Heparin-Binding EGF-like Growth Factor Decreases Neutrophil–Endothelial Cell Interactions

Abstract

Hyperadhesiveness of neutrophils (PMN) to vascular endothelial cells (EC) followed by neutrophil transendothelial migration play important roles in the initiation of ischemia/reperfusion (I/R)-mediated injury. We investigated whether the ability of heparin-binding EGF-like growth factor (HB-EGF) to decrease intestinal injury after intestinal I/R is mediated, in part, by its ability to affect PMN-EC interactions and EC junctional integrity. Human umbilical vein EC monolayers were treated with HB-EGF (100 ng/mL) or phosphate-buffered saline followed by anoxia/reoxygenation (A/R). Simultaneously, labeled human PMN were treated with HB-EGF or phosphate-buffered saline and then co-incubated with EC for determination of PMN-EC adherence and PMN transendothelial migration. EC junctional integrity was also determined. PMN-EC adhesion increased after exposure of EC to A/R compared to EC exposed to normoxia (87% versus 64% binding, P < 0.05, Wilcoxon rank sum test). A/R-induced PMN-EC hyperadherence was significantly decreased by treatment of PMN with HB-EGF compared to nontreated cells (51% versus 87% binding, P < 0.05). HB-EGF significantly decreased PMN transendothelial migration and also augmented EC tight junctional integrity after A/R. HB-EGF significantly reduces A/R-induced PMN-EC adhesion and PMN transendothelial migration and augments junctional integrity in vitro. Thus, HB-EGF acts not only as a potent cytoprotective agent for the intestine, but as an anti-inflammatory agent as well.