Aspirin-induced, neutrophil-mediated injury to vascular endothelium.

Abstract

Previous studies indicate that aspirin can promote neutrophil (PMN) adhesion to endothelial cells and neutrophil-mediated endothelial cell detachment. The objectives of the present study were to determine whether PMN adhesion is a prerequisite for aspirin-induced, PMN-mediated endothelial 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 cells (HUVEC) and coincubated with or without aspirin at a clinically relevant concentration (300 micrograms/ml). Aspirin-activated PMNs induced endothelial cell detachment, but not cell lysis. Endothelial cell detachment was always preceded by retraction of endothelial cells within the monolayer. 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. These studies indicate that aspirin-induced, PMN-mediated endothelial cell retraction and detachment requires PMN adhesion to the target cells and is due to neutrophil-derived elastase. Endothelial cell retraction, induced by activated neutrophils, may represent an exaggeration of a normal physiologic event, i.e., neutrophil emigration.