P-selectin antagonism with recombinant p-selectin glycoprotein ligand-1 (rPSGL-Ig) inhibits circulating activated platelet binding to neutrophils induced by damaged arterial surfaces.
Neutrophil P-selectin glycoprotein ligand-1 (PSGL-1) mediates the initial rolling and adhesion of neutrophils to P-selectin on activated endothelium and platelets. Platelet-neutrophil activation and binding occur in the blood of patients with arterial diseases, suggesting that arterial damage leads to these phenomena. We investigated the influence of endothelial surface integrity on circulating platelet activation and binding to neutrophils and the mechanism involved in these interactions. Expression of P-selectin on human platelets and their binding to neutrophils was determined by flow cytometry at baseline after thrombin activation and after exposure for 15 min to intact and damaged arterial surfaces in flow chambers. Expression of platelet P-selectin at baseline and after perfusion over intact endothelium averaged 13.8 +/- 1.2 and 12.7 +/- 1.8%, respectively, and increased significantly to 19.7 +/- 1.8% (P < 0.05) after perfusion over damaged arteries. In mixed neutrophil/platelet suspensions, the percentage of neutrophils that bind platelets increased significantly also, from 10.8 +/- 1.6% at baseline to 39.7 +/- 2.9% (P < 0.05) after perfusion over damaged arteries compared with 69.7 +/- 2.5% with thrombin. This binding was completely inhibited by a recombinant soluble PSGL-1 (rPSGL-Ig) and anti-P-selectin and PSGL-1-blocking monoclonal antibodies. The inhibitory effect of rPSGL-Ig correlated well with its binding to platelets (r = 0.98, P < 0.001). Circulating platelets are activated upon contact with damaged arteries, thereby enhancing their adhesive interactions with neutrophils via P-selectin and PSGL-1. Inhibition of this binding with rPSGL-Ig may constitute a target in the treatment of inflammatory and thrombotic reactions.
Théorêt
J F
JF
Laboratory of Experimental Pathology, Montreal Heart Institute, University of Montreal, Quebec, Canada.
Bienvenu
J G
JG
Kumar
A
A
Merhi
Y
Y
D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001158:Arteries / Q000473:pathology*; D001792:Blood Platelets / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects*; D019007:P-Selectin / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011994:Recombinant Proteins