Heparin-binding Epidermal Growth Factor-Like Growth Factor Overexpression in Transgenic Mice Increases Resistance to Necrotizing Enterocolitis

J Pediatr Surg. 2010 Oct;45(10):1933-9. doi: 10.1016/j.jpedsurg.2010.05.002.

Abstract

Background: Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency and the leading surgical cause of death in premature infants. We have shown that administration of exogenous heparin-binding epidermal growth factor-like growth factor (HB-EGF) in mice protects the intestines from experimental NEC. The aim of the current study was to evaluate the effect of gain-of-function of endogenous HB-EGF on susceptibility to NEC.

Methods: Neonatal HB-EGF transgenic (TG) mice and their wild-type (WT) counterparts were exposed to experimental NEC. An additional group of HB-EGF TG pups were also exposed to NEC, but received the HB-EGF antagonist cross-reacting material 197 (CRM197) injected subcutaneously immediately after birth. To examine gut barrier function, HB-EGF TG and WT pups received intragastric fluorescein isothiocyanate-labeled dextran under basal and stressed conditions, and serum fluorescein isothiocyanate-labeled dextran levels were measured.

Results: Wild-type mice had an incidence of NEC of 54.2%, whereas HB-EGF TG mice had a significantly decreased incidence of NEC of 22.7% (P = .03). Importantly, administration of CRM197 to HB-EGF TG pups significantly increased the incidence of NEC to 65% (P = .004). HB-EGF TG mice had significantly decreased intestinal permeability compared to WT mice both under basal and stressed conditions.

Conclusions: Our results provide evidence that overexpression of the HB-EGF gene decreases susceptibility to NEC and that administration of the HB-EGF antagonist CRM197 reverses this protective effect.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Bacterial Proteins / pharmacology*
  • Dextrans / pharmacology*
  • Diphtheria Toxin / pharmacology*
  • Disease Models, Animal
  • Enterocolitis, Necrotizing / genetics
  • Enterocolitis, Necrotizing / pathology
  • Enterocolitis, Necrotizing / prevention & control*
  • Fluorescein-5-isothiocyanate / analogs & derivatives*
  • Fluorescein-5-isothiocyanate / pharmacology
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intestinal Mucosa / drug effects
  • Intestines / drug effects
  • Intestines / pathology
  • Mice
  • Mice, Transgenic
  • Permeability / drug effects

Substances

  • Bacterial Proteins
  • Dextrans
  • Diphtheria Toxin
  • HBEGF protein, human
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • fluorescein isothiocyanate dextran
  • CRM197 (non-toxic variant of diphtheria toxin)
  • Fluorescein-5-isothiocyanate