Selectin blockade reduces neutrophil interaction with platelets at the site of deep arterial injury by angioplasty in pigs.
The adhesion of neutrophils to damaged arterial surfaces is increased in the presence of platelets by a mechanism implicating platelet P-selectin. Such interactions may enhance thrombus formation and the vascular response to injury. In this study, we investigated the effects of a selectin blocker (CY-1503), an analogue of sialyl Lewisx, on platelet and neutrophil interactions after arterial injury produced by angioplasty in pigs.51Cr-platelet deposition and 111In-neutrophil adhesion were quantified on intact, mildly and deeply injured carotid arterial segments, produced by balloon dilation, in control (saline, n=8) and treated (CY-1503, 15 mg/kg IV, n=7) pigs. The hematological parameters, the aggregation of whole blood in response to adenosine diphosphate, and the activating clotting time, as well as the heart rate and mean arterial blood pressure, were similar among groups and were not influenced significantly by CY-1503. The level of platelet and neutrophil adhesion increased significantly with the severity of arterial injury but was not influenced by CY-1503 on intact and mildly injured arterial segments. However, at the site of deep arterial injury, CY-1503 treatment was associated with a 58% reduction (P<0.01) in neutrophil adhesion, from 446.7+/-72.6x10(3) neutrophils/cm2 in the control group to 186.8+/-38.7x10(3) neutrophils/cm2 in the CY-1503-treated group, whereas platelet deposition remained unchanged (43.4+/-15.6x10(6) platelets/cm2 versus 50.1+/-12.2x10(6) platelets/cm2 in the control group). In in vitro adhesion experiments, using isolated platelet and neutrophil suspensions, we found that CY-1503 interfered with the adhesion of neutrophils to damaged arterial surfaces only in the presence of platelets. In contact with thrombogenic arterial surfaces, adherent and activated platelets supports neutrophil adhesion at the site of deep injury by an adhesive interaction involving neutrophil sialyl Lewisx. The inhibitory effect of CY-1503 on neutrophil interaction with adherent platelets may be clinically relevant in patients undergoing percutaneous transluminal coronary angioplasty where platelet and neutrophil interactions may enhance the acute and chronic arterial response to injury.
Merhi
Y
Y
Laboratory of Experimental Pathology, Montreal Heart Institute, and the University of Montreal, Quebec, Canada. merhi@icm.umontreal.ca
Provost
P
P
Chauvet
P
P
Théorêt
J F
JF
Phillips
M L
ML
Latour
J G
JG
D017130:Angioplasty / Q000009:adverse effects*; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D020212:Carotid Artery Injuries; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002533:Cerebral Angiography; D005260:Female; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D009844:Oligosaccharides / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000502:physiology; D019087:Selectins / Q000187:drug effects / Q000502:physiology*; D013552:Swine