Heparin-binding epidermal growth factor–like growth factor overexpression in transgenic mice increases resistance to necrotizing enterocolitis

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 EGF-like growth factor (HB-EGF) in 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 (CRM 197) injected subcutaneously immediately after birth. To examine gut barrier function, HB-EGF TG and WT pups received intragastric fluorescein isothiocyanate-labeled dextran (FITC-dextran) under basal and stressed conditions, and serum FITC-dextran levels were measured. Results WT 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=0.03). Importantly, administration of CRM 197 to HB-EGF TG pups significantly increased the incidence of NEC to 65% (p=0.004). 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 over expression of the HB-EGF gene decreases susceptibility to NEC, and that administration of the HB-EGF antagonist CRM 197 reverses this protective effect.

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

“…The shape of the observed intestinal lesions corresponded with those described by several authors using murine NEC models (Figure 2) (12,13). The incidence of severe intestinal lesions Articles (grade 3-4) differed significantly between breastfed mice and animals fed by formula supplemented with pIC (P < 0.01).…”

“…In our model, we used 72-h-old mice and succeeded in inducing intestinal lesions by repetitive application of higher dosages of LPS compared with NEC models with newborn mice (12). Our observation that NEC induction is possible despite preceding breastfeeding is in line with results of others.…”

“…induction, LPS supplementation is used to induce the inflammatory state of NEC (12,14). Neonatal TLR4 (receptor that recognizes LPS) deficient mice do not develop NEC (19).…”

“…Expression levels of proinflammatory chemokines have not been shown so far in comparable studies using murine feeding NEC models (12)(13)(14). Whole organ ileal mRNA expression of the chemokine CXCL1 (KC) and CXCL2 (MIP-2) showed no significant increase in all treatment groups submitted to the NEC protocol compared with age-matched breastfed animals (Supplementary Figure S1 online).…”

“…These are separated during the first day of life and receive a single dose of bacteria or LPS via an orogastric route (12,13). With this protocol, breastfeeding is almost avoided, which has been shown to be protective against NEC in both humans and rodents.…”