Heparin-binding epidermal growth factor-like growth factor reduces intestinal apoptosis in neonatal rats with necrotizing enterocolitis.
OBJECTIVE
We have previously demonstrated that enterally administered heparin-binding epidermal growth factor-like growth factor (HB-EGF) decreases the incidence and severity of necrotizing enterocolitis (NEC) in a neonatal rat model. Because apoptosis contributes to gut barrier failure in this model, the aim of this study was to investigate the effect of HB-EGF on apoptosis during the development of NEC.


METHODS
NEC was induced in neonatal rats by exposure to hypoxia, hypothermia, hypertonic formula feeding (HHHTF) plus enteral administration of lipopolysaccharide (LPS). Fifty-one neonatal rats were randomly divided into the following groups: (1) breast-fed (BF), (2) HHHTF + LPS, and (3) HHHTF + LPS with HB-EGF (600 microg/kg) added to the formula. NEC was evaluated using a standard histological scoring system. Apoptotic cells in intestinal tissues were detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and by active caspase 3 immunohistochemical staining.


RESULTS
The incidence of NEC in the HHHTF + LPS group was higher than that in the BF group (65% vs 0%, P < .05). With administration of HB-EGF, the incidence of NEC significantly decreased to 23.8% (P < .05). The median TUNEL and active caspase 3 scores in the HHHTF + LPS group were higher than those in the BF group (1.9 vs 0.9 and 1.75 vs 0.6, respectively, P < .05). The median TUNEL and active caspase 3 scores were significantly decreased in the HHHTF + LPS + HB-EGF group compared with the HHHTF + LPS group (1.24 vs 1.9 and 1.0 vs 1.75, respectively, P < .05).


CONCLUSIONS
HB-EGF reduces the incidence of NEC in a neonatal rat model in part by decreasing apoptosis. These results support the use of HB-EGF-based clinical regimens for the treatment of NEC.
Department of Pediatric Surgery, Center for Cell and Vascular Biology, Children's Research Institute, Columbus, OH 43205, USA.
Jiexiong
J
Feng
Osama N
ON
El-Assal
Gail E
GE
Besner
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy* / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use*; D006493:Heparin / Q000494:pharmacology* / Q000627:therapeutic use*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley
C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D004815:Epidermal Growth Factor; D006493:Heparin