DOUBLE-STRANDED-RNA INDUCES SICKLE ERYTHROCYTE ADHERENCE TO ENDOTHELIUM - A POTENTIAL ROLE FOR VIRAL-INFECTION IN VASOOCCLUSIVE PAIN EPISODES IN SICKLE-CELL-ANEMIA

Vaso-occlusive pain episodes in sickle cell anemia are hypothesized to be precipitated by adherence of sickle erythrocytes to vascular endot helium in the microcirculation. Febrile episodes, thought to be viral in etiology, are frequently associated with vaso-occlusion; however, a direct link between viral infection and vascular occlusion has not ye t been established. Many pathogenic viruses contain double-stranded RN A or replicate through double-stranded RNA intermediates. Double-stran ded RNA has been shown to induce vascular cell adhesion molecule-1 (VC AM-1) protein expression on endothelial cells, Recently, a new adhesio n pathway has been described between VCAM-1 expressed on cytokine stim ulated endothelium and the alpha(4) beta(1) integrin complex expressed on sickle reticulocytes. Based on these observations, the hypothesis was developed that viral infection, through double-stranded RNA interm ediates, increases endothelial VCAM-1 expression leading to sickle ery throcyte adhesion to endothelium via an alpha(4) beta(1)-VCAM-1-depend ent mechanism. In support of this hypothesis, endothelial cells expose d to the synthetic double-stranded RNA poly(I:C) or the RNA virus para influenza 1 (Sendai virus) express increased levels of VCAM-1 and supp ort increased sickle erythrocyte adherence under continuous flow at 1. 0 dyne/cm(2) shear stress as compared with unstimulated endothelium, B locking antibodies directed against either VCAM-1 on the endothelium o r alpha(4) beta(1) on sickle erythrocytes inhibit nearly all of the in creased sickle cell adherence caused by poly(I:C) or Sendai virus. The se results support the hypothesis that viruses, through double-strande d RNA elements, can induce sickle erythrocyte adherence to endothelium through alpha(4) beta(1)-VCAM-1-mediated adhesion and provide a poten tial link between viral infection and microvascular occlusion precipit ating sickle cell pain episodes. (C) 1995 by The American Society of H ematology.