Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation.
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.
Canalli
Andreia A
AA
Hematology and Hemotherapy Center, State University of Campinas, UNICAMP, Brazil.
Franco-Penteado
Carla F
CF
Saad
Sara T O
ST
Conran
Nicola
N
Costa
Fernando F
FF
D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D040881:CD11a Antigen / Q000032:analysis; D039481:CD11b Antigen / Q000032:analysis; D002448:Cell Adhesion / Q000187:drug effects*; D006152:Cyclic GMP / Q000502:physiology; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D006918:Hydroxyurea / Q000494:pharmacology / Q000627:therapeutic use; D039441:Integrin alpha4 / Q000032:analysis; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D012805:Sickle Cell Trait / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017085:alpha-Thalassemia / Q000097:blood / Q000235:genetics / Q000473:pathology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D040881:CD11a Antigen; D039481:CD11b Antigen; D005353:Fibronectins; D006834:Hydrazines; C509295:ITGAM protein, human; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011720:Pyrazoles; D011725:Pyridines; D011810:Quinoxalines; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4; D009599:Nitroprusside; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D006152:Cyclic GMP; D006918:Hydroxyurea