Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation

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.

Omega 3 (n−3) fatty acids down-regulate nuclear factor-kappa B (NF-κB) gene and blood cell adhesion molecule expression in patients with homozygous sickle cell disease

“…It has been shown that the adhesive molecules involved in increased adhesiveness of granulocytes and monocytes and leukocytes interaction with endothelial cells are the cytokine-induced L-and P-selectin (CD-62L), β2-integrin CD11b/C18 (CD-11b) and LFA-1 (CD11a/CD18) [49][50][51][52]. L-selectin (CD62L) facilitates rolling and temporary arrest of circulating leukocytes on endothelium surface [53], whereas β2-integrin (CD11b) is involved in subsequent stable adhesion [54,55].…”

“…L-selectin (CD62L) facilitates rolling and temporary arrest of circulating leukocytes on endothelium surface [53], whereas β2-integrin (CD11b) is involved in subsequent stable adhesion [54,55]. Therefore, therapeutic approaches to reduce expression of CD62L and CD11B have been important strategies to prevent vaso-occlusion in sickle cell disease [50]. In vitro [56,57] and in vivo [13] studies in conditions other than SCD have revealed that supplementation with n−3 resulted in significant reduction in blood cell adhesive molecules.…”

Genética das doenças hematológicas: as hemoglobinopatias hereditárias

“…Recently, Canalli et al demonstrated that in vitro adhesion of neutrophils to fibronectin and the ICAM-1 protein, which is increased in SCD, is significantly reduced in the presence of pharmacological NO donation agents, such us sodium nitroprusside and diethylamine NONOate (DEANO). 83 These results indicate that the drug is able to donate or increase bioavailability of NO and may represent a promising treatment for reducing vasoocclusion in patients with SCD.…”

Blood Cell Membrane Omega-3 ( n -3) Fatty Acid Abnormality and Supplementation in Patients with Sickle Cell Anemia

“…Second, there no correlation between painful events and the number of sickled cells. Moreover, there is evidence that white blood cells of sickle cell patients, which seem to have a higher propensity to adhere to vascular endothelium, play a critical role vasoocclusion (Canalli et al, 2008;Frenette, 2002Frenette, , 2004. Leukocytes adhesion to vascular endothelium is mediated by the interaction of leukocyte adhesion molecules L-selectin (CD62L), αMβ2 integrine (CD11b/CD18) and LFA-1 (CD11A/CD18) with endothelial adhesion molecules including, intercellular adhesion molecule-1, vascular adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin (Johnson and Telen, 2008;Okpala, 2002;Turhan et al, 2002).…”