A study on the development and application of clinically available new artificial bloods and artificial oxygen carriers

临床新型人造血液和人工氧载体的开发及应用研究

• 批准号: 11557112
• 负责人: SAKUMA Ichiro
• 金额: $ 8.64万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557112/
• 关键词: artificial red blood cell; hemoglobin derivative; nitric oxide; platelet aggregation; platelet adhesion; polyethylene glycol; s-nitrosohemoglobin; perfluorocarbon

A cellular hemoglobin (Hb) derivatives developed as red blood cell substitutes (BCSs) are known to be potent vasoconstrictors due to their EDRF/NO scavenging action. We therefore developed polyethylene glycol-modified Hb (PEG-Hb), and farther modified it to make s-nitrosylated PEG-Hb (SNO-PEG-Hb) as new candidate oxygen carriers, SNO-PEG-Hb possesses desirable properties as an B CS since it can release NO when tissue is hypoxic and absorbs NO when NO is produced to much. Furthermore, using a new machine we synthesized new emulsion to perfluorochemicals (PFCs) and manufactured several PFC compound as BCSs. We found that after injecting those compound to the rat that SNO-PEG-Hb induced least effects on functions and histology of liver and kidney among three Hb-based oxygen carriers (HBOC)s. Using flowcytemetry effects of HBOCs and PFC compounds on platelets were checked and t was suggested that SNO-PEG-Hb and the new PFC compound have least effects. We tried the application of HBOCs on acute anemia induced by Babesia infection in the dog. When SNO-PEG-Hb was infused to the brain ischemia-reperfiision model of the rats, it ameliorated their cognitive function. We applied the PFC compound in a dog model of cardiopulmonary bypass operation and it revealed that the compound can save heart from anemia-induced hypoxia. On this occasion simultaneous infusion of albumin was necessary. The ability of PFC compound for the preservation material in liver transplantation was checked. The acute lexicological test of PFCs compounds were performed and it was suggested that the new compound was the safest. Thus, SNO-PEG-Hb and the new PFC compound are expected to be good candidates for clinically available BCSs.

作为红细胞替代品（BCS）开发的细胞血红蛋白（Hb）衍生物由于其EDRF/NO清除作用而已知是有效的血管收缩剂。因此，我们开发了聚乙二醇修饰的血红蛋白（PEG-Hb），并对其进行进一步修饰，制备了S-亚硝基化的PEG-Hb（SNO-PEG-Hb）作为新的候选氧载体。SNO-PEG-Hb具有良好的B CS性质，当组织缺氧时，它能释放NO，当NO产生过多时，它能吸收NO。在此基础上，利用新的设备合成了新型的全氟化合物乳液，并制备了几种全氟化合物作为BCS。结果表明，在三种血红蛋白氧载体（HBOC）中，SNO-PEG-Hb对大鼠肝肾功能和组织学的影响最小。采用流式细胞仪检测了HBOCs和PFC化合物对血小板的影响，表明SNO-PEG-Hb和新的PFC化合物对血小板的影响最小。本研究尝试应用血红蛋白氧合物治疗犬巴氏杆菌感染所致的急性贫血。脑缺血再灌注模型大鼠脑内注入SNO-PEG-Hb后，其认知功能明显改善。我们将PFC化合物应用于心肺转流手术的狗模型中，结果表明该化合物可以使心脏免受贫血引起的缺氧。在这种情况下，需要同时输注白蛋白。考察了PFC复合物作为肝移植保存材料的能力。对PFCs化合物进行了急性毒性实验，结果表明新化合物是最安全的。因此，预计SNO-PEG-Hb和新的PFC化合物是临床可用BCS的良好候选物。

项目成果

藤井 聡, 富樫廣子, 吉岡充宏, 佐久間一郎, 仲井邦彦, 北畠 顕ほか: "ヘモグロビン系人工酸素運搬体を用いた抗血栓性材料の開発"循環制御. 23(1). 31-34 (2002)

Satoshi Fujii、Hiroko Togashi、Mitsuhiro Yoshioka、Ichiro Sakuma、Kunihiko Nakai、Akira Kitabatake 等：“使用基于血红蛋白的人工氧载体的抗血栓材料的开发”23(1) 循环控制。

藤井ひとみ: "赤血球代替物性能評価の方法の開発と臨床試験"人工血液. 7(1). 7-15 (1999)

Hitomi Fujii：“红细胞替代品性能评估方法的开发和临床试验”Artificial Blood 7(1) (1999)。

Sakanoue, J.: "Oxygen Transport to Tissue XXI"Plenum Press, New York (in press). (2000)

Sakanoue, J.：“Oxygen Transport to Tissue XXI”Plenum Press，纽约（正在出版）。

佐久間一郎、仲井邦彦、菅原 武、佐藤 洋、北畠 顕: "s-ニトロソヘモグロビンの基礎と臨床"THE LUNG perspectives. 9(2). 191-194 (2001)

Ichiro Sakuma、Kunihiko Nakai、Takeshi Sugara、Hiroshi Sato、Akira Kitabatake：“S-亚硝基血红蛋白的基础和临床实践”THE LUNG 观点 9(2)。

Ichiro Sakuma, et al.: "Application of SNO-hemoglobin as an Artificial oxygen carrier"Vessels and Endothelium. 9(Suppl.). 71-82 (1999)

Ichiro Sakuma 等人：“SNO-血红蛋白作为人工氧载体的应用”血管和内皮。