Repurposing pyridoxamine for therapeutic intervention of intravascular cell-cell interactions in mouse models of sickle cell disease.
Repurposing pyridoxamine for therapeutic intervention of intravascular cell-cell interactions in mouse models of sickle cell disease.
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DOI：
10.3324/haematol.2019.226720
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发表时间：
2020-10-01
期刊：
影响因子：
10.1
通讯作者：
Cho J
中科院分区：
文献类型：
--
作者：
Li J;Jeong SY;Xiong B;Tseng A;Mahon AB;Isaacman S;Gordeuk VR;Cho J
在镰状细胞病（SCD）中，血管内皮上粘附的中性粒细胞积极参与细胞聚集和血管闭塞。在本研究中，我们证明了吡哆沙明，维生素B6的衍生物，可能是一种缓解SCD血管内细胞聚集的治疗剂。通过实时活体显微镜观察，我们发现一次口服吡哆沙明，以剂量依赖的方式，增加了中性粒细胞的滚动内流，减少了中性粒细胞对缺氧再氧化SCD小鼠cremaster微血管内皮细胞的粘附。短期治疗还可以减轻微血管中中性粒细胞与内皮细胞和中性粒细胞与血小板的相互作用，提高肿瘤坏死因子-α刺激的SCD小鼠的存活率。吡哆沙胺对血管内细胞-细胞相互作用的抑制作用通过与羟基脲共处理而增强。我们观察到，长期（5.5个月）口服吡多沙胺可显著降低肿瘤坏死因子-α-挑战SCD小鼠中性粒细胞和血小板的粘附功能，下调血管内皮上e-选择素和细胞间粘附分子-1的表达。体外研究发现，经含吡哆沙胺水处理的SCD小鼠的受刺激中性粒细胞中α m - β2整合素的表面量明显减少。使用SCD小鼠和患者的血小板和中性粒细胞的研究表明，吡哆沙明治疗降低了血小板和中性粒细胞的激活状态。这些结果表明，吡哆沙胺可能是一种新的治疗方法和羟脲的补充，以预防和治疗SCD的真空闭塞事件。
Adherent neutrophils on vascular endothelium positively contribute to cell-cell aggregation and vaso-occlusion in sickle cell disease (SCD). In the present study, we demonstrated that pyridoxamine, a derivative of vitamin B6, might be a therapeutic agent to alleviate intravascular cell-cell aggregation in SCD. Using real-time intravital microscopy, we found that one oral administration of pyridoxamine, in a dose-dependent manner, increased the rolling influx of neutrophils and reduced neutrophil adhesion to endothelial cells in cremaster microvessels of SCD mice challenged with hypoxia-reoxygenation. Short-term treatment also mitigated neutrophil-endothelial cell and neutrophil-platelet interactions in the microvessels and improved the survival of SCD mice challenged with tumor necrosis factor-α. The inhibitory effects of pyridoxamine on intravascular cell-cell interactions were enhanced by co-treatment with hydroxyurea. We observed that long-term (5.5 months) oral treatment with pyridoxamine significantly reduced the adhesive function of neutrophils and platelets, and down-regulated the expression of E-selectin and intercellular adhesion molecule-1 on the vascular endothelium in tumor necrosis factor-α-challenged SCD mice. Ex vivo studies revealed that the surface amount of αMβ2 integrin was significantly decreased in stimulated neutrophils isolated from SCD mice treated with pyridoxamine-containing water. Studies using platelets and neutrophils from SCD mice and patients suggested that treatment with pyridoxamine reduced the activation state of platelets and neutrophils. These results suggest that pyridoxamine may be a novel therapeutic and a supplement to hydroxyurea to prevent and treat vaco-occlusion events in SCD.