Kawaguchi Akira T, Yamano Mariko, Haida Munetaka, Ohba Hiroyuki, Kakiuchi Takeharu, Tsukada Hideo
Tokai University School of Medicine, Kanagawa.
Osaka Prefecture University, Osaka.
Artif Organs. 2017 Apr;41(4):336-345. doi: 10.1111/aor.12905.
We tested a hypothesis that liposome-encapsulated hemoglobin (LEH) with high oxygen (O ) affinity (h-LEH, P O = 10 mm Hg) may work better than LEH with low O affinity (l-LEH, P O = 40 mm Hg) in cerebral ischemia and reperfusion injury using positron emission tomography (PET) in primates undergoing middle cerebral artery (MCA) occlusion and reperfusion. Cerebral blood flow (CBF), O extract fraction (OEF), and cerebral metabolic rate of O (CMRO ) were successively determined by PET before ischemia, at 2 h of ischemia, immediately after reperfusion, and 3 h after reperfusion. Five minutes after MCA occlusion, 10 mL/kg of h-LEH (n = 6) was intravenously infused and compared with the results from previous data of monkeys treated with l-LEH (n = 6), empty liposome (n = 4), or saline (n = 8) as control. After the series of PET studies, the integrated area of cerebral infarction was determined histologically in 12 coronal brain slices. There was no significant difference in CBF, OEF, or CMRO up to 2 h of ischemia. A high CBF with a low OEF tended to be suppressed after reperfusion in LEH-treated monkeys. Three hours after reperfusion, the area of mild CMRO reduction (down to -30%) decreased (P < 0.05) and the area of mild CMRO increase (up to 30%) expanded in LEH-treated monkeys (P < 0.05) regardless of O affinity with no difference in the area of moderate-to-severe reduction (<-30%) or increase (<+30%) in CMRO compared to animals treated with empty liposome or saline. Distribution of CMRO reduction and histological damages showed that LEH mainly protected the cerebral cortex rather than basal ganglia where neuronal dendritic processes were severely lost. There was little difference between the animals treated with l-LEH or h-LEH both at 10 mL/kg or between treatment with empty liposome or saline. In conclusion, LEH was effective regardless of O affinity in preserving CMRO and in reducing the area of histological damage in the cerebral cortex, but not in basal ganglia, shortly after occlusion/reperfusion of MCA in monkey.
我们检验了一个假设，即在灵长类动物大脑中动脉（MCA）闭塞和再灌注过程中，使用正电子发射断层扫描（PET）技术，具有高氧（O₂）亲和力（h-LEH，P₅₀ = 10 mmHg）的脂质体包裹血红蛋白（LEH）在脑缺血和再灌注损伤中可能比具有低O₂亲和力（l-LEH，P₅₀ = 40 mmHg）的LEH效果更好。在缺血前、缺血2小时、再灌注后即刻以及再灌注后3小时，通过PET连续测定脑血流量（CBF）、O₂摄取分数（OEF）和脑氧代谢率（CMRO₂）。MCA闭塞5分钟后，静脉输注10 mL/kg的h-LEH（n = 6），并与先前用l-LEH（n = 6）、空脂质体（n = 4）或生理盐水（n = 8）治疗的猴子的数据结果进行比较。在一系列PET研究之后，在12个冠状脑切片上组织学测定脑梗死的积分面积。在缺血长达2小时时，CBF、OEF或CMRO₂没有显著差异。在接受LEH治疗的猴子中，再灌注后高CBF和低OEF倾向于受到抑制。再灌注3小时后，在接受LEH治疗的猴子中，轻度CMRO₂降低（降至-30%）的面积减少（P < 0.⁰5），轻度CMRO₂增加（高达30%）的面积扩大（P < 0.⁰5），无论O₂亲和力如何，与接受空脂质体或生理盐水治疗的动物相比，CMRO₂中度至重度降低（<-30%）或增加（<+30%）的面积没有差异。CMRO₂降低的分布和组织学损伤表明，LEH主要保护大脑皮层，而不是基底神经节，在基底神经节神经元树突过程严重丧失。在10 mL/kg剂量下，接受l-LEH或h-LEH治疗的动物之间，以及接受空脂质体或生理盐水治疗的动物之间几乎没有差异。总之，在猴子MCA闭塞/再灌注后不久，无论O₂亲和力如何，LEH在保存CMRO₂和减少大脑皮层组织学损伤面积方面是有效的，但对基底神经节无效。
