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

Purpose: 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 lipopolysacchride), with pups receiving different doses of HB-EGF (0, 25, 50, 100, 200, 400, 600, and 800 mu g/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 mu m/h, decreased significantly to 2.29 mu m/h in stressed pups, and was significantly improved at 5.95 mu m/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. (c) 2007 Elsevier Inc. All rights reserved.