GBT440对鼠血液氧结合特性的影响以及抗缺氧效果  

Effect of GBT440 on oxygen-carrying characteristics and its anti-hypoxia effect in hypoxia animal model

作　　者：魏铭 黄缄[2] 崔宇[2] 苏文婷 李晓栩[2] 官立彬[2] 沈宜[1,4] WEI Ming;HUANG Jian;CUI Yu;SU Wenting;LI Xiaoxu;GUAN Libin;SHEN Yi(Laboratory of Stem Cell and Tissue Engineering&Department of Pathophysiology,College of Basic Medical Sciences,Chongqing,400016;Department of High Altitude Physiology and High Altitude Biology,Key Laboratory of High Altitude Medicine of PLA,Key Laboratory of Extreme Environmental Medicine of Ministry Education,Faculty of High Altitude Military Medicine,Chongqing,400038,China;Institute of Pathology,First Affiliated Hospital,Army Medical University(Third Military Medical University),Chongqing,400038,China;Experimental Teaching Management Center,Chongqing Medical University,Chongqing,400016)

机构地区：[1]重庆医科大学基础医学院干细胞与组织工程研究室病理生理学教研室,重庆400016 [2]陆军军医大学(第三军医大学)高原军事医学系高原生理学与病理学教研室,全军高原医学重点实验室,特殊环境医学教育部重点实验室,重庆400038 [3]陆军军医大学(第三军医大学)高原军事医学系高原生理学与病理学教研室,全军高原医学重点实验室第一附属医院全军病理学研究所,重庆400038 [4]重庆医科大学基础医学院干细胞与组织工程研究室实验教学管理中心,重庆400016

出　　处：《第三军医大学学报》2020年第9期923-928,共6页Journal of Third Military Medical University

基　　金：军队医学科技青年培育计划(20QNPY002);全军后勤科研重点项目(BWS17J031);全军后勤科研重大项目(AWS14L005)。

摘　　要：目的观察血红蛋白变构剂Voxelotor(GBT440)对血液携氧特性的影响及其抗缺氧作用。方法将不同浓度GBT440与小鼠全血在37℃孵育1 h,通过血氧分析仪绘制氧解离曲线(oxygen dissociation curves,ODCs)并计算P50,且通过分别添加酸、碱改变样本pH值,检测ODCs的变化。将24只SD雄性大鼠按随机数表法分为常氧对照、常氧用药、缺氧对照、缺氧用药组(n=6)。对照组和用药组大鼠分别以0、100 mg/kg GBT440灌胃,1 h后将常氧组和缺氧组大鼠分别置于21%O2和10%O2的密闭小室中;6 h后取所有大鼠腹主动脉血,进行血气检测。另将C57雄性小鼠同以上的分组和实验处理,取材前1.5 h腹腔注射缺氧探针派诺硝唑,用免疫组织化学方法检测小鼠肝、肾、脑组织的缺氧程度。结果随着与血液孵育的GBT440浓度的增加,ODCs呈剂量依赖性左移,P50降低(P<0.05),加酸后ODCs右移,加碱后ODCs左移。未使用GBT440时,与常氧组相比,缺氧组动脉氧分压[p(O2)]、动脉血氧饱和度(SpO2)均显著降低(P<0.05),肝、肾、脑组织缺氧程度明显加重;使用GBT440后,上述变化得以改善,与缺氧对照组相比,缺氧用药组p(O2)增加了21.35%;SpO2增加了8.14%(P<0.05),肝、肾、脑组织缺氧程度明显减轻。结论GBT440能提高血液的携氧能力,改善组织的缺氧程度,有望成为一种有效的抗缺氧药物。Objective To study the effect of hemoglobin allosteric agent Voxelotor(GBT440)on oxygen-carrying characteristics of blood and its anti-hypoxia effect.Methods Whole arterial blood of mice were incubated with different concentrations of GBT440 at 37℃for 1 h,then hemoglobin oxygen dissociation curves(ODCs)were detected by Hemox Analyzer and the P50 was calculated.After the pH value of blood samples changed by adding acid and alkali,the changes of ODCs were detected.SD rats were randomly divided into normoxia control group,normoxia treatment group,hypoxia control group and hypoxia treatment group(n=6).The rats in the control group and the treatment group were given 0 and 100 mg/kg GBT440 respectively by gavage.In 1 h later,the normoxia group and the hypoxia group were respectively placed in closed chambers containing 21%O2 and 10%O2,and their abdominal aortic blood samples were collected for blood-gas test in another 6 h.The male C57 mice were divided into groups and treated as above.The hypoxyprobe was injected intraperitoneally at 1.5 h before the sampling,and the hypoxia level of the liver,kidney and brain tissues of the mice were detected by immunohistochemistry.Results With the increase concentrations of GBT440,ODCs were shifted to the left in a dose-dependent manner and P50 were significantly decreased(P<0.05).In the present of GBT440,adding acid induced ODCs right-shift,while adding alkali resulted in it left-shift.In the absence of GBT440,p(O2)and SpO2 in the hypoxic group were significantly reduced when compared with the normal group(P<0.05),and the hypoxic conditions in the liver,kidney and brain tissues were significantly severer.In the presence of GBT440,these indicators were improved in the hypoxia+GBT440 group than the hypoxia group,p(O2)was increased by 21.35%and SpO2 by 8.14%(P<0.05),and the hypoxic conditions in above organs were obviously ameliorated.Conclusion GBT440 can improve the oxygen carrying capacity of blood and the hypoxic conditions in tissues,and is expected to be an effective anti-hyp

关 键 词：GBT440 缺氧 血红蛋白 氧亲和力 

分 类 号：R331.141[医药卫生—人体生理学] R364.4[医药卫生—基础医学]