Kim-Shapiro Daniel B, Gladwin Mark T
Department of Physics, Wake Forest University, Winston-Salem, NC, USA.
Translational Science Center, Wake Forest University, Winston-Salem, NC, USA.
Clin Hemorheol Microcirc. 2018;68(2-3):223-237. doi: 10.3233/CH-189009.
Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions which leads to red blood cell (RBC) distortion, calcium-influx mediated RBC dehydration, increased RBC adhesivity, reduced RBC deformability, increased RBC fragility, and hemolysis. These impairments in RBC structure and function result in multifaceted downstream pathology including inflammation, endothelial cell activation, platelet and leukocyte activation and adhesion, and thrombosis, all of which contribute vascular occlusion and substantial morbidity and mortality. Hemoglobin released upon RBC hemolysis scavenges nitric oxide (NO) and generates reactive oxygen species (ROS) and thereby decreases bioavailability of this important signaling molecule. As the endothelium-derived relaxing factor, NO acts as a vasodilator and also decreases platelet, leukocyte, and endothelial cell activation. Thus, low NO bioavailability contributes to pathology in sickle cell disease and its restoration could serve as an effective treatment. Despite its promise, clinical trials based on restoring NO bioavailability have so far been mainly disappointing. However, particular "NO donating" agents such as nitrite, which unlike some other NO donors can improve sickle RBC properties, may yet prove effective.
镰状细胞病由一种突变形式的血红蛋白引起，该血红蛋白在缺氧条件下会发生聚合，进而导致红细胞（RBC）变形、钙内流介导的红细胞脱水、红细胞黏附性增加、红细胞变形性降低、红细胞脆性增加以及溶血。红细胞结构和功能的这些损伤会导致多方面的下游病理变化，包括炎症、内皮细胞活化、血小板和白细胞活化及黏附，以及血栓形成，所有这些都会导致血管阻塞以及严重的发病率和死亡率。红细胞溶血时释放的血红蛋白会清除一氧化氮（NO）并产生活性氧（ROS），从而降低这种重要信号分子的生物利用度。作为内皮源性舒张因子，NO起到血管舒张剂的作用，还能降低血小板、白细胞和内皮细胞的活化。因此，低NO生物利用度会导致镰状细胞病的病理变化，恢复其生物利用度可能是一种有效的治疗方法。尽管前景广阔，但迄今为止，基于恢复NO生物利用度的临床试验大多令人失望。然而，某些特定的“供NO”剂，如亚硝酸盐，与其他一些NO供体不同，它可以改善镰状红细胞的特性，可能最终被证明是有效的。
