REACTIVE SPECIES IN SICKLE CELL DISEASE

镰状细胞病患者存活至成年的发病率和死亡率 与血管紧张素Ⅱ诱导的缺血和终末器官损伤直接相关 闭塞虽然间歇性疼痛事件也被认为是由 微血管闭塞，没有相关的定量增加， 在这些事件中镰状红细胞的比例。因此，β-珠蛋白 导致镰状细胞病的突变是必要的，但不足以 血管闭塞，不直接诱发发作性症状 与镰状细胞病有关据推测， 疼痛、器官血流异常和急性胸部综合征 镰状细胞病是由于有缺陷一氧化氮（.NO）依赖性 血管松弛初步观察支持他的概念， 就像血浆L-精氨酸，NO生物合成的前体， NO代谢物、硝酸盐（NO2）和 硝酸盐（NO3）在患有镰状细胞病的患者中的应用。 此外，同型半胱氨酸水平升高，这种氨基酸 代谢产物是内皮功能丧失的公认风险因素， 静脉/动脉闭塞。为了确立.NO在 介导镰状细胞病患者的血管病理学 三个具体目标： 1. NO在血管内皮依赖性舒张功能受损中的作用 血管闭塞危象和缺血性组织损伤的发展将是 在镰状细胞病患者中测定。 2.旨在增强NO依赖性的干预措施的治疗作用 镰状细胞病患者的内皮松弛将是 考察这包括L-精氨酸的前瞻性随机试验 输液治疗急性血管闭塞危象 一氧化氮吸入治疗急性呼吸道感染的前瞻性随机试验 胸部综合征和前瞻性评估的治疗，旨在降低 成人镰状细胞病患者的同型半胱氨酸水平 3.最后，为了开发更多的策略， 镰状细胞患者的血流异常， NO依赖性内皮舒张的调节剂将在 培养血管内皮细胞和镰状细胞转基因小鼠模型 疾病成功实现拟议目标将提供 关于血管性心脏病发病机制的基本机制信息 与镰状细胞病相关的异常，并将提供新的 镰状细胞病的临床治疗策略。

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.