Functional alpha4-integrin: a newly identified pathway of neutrophil recruitment in critically ill septic patients.
Using a novel flow chamber assay system and whole blood, we show that leukocytes from septic individuals have a four-fold elevation of adhesion, but not rolling, on a P-selectin/beta2-integrin substrate. Most leukocytes from septic patients (but not healthy controls) that bound vascular cell adhesion molecule 1 (VCAM-1) were neutrophils. All adhesion was inhibited with an antibody specific for the VCAM-1 ligand alpha4-integrin. The alpha4-integrin was present on neutrophils from septic patients but not on neutrophils from patients with localized bacterial infections. The plasma milieu of septic patients was sufficient to induce neutrophils from healthy subjects to bind VCAM-1 under flow conditions. This is the first description of alpha4-integrin/VCAM-1 pathway of neutrophil recruitment in human disease. This pathway may provide a new therapeutic target to reduce inappropriate neutrophil adhesion without altering the normal yet critical beta2-integrin-mediated adhesive function of neutrophils.
Department of Physiology and Biophysics, and The Immunology Research Group, University of Calgary Medical Center, Calgary, Alberta, Canada.
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Ibbotson
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Doig
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Kaur
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Gill
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Ostrovsky
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Fairhead
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Kubes
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000502:physiology*; D018821:CD18 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D002448:Cell Adhesion; D002465:Cell Movement; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D039441:Integrin alpha4; D007962:Leukocytes / Q000502:physiology; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000502:physiology*; D019007:P-Selectin / Q000502:physiology; D012772:Shock, Septic / Q000209:etiology / Q000503:physiopathology*; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000503:physiopathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D015703:Antigens, CD; D018821:CD18 Antigens; D008024:Ligands; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4