a Department of Medicine, Albert Einstein College of Medicine , Bronx , NY , USA.
b Laboratory of Biochemistry and Vascular Biology , Center for Biologics Evaluation and Research, Food and Drug Administration , Silver Spring , MA , USA.
Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):73-82. doi: 10.1080/21691401.2018.1543194.
Compromised microcirculation and endothelial dysfunction are hallmarks of sickle cell disease (SCD). EAF PEG Haemoglobin (Hb) and EAF PEG Albumin (Alb) represent a novel class of semisynthetic colloidal supra plasma expanders that improve microcirculation. The therapeutic activity of supra plasma expanders to attenuate vaso-occlusion and restore the haemodynamic functions in patients with SCD has been investigated using NY1DD, a transgenic mouse model of mild SCD without anaemia. Vaso-occlusion and perturbation of haemodynamics are amplified in NY1DD by hypoxia-reoxygenation protocol. EAF P5K6 Alb and Alb T12 (Alb conjugated with 12 copies of antioxidant tempo) attenuate vaso-occlusion when infused at the start of reoxygenation. However, only EAF PEG Alb restores haemodynamics close to levels in control C57BL. EAF P5K6 Alb-T12, active plasma expander conjugated with antioxidant, completely clears vaso-occlusion and restores normal haemodynamics. EAF PEG Hb also completely clears vaso-occlusion and restores normal haemodynamics. Pretreating NY1DD with EAF PEG Hb protects it from hypoxia reoxygenation-induced damages. EAF P5K6 Alb T12 attenuates the endothelial dysfunction in S + S Antilles mice as reflected by the vasodilatory response of its arteries and arterioles to vaso-dilators. Active plasma expanders are novel therapeutics to restore normal haemodynamics in SCD patients to improve tissue oxygenation during episodes of painful vaso-occlusive crisis. Abbreviations: 2-IT: 2-immothiolane; Mal-T: 4-Maleimido tempo; Alb: human serum albumin (HSA); Alb-T12: human albumin conjugated with 12 copies of tempo; EAF: extension arm facilitated; EAF PEG Hb: extension arm facilitated PEGylated haemoglobin; EAF PEG Alb: extension arm facilitated PEGylated albumin; EAF P3K6 Hb: extension arm facilitated PEGylated haemoglobin conjugated with 6 copies of PEG3K; EAF P5K6 Alb T12: extension arm facilitated PEGylated albumin conjugated with 6 copies of PEG5K and 12 copies of tempo; Hb: haemoglobin; HAS: human serum albumin (Alb); PEG: polyethylene glycol; MP4: MalPEG Hb, is formulated at 4.2 g/dL in lactated Ringer's solution, a product of Sangart; SCD: sickle cell disease; NO: nitric oxide; SEC: size exclusive chromatography; Vrbc: red cell velocity; Q: volumetric flow rates, Q; SNP: sodium nitroprusside.
受损的微循环和内皮功能障碍是镰状细胞病 (SCD) 的特征。EAF PEG 血红蛋白 (Hb) 和 EAF PEG 白蛋白 (Alb) 代表一类新型的半合成胶体超血浆扩张剂，可改善微循环。使用 NY1DD，一种没有贫血的轻度 SCD 的转基因小鼠模型，研究了超血浆扩张剂减轻血管阻塞和恢复 SCD 患者血液动力学功能的治疗活性。缺氧-再氧合方案放大了 NY1DD 中的血管阻塞和血液动力学紊乱。EAF P5K6 Alb 和 Alb T12（与 12 个抗氧化剂 tempo 结合的 Alb）在再氧合开始时输注时可减轻血管阻塞。然而，只有 EAF PEG Alb 可将血液动力学恢复到接近 C57BL 对照的水平。EAF P5K6 Alb-T12，一种与抗氧化剂结合的活性血浆扩张剂，可完全清除血管阻塞并恢复正常血液动力学。EAF PEG Hb 也可完全清除血管阻塞并恢复正常血液动力学。用 EAF PEG Hb 预处理 NY1DD 可防止其免受缺氧再氧合引起的损伤。EAF P5K6 Alb T12 通过其动脉和小动脉对血管扩张剂的血管舒张反应来减轻 S+S 安的列斯小鼠的内皮功能障碍。活性血浆扩张剂是恢复 SCD 患者正常血液动力学的新型治疗方法，可在疼痛性血管阻塞危象期间改善组织氧合。缩写：2-IT：2-碘乙酰胺；Mal-T：4-马来酰亚胺 tempo；Alb：人血清白蛋白（HSA）；Alb-T12：与人白蛋白结合的 12 个拷贝的 tempo；EAF：扩展臂促进；EAF PEG Hb：扩展臂促进 PEGylated 血红蛋白；EAF PEG Alb：扩展臂促进 PEGylated 白蛋白；EAF P3K6 Hb：扩展臂促进与 6 个拷贝的 PEG3K 结合的 PEGylated 血红蛋白；EAF P5K6 Alb T12：扩展臂促进与 6 个拷贝的 PEG5K 和 12 个拷贝的 tempo 结合的 PEGylated 白蛋白；Hb：血红蛋白；HAS：人血清白蛋白（Alb）；PEG：聚乙二醇；MP4：MalPEG Hb，在乳酸林格氏液中配制为 4.2 g/dL，是 Sangart 的产品；SCD：镰状细胞病；NO：一氧化氮；SEC：尺寸排除色谱法；Vrbc：红细胞速度；Q：体积流量率，Q；SNP：硝普钠。
