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Heparin-binding EGF–like growth factor (HB-EGF) protects the intestines in vivo by inducing mediators of restitution in murine necrotizing enterocolitis

Research Scholar

Jixin Yang, Children's Hospital - Pediatrics (China)
Chun-Liang Chen, Co-Researcher
Gail Besner, Faculty Mentor


Jixin Yang is an international scholar from Wuhan, China. He graduated from Tongji Medical College of Huazhong University of Science and Technology, receiving his medical degree in 2008. From July 2008 to May 2010, he received residency training in Pediatric Surgery at Tongji Hospital. He applied for an international scholar position at The Ohio State University and was accepted as a post-doctoral scientist in the laboratory of Dr. Gail Besner at Nationwide Children's Hospital. Under Dr. Besner's mentorship since May 2010, Dr.Yang has been investigating the mechanisms by which HB-EGF protects the intestines from injury, with particular emphasis on neonatal necrotizing enterocolitis.

What is the issue or problem addressed in your research?

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency and the leading surgical cause of death in premature neonates. We have shown that administration of HB-EGF protects the intestines from experimental NEC. The current study was designed to investigate the role of HB-EGF in promoting intestinal restitution during experimental NEC.

What methodology did you use in your research?

Experimental NEC was induced in neonatal mice delivered prematurely on E18.5 by exposure to hypoxia, hypothermia, hypertonic feedings and LPS. Mice were randomized to breast-feeding, NEC, or NEC with administration of HB-EGF (800 µg/kg) added to the feeds. Additional pups were exposed to NEC+ HB-EGF, but received the HB-EGF antagonist cross-reacting material 197 (CRM 197) intraperitoneally (IP). Intestinal histological injury grading and intestinal permeability were determined after 72h. mRNA expression and protein production of integrin subunits and mediators of restitution were examined in the intestines by RT-PCR and Western blotting respectively.

What are the purpose/rationale and implications of your research?

The incidence of NEC in non-HB-EGF-treated mice was 68.7%, whereas mice subjected to NEC+HB-EGF had a significantly decreased incidence of 35.3% (p<0.01). Mice subjected to NEC+HB-EGF had significantly decreased intestinal permeability compared to mice subjected to NEC without HB-EGF (p<0.05). The mRNA levels of integrin subunits α3, α5, β1, paxillin, RhoA, Rac and Cdc42 were significantly down-regulated in mice subjected to NEC, whereas the mRNA levels of α5, β1, paxillin, RhoA, Rac and Cdc42 were significantly up-regulated in mice subjected to NEC+HB-EGF (all with p<0.05). The phosphorylation of integrin α5β1, FAK, Paxillin and Rac/Cdc42 decreased in animals exposed to NEC, whereas the phosphorylation levels were increased in animals exposed to NEC+HB-EGF (all with p<0.05). Importantly, IP CRM 197 injection in pups that received HB-EGF during NEC significantly decreased phosphorylation of the mediators of restitution (all with p<0.05). We conclude that administration of HB-EGF protects the intestines during experimental NEC by inducing mediators of intestinal restitution.