Epidermal growth factor reduces hepatic sequelae in experimental necrotizing enterocolitis.
OBJECTIVE
Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants. We recently demonstrated that the gut/liver axis plays an important role in the pathophysiology of NEC through the release of inflammatory mediators into the intestinal lumen. We have also shown that supplementation of formula with epidermal growth factor (EGF) dramatically decreases ileal pathology associated with experimental NEC. In this study, we examined the effects of EGF on the liver portion of the gut/liver axis in the neonatal rat model of NEC.


METHODS
Newborn rats were divided into three experimental groups, NEC, hand-fed with growth-factor free formula; NEC + EGF, hand-fed with formula supplemented with 500 ng/ml rat EGF; or DF, dam fed. All animals were exposed to asphyxia and cold stress twice daily for 4 days to develop NEC.


RESULTS
EGF receptor expression was significantly (p <or= 0.01) decreased in the NEC+EGF group compared to the NEC group. EGF supplementation significantly decreased Kupffer cell numbers (p <or= 0.01) as well as hepatic tumor necrosis factor (TNF)-alpha and interleukin-18 production (p <or= 0.05). Further, TNF-alpha in the intestinal luminal contents of the NEC+EGF group were normalized to levels observed in DF controls compared to the NEC group (p <or= 0.05). Activated nuclear factor-kappaB was also substantially decreased in the NEC+EGF group versus the NEC group.


CONCLUSIONS
The results of this study indicate that EGF normalizes cytokine overproduction in the liver of neonatal rats with NEC, which contributes to diminished intestinal damage during the development of experimental NEC. These data suggest that supplementation of formula with EGF can have beneficial effects on the gut/liver axis during NEC pathogenesis.
Halpern
Melissa D
MD
Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, Ariz., USA. mhalpern@peds.arizona.edu
Holubec
Hana
H
Clark
Jessica A
JA
Saunders
Tara A
TA
Williams
Catherine S
CS
Dvorak
Katerina
K
Dvorak
Bohuslav
B
D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D004815:Epidermal Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; D016328:NF-kappa B; D004815:Epidermal Growth Factor; D066246:ErbB Receptors