Epidermal growth factor reduces autophagy in intestinal epithelium and in the rat model of necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature infants. Epidermal growth factor (EGF) is one of the most promising candidates in NEC prophylaxis. Autophagy regulates cell homeostasis, but uncontrolled activation of autophagy may lead to cellular injury. The aim was to evaluate the effects of EGF on intestinal autophagy in epithelial cells and in the rat NEC model and measure autophagy in NEC patients. Intestinal epithelial cells (IEC-6) and the rat NEC model were used to study the effect of EGF on intestinal autophagy. Protein levels of Beclin 1 and LC3II were measured in the intestinal epithelium in both in vivo and in vitro models. Ultrastructural changes in intestinal epithelium were studied by electron microscopy. Expression of Beclin 1, LC3II, and p62 protein was evaluated in biopsies from NEC patients. Autophagy was induced in IEC-6 cells and inhibited by adding EGF into the culture. In the rat NEC model, EGF treatment of NEC reduced expression of Beclin 1 and LC3II in ileal epithelium. Morphologically, typical signs of autophagy were observed in the epithelium of the NEC group, but not in the EGF group. A strong signal for Beclin 1 and LC3II was detected in the intestine from patients with NEC. Autophagy is activated in the intestinal epithelium of NEC patients and in the ileum of NEC rats. Supplementation of EGF blocks intestinal autophagy in both in vivo and in vitro conditions. Results from this study indicate that EGF-mediated protection against NEC injury is associated with regulation of intestinal autophagy.
Dept. of Pediatrics, Univ. of Arizona, Tucson, 85724-5073, USA.
Andrew A
AA
Maynard
Katerina
K
Dvorak
Ludmila
L
Khailova
Holly
H
Dobrenen
Kelly M
KM
Arganbright
Melissa D
MD
Halpern
Ashish R
AR
Kurundkar
Akhil
A
Maheshwari
Bohuslav
B
Dvorak
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D002460:Cell Line; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015994:Incidence; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D004815:Epidermal Growth Factor; D008869:Microtubule-Associated Proteins; C512829:Becn1 protein, rat; C526109:Anxa3 protein, rat