Heparin-binding EGF-like growth factor downregulates expression of adhesion molecules and infiltration of inflammatory cells after intestinal ischemia/reperfusion injury

Background/Purpose: 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 μg/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 (Mφ). 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 Mφ into wounded tissue 24 hours after I/R compared with normal intestine. HB-EGF treatment significantly decreased PMN and Mφ 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 Mφ after intestinal I/R injury.