Heparin-binding epidermal growth factor–like growth factor promotes enterocyte migration and proliferation in neonatal rats with necrotizing enterocolitis

PurposeWe 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.MethodsNecrotizing enterocolitis was induced in newborn rats by exposure to stress (hypoxia, hypothermia, hypertonic feedings, and lipopolysacchride), with pups receiving different doses of HB-EGF (0, 25, 50, 100, 200, 400, 600, and 800 μg/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.ResultsThe 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 μm/h, decreased significantly to 2.29 μm/h in stressed pups, and was significantly improved at 5.95 μm/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).ConclusionsThese 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.