Nitric oxide attenuates normal and sickle red blood cell adherence to pulmonary endothelium.
Increased adherence of sickle red blood cells (RBC) to endothelium is implicated as an initiating event of vaso-occlusion in sickle cell disease. Although much is known about the humoral influences of this interaction, there has been little investigation regarding endothelial contributions. Endothelial derived nitric oxide (NO) inhibits adhesion of platelets and leukocytes to endothelium and decreases expression of VCAM-1, an endothelial adhesion site implicated in sickle RBC/endothelial adherence. However, whether NO inhibits RBC adherence to endothelium is unexplored. We tested this hypothesis with endothelial monolayers exposed to RBC from normal (Hb AA) and sickle cell (Hb SS) volunteers in a parallel plate flow chamber. To decrease NO production, endothelial monolayers were exposed to 100 microM nitro-L-arginine (NLA), an inhibitor of nitric oxide synthase, resulting in an 87% increase in normal RBC adherence (P = 0.002). Because adherence of normal RBC to endothelium was low, the effect of DETA-NO, an NO donor, was tested after activation of endothelium with TNF-alpha increased adherence by 130% (P < 0.001). Subsequent addition of 2 mM DETA-NO produced a 75% decrease in adherence of normal RBC to endothelium (P = 0.03). At baseline, sickle RBC were significantly more adherent than normal RBC (P < 0.001) and DETA-NO decreased sickle RBC adherence by 54% (P = 0.04). Thus, NO inhibits both normal and sickle RBC adherence to endothelium. Strategies that enhance NO activity may be therapeutic in sickle cell disease.
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Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado. sharon.space@uchsc.edu
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Pickett
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Weil
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D000293:Adolescent; D002448:Cell Adhesion / Q000187:drug effects; D002648:Child; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000166:cytology*; D006801:Humans; D009569:Nitric Oxide / Q000494:pharmacology*; D019335:Nitroarginine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology; D012805:Sickle Cell Trait / Q000097:blood; D014226:Triazenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D004791:Enzyme Inhibitors; D014226:Triazenes; D014409:Tumor Necrosis Factor-alpha; D019335:Nitroarginine; D009569:Nitric Oxide