P-selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease. Arterioscler Thromb Vasc Biol 2010 Dec;30(12):2392-9
Date
11/13/2010Pubmed ID
21071696Pubmed Central ID
PMC3058044DOI
10.1161/ATVBAHA.110.211615Scopus ID
2-s2.0-78650419600 (requires institutional sign-in at Scopus site) 137 CitationsAbstract
OBJECTIVE: To determine the role of platelets in stimulating mouse and human neutrophil activation and pulmonary injury in sickle cell disease (SCD).
METHODS AND RESULTS: Both platelet and neutrophil activation occur in SCD, but the interdependence of these events is unknown. Platelet activation and binding to leukocytes were measured in mice and patients with SCD and in controls. Relative to controls, blood obtained from mice or patients with SCD contained significantly elevated platelet-neutrophil aggregates (PNAs). Both platelets and neutrophils found in sickle PNAs were activated. Multispectral imaging (ImageStream) and conventional flow cytometry revealed a subpopulation of activated neutrophils with multiple adhered platelets that expressed significantly more CD11b and exhibited greater oxidative activity than single neutrophils. On average, wild-type and sickle PNAs contained 1.1 and 2.6 platelets per neutrophil, respectively. Hypoxia/reoxygenation induced a further increase in PNAs in mice with SCD and additional activation of both platelets and neutrophils. The pretreatment of mice with SCD with clopidogrel or P-selectin antibody reduced the formation of PNAs and neutrophil activation and decreased lung vascular permeability.
CONCLUSIONS: Our findings suggest that platelet binding activates neutrophils and contributes to a chronic inflammatory state and pulmonary dysfunction in SCD. The inhibition of platelet activation may be useful to decrease tissue injury in SCD, particularly during the early stages of vaso-occlusive crises.
Author List
Polanowska-Grabowska R, Wallace K, Field JJ, Chen L, Marshall MA, Figler R, Gear AR, Linden JAuthor
Joshua J. Field MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Anemia, Sickle CellAnimals
Antibodies
Blood Platelets
CD11b Antigen
CD40 Ligand
Capillary Permeability
Case-Control Studies
Flow Cytometry
Hemoglobin Subunits
Humans
Hypoxia
Lung
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neutrophil Activation
Neutrophils
P-Selectin
Platelet Activation
Platelet Adhesiveness
Platelet Aggregation Inhibitors
Platelet Glycoprotein GPIIb-IIIa Complex
Respiratory Burst
Ticlopidine