Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) disease of premature infants with excessive morbidity and mortality that afflicts 3 000 to 4,000 babies in the United States each year. Many factors contribute to the development of NEC, mainly prematurity, enteral feeding, infectious agents and/or intestinal hypoxia-ischemia Enteral feeding is nearly always a prerequisite for the development of NEC. However, the exact mechanism of NEC pathogenesis is poorly understood. In humans, multicenter trials with 926 neonates have shown that NEC is 6-10 times more common in formula-fed infants compared to those fed with human milk. In animal experiments, maternal milk also prevents NEC. These findings have stimulated the search for various components of milk that protects against NEC. Epidermal growth factor (EGF) is one of the most promising candidates for the treatment of NEC. Mammalian milk of many species contains high concentrations of EGF. Moreover, maternal milk is the major source of EGF for neonates during the suckling period. In contrast, EGF is absent in all commercial infant formulas. EGF accelerates healing of injured gastrointestinal epithelium. Another peptide closely related to EGF is transforming growth factor-alpha (TGF-alpha). TGF-alpha is a member of the family of EGF-related peptides, sharing with EGF significant amino acid sequence homology, similar biological effects, and high affinity to the same receptor - EGF- receptor (EGF-R). Both EGF and TGF-alpha are presented in the neonatal gastrointestinal tract and their direct effects on healing processes in the gastrointestinal epithelium are well established. Since TGF-alpha is absent in the milk of most mammals, the major source of intestinal TGF-a in neonates is intestinal endogenous production and pancreatic secretion. Recently, we have shown that milk-borne EGF modulates intestinal TGF-alpha synthesis in neonatal rats. Our long-term goal is to understand the role of milk-borne biologically active substances in the pathogenesis of NEC. The central hypothesis of this proposal is that EGF will prevent the development of NEC in newborn rats. One of the best experimental models to study the etiology of NEC are suckling rats. Our laboratory has many years of experience with artificial rearing of suckling rats and therefore we are well positioned to pursue this hypothesis. Currently, there is no efficient treatment to prevent the incidence of NEC. The rationale of this proposal is that the effect of EGF on neonates at the molecular and cellular pathology level must be understood before an adequate therapy of necrotizing enterocolitis can be developed Specific Aim I will test the hypothesis that milk-borne EGF will prevent the development of NEC in suckling rats.
Specific Aim II will test the hypothesis that parenteral administration of EGF will prevent NEC and improve healing of NEC in suckling rats.
Specific Aim III will test the hypothesis that the treatment of NEC with exogenous EGF will upregulate intestinal expression of EGF receptor and TGF-alpha in suckling rats with NEC.
| Underwood, Mark A; Arriola, Jennifer; Gerber, Colin W et al. (2014) Bifidobacterium longum subsp. infantis in experimental necrotizing enterocolitis: alterations in inflammation, innate immune response, and the microbiota. Pediatr Res 76:326-33 |
| Dvorak, Katerina; Coursodon-Boyiddle, Christine F; Snarrenberg, Chelsea L et al. (2013) Helicobacter hepaticus increases intestinal injury in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 305:G585-92 |
| Underwood, Mark A; Kananurak, Anchasa; Coursodon, Christine F et al. (2012) Bifidobacterium bifidum in a rat model of necrotizing enterocolitis: antimicrobial peptide and protein responses. Pediatr Res 71:546-51 |
| Coursodon-Boyiddle, Christine F; Snarrenberg, Chelsea L; Adkins-Rieck, Camille K et al. (2012) Pomegranate seed oil reduces intestinal damage in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 303:G744-51 |
| Goldman, Aaron; Chen, Hwu Dau Rw; Roesly, Heather B et al. (2011) Characterization of squamous esophageal cells resistant to bile acids at acidic pH: implication for Barrett's esophagus pathogenesis. Am J Physiol Gastrointest Liver Physiol 300:G292-302 |
| Ran-Ressler, Rinat R; Khailova, Ludmila; Arganbright, Kelly M et al. (2011) Branched chain fatty acids reduce the incidence of necrotizing enterocolitis and alter gastrointestinal microbial ecology in a neonatal rat model. PLoS One 6:e29032 |
| Maynard, Andrew A; Dvorak, Katerina; Khailova, Ludmila et al. (2010) Epidermal growth factor reduces autophagy in intestinal epithelium and in the rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 299:G614-22 |
| Dvorak, Bohuslav (2010) Milk epidermal growth factor and gut protection. J Pediatr 156:S31-5 |
| Khailova, Ludmila; Mount Patrick, Sarah K; Arganbright, Kelly M et al. (2010) Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 299:G1118-27 |
| Khailova, Ludmila; Dvorak, Katerina; Arganbright, Kelly M et al. (2009) Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 297:G940-9 |
Showing the most recent 10 out of 27 publications
