Vasoocclusive crisis is the major cause of morbidity and mortality in sickle cell disease (SCD). The molecular cascade giving rise to slowed blood-vessel flow remains elusive. Slowing of blood flow and hence oxygen delivery to tissues very likely relates to the adherence of sickle cell (SS) RBC to vascular endothelium, localized tissue hypoxia secondary to blood stasis and/or inflammation common in SCD. SS RBC adherence may affect blood flow by promoting, via surface expression of counter- receptors on the endothelium, the additional binding of SS RBC and leukocytes. We hypothesize that SS RBC adherence to endothelium generates cellular oxidant stress (evidenced by lipid peroxide formation and activation of transcription factor NF-kb), leading to a surface expression (SE) of a subset of cell adhesion molecules (CAMs), ICAM-1, E- selectin and BCAM-1. Similarly, infection/inflammation causes an increase in CAM expression. The induced SE of VCAM-1 leads to a greater adherence of less dense SS RBC through their alpha4beta1 ligand. The adherence and subsequent diapedesis of PMN and monocytes occurs via the increased SE of CAMs, which act as counter-receptors for integrins on these cells. Because the activation of NF-kB occurs partly through lipid peroxides generated by oxidant stresses such as vasoocclusion, e plan to determine whether overexpression of bcl-2 (a lipid peroxide-suppressing protooncogene) in cultured human umbilical vein endothelial cells (HUVEC) will prevent lipid peroxidation, NF-Kb activation and a CAM induction when transfected HUVEC are incubated with SS RBC. Dense deoxygenated SS RBC display phosphatidylserine (PS) on the external leaflet of the RBC bilayer and adhere to HUVEC through the PS receptor, so we will determine whether LPS and cytokines, which induce the expression of PS receptor, potentiate dense deoxygenated SS RBC adherence. Additionally, hypoxia increases monocyte trans endothelial migration, which may contribute to vasoocclusion; thus we propose investigating the mechanism of hypoxia-induced diapedesis of PMN and monocytes. We will also examine the mechanism(s) by which SS RBC, LPS and cytokine interaction with HUVEC alters CAM expression, the concomitant adherence of PMN and monocytes, and the augmented SS RBC adherence. Moreover, we will investigate CAM induction in endothelial cells derived from distinct vascular beds (pulmonary microvessel, pulmonary artery and brain), and potential differences in such induction effected by various shear stresses, mimicking conditions prevalent in various vascular beds. These completed studies will provide insight into new pharmacological and/or molecular approaches to ameliorate the clinical manifestations of vasoocclusion in sickle cell disease.
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