223]
97. Lewis HD, Liddle J, Coote JE, et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and
human NET formation. Nat Chem Biol 2015;11:189–91. [PubMed: 25622091]
98. Bilyy R, Fedorov V, Vovk V, et al. Neutrophil Extracellular Traps Form a Barrier between Necrotic
and Viable Areas in Acute Abdominal Inflammation. Front Immunol 2016;7:424. [PubMed:
27777576]
99. Penttila AK, Rouhiainen A, Kylanpaa L, et al. Circulating nucleosomes as predictive markers of
severe acute pancreatitis. J Intensive Care 2016;4:14. [PubMed: 26893906]
100. Yasuda T, Ueda T, Takeyama Y, et al. Significant increase of serum high-mobility group box
chromosomal protein 1 levels in patients with severe acute pancreatitis. Pancreas 2006;33:359–
63. [PubMed: 17079940]
101. Lindstrom O, Tukiainen E, Kylanpaa L, et al. Circulating levels of a soluble form of receptor for
advanced glycation end products and high-mobility group box chromosomal protein 1 in patients
with acute pancreatitis. Pancreas 2009;38:e215–20. [PubMed: 19786934]
102. Liu T, Huang W, Szatmary P, et al. Accuracy of circulating histones in predicting persistent organ
failure and mortality in patients with acute pancreatitis. Br J Surg 2017.
103. Hoque R, Sohail M, Malik A, et al. TLR9 and the NLRP3 inflammasome link acinar cell death
with inflammation in acute pancreatitis. Gastroenterology 2011;141:358–69. [PubMed:
21439959]
104. Kang R, Zhang Q, Hou W, et al. Intracellular Hmgb1 inhibits inflammatory nucleosome release
and limits acute pancreatitis in mice. Gastroenterology 2014;146:1097–107. [PubMed:
24361123]
105. 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: 25695079]
106. Hoque R, Mehal WZ. Inflammasomes in pancreatic physiology and disease. Am J Physiol
Gastrointest Liver Physiol 2015;308:G643–51. [PubMed: 25700081]
107. Hoque R, Malik AF, Gorelick F, et al. Sterile inflammatory response in acute pancreatitis.
Pancreas 2012;41:353–7. [PubMed: 22415665]
108. Szatmary P, Liu T, Abrams ST, et al. Systemic histone release disrupts plasmalemma and
contributes to necrosis in acute pancreatitis. Pancreatology 2017;17:884–892. [PubMed:
29102149]
109. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation
of inflammatory caspases and processing of proIL-beta. Mol Cell 2002;10:417–26. [PubMed:
12191486]
110. Algaba-Chueca F, de-Madaria E, Lozano-Ruiz B, et al. The expression and activation of the
AIM2 inflammasome correlates with inflammation and disease severity in patients with acute
pancreatitis. Pancreatology 2017;17:364–371. [PubMed: 28342645]
111. Hirota M, Nozawa F, Okabe A, et al. Relationship between plasma cytokine concentration and
multiple organ failure in patients with acute pancreatitis. Pancreas 2000;21:141–6. [PubMed:
10975707]
112. Martin MA, Saracibar E, Santamaria A, et al. [Interleukin 18 (IL-18) and other immunological
parameters as markers of severity in acute pancreatitis]. Rev Esp Enferm Dig 2008;100:768–73.
[PubMed: 19222336]
113. Zhang XH, Li ML, Wang B, et al. Caspase-1 inhibition alleviates acute renal injury in rats with
severe acute pancreatitis. World J Gastroenterol 2014;20:10457–63. [PubMed: 25132762]
Garg and Singh
Page 18
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
114. Janiak A, Lesniowski B, Jasinska A, et al. Interleukin 18 as an early marker or prognostic factor
in acute pancreatitis. Prz Gastroenterol 2015;10:203–7. [PubMed: 26759626]
115. Yuan H, Jin X, Sun J, et al. Protective effect of HMGB1 a box on organ injury of acute
pancreatitis in mice. Pancreas 2009;38:143–8. [PubMed: 18665013]
116. Kang R, Chen R, Xie M, et al. The Receptor for Advanced Glycation End Products Activates the
AIM2 Inflammasome in Acute Pancreatitis. J Immunol 2016;196:4331–7. [PubMed: 27045109]
117. Sennello JA, Fayad R, Pini M, et al. Interleukin-18, together with interleukin-12, induces severe
acute pancreatitis in obese but not in nonobese leptin-deficient mice. Proc Natl Acad Sci U S A
2008;105:8085–90. [PubMed: 18515422]
118. Pini M, Sennello JA, Cabay RJ, et al. Effect of diet-induced obesity on acute pancreatitis induced
by administration of interleukin-12 plus interleukin-18 in mice. Obesity 2010;18:476–81.
[PubMed: 19696761]
119. Schaffler A, Hamer O, Dickopf J, et al. Admission resistin levels predict peripancreatic necrosis
and clinical severity in acute pancreatitis. The American journal of gastroenterology
2010;105:2474–84. [PubMed: 20648005]
120. Schaffler A, Hamer OW, Dickopf J, et al. Admission visfatin levels predict pancreatic and
peripancreatic necrosis in acute pancreatitis and correlate with clinical severity. Am J
Gastroenterol;106:957–67. [PubMed: 21245835]
121. Messmann H, Vogt W, Falk W, et al. Interleukins and their antagonists but not TNF and its
receptors are released in post-ERP pancreatitis. Eur J Gastroenterol Hepatol 1998;10:611–7.
[PubMed: 9855088]
122. Brivet FG, Emilie D, Galanaud P. Pro- and anti-inflammatory cytokines during acute severe
pancreatitis: an early and sustained response, although unpredictable of death. Parisian Study
Group on Acute Pancreatitis. Crit Care Med 1999;27:749–55. [PubMed: 10321665]
123. Dambrauskas Z, Giese N, Gulbinas A, et al. Different profiles of cytokine expression during mild
and severe acute pancreatitis. World J Gastroenterol;16:1845–53.
124. Aoun E, Chen J, Reighard D, et al. Diagnostic accuracy of interleukin-6 and interleukin-8 in
predicting severe acute pancreatitis: a meta-analysis. Pancreatology 2009;9:777–85. [PubMed:
20110745]
125. Amin M, Simerman A, Cho M, et al. 21-Hydroxylase-derived steroids in follicles of nonobese
women undergoing ovarian stimulation for in vitro fertilization (IVF) positively correlate with
lipid content of luteinized granulosa cells (LGCs) as a source of cholesterol for steroid synthesis.
The Journal of clinical endocrinology and metabolism 2014;99:1299–306. [PubMed: 24423334]
126. Regner S, Appelros S, Hjalmarsson C, et al. Monocyte chemoattractant protein 1, active
carboxypeptidase B and CAPAP at hospital admission are predictive markers for severe acute
pancreatitis. Pancreatology 2008;8:42–9. [PubMed: 18235216]
127. Daniel P, Lesniowski B, Mokrowiecka A, et al. Circulating levels of visfatin, resistin and pro-
inflammatory cytokine interleukin-8 in acute pancreatitis. Pancreatology : official journal of the
International Association of Pancreatology 2010;10:477–82.
128. Ueda T, Takeyama Y, Yasuda T, et al. Significant elevation of serum interleukin-18 levels in
patients with acute pancreatitis. J Gastroenterol 2006;41:158–65. [PubMed: 16568375]
129. 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. [PubMed: 20397261]
130. Batra S, Cai S, Balamayooran G, et al. Intrapulmonary administration of leukotriene B(4)
augments neutrophil accumulation and responses in the lung to Klebsiella infection in CXCL1
knockout mice. Journal of immunology 2012;188:3458–68.
131. Starkie R, Ostrowski SR, Jauffred S, et al. Exercise and IL-6 infusion inhibit endotoxin-induced
TNF-alpha production in humans. FASEB J 2003;17:884–6. [PubMed: 12626436]
132. Nieken J, Mulder NH, Buter J, et al. Recombinant human interleukin-6 induces a rapid and
reversible anemia in cancer patients. Blood 1995;86:900–5. [PubMed: 7542502]
133. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing
the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271–6. [PubMed:
15124018]
Garg and Singh
Page 19
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
134. Cuzzocrea S, Mazzon E, Dugo L, et al. Absence of endogenous interleukin-6 enhances the
inflammatory response during acute pancreatitis induced by cerulein in mice. Cytokine
2002;18:274–85. [PubMed: 12161103]
135. Guice KS, Oldham KT, Remick DG, et al. Anti-tumor necrosis factor antibody augments edema
formation in caerulein-induced acute pancreatitis. The Journal of surgical research 1991;51:495–
9. [PubMed: 1943086]
136. Wang LZ, Su JY, Lu CY, et al. Effects of recombinant human endothelial-derived interleukin-8 on
hemorrhagic shock in rats. Zhongguo Yao Li Xue Bao 1997;18:434–6. [PubMed: 10322935]
137. Morimoto K, Morimoto A, Nakamori T, et al. Cardiovascular responses induced in free-moving
rats by immune cytokines. J Physiol 1992;448:307–20. [PubMed: 1593469]
138. Wogensen L, Jensen M, Svensson P, et al. Pancreatic beta-cell function and interleukin-1 beta in
plasma during the acute phase response in patients with major burn injuries. Eur J Clin Invest
1993;23:311–9. [PubMed: 8354339]
139. Li S, Ballou LR, Morham SG, et al. Cyclooxygenase-2 mediates the febrile response of mice to
interleukin-1beta. Brain Res 2001;910:163–73. [PubMed: 11489266]
140. Bhargava R, Janssen W, Altmann C, et al. Intratracheal IL-6 protects against lung inflammation in
direct, but not indirect, causes of acute lung injury in mice. PloS one 2013;8:e61405. [PubMed:
23667439]
141. Hackert T, Werner J, Gebhard MM, et al. Effects of heparin in experimental models of acute
pancreatitis and post-ERCP pancreatitis. Surgery 2004;135:131–8. [PubMed: 14739847]
142. Emanuelli G, Montrucchio G, Gaia E, et al. Experimental acute pancreatitis induced by platelet-
activating factor in rabbits. Am J Pathol 1989;134:315–26. [PubMed: 2464939]
143. Prescott SM, Zimmerman GA, Stafforini DM, et al. Platelet-activating factor and related lipid
mediators. Annu Rev Biochem 2000;69:419–45. [PubMed: 10966465]
144. Seyfried CE, Schweickart VL, Godiska R, et al. The human platelet-activating factor receptor
gene (PTAFR) contains no introns and maps to chromosome 1. Genomics 1992;13:832–4.
[PubMed: 1322356]
145. Liu LR, Xia SH. Role of platelet-activating factor in the pathogenesis of acute pancreatitis. World
J Gastroenterol 2006;12:539–45. [PubMed: 16489665]
146. Ais G, Lopez-Farre A, Gomez-Garre DN, et al. Role of platelet-activating factor in hemodynamic
derangements in an acute rodent pancreatic model. Gastroenterology 1992;102:181–7. [PubMed:
1727752]
147. Zhou W, McCollum MO, Levine BA, et al. Role of platelet-activating factor in pancreatitis-
associated acute lung injury in the rat. Am J Pathol 1992;140:971–9. [PubMed: 1562055]
148. Leonhardt U, Fayyazzi A, Seidensticker F, et al. Influence of a platelet activating factor antagonist
on severe pancreatitis in two experimental models. Int J Pancreatol 1992;12:161–6. [PubMed:
1460331]
149. McKay CJ, Curran F, Sharples C, et al. Prospective placebo-controlled randomized trial of
lexipafant in predicted severe acute pancreatitis. Br J Surg 1997;84:1239–43. [PubMed: 9313702]
150. 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. [PubMed: 11115824]
151. Sadr-Azodi O, Orsini N, Andren-Sandberg A, et al. Abdominal and total adiposity and the risk of
acute pancreatitis: a population-based prospective cohort study. The American journal of
gastroenterology 2013;108:133–9. [PubMed: 23147519]
152. O'Leary DP, O'Neill D, McLaughlin P, et al. Effects of abdominal fat distribution parameters on
severity of acute pancreatitis. World journal of surgery 2012;36:1679–85. [PubMed: 22491816]
153. Yashima Y, Isayama H, Tsujino T, et al. A large volume of visceral adipose tissue leads to severe
acute pancreatitis. Journal of gastroenterology 2011;46:1213–8. [PubMed: 21805069]
154. Funnell IC, Bornman PC, Weakley SP, et al. Obesity: an important prognostic factor in acute
pancreatitis. The British journal of surgery 1993;80:484–6. [PubMed: 8495317]
155. Choh AC, Demerath EW, Lee M, et al. Genetic analysis of self-reported physical activity and
adiposity: the Southwest Ohio Family Study. Public health nutrition 2009;12:1052–60. [PubMed:
18778532]
Garg and Singh
Page 20
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
156. Ren J, Dimitrov I, Sherry AD, et al. Composition of adipose tissue and marrow fat in humans by
1H NMR at 7 Tesla. Journal of lipid research 2008;49:2055–62. [PubMed: 18509197]
157. Thomas LW. The chemical composition of adipose tissue of man and mice. Quarterly journal of
experimental physiology and cognate medical sciences 1962;47:179–88. [PubMed: 13920823]
158. Garaulet M, Hernandez-Morante JJ, Lujan J, et al. Relationship between fat cell size and number
and fatty acid composition in adipose tissue from different fat depots in overweight/obese
humans. International journal of obesity 2006;30:899–905. [PubMed: 16446749]
159. Pinnick KE, Collins SC, Londos C, et al. Pancreatic ectopic fat is characterized by adipocyte
infiltration and altered lipid composition. Obesity (Silver Spring) 2008;16:522–30. [PubMed:
18239594]
160. Panek J, Sztefko K, Drozdz W. Composition of free fatty acid and triglyceride fractions in human
necrotic pancreatic tissue. Med Sci Monit 2001;7:894–8. [PubMed: 11535930]
161. Guyenet SJ, Carlson SE. Increase in adipose tissue linoleic acid of US adults in the last half
century. Adv Nutr 2015;6:660–4. [PubMed: 26567191]
162. Aho HJ, Sternby B, Nevalainen TJ. Fat necrosis in human acute pancreatitis. An
immunohistological study. Acta pathologica, microbiologica, et immunologica Scandinavica.
Section A, Pathology 1986;94:101–5.
163. Koutroumpakis E, Dasyam AK, Furlan A, et al. Isolated Peripancreatic Necrosis in Acute
Pancreatitis Is Infrequent and Leads to Severe Clinical Course Only When Extensive: A
Prospective Study From a US Tertiary Center. J Clin Gastroenterol 2016;50:589–95. [PubMed:
26828244]
164. Bakker OJ, van Santvoort H, Besselink MG, et al. Extrapancreatic necrosis without pancreatic
parenchymal necrosis: a separate entity in necrotising pancreatitis? Gut 2013;62:1475–80.
[PubMed: 22773550]
165. Sztefko K, Panek J. Serum free fatty acid concentration in patients with acute pancreatitis.
Pancreatology 2001;1:230–6. [PubMed: 12120200]
166. Domschke S, Malfertheiner P, Uhl W, et al. Free fatty acids in serum of patients with acute
necrotizing or edematous pancreatitis. Int J Pancreatol 1993;13:105–10. [PubMed: 8501351]
167. Goncalves-de-Albuquerque CF, Burth P, Silva AR, et al. Oleic acid inhibits lung Na/K-ATPase in
mice and induces injury with lipid body formation in leukocytes and eicosanoid production.
Journal of inflammation 2013;10:34. [PubMed: 24175969]
168. Hussain N, Wu F, Zhu L, et al. Neutrophil apoptosis during the development and resolution of
oleic acid-induced acute lung injury in the rat. Am J Respir Cell Mol Biol 1998;19:867–74.
[PubMed: 9843920]
169. Patel K, Durgampudi C, Noel P, et al. Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent
Fatty Acids Generated during Acute Pancreatitis. Am J Pathol 2016;186:874–84. [PubMed:
26878214]
170. Thiruvengadam NR, Forde KA, Ma GK, et al. Rectal Indomethacin Reduces Pancreatitis in High-
and Low-Risk Patients Undergoing Endoscopic Retrograde Cholangiopancreatography.
Gastroenterology 2016;151:288–297 e4. [PubMed: 27215656]
171. Flint RS, Phillips AR, Power SE, et al. Acute pancreatitis severity is exacerbated by intestinal
ischemia-reperfusion conditioned mesenteric lymph. Surgery 2008;143:404–13. [PubMed:
18291262]
172. Fish RE, Lang CH, Spitzer JA. Regional blood flow during continuous low-dose endotoxin
infusion. Circ Shock 1986;18:267–75. [PubMed: 3516440]
173. Hiltebrand LB, Krejci V, Banic A, et al. Dynamic study of the distribution of microcirculatory
blood flow in multiple splanchnic organs in septic shock. Crit Care Med 2000;28:3233–41.
[PubMed: 11008987]
174. Krejci V, Hiltebrand L, Banic A, et al. Continuous measurements of microcirculatory blood flow
in gastrointestinal organs during acute haemorrhage. Br J Anaesth 2000;84:468–75. [PubMed:
10823098]
175. Juvonen PO, Tenhunen JJ, Heino AA, et al. Splanchnic tissue perfusion in acute experimental
pancreatitis. Scand J Gastroenterol 1999;34:308–14. [PubMed: 10232878]
Garg and Singh
Page 21
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
176. Farrant GJ, Abu-Zidan FM, Liu X, et al. The impact of intestinal ischaemia-reperfusion on
caerulein-induced oedematous experimental pancreatitis. Eur Surg Res 2003;35:395–400.
[PubMed: 12802103]
177. Bonham MJ, Abu-Zidan FM, Simovic MO, et al. Gastric intramucosal pH predicts death in severe
acute pancreatitis. Br J Surg 1997;84:1670–4. [PubMed: 9448612]
178. Tian R, Tan JT, Wang RL, et al. The role of intestinal mucosa oxidative stress in gut barrier
dysfunction of severe acute pancreatitis. Eur Rev Med Pharmacol Sci 2013;17:349–55. [PubMed:
23426538]
179. Flint RS, Windsor JA. The role of the intestine in the pathophysiology and management of severe
acute pancreatitis. HPB (Oxford) 2003;5:69–85. [PubMed: 18332961]
180. Capurso G, Zerboni G, Signoretti M, et al. Role of the gut barrier in acute pancreatitis. J Clin
Gastroenterol 2012;46 Suppl:S46–51. [PubMed: 22955357]
181. Wu LM, Sankaran SJ, Plank LD, et al. Meta-analysis of gut barrier dysfunction in patients with
acute pancreatitis. Br J Surg 2014;101:1644–56. [PubMed: 25334028]
182. Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and
Crohn's disease. Gut 2017;66:839–851. [PubMed: 26893500]
183. Lockhart PB, Brennan MT, Sasser HC, et al. Bacteremia associated with toothbrushing and dental
extraction. Circulation 2008;117:3118–25. [PubMed: 18541739]
184. Shorvon PJ, Eykyn SJ, Cotton PB. Gastrointestinal instrumentation, bacteraemia, and
endocarditis. Gut 1983;24:1078–93. [PubMed: 6354885]
185. Singer M The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence
2014;5:66–72. [PubMed: 24185508]
186. Takasu O, Gaut JP, Watanabe E, et al. Mechanisms of cardiac and renal dysfunction in patients
dying of sepsis. Am J Respir Crit Care Med 2013;187:509–17. [PubMed: 23348975]
187. de-Madaria E, Herrera-Marante I, Gonzalez-Camacho V, et al. Fluid resuscitation with lactated
Ringer's solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled
trial. United European Gastroenterol J 2018;6:63–72.
188. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer's solution reduces systemic inflammation
compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:710–
717.e1. [PubMed: 21645639]
189. de-Madaria E, Garg PK. Fluid therapy in acute pancreatitis - aggressive or adequate? Time for
reappraisal. Pancreatology 2014;14:433–5. [PubMed: 25455538]
190. Mao EQ, Fei J, Peng YB, et al. Rapid hemodilution is associated with increased sepsis and
mortality among patients with severe acute pancreatitis. Chin Med J (Engl) 2010;123:1639–44.
[PubMed: 20819621]
191. Vaughn VM, Shuster D, Rogers MAM, et al. Early Versus Delayed Feeding in Patients With
Acute Pancreatitis: A Systematic Review. Ann Intern Med 2017;166:883–892. [PubMed:
28505667]
192. Siriwardena AK, Mason JM, Balachandra S, et al. Randomised, double blind, placebo controlled
trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in severe acute
pancreatitis. Gut 2007;56:1439–44. [PubMed: 17356040]
193. 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–
659. [PubMed: 18279948]
194. Vege SS, Atwal T, Bi Y, et al. Pentoxifylline Treatment in Severe Acute Pancreatitis: A Pilot,
Double-Blind, Placebo-Controlled, Randomized Trial. Gastroenterology 2015;149:318–20.e3.
[PubMed: 26112745]
195. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in
rheumatoid arthritis. N Engl J Med 2012;367:508–19. [PubMed: 22873531]
196. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as Induction and Maintenance Therapy
for Crohn's Disease. N Engl J Med 2016;375:1946–1960. [PubMed: 27959607]
197. Wen L, Voronina S, Javed MA, et al. Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated
Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models.
Gastroenterology 2015;149:481–92 e7. [PubMed: 25917787]
Garg and Singh
Page 22
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
198. Ahuja M, Schwartz DM, Tandon M, et al. Orai1-Mediated Antimicrobial Secretion from
Pancreatic Acini Shapes the Gut Microbiome and Regulates Gut Innate Immunity. Cell Metab
2017;25:635–646. [PubMed: 28273482]
199. Gukovsky I, Gukovskaya AS, Blinman TA, et al. Early NF-kappaB activation is associated with
hormone-induced pancreatitis. Am J Physiol 1998;275:G1402–14. [PubMed: 9843778]
200. 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:G1197–208. [PubMed: 11352813]
201. Neuhofer P, Liang S, Einwachter H, et al. Deletion of IkappaBalpha activates RelA to reduce
acute pancreatitis in mice through up-regulation of Spi2A. Gastroenterology 2013;144:192–201.
[PubMed: 23041330]
202. Szabolcs A, Biczo G, Rakonczay Z, et al. Simultaneous proteosome inhibition and heat shock
protein induction by bortezomib is beneficial in experimental pancreatitis. Eur J Pharmacol
2009;616:270–4. [PubMed: 19486901]
203. Mole DJ, Webster SP, Uings I, et al. Kynurenine-3-monooxygenase inhibition prevents multiple
organ failure in rodent models of acute pancreatitis. Nat Med 2016;22:202–9. [PubMed:
26752518]
Garg and Singh
Page 23
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
A
uthor Man
uscr
ipt
|