Heparin-binding EGF-like growth factor downregulates expression of adhesion molecules and infiltration of inflammatory cells after intestinal ischemia/reperfusion injury.
OBJECTIVE
This study examined whether heparin-binding epidermal growth factor (EGF) like growth factor (HB-EGF), a proven intestinal cytoprotective molecule, exerts its protective effects through modulation of adhesion molecule expression and inflammatory cell infiltration, important pathogenic mediators of ischemia/reperfusion (I/R) injury.


METHODS
Total midgut I/R injury in rats was achieved by occlusion of the superior mesenteric artery for 90 minutes followed by reperfusion. Rats were treated intraluminally with 600 microg/kg HB-EGF or with PBS 45 minutes after the onset of ischemia. Four- or 24-hours post-I/R, ileum was harvested and processed for immunhistochemical detection of P-/E-selectins, intercellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1 (VCAM-1), and polymorphonuclear cells (PMN)/macrophages (MPhi).


RESULTS
P-/E-selectins were significantly induced in vascular endothelia 4 hours after I/R injury compared with normal intestine. HB-EGF treatment significantly down-regulated the expression of P-/E-selectins. I/R-injured intestine displayed overexpression of ICAM-1 and VCAM-1, which were significantly down-regulated by HB-EGF treatment. Lastly, I/R injury caused significant infiltration of PMN and MPhi into wounded tissue 24 hours after I/R compared with normal intestine. HB-EGF treatment significantly decreased PMN and MPhi infiltration into the injured tissue.


CONCLUSIONS
HB-EGF intestinal cytoprotection is mediated, in part, by down-regulation of expression of adhesion molecules and infiltration of PMN and MPhi after intestinal I/R injury.
Xia
Guliang
G
Department of Pediatric Surgery, Children's Hospital and The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43205, USA.
Martin
Abigail E
AE
Besner
Gail E
GE
D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003250:Constriction; D003864:Depression, Chemical; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects*; D066257:Heparin-binding EGF-like Growth Factor; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D007422:Intestines / Q000098:blood supply*; D007511:Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D017538:Mesenteric Artery, Superior; D009504:Neutrophils / Q000187:drug effects; D019007:P-Selectin / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D015815:Cell Adhesion Molecules; D019040:E-Selectin; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D019007:P-Selectin; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D004815:Epidermal Growth Factor