Management Modalities for Necrotising Enterocolitis: Targeting Toll Like Receptors
Keywords:
Necrotizing Enterocolitis, Toll Like Receptor, Heat Shock Protein, Epidermal Growth Factor, Probiotics, Prebiotics
Abstract
In spite of advances in the management of newborn infants, Necrotizing Enterocolitis(NEC) continues to be a complicated disease all over the world. Gradual development in the field of NEC discovered ‘Toll-like receptor 4’(TLR4), which is a bacterial receptor having role in pathogenesis of the disease. TLR4 expression is increased in bowel mucosa of NEC babies and TLR4 activation causes mucosal injury and enterocyte apoptosis. Breast feeding is considered to decrease the risk of necrotizing enterocolitis. But, we neither have a definite molecule for the treatment of the disease nor for its prevention. CpG DNA which is present in the probiotic preparations and muramyl-di-peptide(MDP), inhibit TLR4 signaling may decrease NEC severity. Epidermal growth factors(EGF) present in amniotic fluid also reduce TLR4 signaling. Heparin binding EGF( HB-EGF) and Heat shock protein(Hsp 70) are possible approaches for management of NEC because of their action on TLR4. These may be considered as future management approach for this common and compromising disease of the newborn.References
1. Patel BK and Shah JS. Necrotizing Enterocolitis in Very Low Birth Weight Infants: A Systemic Review. ISRN Gastroenterology 2012; 2012:1-7. Article ID 562594.doi:10.5402/2012/562594.
2. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997; 388: 394-397.
3. Afrazi A, Sodhi CP, Richardson W, Neal M, Good M, Siggers R, Hackman DJ. New Insights Into the Pathogenesis and Treatment of Necrotizing Enterocolitis: Toll-Like Receptors and Beyond. Pediatric Research 2011; 69(3): 183-188.
4. Frost BL, Caplan MS. Necrotizing Enterocolitis: Pathophysiology, platelet-activating factor, and probiotics. Seminars in Pediatric Surgery 2013;22(2):88-93.http://dx.doi.org/10.1053/j.sempedsurg.2013.01.005.
5. Chan KL, Wong KF, Luk LM. Role of LPS/CD14/TLR-4 mediated inflammation in necrotizing enterocolitis: pathogenesis, and therapeutic implications. World J Gastroenterol 2009; 15:4745-4752.
6. Lu J, Jiling T, Li D, Caplan MS. Polyunsaturted fatty acid supplementation alters proinflammatory gene expression and reduces the incidence of necrotizing enterocolitis in a neonatal rat model. Pediatr Res 2007; 61:427-432.
7. David J. Hackam, Amin Afrazi, Misty Good, and Chhinder P. Sodhi. Innate Immune Signaling in the Pathogenesis of Necrotizing Enterocolitis. Clinical and Developmental Immunology Vol. 2013, Article ID 475415, 10 pages, 2013. doi:10.1155/2013/475415
8. Curtis MD, Terrin G. Necrotizing enterocolitis(NEC): what’s going on. J Pediatr Neonat Individual Med 2013;2(2):e020218. doi:10.7363/020218.
9. Jiling T, Simon D, Lu J, Meng FJ, Li D, Schy R, et al. The roles of bacteria and TLR4 in rat and murine models of necrotizing necrocolitis. J Immunol 2006; 177(5):33272-3282. doi: 10.4049/jimmunol.177.5.3273
10. Alcamo AM, Schanbacher BL, Huang H, Nankervis CA, Bauer JA, Glannone PJ. Cellular strain amplifies LPS-induced stress signaling in immature enterocytes: potential implications for preterm infants NCPAP. Pediatric Research 2012; 72(3): 256-261. doi: 10.1038/pr.2012.77.
11. Chu A, Hageman JR, Caplan MS. Necrotizing Enterocolitis: Predictive Markers and Preventive Strategies. NeoReviews. 2013;14(3):e113-118. Downloaded from http://neoreviews.aapublications.org/at UNIV OF CHICAGO on March7, 2013.
12. Fox TP, Godavitarne C. What really causes Necrotizing Enterocolitis? ISRN Gastroenterology 2012; 2012:1-9. doi:10.5402/2012/628317.
13. Cetin S, Ford HR, Sysko LR, Agarwal C, Wang J, Neal MD, et al. Endotoxin inhibits intestinal epithelial restitution through activation of Rho-GTPase and increased focal adhesions. J Biol Chem 2004; 279(23):24592-24600. doi:10.1074/jbc.M313620200.
14. Dai S, Sodhi C, Cetin S, Richardson W, Branca M, Neal MD, et al. Extracellular high mobility group box-1(HMGB1) inhibits enterocyte migration via activation of toll-like receptor-4 and increased cell-matrix adhesiveness. J Bio Chem 2010; 285(7):4995-5002. doi: 10.1074/jbc.M109.067454.
15. Siggers RH and Hackman DJ. The role of innate immune-stimulated epithelial apoptosis during gastrointestinal inflammatory diseases. Cell Mol Life Sci 2011; 68(22):3623-3634. doi: 10.1007/s00018-011-0821-4.
16. Afrazi A, Sodhi CP, Good M, Jia H, Siggers R, Yazji I, et al. Intracellular heat shock protein-70 negatively regulates TLR4 signaling in the newborn intestinal epithelium. J Immunol 2012; 188(9):4543-4557. doi: 10.4049/jimmunol.1103114.
17. Sodhi CP, Shi XH, Richardson WM, Grant ZS, Shapiro RA, Prindle T Jr, et al. Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis. Gastroenterology 2010; 138(1): 185-196. doi: 10.1053/j.gastro.2009.09.045.
18. Caplan MS. Probiotic and prebiotic supplementation for the prevention of neonatal necrotizing enterocolitis. J Perinatol 2009; 29(Suppl2):S2-6. doi: 10.1038/jp.2009.21.
19. Chen CC, Walker Allan. Probiotics and the mechanism of necrotizing enterocolitis. Seminars in Pediatric Surgery 2013; 22(2):94-100. http://dx.doi.org/10.1053/jj.sempedsurg.2013.01.006.
20. Al Faleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2014;4:CD005496. doi:10.1002/14651858. CD005496.pub4.
21. Coran AG, Caldamone A, Adzick NS, Krimmel TM, Laberge JM, Shamberger R. Pediatric Surgery. 7th Edition, Philadelphia, USA, Elsevier Saunders, 2012, Chapter 94;2: 1187-1207. ISBN: 978-0-323-07255-7.
22. Tarnow Mordi W, Soll RF. Probiotic supplementation in preterm infants: it is time to change practice. J Pediatri 2014; 164(5):959-60. doi:10.1016/j.jpeds.2013.12.050
23. Richardson WM, Sodhi CP, Russo A, Siggers RH, Afrazi A, Gribar SC, et al. Nucleotide-binding oligomerization domain-2 inhibits Toll-like receptor-4 signaling in the intestinal epithelium. Gastroenterology 2010; 139(3):904-917. doi: 10.1053/j.gastro.2010.05.038.
24. Joly AL, Wettstein G, Mignot F, Ghiringhelli and Garrido C. Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J Innate Immun 2010; 2(3):238-247. doi: 10.1159/000296508.
25. Good M, Siggers RH, Sodhi CP, Afrazi A, Alkhudar F, Egan CE, et al. Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Pro Natl Acad Sci U S A 2012;109(28):11330-11335. doi: 10.1073/pnas.1200856109.
26. Rowland KJ, Choi PM, Warner BW. The role of growth factors in intestinal regeneration and repair in necrotizing enterocolitis. Seminars in Pediatric Surgery2013;22(2):101-111. http://dx.doi.org/10.1053/j.sempedsurg.2013.01.007.
27. Chen CL, Yu X, James IO, et al. Heparin-binding EGF-like growth factor protects intestinal stem cells from injury in a rat model of necrotizing enterocolitis. Lab Invest 2012;92:331-344.
28. Yang J, Watkins D, Chen CL, Bhushan B, Zhou Yu Besner GE. Heparin-binding epidermal growth factor like growth factor and mesenchymal stem cells act synergistically to prevent experimental necrotizing enterocolitis. J AM Coll Surg 2012; 215:534-545.
29. Heather J.L. Brooks, Michelle A. McConnell and Roland S. Broadbent. Microbes and the Inflammatory Response in Necrotising Enterocolitis, Preterm Birth. Dr. Offer Erez (Ed.), 2013. ISBN: 978-953-51-0952-5, InTech, DOI: 10.5772/55039. Available from: http://www.intechopen.com/books/preterm-birth/microbes-and-the-inflammatory-response-in-necrotising-enterocolitis
30. Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotizing enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2013;5:CD001970.doi:10.1002/14651858.
31. Dai D, Nanthkumar NN, Newburg DS, Walker WA. Role of oligosaccharides and glycoconjugates in intestinal host defense. J Pediatr Gastroenterol Nutr 2000; 30: S23-S33.
2. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997; 388: 394-397.
3. Afrazi A, Sodhi CP, Richardson W, Neal M, Good M, Siggers R, Hackman DJ. New Insights Into the Pathogenesis and Treatment of Necrotizing Enterocolitis: Toll-Like Receptors and Beyond. Pediatric Research 2011; 69(3): 183-188.
4. Frost BL, Caplan MS. Necrotizing Enterocolitis: Pathophysiology, platelet-activating factor, and probiotics. Seminars in Pediatric Surgery 2013;22(2):88-93.http://dx.doi.org/10.1053/j.sempedsurg.2013.01.005.
5. Chan KL, Wong KF, Luk LM. Role of LPS/CD14/TLR-4 mediated inflammation in necrotizing enterocolitis: pathogenesis, and therapeutic implications. World J Gastroenterol 2009; 15:4745-4752.
6. Lu J, Jiling T, Li D, Caplan MS. Polyunsaturted fatty acid supplementation alters proinflammatory gene expression and reduces the incidence of necrotizing enterocolitis in a neonatal rat model. Pediatr Res 2007; 61:427-432.
7. David J. Hackam, Amin Afrazi, Misty Good, and Chhinder P. Sodhi. Innate Immune Signaling in the Pathogenesis of Necrotizing Enterocolitis. Clinical and Developmental Immunology Vol. 2013, Article ID 475415, 10 pages, 2013. doi:10.1155/2013/475415
8. Curtis MD, Terrin G. Necrotizing enterocolitis(NEC): what’s going on. J Pediatr Neonat Individual Med 2013;2(2):e020218. doi:10.7363/020218.
9. Jiling T, Simon D, Lu J, Meng FJ, Li D, Schy R, et al. The roles of bacteria and TLR4 in rat and murine models of necrotizing necrocolitis. J Immunol 2006; 177(5):33272-3282. doi: 10.4049/jimmunol.177.5.3273
10. Alcamo AM, Schanbacher BL, Huang H, Nankervis CA, Bauer JA, Glannone PJ. Cellular strain amplifies LPS-induced stress signaling in immature enterocytes: potential implications for preterm infants NCPAP. Pediatric Research 2012; 72(3): 256-261. doi: 10.1038/pr.2012.77.
11. Chu A, Hageman JR, Caplan MS. Necrotizing Enterocolitis: Predictive Markers and Preventive Strategies. NeoReviews. 2013;14(3):e113-118. Downloaded from http://neoreviews.aapublications.org/at UNIV OF CHICAGO on March7, 2013.
12. Fox TP, Godavitarne C. What really causes Necrotizing Enterocolitis? ISRN Gastroenterology 2012; 2012:1-9. doi:10.5402/2012/628317.
13. Cetin S, Ford HR, Sysko LR, Agarwal C, Wang J, Neal MD, et al. Endotoxin inhibits intestinal epithelial restitution through activation of Rho-GTPase and increased focal adhesions. J Biol Chem 2004; 279(23):24592-24600. doi:10.1074/jbc.M313620200.
14. Dai S, Sodhi C, Cetin S, Richardson W, Branca M, Neal MD, et al. Extracellular high mobility group box-1(HMGB1) inhibits enterocyte migration via activation of toll-like receptor-4 and increased cell-matrix adhesiveness. J Bio Chem 2010; 285(7):4995-5002. doi: 10.1074/jbc.M109.067454.
15. Siggers RH and Hackman DJ. The role of innate immune-stimulated epithelial apoptosis during gastrointestinal inflammatory diseases. Cell Mol Life Sci 2011; 68(22):3623-3634. doi: 10.1007/s00018-011-0821-4.
16. Afrazi A, Sodhi CP, Good M, Jia H, Siggers R, Yazji I, et al. Intracellular heat shock protein-70 negatively regulates TLR4 signaling in the newborn intestinal epithelium. J Immunol 2012; 188(9):4543-4557. doi: 10.4049/jimmunol.1103114.
17. Sodhi CP, Shi XH, Richardson WM, Grant ZS, Shapiro RA, Prindle T Jr, et al. Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis. Gastroenterology 2010; 138(1): 185-196. doi: 10.1053/j.gastro.2009.09.045.
18. Caplan MS. Probiotic and prebiotic supplementation for the prevention of neonatal necrotizing enterocolitis. J Perinatol 2009; 29(Suppl2):S2-6. doi: 10.1038/jp.2009.21.
19. Chen CC, Walker Allan. Probiotics and the mechanism of necrotizing enterocolitis. Seminars in Pediatric Surgery 2013; 22(2):94-100. http://dx.doi.org/10.1053/jj.sempedsurg.2013.01.006.
20. Al Faleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2014;4:CD005496. doi:10.1002/14651858. CD005496.pub4.
21. Coran AG, Caldamone A, Adzick NS, Krimmel TM, Laberge JM, Shamberger R. Pediatric Surgery. 7th Edition, Philadelphia, USA, Elsevier Saunders, 2012, Chapter 94;2: 1187-1207. ISBN: 978-0-323-07255-7.
22. Tarnow Mordi W, Soll RF. Probiotic supplementation in preterm infants: it is time to change practice. J Pediatri 2014; 164(5):959-60. doi:10.1016/j.jpeds.2013.12.050
23. Richardson WM, Sodhi CP, Russo A, Siggers RH, Afrazi A, Gribar SC, et al. Nucleotide-binding oligomerization domain-2 inhibits Toll-like receptor-4 signaling in the intestinal epithelium. Gastroenterology 2010; 139(3):904-917. doi: 10.1053/j.gastro.2010.05.038.
24. Joly AL, Wettstein G, Mignot F, Ghiringhelli and Garrido C. Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J Innate Immun 2010; 2(3):238-247. doi: 10.1159/000296508.
25. Good M, Siggers RH, Sodhi CP, Afrazi A, Alkhudar F, Egan CE, et al. Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Pro Natl Acad Sci U S A 2012;109(28):11330-11335. doi: 10.1073/pnas.1200856109.
26. Rowland KJ, Choi PM, Warner BW. The role of growth factors in intestinal regeneration and repair in necrotizing enterocolitis. Seminars in Pediatric Surgery2013;22(2):101-111. http://dx.doi.org/10.1053/j.sempedsurg.2013.01.007.
27. Chen CL, Yu X, James IO, et al. Heparin-binding EGF-like growth factor protects intestinal stem cells from injury in a rat model of necrotizing enterocolitis. Lab Invest 2012;92:331-344.
28. Yang J, Watkins D, Chen CL, Bhushan B, Zhou Yu Besner GE. Heparin-binding epidermal growth factor like growth factor and mesenchymal stem cells act synergistically to prevent experimental necrotizing enterocolitis. J AM Coll Surg 2012; 215:534-545.
29. Heather J.L. Brooks, Michelle A. McConnell and Roland S. Broadbent. Microbes and the Inflammatory Response in Necrotising Enterocolitis, Preterm Birth. Dr. Offer Erez (Ed.), 2013. ISBN: 978-953-51-0952-5, InTech, DOI: 10.5772/55039. Available from: http://www.intechopen.com/books/preterm-birth/microbes-and-the-inflammatory-response-in-necrotising-enterocolitis
30. Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotizing enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2013;5:CD001970.doi:10.1002/14651858.
31. Dai D, Nanthkumar NN, Newburg DS, Walker WA. Role of oligosaccharides and glycoconjugates in intestinal host defense. J Pediatr Gastroenterol Nutr 2000; 30: S23-S33.
Published
2016-01-02
Issue
Section
Review Articles
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
