Pathogenesis of neonatal necrotizing enterocolitis

Pediatric Surgery International

Volumn 31, Issue 6, 2015, Pages 509-518

  Lim, Joanna C ^a   Golden, Jamie M ^a   Ford, Henri R ^a,b  

^a CHILDREN S HOSPITAL LOS ANGELES   (United States)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Necrotizing enterocolitis; Neonatal intensive care unit; Pathophysiology; Pediatric surgery

Indexed keywords

HUMAN; INTESTINE; INTESTINE MUCOSA; NECROTIZING ENTEROCOLITIS; NEWBORN; NEWBORN DISEASE; PATHOLOGY;

ENTEROCOLITIS, NECROTIZING; HUMANS; INFANT, NEWBORN; INFANT, NEWBORN, DISEASES; INTESTINAL MUCOSA; INTESTINES;

EID: 84937761055     PISSN: 01790358     EISSN: 14379813     Source Type: Journal    
DOI: 10.1007/s00383-015-3697-9     Document Type: Review

References (128)

1. Papillon S, Castle SL, Gayer CP, Ford HR (2013) Necrotizing enterocolitis: contemporary management and outcomes. Adv Pediatr 60:263–279
2. Neu J, Walker WA (2011) Necrotizing enterocolitis. N Engl J Med 364:255–264
3. Eichenwald EC, Stark AR (2008) Management and outcomes of very low birth weight. N Engl J Med 358:1700–1711
4. Battersby AJ, Gibbons DL (2013) The gut mucosal immune system in the neonatal period. Pediatr Allergy Immunol 24:414–421
5. Musemeche CA, Kosloske AM, Bartow SA, Umland ET (1986) Comparative effects of ischemia, bacteria, and substrate on the pathogenesis of intestinal necrosis. J Pediatr Surg 21:536–538
6. Fouhy F, Ross RP, Fitzgerald GF, Stanton C, Cotter PD (2012) Composition of the early intestinal microbiota: knowledge, knowledge gaps and the use of high-throughput sequencing to address these gaps. Gut Microbes 3:203–220
7. Adlerberth I, Wold AE (2009) Establishment of the gut microbiota in Western infants. Acta Paediatr 98:229–238
8. Penders J, Thijs C, Vink C, Stelma FF, Snijders B et al (2006) Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118:511–521
9. Grönlund MM, Lehtonen OP, Eerola E, Kero P (1999) Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery. J Pediatr Gastroenterol Nutr 28:19–25
10. Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J et al (2011) Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci USA 108(Suppl 1):4578–4585
11. Morowitz MJ, Denef VJ, Costello EK, Thomas BC, Poroyko V et al (2011) Strain-resolved community genomic analysis of gut microbial colonization in a premature infant. Proc Natl Acad Sci USA 108:1128–1133
12. Sharon I, Morowitz MJ, Thomas BC, Costello EK, Relman DA et al (2013) Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization. Genome Res 23:111–120
13. Dai D, Walker WA (1999) Protective nutrients and bacterial colonization in the immature human gut. Adv Pediatr 46:353–382
14. Claud EC, Walker WA (2001) Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis. FASEB J 15:1398–1403
15. Yoshioka H, Iseki K, Fujita K (1983) Development and differences of intestinal flora in the neonatal period in breast-fed and bottle-fed infants. Pediatrics 72:317–321
16. Dai D, Walker WA (1998) Role of bacterial colonization in neonatal necrotizing enterocolitis and its prevention. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 39:357–365
17. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR (2011) Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr 159:720–725
18. Cotten CM, Taylor S, Stoll B, Goldberg RN, Hansen NI et al (2009) Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 123:58–66
19. Normann E, Fahlén A, Engstrand L, Lilja HE (2013) Intestinal microbial profiles in extremely preterm infants with and without necrotizing enterocolitis. Acta Paediatr 102:129–136
20. Stewart CJ, Marrs EC, Magorrian S, Nelson A, Lanyon C et al (2012) The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection. Acta Paediatr 101:1121–1127
21. Mai V, Young CM, Ukhanova M, Wang X, Sun Y et al (2011) Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One 6:e20647
22. Grishin A, Papillon S, Bell B, Wang J, Ford HR (2013) The role of the intestinal microbiota in the pathogenesis of necrotizing enterocolitis. Semin Pediatr Surg 22:69–75
23. Butel MJ, Roland N, Hibert A, Popot F, Favre A et al (1998) Clostridial pathogenicity in experimental necrotising enterocolitis in gnotobiotic quails and protective role of bifidobacteria. J Med Microbiol 47:391–399
24. Hunter CJ, Singamsetty VK, Chokshi NK, Boyle P, Camerini V et al (2008) Enterobacter sakazakii enhances epithelial cell injury by inducing apoptosis in a rat model of necrotizing enterocolitis. J Infect Dis 198:586–593
25. Hunter CJ, Williams M, Petrosyan M, Guner Y, Mittal R et al (2009) Lactobacillus bulgaricus prevents intestinal epithelial cell injury caused by Enterobacter sakazakii-induced nitric oxide both in vitro and in the newborn rat model of necrotizing enterocolitis. Infect Immun 77:1031–1043
26. Liu Q, Mittal R, Emami CN, Iversen C, Ford HR et al (2012) Human isolates of Cronobactersakazakii bind efficiently to intestinal epithelial cells in vitro to induce monolayer permeability and apoptosis. J Surg Res 176:437–447
27. Alverdy J, Gilbert J, DeFazio JR, Sadowsky MJ, Chang EB et al (2014) Proceedings of the 2013 A.S.P.E.N. Research workshop: the interface between nutrition and the gut microbiome: implications and applications for human health [corrected]. JPEN 38:167–178
28. Bury RG, Tudehope D (2001) Enteral antibiotics for preventing necrotizing enterocolitis in low birthweight or preterm infants. Cochrane Database Syst Rev 1:CD000405
29. Downard CD, Renaud E, St Peter SD, Abdullah F, Islam S et al (2012) Treatment of necrotizing enterocolitis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J Pediatr Surg 47:2111–2122
30. Corthésy B, Gaskins HR, Mercenier A (2007) Cross-talk between probiotic bacteria and the host immune system. J Nutr 137:781S–790S
31. Cc C, Ww A (2013) Probiotics and the mechanism of necrotizing enterocolitis. Semin Pediatr Surg 22:94–100
32. Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF et al (2008) Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 122:693–700
33. Samanta M, Sarkar M, Ghosh P, Ghosh J, Sinha M et al (2009) Prophylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns. J Trop Pediatr 55:128–131
34. Deshpande G, Rao S, Patole S, Bulsara M (2010) Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 125:921–930
35. Deshpande GC, Rao SC, Keil AD, Patole SK (2011) Evidence-based guidelines for use of probiotics in preterm neonates. BMC Med 9:92
36. Raval MV, Hall NJ, Pierro A, Moss RL (2013) Evidence-based prevention and surgical treatment of necrotizing enterocolitis-a review of randomized controlled trials. Semin Pediatr Surg 22:117–121
37. Neu J (2014) Probiotics and necrotizing enterocolitis. Clin Perinatol 41:967–978
38. Schanler RJ, Lau C, Hurst NM, Smith EO (2005) Randomized trial of donor human milk versus preterm formula as substitutes for mothers’ own milk in the feeding of extremely premature infants. Pediatrics 116:400–406
39. Quigley MA, Henderson G, Anthony MY, McGuire W (2007) Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev CD002971
40. Iyengar SR, Walker WA (2012) Immune factors in breast milk and the development of atopic disease. J Pediatr Gastroenterol Nutr 55:641–647
41. Jantscher-Krenn E, Zherebtsov M, Nissan C, Goth K, Guner YS et al (2012) The human milk oligosaccharide disialyllacto-N-tetraose prevents necrotising enterocolitis in neonatal rats. Gut 61:1417–1425
42. Guner YS, Franklin AL, Chokshi NK, Castle SL, Pontarelli E et al (2011) P-glycoprotein induction by breast milk attenuates intestinal inflammation in experimental necrotizing enterocolitis. Lab Invest 91:1668–1679
43. Karagianni P, Briana DD, Mitsiakos G, Elias A, Theodoridis T et al (2010) Early versus delayed minimal enteral feeding and risk for necrotizing enterocolitis in preterm growth-restricted infants with abnormal antenatal Doppler results. Am J Perinatol 27:367–373
44. Leaf A, Dorling J, Kempley S, McCormick K, Mannix P et al (2012) Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial. Pediatrics 129:e1260–e1268
45. Rowland KJ, Choi PM, Warner BW (2013) The role of growth factors in intestinal regeneration and repair in necrotizing enterocolitis. Semin Pediatr Surg 22:101–111
46. Abud HE, Watson N, Heath JK (2005) Growth of intestinal epithelium in organ culture is dependent on EGF signalling. Exp Cell Res 303:252–262
47. Scott SM, Buenaflor GG, Orth DN (1989) Immunoreactive human epidermal growth factor concentrations in amniotic fluid, umbilical artery and vein serum, and placenta in full-term and preterm infants. Biol Neonate 56:246–251
48. Playford RJ, Wright NA (1996) Why is epidermal growth factor present in the gut lumen? Gut 38:303–305
49. Dvorak B, Fituch CC, Williams CS, Hurst NM, Schanler RJ (2003) Increased epidermal growth factor levels in human milk of mothers with extremely premature infants. Pediatr Res 54:15–19
50. Dvorak B, Fituch CC, Williams CS, Hurst NM, Schanler RJ (2004) Concentrations of epidermal growth factor and transforming growth factor-alpha in preterm milk. Adv Exp Med Biol 554:407–409
51. Buchmiller TL, Shaw KS, Chopourian HL, Lloyd KC, Gregg JP et al (1993) Effect of transamniotic administration of epidermal growth factor on fetal rabbit small intestinal nutrient transport and disaccharidase development. J Pediatr Surg 28:1239–1244
52. Helmrath MA, VanderKolk WE, Can G, Erwin CR, Warner BW (1996) Intestinal adaptation following massive small bowel resection in the mouse. J Am Coll Surg 183:441–449
53. Chaet MS, Arya G, Ziegler MM, Warner BW (1994) Epidermal growth factor enhances intestinal adaptation after massive small bowel resection. J Pediatr Surg 29:1035–1038 (discussion 1038–1039)
54. Helmrath MA, Erwin CR, Warner BW (1997) A defective EGF-receptor in waved-2 mice attenuates intestinal adaptation. J Surg Res 69:76–80
55. Helmrath MA, Shin CE, Fox JW, Erwin CR, Warner BW (1998) Adaptation after small bowel resection is attenuated by sialoadenectomy: the role for endogenous epidermal growth factor. Surgery 124:848–854
56. Shin CE, Helmrath MA, Falcone RA, Fox JW, Duane KR et al (1998) Epidermal growth factor augments adaptation following small bowel resection: optimal dosage, route, and timing of administration. J Surg Res 77:11–16
57. Erwin CR, Helmrath MA, Shin CE, Falcone RA, Stern LE et al (1999) Intestinal overexpression of EGF in transgenic mice enhances adaptation after small bowel resection. Am J Physiol 277:G533–G540
58. Shin CE, Falcone RA, Duane KR, Erwin CR, Warner BW (1999) The distribution of endogenous epidermal growth factor after small bowel resection suggests increased intestinal utilization during adaptation. J Pediatr Surg 34:22–26
59. O’Brien DP, Nelson LA, Williams JL, Kemp CJ, Erwin CR et al (2002) Selective inhibition of the epidermal growth factor receptor impairs intestinal adaptation after small bowel resection. J Surg Res 105:25–30
60. Knott AW, Erwin CR, Profitt SA, Juno RJ, Warner BW (2003) Localization of postresection EGF receptor expression using laser capture microdissection. J Pediatr Surg 38:440–445
61. Dvorak B, Halpern MD, Holubec H, Williams CS, McWilliam DL et al (2002) Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model. Am J Physiol Gastrointest Liver Physiol 282:G156–G164
62. Dvorak B (2004) Epidermal growth factor and necrotizing enterocolitis. Clin Perinatol 31:183–192
63. Clark JA, Doelle SM, Halpern MD, Saunders TA, Holubec H et al (2006) Intestinal barrier failure during experimental necrotizing enterocolitis: protective effect of EGF treatment. Am J Physiol Gastrointest Liver Physiol 291:G938–G949
64. Michalsky MP, Lara-Marquez M, Chun L, Besner GE (2002) Heparin-binding EGF-like growth factor is present in human amniotic fluid and breast milk. J Pediatr Surg 37:1–6
65. Feng J, El-Assal ON, Besner GE (2005) Heparin-binding EGF-like growth factor (HB-EGF) and necrotizing enterocolitis. Semin Pediatr Surg 14:167–174
66. Feng J, El-Assal ON, Besner GE (2006) Heparin-binding epidermal growth factor-like growth factor decreases the incidence of necrotizing enterocolitis in neonatal rats. J Pediatr Surg 41:144–149 (discussion 144–149)
67. Feng J, El-Assal ON, Besner GE (2006) Heparin-binding epidermal growth factor-like growth factor reduces intestinal apoptosis in neonatal rats with necrotizing enterocolitis. J Pediatr Surg 41:742–747 (discussion 742–747)
68. Feng J, Besner GE (2007) Heparin-binding epidermal growth factor-like growth factor promotes enterocyte migration and proliferation in neonatal rats with necrotizing enterocolitis. J Pediatr Surg 42:214–220
69. Watkins DJ, Besner GE (2013) The role of the intestinal microcirculation in necrotizing enterocolitis. Semin Pediatr Surg 22:83–87
70. Nankervis CA, Nowicki PT (2000) Role of endothelin-1 in regulation of the postnatal intestinal circulation. Am J Physiol Gastrointest Liver Physiol 278:G367–G375
71. Ito Y, Doelle SM, Clark JA, Halpern MD, McCuskey RS et al (2007) Intestinal microcirculatory dysfunction during the development of experimental necrotizing enterocolitis. Pediatr Res 61:180–184
72. Nowicki PT, Dunaway DJ, Nankervis CA, Giannone PJ, Giannnone PJ et al (2005) Endothelin-1 in human intestine resected for necrotizing enterocolitis. J Pediatr 146:805–810
73. Petrosyan M, Guner YS, Williams M, Grishin A, Ford HR (2009) Current concepts regarding the pathogenesis of necrotizing enterocolitis. Pediatr Surg Int 25:309–318
74. Mitchell K, Lyttle A, Amin H, Shaireen H, Robertson HL et al (2014) Arginine supplementation in prevention of necrotizing enterocolitis in the premature infant: an updated systematic review. BMC Pediatr 14:226
75. Chokshi NK, Guner YS, Hunter CJ, Upperman JS, Grishin A et al (2008) The role of nitric oxide in intestinal epithelial injury and restitution in neonatal necrotizing enterocolitis. Semin Perinatol 32:92–99
76. Hunter CJ, De Plaen IG (2014) Inflammatory signaling in NEC: role of NF-κB, cytokines and other inflammatory mediators. Pathophysiology 21:55–65
77. Lancaster JR (1994) Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci USA 91:8137–8141
78. Hackam DJ, Upperman JS, Grishin A, Ford HR (2005) Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis. Semin Pediatr Surg 14:49–57
79. Hutcheson IR, Whittle BJ, Boughton-Smith NK (1990) Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol 101:815–820
80. De Groote MA, Fang FC (1995) NO inhibitions: antimicrobial properties of nitric oxide. Clin Infect Dis 21(Suppl 2):S162–S165
81. Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:C1424–C1437
82. Potoka DA, Nadler EP, Upperman JS, Ford HR (2002) Role of nitric oxide and peroxynitrite in gut barrier failure. World J Surg 26:806–811
83. Ford H, Watkins S, Reblock K, Rowe M (1997) The role of inflammatory cytokines and nitric oxide in the pathogenesis of necrotizing enterocolitis. J Pediatr Surg 32:275–282
84. Sorrells DL, Friend C, Koltuksuz U, Courcoulas A, Boyle P et al (1996) Inhibition of nitric oxide with aminoguanidine reduces bacterial translocation after endotoxin challenge in vivo. Arch Surg 131:1155–1163
85. Guner YS, Ochoa CJ, Wang J, Zhang X, Steinhauser S et al (2009) Peroxynitrite-induced p38 MAPK pro-apoptotic signaling in enterocytes. Biochem Biophys Res Commun 384:221–225
86. Nadler EP, Dickinson E, Knisely A, Zhang XR, Boyle P et al (2000) Expression of inducible nitric oxide synthase and interleukin-12 in experimental necrotizing enterocolitis. J Surg Res 92:71–77
87. Zamora SA, Amin HJ, McMillan DD, Kubes P, Fick GH et al (1997) Plasma l-arginine concentrations in premature infants with necrotizing enterocolitis. J Pediatr 131:226–232
88. Chen K, Inoue M, Okada A (1996) Expression of inducible nitric oxide synthase mRNA in rat digestive tissues after endotoxin and its role in intestinal mucosal injury. Biochem Biophys Res Commun 224:703–708
89. Ciftçi I, Dilsiz A, Aktan TM, Gürbilek M, Duman S (2004) Effects of nitric oxide synthase inhibition on intestinal damage in rats with experimental necrotizing enterocolitis. Eur J Pediatr Surg 14:398–403
90. MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS et al (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81:641–650
91. Mishima S, Xu D, Lu Q, Deitch EA (1997) Bacterial translocation is inhibited in inducible nitric oxide synthase knockout mice after endotoxin challenge but not in a model of bacterial overgrowth. Arch Surg 132:1190–1195
92. Nanthakumar N, Meng D, Goldstein AM, Zhu W, Lu L et al (2011) The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response. PLoS One 6:e17776
93. Neal MD, Leaphart C, Levy R, Prince J, Billiar TR et al (2006) Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J Immunol 176:3070–3079
94. Hackam DJ, Good M, Sodhi CP (2013) Mechanisms of gut barrier failure in the pathogenesis of necrotizing enterocolitis: toll-like receptors throw the switch. Semin Pediatr Surg 22:76–82
95. Leaphart CL, Cavallo J, Gribar SC, Cetin S, Li J et al (2007) A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J Immunol 179:4808–4820
96. Qureshi FG, Leaphart C, Cetin S, Li J, Grishin A et al (2005) Increased expression and function of integrins in enterocytes by endotoxin impairs epithelial restitution. Gastroenterology 128:1012–1022
97. Sodhi CP, Shi XH, Richardson WM, Grant ZS, Shapiro RA et al (2010) Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis. Gastroenterology 138:185–196
98. Sodhi CP, Neal MD, Siggers R, Sho S, Ma C, et al (2012) Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice. Gastroenterology 143:708–718 (e701–e705)
99. Jilling T, Simon D, Lu J, Meng FJ, Li D et al (2006) The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis. J Immunol 177:3273–3282
100. Gribar SC, Sodhi CP, Richardson WM, Anand RJ, Gittes GK et al (2009) Reciprocal expression and signaling of TLR4 and TLR9 in the pathogenesis and treatment of necrotizing enterocolitis. J Immunol 182:636–646
101. Frost BL, Caplan MS (2013) Necrotizing enterocolitis: pathophysiology, platelet-activating factor, and probiotics. Semin Pediatr Surg 22:88–93
102. Caplan M, Hsueh W, Kelly A, Donovan M (1990) Serum PAF acetylhydrolase increases during neonatal maturation. Prostaglandins 39:705–714
103. Gonzalez-Crussi F, Hsueh W (1983) Experimental model of ischemic bowel necrosis. The role of platelet-activating factor and endotoxin. Am J Pathol 112:127–135
104. Furukawa M, Lee EL, Johnston JM (1993) Platelet-activating factor-induced ischemic bowel necrosis: the effect of platelet-activating factor acetylhydrolase. Pediatr Res 34:237–241
105. Soliman A, Michelsen KS, Karahashi H, Lu J, Meng FJ et al (2010) Platelet-activating factor induces TLR4 expression in intestinal epithelial cells: implication for the pathogenesis of necrotizing enterocolitis. PLoS One 5:e15044
106. Caplan MS, Hedlund E, Adler L, Lickerman M, Hsueh W (1997) The platelet-activating factor receptor antagonist WEB 2170 prevents neonatal necrotizing enterocolitis in rats. J Pediatr Gastroenterol Nutr 24:296–301
107. Caplan MS, Lickerman M, Adler L, Dietsch GN, Yu A (1997) The role of recombinant platelet-activating factor acetylhydrolase in a neonatal rat model of necrotizing enterocolitis. Pediatr Res 42:779–783
108. Caplan MS, Sun XM, Hseuh W, Hageman JR (1990) Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J Pediatr 116:960–964
109. Amer MD, Hedlund E, Rochester J, Caplan MS (2004) Platelet-activating factor concentration in the stool of human newborns: effects of enteral feeding and neonatal necrotizing enterocolitis. Biol Neonate 85:159–166
110. Moya FR, Eguchi H, Zhao B, Furukawa M, Sfeir J et al (1994) Platelet-activating factor acetylhydrolase in term and preterm human milk: a preliminary report. J Pediatr Gastroenterol Nutr 19:236–239
111. Furukawa M, Narahara H, Yasuda K, Johnston JM (1993) Presence of platelet-activating factor-acetylhydrolase in milk. J Lipid Res 34:1603–1609
112. Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA (2000) Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci USA 97:6043–6048
113. Lugo B, Ford HR, Grishin A (2007) Molecular signaling in necrotizing enterocolitis: regulation of intestinal COX-2 expression. J Pediatr Surg 42:1165–1171
114. Bos CL, Richel DJ, Ritsema T, Peppelenbosch MP, Versteeg HH (2004) Prostanoids and prostanoid receptors in signal transduction. Int J Biochem Cell Biol 36:1187–1205
115. Dey I, Lejeune M, Chadee K (2006) Prostaglandin E2 receptor distribution and function in the gastrointestinal tract. Br J Pharmacol 149:611–623
116. Wallace JL, Devchand PR (2005) Emerging roles for cyclooxygenase-2 in gastrointestinal mucosal defense. Br J Pharmacol 145:275–282
117. Tsujii M, DuBois RN (1995) Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83:493–501
118. Shao J, Sheng GG, Mifflin RC, Powell DW, Sheng H (2006) Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis. Cancer Res 66:846–855
119. Wallace JL (2001) Prostaglandin biology in inflammatory bowel disease. Gastroenterol Clin North Am 30:971–980
120. Buchanan FG, Wang D, Bargiacchi F, DuBois RN (2003) Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 278:35451–35457
121. Loftin CD, Tiano HF, Langenbach R (2002) Phenotypes of the COX-deficient mice indicate physiological and pathophysiological roles for COX-1 and COX-2. Prostaglandins Other Lipid Mediat 68–69:177–185
122. Short SS, Wang J, Castle SL, Fernandez GE, Smiley N et al (2013) Low doses of celecoxib attenuate gut barrier failure during experimental peritonitis. Lab Invest 93:1265–1275
123. Wang D, Dubois RN (2010) The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 29:781–788
124. Chung DH, Ethridge RT, Kim S, Owens-Stovall S, Hernandez A et al (2001) Molecular mechanisms contributing to necrotizing enterocolitis. Ann Surg 233:835–842
125. Grishin AV, Wang J, Potoka DA, Hackam DJ, Upperman JS et al (2006) Lipopolysaccharide induces cyclooxygenase-2 in intestinal epithelium via a non-canonical p38 MAPK pathway. J Immunol 176:580–588
126. Bergholz R, Zschiegner M, Eschenburg G, Wenke K, Tiemann B et al (2013) Mucosal loss with increased expression of IL-6, IL-8, and COX-2 in a formula-feeding only neonatal rat model of necrotizing enterocolitis. J Pediatr Surg 48:2301–2307
127. Grosfeld JL, Chaet M, Molinari F, Engle W, Engum SA et al (1996) Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Ann Surg 224:350–355 (discussion 355–357)
128. Walker SK, Matheson PJ, Galganski LA, Garrison RN, Downard CD (2014) Application of prostaglandin E2 improves ileal blood flow in NEC. J Pediatric Surg 49:945–949