Ionophore-mediated swelling of erythrocytes as a therapeutic mechanism in sickle cell disease.

Sickle cell disease (SCD) is characterized by sickle hemoglobin (HbS) which polymerizes under deoxygenated conditions to form a stiff, sickled erythrocyte. The dehydration of sickle erythrocytes increases intracellular HbS concentration and the propensity of erythrocyte sickling. Prevention of this mechanism may provide a target for potential SCD therapy investigation. Ionophores such as monensin can increase erythrocyte sodium permeability by facilitating its transmembrane transport, leading to osmotic swelling of the erythrocyte and decreased hemoglobin concentration. In this study, we treated 13 blood samples from patients with SCD with 10 nM of monensin ex vivo. We measured changes in cell volume and hemoglobin concentration in response to monensin treatment, and we perfused treated blood samples through a microfluidic device that permits quantification of blood flow under controlled hypoxia. Monensin treatment led to increases in cell volume and reductions in hemoglobin concentration in most blood samples, though the degree of response varied across samples. Monensin-treated samples also demonstrated reduced blood flow impairment under hypoxic conditions relative to untreated controls. Moreover, there was a significant correlation between the improvement in blood flow and the decrease in hemoglobin concentration. Thus, our results demonstrate that a reduction in intracellular HbS concentration by osmotic swelling improves blood flow under hypoxic conditions. Although the toxicity of monensin will likely prevent it from being a viable clinical treatment, these results suggest that osmotic swelling should be investigated further as a potential mechanism for SCD therapy.

镰状细胞病（SCD）的特征是镰状血红蛋白（HbS），它在缺氧条件下聚合形成僵硬的镰状红细胞。镰状红细胞脱水会增加细胞内HbS浓度以及红细胞镰变的倾向。对这一机制的预防可能为潜在的SCD治疗研究提供一个靶点。离子载体如莫能菌素可通过促进红细胞膜对钠的跨膜转运来增加红细胞对钠的通透性，导致红细胞渗透性肿胀以及血红蛋白浓度降低。在这项研究中，我们在体外使用10 nM的莫能菌素处理了来自13名SCD患者的血液样本。我们测量了莫能菌素处理后细胞体积和血红蛋白浓度的变化，并将处理后的血液样本灌注到一个微流体装置中，该装置可在控制缺氧的条件下对血流进行定量。莫能菌素处理导致大多数血液样本的细胞体积增加和血红蛋白浓度降低，尽管不同样本的反应程度有所不同。与未处理的对照组相比，莫能菌素处理的样本在缺氧条件下血流障碍也有所减轻。此外，血流改善与血红蛋白浓度降低之间存在显著相关性。因此，我们的结果表明，通过渗透性肿胀降低细胞内HbS浓度可改善缺氧条件下的血流。尽管莫能菌素的毒性可能使其无法成为一种可行的临床治疗方法，但这些结果表明，渗透性肿胀作为SCD治疗的一种潜在机制应进一步研究。