Intestinal phenotype in mice overexpressing a heparin-binding EGF-like growth factor transgene in enterocytes

Chen, Chun-Liang; Mehta, Veela B.; Zhang, Hong Yi; Wu, Dana; Otabor, Iyore; Radulescu, Andrei; El-Assal, Osama N.; Feng, Jiexiong; Chen, Yan; Besner, Gail E.

doi:10.3109/08977190903407365

Cited by 10 publications

(19 citation statements)

References 52 publications

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“…We have shown that endogenous HB-EGF is increased in intestinal epithelial cells (IEC) in response to anoxia/reoxygenation and in intestine in response to I/R injury (11). We have also shown that HB-EGF knockout (KO) mice have increased intestinal injury in animal models of intestinal I/R (12), hemorrhagic shock and resuscitation (HS/R) (13) and necrotizing enterocolitis (NEC) (14), and that HB-EGF transgenic mice have decreased intestinal injury after HS/R (15) and improved intestinal anastomotic wound healing (unpublished data). Lastly, administration of exogenous HB-EGF protects the intestines from injury in animal models of I/R, HS/R and NEC (16, 17, 18).…”

Section: Introductionmentioning

confidence: 91%

HB-EGF Protects the Lungs after Intestinal Ischemia/Reperfusion Injury

James

Chen

Huang

et al. 2010

Journal of Surgical Research

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Background Acute respiratory distress syndrome continues to be a major source of morbidity and mortality in critically-ill patients. Heparin binding EGF-like growth factor (HB-EGF) is a biologically active protein that acts as an intestinal cytoprotective agent. We have previously demonstrated that HB-EGF protects the intestines from injury in several different animal models of intestinal injury. In the current study, we investigated the ability of HB-EGF to protect the lungs from remote organ injury after intestinal ischemia/reperfusion (I/R). Methods Mice were randomly assigned to one of the following groups: 1) sham-operated; 2) sham + HB-EGF (1200 µg/kg in 0.6 mL administered by intra-luminal injection at the jejuno-ileal junction immediately after identification of the superior mesenteric artery); 3) superior mesenteric artery occlusion for 45 min followed by reperfusion for 6 h (I/R); or 4) I/R+HB-EGF (1200 µg/kg in 0.6 mL) administered 15 min after vascular occlusion. The severity of acute lung injury was determined by histology, morphometric analysis and invasive pulmonary function testing. Animal survival was evaluated using Kaplan-Meier analysis. Results Mice subjected to intestinal I/R injury showed histological and functional evidence of acute lung injury and decreased survival compared to sham-operated animals. Compared to mice treated with HB-EGF (I/R + HB-EGF), the I/R group had more severe acute lung injury, and decreased survival. Conclusion Our results demonstrate that HB-EGF reduces the severity of acute lung injury after intestinal I/R in mice. These data demonstrate that HB-EGF may be a potential novel systemic anti-inflammatory agent for the prevention of the systemic inflammatory response syndrome (SIRS) after intestinal injury.

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Section: Introductionmentioning

confidence: 91%

HB-EGF Protects the Lungs after Intestinal Ischemia/Reperfusion Injury

James

Chen

Huang

et al. 2010

Journal of Surgical Research

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“…Although growth factors can promote wound healing, they are also involved in tumor progression. In preparation for human clinical administration of HB-EGF, we have developed and studied HB-EGF transgenic (TG) mice that specifically over-express HB-EGF in the gastrointestinal tract from the stomach to the colon under the direction of the villin promoter [94]. Upon examining the intestines of these HBEGF TG mice from newborn to geriatric ages, we were unable to identify any intestinal abnormalities, polyps or tumors [94].…”

Section: Effects Of Hb-egf During Intestinal Injurymentioning

confidence: 99%

Heparin-binding EGF-like growth factor (HB-EGF) therapy for intestinal injury: Application and future prospects

Yang

Zhou

et al. 2014

Pathophysiology

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Throughout the past 20 years, we have been investigating the potential therapeutic roles of heparin-binding EGF-like growth factor (HB-EGF), a member of the epidermal growth factor family, in various models of intestinal injury including necrotizing enterocolitis (NEC), intestinal ischemia/reperfusion (I/R) injury, and hemorrhagic shock and resuscitation (HS/R). Our studies have demonstrated that HB-EGF acts as an effective mitogen, a restitution-inducing reagent, a cellular trophic factor, an anti-apoptotic protein and a vasodilator, via its effects on various cell types in the intestine. In the current paper, we have reviewed the application and therapeutic effects of HB-EGF in three classic animal models of intestinal injury, with particular emphasis on its protection of the intestines from NEC. Additionally, we have summarized the protective functions of HB-EGF on various target cells in the intestine. Lastly, we have provided a brief discussion focusing on the future development of HB-EGF clinical applications for the treatment of various forms of intestinal injury including NEC.

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“…These mice were designed to specifically overexpress the human HB-EGF precursor (proHB-EGF) in the intestine using a 12.4 kb villin regulatory and promoter sequence to drive human proHB-EGF gene expression. [15] The villin promoter ensures the constant expression of HB-EGF throughout the entire intestine from the duodenum to the colon, throughout the entire crypt-villous axis.…”

Section: Introductionmentioning

confidence: 99%

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

Radulescu

Zhang

et al. 2010

Journal of Pediatric Surgery

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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.

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Intestinal phenotype in mice overexpressing a heparin-binding EGF-like growth factor transgene in enterocytes

Cited by 10 publications

References 52 publications

HB-EGF Protects the Lungs after Intestinal Ischemia/Reperfusion Injury

HB-EGF Protects the Lungs after Intestinal Ischemia/Reperfusion Injury

Heparin-binding EGF-like growth factor (HB-EGF) therapy for intestinal injury: Application and future prospects

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

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