Mice overexpressing the gene for heparin-binding epidermal growth factor-like growth factor (HB-EGF) have increased resistance to hemorrhagic shock and resuscitation.
BACKGROUND
The aim of the current study was to determine whether overexpression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) could protect the intestines from injury after hemorrhagic shock and resuscitation in mice.


METHODS
Hemorrhagic shock and resuscitation was induced in HB-EGF transgenic and wild type mice. Cross-reacting material 197 (5 mg/kg) was administered to a subset of HB-EGF transgenic mice to block the overexpressed HB-EGF. Intestinal histologic injury scores, intestinal epithelial cell apoptosis indices, and gut barrier function were determined. The Student t test and 1-way analysis of variance were employed to compare the differences between groups.


RESULTS
All mice subjected to hemorrhagic shock and resuscitation had significantly increased intestinal histologic injury scores, apoptosis indices, and intestinal permeability compared with sham-operated mice. Compared with wild type mice, HB-EGF transgenic mice had significantly decreased histologic injury (mean injury grade 2.79 ± 0.84 vs 3.88 ± 1.43, P = .02), apoptosis indices (mean apoptosis index 8.77 ± 5.23 vs 17.91 ± 13.23, P = .03), and mucosal permeability (FITC-dextran 4 clearance 13.06 ± 5.67 vs 20.03 ± 7.81 nL/min/ m(2), P = .02) at 3 hours of reperfusion. HB-EGF transgenic mice subjected to hemorrhagic shock and resuscitation and treated with cross-reacting material 197 had a significantly increased histologic injury (mean injury grade 3.63 ± 1.00 vs 2.79 ± 0.84, P = .04) and mucosal permeability (FITC-dextran 4 clearance 22.87 ± 9.69 vs 13.06 ± 5.67 nL/min/cm2, P = .01) at 3 hours of reperfusion compared with non-cross-reacting material 197 treated transgenic mice, with no significant changes in apoptosis indices. Cross-reacting material 197 did not reverse the decreased apoptosis observed in HB-EGF transgenic mice subjected to hemorrhagic shock and resuscitation, which suggests that mechanisms in addition to decreased apoptosis may be responsible for the intestinal cytoprotective effects of endogenous HB-EGF overexpression.


CONCLUSIONS
Overexpression of HB-EGF increases resistance to hemorrhagic shock and resuscitation in mice.
Zhang
Hong-yi
HY
Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.
Radulescu
Andrei
A
Chen
Chun-liang
CL
Olson
Jacob K
JK
Darbyshire
Amanda K
AK
Besner
Gail E
GE
D000818:Animals; D017209:Apoptosis; D019610:Cytoprotection; D005786:Gene Expression Regulation; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007422:Intestines / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015427:Reperfusion Injury / Q000517:prevention & control*; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000150:complications*
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins