Effects of Nitric Oxide in Sickle Cell Blood

镰状细胞病是由一种营养形式的血红蛋白引起的，当暴露在低氧环境中时， 张力聚合作用使红细胞变硬，使其不能穿过某些血管 导致这些血管的阻塞，然后导致显著的发病率和死亡率。虽然 聚合可以被认为是疾病的主要原因，临床表现包括 由包括急性和慢性炎症，停滞， 再灌注损伤、内皮活化和功能障碍、凝血活化和过量氧化应激。 聚合和这些病理之间的联系尚不清楚。然而，部分链接可能与 一氧化氮（NO）是一种重要的信号分子。一氧化氮是在血管内皮细胞中合成的， 血管并扩散到邻近的平滑肌细胞，在那里它充当信号分子， 引起肌肉松弛和血管舒张。它还能降低内皮细胞和血小板的活化， 抗氧化剂和抗炎剂。 镰状红细胞是脆弱的，在循环过程中破裂（溶血）。几个团体已经 假设在溶血时释放的无细胞血红蛋白有效地清除NO，导致 一种与镰状细胞病有关的NO相关缺乏症。溶血和NO在镰状细胞中的作用 疾病仍然存在争议。本项目旨在探索这些角色，同时研究 聚合、溶血和镰状细胞病中的其他病理后果。该项目还将 检查治疗干预的各个方面，包括通过亚硝酸盐增加一氧化氮的生物利用度 疗法参与该项目的实验室最近表明，与现有的 在一个范例中，亚硝酸盐在人体循环中充当血管扩张剂，其优先在低氧下释放 条件从这个项目的结果将阐明机制的途径在病理镰状细胞 疾病和一氧化氮生物学，并将这些见解扩展到转化研究。因为NO在 许多疾病，这里获得的信息将有广泛的应用。

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.