The Protective Role of Epidermal Growth Factor in Neonatal Necrotizing Enterocolitis

Persistent Link:
http://hdl.handle.net/10150/195517
Title:
The Protective Role of Epidermal Growth Factor in Neonatal Necrotizing Enterocolitis
Author:
Clark, Jessica Ann
Issue Date:
2006
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal disease in premature babies. Despite significant morbidity and mortality, the cause of this disease remains unclear and there are no preventative treatments available. Prematurity and enteral feeding of infant formula are considered to be the primary risk factors for development of NEC. Interestingly, the incidence of NEC is six to ten times lower in breast-fed babies compared to those that were formula-fed. The factors responsible for the protective effect of breast milk against NEC have not been identified, but epidermal growth factor (EGF) is one of the most promising candidates. EGF is found at high concentrations in human milk, but is not present in any commercial formula. Mothers with extremely premature babies have 50-80% higher levels of EGF in their breast milk compared to mothers with full term infants. This suggests that EGF plays an important role in the development of premature infants. Our studies have shown that supplementation of EGF into formula significantly reduces the incidence of NEC in a neonatal rat model. However, the mechanisms underlying this EGF-mediated reduction of NEC are not understood. The overall hypothesis of this dissertation is that the protective effect of EGF in NEC pathogenesis is mediated via increased expression of pro-survival genes and strengthening of the mucosal barrier. The results of the studies within this dissertation demonstrate that treatment with EGF significantly decreases intestinal epithelial cell apoptosis at the site of NEC injury by up-regulating anti-apoptotic genes and down-regulating pro-apoptotic genes. Furthermore, supplementation of formula with EGF strengthens the mucosal barrier by inducing accelerated maturation of ileal goblet cells and mucin-2 production. In addition, EGF treatment normalizes expression of crucial tight junction proteins in the ileum. Consequently, EGF treatment results in a significant decrease in intestinal paracellular permeability and improved barrier function. Results from these studies will provide significant contributions to the understanding of EGF-mediated reduction of NEC, which may lead to development of therapeutic strategies for the treatment of human NEC.
Type:
text; Electronic Dissertation
Keywords:
neonatal; intestine; apoptosis; tight junctions; intestinal barrier
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Physiological Sciences; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Dvorak, Bohuslav

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleThe Protective Role of Epidermal Growth Factor in Neonatal Necrotizing Enterocolitisen_US
dc.creatorClark, Jessica Annen_US
dc.contributor.authorClark, Jessica Annen_US
dc.date.issued2006en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractNeonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal disease in premature babies. Despite significant morbidity and mortality, the cause of this disease remains unclear and there are no preventative treatments available. Prematurity and enteral feeding of infant formula are considered to be the primary risk factors for development of NEC. Interestingly, the incidence of NEC is six to ten times lower in breast-fed babies compared to those that were formula-fed. The factors responsible for the protective effect of breast milk against NEC have not been identified, but epidermal growth factor (EGF) is one of the most promising candidates. EGF is found at high concentrations in human milk, but is not present in any commercial formula. Mothers with extremely premature babies have 50-80% higher levels of EGF in their breast milk compared to mothers with full term infants. This suggests that EGF plays an important role in the development of premature infants. Our studies have shown that supplementation of EGF into formula significantly reduces the incidence of NEC in a neonatal rat model. However, the mechanisms underlying this EGF-mediated reduction of NEC are not understood. The overall hypothesis of this dissertation is that the protective effect of EGF in NEC pathogenesis is mediated via increased expression of pro-survival genes and strengthening of the mucosal barrier. The results of the studies within this dissertation demonstrate that treatment with EGF significantly decreases intestinal epithelial cell apoptosis at the site of NEC injury by up-regulating anti-apoptotic genes and down-regulating pro-apoptotic genes. Furthermore, supplementation of formula with EGF strengthens the mucosal barrier by inducing accelerated maturation of ileal goblet cells and mucin-2 production. In addition, EGF treatment normalizes expression of crucial tight junction proteins in the ileum. Consequently, EGF treatment results in a significant decrease in intestinal paracellular permeability and improved barrier function. Results from these studies will provide significant contributions to the understanding of EGF-mediated reduction of NEC, which may lead to development of therapeutic strategies for the treatment of human NEC.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectneonatalen_US
dc.subjectintestineen_US
dc.subjectapoptosisen_US
dc.subjecttight junctionsen_US
dc.subjectintestinal barrieren_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairDvorak, Bohuslaven_US
dc.contributor.committeememberBoitano, Scotten_US
dc.contributor.committeememberGhishan, Fayezen_US
dc.contributor.committeememberHaussler, Marken_US
dc.contributor.committeememberPayne, Claireen_US
dc.contributor.committeememberWispe, Jonen_US
dc.identifier.proquest1532en_US
dc.identifier.oclc137356378en_US
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