Abstract
Increased leukocyte adhesion to vascular endothelium contributes to vaso-occlusion in sickle cell disease. Since nitric oxide bioavailability is decreased in sickle cell disease and nitric oxide may inhibit leukocyte adhesion, we investigated whether stimulation of NO-signaling pathways can reduce the adhesive properties of neutrophils from sickle cell disease individuals (sickle cell diseaseneu). sickle cell diseaseneu presented greater adhesion in vitro to both fibronectin and ICAM-1 than control neutrophils. Co-incubation of sickle cell diseaseneu with the nitric oxide-donor agents, sodium nitroprusside and dietheylamine NONOate (DEANO), and the guanylate cyclase stimulator, BAY41-2272, all significantly reduced the increased adhesion to fibronectin/ICAM-1. Oxadiazolo[4,3-a]quinoxalin-1-one, a guanylate cyclase inhibitor, reversed sodium nitroprusside/DEANO-diminished adhesion to fibronectin, implicating cGMP-dependent signaling in this mechanism. Interestingly, intracellular cGMP was significantly higher in neutrophils from sickle cell disease individuals on hydroxyurea (sickle cell diseaseHUneu). Accordingly, sickle cell diseaseHUneu adhesion to fibronectin/ICAM-1 was significantly lower than that of sickle cell diseaseneu. Agents that stimulate the nitric oxide/cGMP-dependent pathway may have beneficial effects on leukocyte function if used in these subjects.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Anemia, Sickle Cell / blood*
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Anemia, Sickle Cell / drug therapy
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Anemia, Sickle Cell / pathology
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CD11a Antigen / analysis
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CD11b Antigen / analysis
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Cell Adhesion / drug effects*
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Cyclic GMP / physiology
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Endothelial Cells / pathology
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Female
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Fibronectins / metabolism
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Humans
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Hydrazines / pharmacology*
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Hydroxyurea / pharmacology
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Hydroxyurea / therapeutic use
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Integrin alpha4 / analysis
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Intercellular Adhesion Molecule-1 / metabolism
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Male
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Middle Aged
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Neutrophils / drug effects*
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Neutrophils / pathology
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Nitric Oxide / physiology*
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Nitric Oxide Donors / pharmacology*
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Nitroprusside / pharmacology*
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Oxadiazoles / pharmacology
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Pyrazoles / pharmacology*
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Pyridines / pharmacology*
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Quinoxalines / pharmacology
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Sickle Cell Trait / blood
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Sickle Cell Trait / drug therapy
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Sickle Cell Trait / genetics
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Sickle Cell Trait / pathology
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alpha-Thalassemia / blood
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alpha-Thalassemia / genetics
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alpha-Thalassemia / pathology
Substances
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1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
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3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
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CD11a Antigen
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CD11b Antigen
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Fibronectins
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Hydrazines
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ITGAM protein, human
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Nitric Oxide Donors
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Oxadiazoles
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Pyrazoles
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Pyridines
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Quinoxalines
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Intercellular Adhesion Molecule-1
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Integrin alpha4
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Nitroprusside
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Nitric Oxide
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1,1-diethyl-2-hydroxy-2-nitrosohydrazine
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Cyclic GMP
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Hydroxyurea