Effects of Nitric Oxide in Sickle Cell Blood

镰状细胞病是由一种突变形式的血红蛋白引起的，当暴露在低氧环境中时，这种血红蛋白会聚合。 紧张。聚合作用使红细胞变硬，使其不能穿过某些血管。 导致这些血管堵塞，继而导致严重的发病率和死亡率。虽然 聚合性可被认为是疾病的主要原因，临床表现包括 由一系列病理状态引起的症状，包括急性和慢性炎症、瘀血、 再灌注损伤、内皮激活和功能障碍、凝血激活和过量氧化应激。 聚合反应和这些病理之间的联系尚不清楚。但是，链接的一部分可能被绑定到 一氧化氮(NO)是一种重要的信号分子。一氧化氮在血管内皮细胞中合成 血管并扩散到邻近的平滑肌细胞，在那里它充当信号分子， 导致肌肉松弛和血管扩张。它还会减少内皮细胞和血小板的激活，起到 抗氧化剂，具有抗炎作用。 镰刀状红细胞很脆弱，在循环中的运输过程中破裂(溶血)。有几个组织已经 假设溶血时释放的无细胞血红蛋白有效地清除一氧化氮，导致 一种与镰状细胞疾病相关的一氧化氮缺乏症。溶血和一氧化氮在镰状细胞中的作用 疾病仍然存在争议。该项目旨在探索这些角色，同时检查 镰状细胞病中的聚合、溶血和其他病理后果。该项目还将 检查涉及通过亚硝酸盐提高一氧化氮生物利用度的治疗干预的各个方面 心理治疗。参与该项目的实验室最近表明，与现有的 范式，亚硝酸盐在人体循环中作为血管扩张剂，在低氧条件下优先释放 条件。该项目的结果将阐明镰状细胞的病理机制。 疾病和一氧化氮生物学，并将这些见解扩展到翻译研究。因为NO在中国很重要 许多疾病，在这里获得的信息将会有广泛的应用。

Sickle cell disease is caused by a nnutant form of hemoglobin that polymerizes when exposed to low oxygen tension. Polymerization makes the red blood cells rigid so that they cannot traverse some blood vessels leading to blockage of these vessels which then leads to significant morbidity and mortality. Although polymerization can be thought of as the primary cause of the disease, clinical presentation includes symptoms that result from a host of pathological states including acute and chronic inflammation, stasis, reperfusion injury, endothelial activation and dysfunction, coagulation activation, and excess oxidant stress. The link between polymerization and these pathologies is not clear. However, part ofthe link may be tied to the function of Nitric Oxide (NO), an important signaling molecule. NO is synthesized in endothelial cells of blood vessels and diffuses to neighboring smooth muscle cells where it acts as a signaling molecule, causing muscle relaxation and vasodilation. It also decreases endothelial and platelet activation, acts as an anti-oxidant, and is anti-inflammatory. Sickle red blood cells are fragile, rupturing during transit in the circulation (hemolysis). Several groups have hypothesized that cell-free hemoglobin that is released upon hemolysis efficiently scavenges NO, leading to an NO-related deficiency associated with sickle cell disease. The roles of hemolysis and NO in sickle cell disease remain controversial. This project aims to explore those roles while examining the links between polymerization, hemolysis, and other pathological consequences in sickle cell disease. This project will also examine aspects of therapeutic interventions that involve increasing nitric oxide bioavailability via nitrite therapy. The laboratories participating in this project have recently shown that, contrary to the existing paradigm, nitrite acts as a vasodilator in human circulation that is preferentially released under low oxygen conditions. Results from this project will elucidate mechanistic pathways in the pathology of sickle cell disease and nitric oxide biology and extend these insights to translational studies. As NO is important in many diseases, information gained herein will have wide application.