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1 Department of Pediatrics and Steele Memorial Children's Research Center, University of Arizona, Tucson, AZ, USA
2 Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
3 Department of Cell Biology and Anatomy, University of Arizona, Tucson, AZ, USA
4 Department of Pediatrics and Steele Memorial Children's Research Center, University of Arizona, Tucson, AZ, USA; Department of Cell Biology and Anatomy, University of Arizona, Tucson, AZ, USA
* To whom correspondence should be addressed. E-mail: dvorakb{at}peds.arizona.edu.
Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature infants. Although end-stage NEC is characterized histopathologically as extensive necrosis, apoptosis may account for the initial loss of epithelium prior to full development of disease. We have previously shown that epidermal growth factor (EGF) reduces the incidence of NEC in a rat model. While EGF has been shown to protect intestinal enterocytes from apoptosis, the mechanism of EGF-mediated protection against NEC is not known. The aim of this study was to investigate if EGF treatment elicits changes in expression of apoptotic markers in the ileum during the development of NEC. Using a well-established neonatal rat model of NEC, rats were divided into three experimental groups, dam fed (DF), milk formula fed (NEC), or fed with formula supplemented with 500 ng/ml EGF (NEC+EGF). Changes in ileal morphology, gene and protein expression, and histological localization of apoptotic regulators were evaluated. Anti-apoptotic Bcl-2 mRNA levels were markedly reduced and pro-apoptotic Bax mRNA levels were markedly elevated in the NEC group compared to DF controls. Supplementation of EGF into formula significantly increased anti-apoptotic Bcl-2 mRNA while pro-apoptotic Bax was significantly decreased. The Bax/Bcl-2 ratio for mRNA and protein were markedly decreased in NEC+EGF animals compared to the NEC group. The presence of caspase-3 positive epithelial cells was markedly reduced in EGF-treated rats. These data suggest that alteration of the balance between pro-and anti-apoptotic proteins in the site of injury is a possible mechanism by which EGF maintains intestinal integrity and protects intestinal epithelium against NEC injury.
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