REACTIVE SPECIES IN SICKLE CELL DISEASE

存活至成年期的镰状细胞患者的发病率和死亡率 与血管引起的缺血和终末器官损伤直接相关 遮挡。虽然间歇性痛苦事件被认为也是由 微血管闭塞，没有相关的数量增加 在这些事件中镰刀状红细胞的比例。因此，β-珠蛋白 导致镰状细胞病的突变是必要的，但不是充分的 血管闭塞，不直接引起发作性症状 与镰状细胞病有关。据推测，这段插曲 出现疼痛、器官血流异常和急性胸腔综合征 镰状细胞疾病是由一氧化氮(.NO)依赖缺陷引起的 血管松弛。初步观察结果支持他在AS中的概念 就像血浆中NO生物合成的前体L-精氨酸一样 血清和血浆中NO代谢物、硝酸盐(N02)和 镰状细胞病患者的硝酸盐(N03)。 此外，有了这种氨基酸，同型半胱氨酸水平会升高 代谢物是公认的内皮功能丧失的危险因素 静脉/动脉闭塞。为了确立.NO在中的作用 介导镰状细胞病患者的血管病理生物学 疾病方面将追求三个具体目标： 1.一氧化氮在血管内皮依赖性松弛受损中的作用 血管闭塞危机和缺血性组织损伤的发展将是 在镰状细胞病患者中检测。 2.旨在增强NO依赖的干预措施的治疗作用 镰状细胞病患者的内皮松弛将是 检查过了。这包括一项L-精氨酸的前瞻性随机试验 输液治疗急性血管闭塞危象 吸入.NO治疗急性呼吸窘迫综合征的前瞻性随机试验 胸部综合征与一项旨在降低胸痛的治疗的前瞻性评估 成人镰状细胞病患者的同型半胱氨酸水平。 3.最后，为了制定更多的止血策略 镰状细胞患者的血流异常，危重患者的行为 NO依赖的内皮松弛调节剂将在 血管内皮细胞培养及镰状细胞转基因小鼠模型的建立 疾病。成功实现拟议的目标将提供 关于血管发病机制的基本信息 与镰状细胞疾病相关的异常，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.