Deletion of the heparin-binding epidermal growth factor-like growth factor gene increases susceptibility to necrotizing enterocolitis.
BACKGROUND
Necrotizing enterocolitis (NEC) is the leading surgical cause of death in premature infants. We have accumulated evidence supporting a role for heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) in protection of the intestines from NEC. The aim of the current study was to evaluate the effect of loss-of-function of endogenous HB-EGF on susceptibility to NEC.


METHODS
Neonatal HB-EGF((-/-)) knockout (KO) mice and their HB-EGF((+/+)) wild-type (WT) counterparts were exposed to experimental NEC. An additional group of HB-EGF KO pups were also exposed to NEC but had HB-EGF added to their formula. To examine gut barrier function, HB-EGF KO and WT pups received intragastric fluorescein isothiocyanate-labeled dextran (FITC dextran) under basal and stressed conditions, and serum FITC dextran levels were measured.


RESULTS
The WT mice had an incidence of NEC of 53%, whereas HB-EGF KO mice had a significantly increased incidence of NEC of 80% (P = .04). Importantly, administration of exogenous HB-EGF to HB-EGF KO pups significantly reduced the incidence of NEC to 45% (P = .04). Heparin-binding EGF KO mice had significantly increased intestinal permeability compared to WT mice under basal and stressed conditions.


CONCLUSIONS
Our results provide evidence that loss of the HB-EGF gene increases susceptibility to NEC and that administration of exogenous HB-EGF reverses this susceptibility.
Radulescu
Andrei
A
Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Yu
Xiaoyi
X
Orvets
Nathan D
ND
Chen
Yan
Y
Zhang
Hong-Yi
HY
Besner
Gail E
GE
D000818:Animals; D000831:Animals, Newborn; D020345:Enterocolitis, Necrotizing / Q000235:genetics* / Q000517:prevention & control; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins
J Pediatr Surg. 2001 Apr;36(4):587-92
11283883
Curr Opin Infect Dis. 2003 Aug;16(4):349-55
12861088
Arch Dis Child. 1984 Mar;59(3):236-41
6424583
J Immunol. 2006 Sep 1;177(5):3273-82
16920968
EMBO J. 2001 Jul 2;20(13):3342-50
11432822
J Pediatr Surg. 2008 Jun;43(6):1182-90
18558204
Mol Cell Biol. 2003 Mar;23(5):1581-9
12588978
Gastroenterology. 2005 Aug;129(2):609-25
16083716
EMBO J. 2003 Jun 2;22(11):2704-16
12773386
Pediatr Pathol. 1994 Nov-Dec;14(6):1017-28
7855004
Cell Regul. 1990 Oct;1(11):811-9
2088527
Surgery. 2009 Aug;146(2):334-9
19628093
Semin Perinatol. 2004 Jun;28(3):221-33
15283101
Am J Physiol. 1997 Aug;273(2 Pt 1):G253-7
9277401
J Pediatr Surg. 2006 Jan;41(1):144-9; discussion 144-9
16410124
Am J Respir Crit Care Med. 1995 Nov;152(5 Pt 1):1545-8
7582291
Arch Surg. 1990 Mar;125(3):403-4
2407230
N Engl J Med. 1984 Apr 26;310(17):1093-103
6369134
J Pediatr Surg. 2006 Apr;41(4):742-7; discussion 742-7
16567187
J Pediatr Surg. 1974 Oct;9(5):587-95
4138917
J Neurosci. 2002 Jul 1;22(13):5365-73
12097488
Arch Dis Child. 1982 Feb;57(2):141-5
7065710
Arterioscler Thromb Vasc Biol. 2005 Sep;25(9):1884-90
15994441
J Invest Surg. 2003 Mar-Apr;16(2):57-63
12746188
Surgery. 2007 Aug;142(2):234-42
17689691
Trends Cardiovasc Med. 2000 Oct;10(7):304-10
11343971
J Burn Care Rehabil. 2002 Mar-Apr;23(2):116-25
11882801
J Invest Dermatol. 1996 Jan;106(1):49-56
8592081
Gastroenterology. 1999 Sep;117(3):577-83
10464133
Semin Pediatr Surg. 2005 Aug;14(3):167-74
16084404
Science. 1991 Feb 22;251(4996):936-9
1840698
Pediatr Res. 2009 Apr;65(4):437-42
19127210