Heparin-binding epidermal growth factor-like growth factor promotes enterocyte migration and proliferation in neonatal rats with necrotizing enterocolitis.
OBJECTIVE
We have shown that heparin-binding epidermal growth factor-like growth factor (HB-EGF) decreases experimental necrotizing enterocolitis (NEC). Intestinal epithelial cell (IEC) migration (restitution) and proliferation are key elements in recovery from intestinal injury. Here, we investigated whether the beneficial effects of HB-EGF are mediated, in part, by its ability to affect these processes.


METHODS
Necrotizing enterocolitis was induced in newborn rats by exposure to stress (hypoxia, hypothermia, hypertonic feedings, and lipopolysaccharide), with pups receiving different doses of HB-EGF (0, 25, 50, 100, 200, 400, 600, and 800 microg/kg). To investigate the effect of HB-EGF on enterocyte proliferation and migration, bromodeoxyuridine was administered intraperitoneally 18 hours before sacrifice, with intestine subjected to bromodeoxy-uridine immunohistochemistry.


RESULTS
The incidence and severity of experimental NEC decreased, and the survival rate increased, with increasing doses of HB-EGF. Results were confirmed using scanning electron microscopy. Migration of IEC in breast-fed pups was 7.07 microm/h, decreased significantly to 2.29 microm/h in stressed pups, and was significantly improved at 5.95 microm/h in pups subjected to stress but treated with HB-EGF (P < .05). Quantification of IEC proliferation revealed 208 (+) cells per high-power field (HPF) in breast-fed pups, which decreased significantly to 99 (+) cells per HPF in stressed pups and increased to 190 (+) cells per HPF in stressed pups treated with HB-EGF (P < .05).


CONCLUSIONS
These results demonstrate that HB-EGF protects newborn rats from experimental NEC in a dose-dependent fashion. The ability of HB-EGF to protect the intestines from NEC is due, in part, to the ability of HB-EGF to preserve enterocyte migration and proliferation.
Feng
Jiexiong
J
Department of Pediatric Surgery, Center for Cell and Vascular Biology, Children's Research Institute and The Ohio State University College of Medicine and Public Health, Columbus, OH 43205, USA.
Besner
Gail E
GE
D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000503:physiopathology* / Q000628:therapy; D020895:Enterocytes / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; 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