ABSTRACT: We have shown that heparin-binding epidermal growth factor-like growth factor (HB-EGF) protects the intestines from injury in several different animal models, including hemorrhagic shock and resuscitation (HS/R). The current study was designed to explore the mechanisms underlying the anti-inflammatory role of HB-EGF in preservation of gut barrier function after injury.
In vivo, HS/R was induced in wild-type and neutropenic mice, with or without administration of HB-EGF, and intestinal permeability determined by use of the everted gut sac method. In vitro, cultured human umbilical vein endothelial cells (HUVECs) and freshly isolated human peripheral blood mononuclear cells (PMNs) were used to determine the effects of HB-EGF on HUVEC-PMN adhesion, reactive oxygen species production in PMN, adhesion molecule expression in HUVEC and PMN, and the signaling pathways involved.
We found that administration of HB-EGF to healthy mice led to preservation of gut barrier function after HS/R. Likewise, induction of neutropenia in mice also led to preservation of gut barrier function after HS/R. Administration of HB-EGF to neutropenic mice did not lead to further improvement in gut barrier function. In vitro studies showed that HB-EGF decreased neutrophil-endothelial cell (PMN-EC) adherence by down-regulating adhesion molecule expression in EC via the phosphoinositide 3-kinase-Akt pathway, and by inhibiting adhesion molecule surface mobilization and reactive oxygen species production in PMN.
These results indicate that HB-EGF preserves gut barrier function by inhibiting PMN and EC activation, thereby blocking PMN-EC adherence after HS/R in mice, and support the future use of HB-EGF in disease states manifested by hypoperfusion injury.
Surgery 12/2011; 151(4):594-605. · 3.10 Impact Factor
ABSTRACT: The goal of this study was to determine the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) as a mediator of gut microcirculation after hemorrhagic shock and resuscitation (HS/R) in mice.
HS/R was induced in HB-EGF knockout (KO) and wild type (WT) mice. Ink-gelatin injection and vascular corrosion casting were performed to visualize the gut microvasculature. The degree of gut microcirculatory injury was graded using five patterns of injury (1-5) according to the severity of microvascular hypoperfusion. Statistical analyses were performed using linear mixed models with P < 0.05 considered statistically significant.
HB-EGF KO mice subjected to HS/R had significantly decreased perfusion of the gut microvasculature compared with WT mice subjected to HS/R (P = 0.0001). HB-EGF KO mice subjected to HS/R and treated with exogenous HB-EGF had significantly increased gut microvascular perfusion compared with non-HB-EGF treated KO mice (P = 0.01). Lastly, WT mice subjected to HS/R and treated with HB-EGF had significantly increased gut microvascular perfusion compared with non-HB-EGF-treated WT mice (P = 0.04).
HB-EGF improves gut microcirculation after HS/R. These findings support the clinical use of HB-EGF in protection of the intestines from disease states associated with intestinal hypoperfusion injury.
Journal of Surgical Research 11/2011; 171(1):218-25. · 2.25 Impact Factor
ABSTRACT: 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.
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.
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.
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.
Journal of Pediatric Surgery 10/2010; 45(10):1933-9. · 1.45 Impact Factor