REACTIVE SPECIES IN SICKLE CELL DISEASE

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The morbidity and mortality of sickle cell patients surviving to adulthood is directly related to ischemia and end organ damage induced by vascular occlusion. While episodic painful events are proposed to also result from microvascular occlusion, there is no associated quantitative increase in proportions of sickle erythrocytes during these events. Thus, beta-globin mutations causing sickle cell disease are necessary but not sufficient for vascular occlusion and do not directly induce the episodic symptoms associated with sickle cell disease. It is hypothesized that the episodic pain, organ flow abnormalities and acute chest syndrome occurring from sickle cell disease are due to defective nitric oxide (.NO)-dependent vascular relaxation. Preliminary observations support his concept in as much as plasma L-arginine, the precursor for .NO biosynthesis, is decreased, as are serum and plasma .NO metabolites, nitrate (N02) and nitrate (N03) in patients suffering from sickle cell disease. Additionally, homocysteine levels are elevated, with this amino acid metabolite a recognized risk factor for loss of endothelial function and venous/arterial occlusion. In order to establish the role of .NO in mediating the vascular pathobiology of patients suffering from sickle cell disease three Specific Aims will be pursued: 1. The role of .NO in impaired endothelial-dependent relaxation in a development of vaso-occlusive crisis and ischemic tissue damage will be determined in patients with sickle cell disease. 2. The therapeutic role of interventions designed to augment .NO-dependent endothelial relaxation in patients having sickle cell disease will be examined. This includes a prospective, randomized trial of L-arginine infusion in the treatment of acute vascular occlusive crisis, a prospective randomized trial of inhaled .NO for the treatment of acute chest syndrome and a prospective evaluation of therapies designed to lower homocysteine levels in adults with sickle cell disease. 3. Finally, in order to develop additional strategies for relieving blood flow abnormalities in sickle cell patients, the actions of critical modulators of .NO-dependent endothelial relaxation will be assessed in cultured vascular endothelium and a transgenic mouse model of sickle cell disease. Successful accomplishment of the proposed aims will provide fundamental mechanistic information regarding the pathogenesis of vascular abnormalities associated with sickle cell disease and will provide novel clinical strategies for treatment of sickle cell disease.