title: 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.
authors.affiliation: Department of Physiology, Louisiana State University Medical Center, Shreveport, USA.
authors.forename: N
authors.initials: N
authors.lastname: Yoshida
authors.forename: G
authors.initials: G
authors.lastname: Cepinskas
authors.forename: D N
authors.initials: DN
authors.lastname: Granger
authors.forename: D C
authors.initials: DC
authors.lastname: Anderson
authors.forename: R E
authors.initials: RE
authors.lastname: Wolf
authors.forename: P R
authors.initials: PR
authors.lastname: Kvietys
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology / Q000633:toxicity*; D002374:Catalase / Q000037:antagonists & inhibitors; D002448:Cell Adhesion / Q000187:drug effects; D048429:Cell Size; D002478:Cells, Cultured; D002511:Cephalosporins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D019272:Leukocyte Elastase; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D002511:Cephalosporins; D016177:Macrophage-1 Antigen; C065332:L 658758; D002374:Catalase; D013482:Superoxide Dismutase; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D001241:Aspirin