Artificial Red Cells : Physiological Importance of the Ligand Reaction Dynamism and the New Application for Ligand Therapy

化学修饰的血红蛋白（Hb）作为人工氧载体，能引起血管收缩和高血压，这可能是由于Hb对内源性NO和CO的高亲和力和O_2的快速释放引起血管的自身调节性收缩所致。另一方面，细胞型Hb-vesicle（HbV）不诱导这样的副作用。本文采用物理化学方法分析了HbV与配体气体分子的反应，发现HbV的反应速度慢得多，这是由于浓血红蛋白溶液引起的细胞内气体扩散屏障，以及HbV在窄管内流动时的侧向扩散受阻所致。此外，我们测试了作为外源性CO载体的HbV，因为内源性CO具有细胞保护性。在诱导失血性休克后，用CO结合的HbV复苏大鼠。在再灌注时表现出细胞保护作用，CO迅速解离并经肺呼出。未检测到与CO毒性相关的症状。这些结果暗示了人工红细胞用于新的配体治疗的可能性。

Chemically modified hemoglobin (Hb) solutions as artificial O_2 carriers show vasoconstriction and hypertension presumably due to the high affinity for endogenous NO and CO as vasorelaxation factors, and due to the faster O_2-release that induces autoregulatory vasoconstriction. On the other hand, cellular-type Hb-vesicle (HbV) does not induce such side effects. Herein we analyzed the reactions of ligand gaseous molecules by physicochemical techniques, and found out that HbV shows much slower reactions and it is due to the intracellular gas diffusion barrier induced by a concentrated Hb solution, and the retarded lateral diffusion of HbV when it flows in a narrow tube. In addition, we tested HbV as an exogenous CO carrier because endogenous CO is cytoprotective. After inducing hemorrhagic shock, rats were resuscitated with CO-bound HbV. It showed cytoprotective effect at reperfusion, and CO was dissociated rapidly and exhaled through the lung. No symptom related to toxicity of CO was detected. The results imply the possibility of artificial red cells for a new ligand therapy.