GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise.
GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise.
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DOI：
10.4081/hr.2016.6637
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发表时间：
2016-09-28
影响因子：
0.9
通讯作者：
Oksenberg D
中科院分区：
文献类型：
--
作者：
Dufu K;Lehrer-Graiwer J;Ramos E;Oksenberg D
在镰状细胞性状（SCT）中，血红蛋白A（HbA）和S（HbS）在每个红细胞（RBC）中共表达。虽然HbS（HbSS）的纯合表达导致RBC的聚合和镰状化，从而导致以溶血性贫血、疼痛的血管闭塞发作和缩短的寿命为特征的镰状细胞病（SCD），但SCT被认为是良性病症，通常具有与镰状化相关的轻微并发症或没有与镰状化相关的并发症。然而，导致组织需氧量增加、脱水和/或代谢性酸中毒的身体活动导致HbS聚合增加和危及生命的并发症，包括死亡。我们报告说，GBT 440，一种正在开发的SCD治疗剂，增加了氧对Hb的亲和力，并抑制模拟SCT血液的HbS和HbA混合物的体外聚合。此外，GBT 440可防止SCT血液在模拟剧烈运动的体外条件下出现镰状化，包括缺氧、脱水和酸中毒。总之，我们的研究结果表明，GBT 440可能有可能保护SCT个体在有利于HbS聚合的条件下免受镰状相关并发症的影响。
In sickle cell trait (SCT), hemoglobin A (HbA) and S (HbS) are co-expressed in each red blood cell (RBC). While homozygous expression of HbS (HbSS) leads to polymerization and sickling of RBCs resulting in sickle cell disease (SCD) characterized by hemolytic anemia, painful vaso-occlusive episodes and shortened life-span, SCT is considered a benign condition usually with minor or no complications related to sickling. However, physical activities that cause increased tissue oxygen demand, dehydration and/or metabolic acidosis leads to increased HbS polymerization and life-threatening complications including death. We report that GBT440, an agent being developed for the treatment of SCD, increases the affinity of oxygen for Hb and inhibits in vitro polymerization of a mixture of HbS and HbA that simulates SCT blood. Moreover, GBT440 prevents sickling of SCT blood under in vitro conditions mimicking strenuous exercise with hypoxia, dehydration and acidosis. Together, our results indicate that GBT440 may have the potential to protect SCT individuals from sickling-related complications during conditions that favor HbS polymerization.