ASPIRIN-INDUCED, NEUTROPHIL-MEDIATED INJURY TO VASCULAR ENDOTHELIUM

Previous studies indicate that aspirin can promote neutrophil (PMN) ad hesion to endothelial cells and neutrophil-mediated endothelial cell d etachment. The objectives of the present study were to determine wheth er PMN adhesion is a prerequisite for aspirin-induced, PMN-mediated en dothelial cell detachment and whether neutrophil-derived oxidants and/ or proteases are responsible for the cell detachment. Human PMNs were added to confluent monolayers of human umbilical vein endothelial cell s (HUVEC) and coincubated with or without aspirin at a clinically rele vant concentration (300 mu g/ml). Aspirin-activated PMNs induced endot helial cell detachment, but not cell lysis. Endothelial cell detachmen t was always preceded by retraction of endothelial cells within the mo nolayer. The aspirin-induced, neutrophil-mediated cell detachment was prevented by a monoclonal antibody directed against CD11/CD18 adhesion integrins on PMNs. Elastase inhibitors, but not superoxide dismutase or catalase, prevented both endothelial cell retraction and detachment . If aspirin-activated neutrophils were allowed to migrate across the monolayers, endothelial cell retraction or detachment did not occur. T hese studies indicate that aspirin-induced, PMN-mediated endothelial c ell retraction and detachment requires PMN adhesion to the target cell s and is due to neutrophil-derived elastase. Endothelial cell retracti on, induced by activated neutrophils, may represent an exaggeration of a normal physiologic event, i.e., neutrophil emigration.