浏览全部资源
扫码关注微信
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
- 第三军医大学学报 2020年42卷第9期 页码：923-928
- 作者机构：
1.400016 重庆，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
2.400038 重庆，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
3.第一附属医院全军病理学研究所
4.400016 重庆，重庆医科大学：实验教学管理中心
- 作者简介：
[沈宜, E-mail:shenyicq@163.comSHEN Yi, E-mail: shenyicq@163.com
- 基金信息：军队医学科技青年培育计划(20QNPY002);“十三五”全军后勤科研重点项目(BWS17J031);全军后勤科研“十二五”重大项目S(AWS14L005)
DOI：10.16016/j.1000-5404.201911150
中图分类号： R331.141;R364.4;R965收稿：2019-11-18，
修回：2020-02-05，
纸质出版：2020-05-15
- 稿件说明：
移动端阅览
魏铭, 黄缄, 崔宇, 等. GBT440对鼠血液氧结合特性的影响以及抗缺氧效果[J]. 第三军医大学学报, 2020,42(9):923-928.
Ming WEI, Jian HUANG, Yu CUI, et al. Effect of GBT440 on oxygen-carrying characteristics and its anti-hypoxia effect in hypoxia animal model[J]. Journal of Third Military Medical University, 2020, 42(9): 923-928.
魏铭, 黄缄, 崔宇, 等. GBT440对鼠血液氧结合特性的影响以及抗缺氧效果[J]. 第三军医大学学报, 2020,42(9):923-928. DOI： 10.16016/j.1000-5404.201911150.
Ming WEI, Jian HUANG, Yu CUI, et al. Effect of GBT440 on oxygen-carrying characteristics and its anti-hypoxia effect in hypoxia animal model[J]. Journal of Third Military Medical University, 2020, 42(9): 923-928. DOI： 10.16016/j.1000-5404.201911150.
摘要
目的
2
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
2
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%O
2
和10%O
2
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
2
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
(O
2
)
]
、动脉血氧饱和度(SpO
2
)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
(O
2
)增加了21.35%；SpO
2
增加了8.14%(
P
<
0.05)，肝、肾、脑组织缺氧程度明显减轻。
结论
2
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。
Abstract
Objective
2
To study the effect of hemoglobin allosteric agent Voxelotor(GBT440) on oxygen-carrying characteristics of blood and its anti-hypoxia effect.
Methods
2
Whole arterial blood of mice were incubated with different concentrations of GBT440 at 37 ℃ for 1 h
then hemoglobin oxygen dissociation cu
rves(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% O
2
and 10%O
2
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
2
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
(O
2
) and SpO
2
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
(O
2
) was increased by 21.35% and SpO
2
by 8.14%(
P
<
0.05)
and the hypoxic conditions in above organs were obviously ameliorated.
Conclusion
2
GBT440 can improve the oxygen carrying capacity of blood and the hypoxic conditions in tissues
and is expected to be an effective anti-hypoxia drug.
关键词
Keywords
references
GELL D A. Structure and function of haemoglobins[J]. Blood Cells Mol Dis, 2018, 70: 13-42. DOI: 10.1016/j.bcmd.2017.10.006.
SRINIVASAN A J, MORKANE C, MARTIN D S, et al . Should modulation of p50 be a therapeutic target in the critically ill?[J ] . Expert Rev Hematol, 2017, 10(5): 449-458. DOI: 10.1080/17474086.2017.1313699.
FERRONE F A. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease[J]. Br J Haematol, 2016, 174(4): 499-500. DOI: 10.1111/bjh.14212.
DUFU K, LEHERE-GRAIWER J, RAMOS E, et al . GBT440 inhibits sickling of sickle cell trait blood under in vitro conditions mimicking strenuous exercise[J ] . Hematol Rep, 2016, 8(3): 6637. DOI: 10.4081/hr. 2016.6637..
YUAN Y, TAM M F, SIMPLACEANU V, et al . New look at hemoglobin allostery[J ] . Chem Rev, 2015, 115(4): 1702-1724. DOI: 10.1021/cr500495x.
SEIFETR J L, CHANG H Y. Disorders of acid-base balance: new perspectives[J]. Kidney Dis(Basel), 2017, 2(4): 170-186. DOI: 10.1159 /000453028.
HUTCHALEELAHA A, PATEL M, WASHINGTON C, et al . Pharmacokinetics andpharmacodynamics of voxelotor(GBT440) in healthy adults and patients with sickle cell disease[J ] . Br J Clin Pharmacol, 2019, 85(6): 1290-1302. DOI:10.1111/bcp.13896.
ZHENG G, SCHAEFER M, KARPLUS M. Hemoglobin Bohr effects: atomic origin of the histidine residue contributions[J]. Biochemistry, 2013, 52(47): 8539-8555. DOI: 10.1021/bi401126z.
HOCHRAINERM, FUNK G C. Interpretation of acid-base disorders[J]. Med Klin Intensivmed Notfmed, 2019, 114(8): 765-776. DOI:10.1007/s00063-019-00621-x.
SPITAL A. Physiological approach to assessment of acid-base disturbances[J]. N Engl J Med, 2015, 372(2): 193. DOI: 10.1056/NEJMc1413880.
JENDROS A, MALTE H, OVERGAARD C B, et al . Allosteric mechanisms underlying the adaptive increase in hemoglobin-oxygen affinity of the bar-headed goose[J ] . J Exp Biol, 2018, 221(Pt 18): jeb185470. DOI: 10.1242/jeb.185470.
YALCIN O, CABRALES P. Increased hemoglobin O 2 affinity protects during acute hypoxia[J ] . Am J Physiol Heart Circ Physiol, 2012, 303(3): H271-H281. DOI: 10.115 2/ajpheart.00078.2012.
LI C, LI X, LIU J, et al . Investigation of the differences between the Tibetan and Han populations in the hemoglobin- oxygen affinity of red blood cells and in the adaptation to high-altitude environments[J ] . Hematology(Amsterdam, Netherlands), 2018, 23(5): 309-313. DOI: 10.1080/10245332. 2017.1396046.
STORZ J F. Hemoglobin-oxygen affinity in high-altitudevertebrates: is there evidence for an adaptive trend?[J]. J Exp Biol, 2016, 219(20): 3190-3203. DOI: 10.1242/jeb.127134.
0
浏览量
0
下载量
0
CSCD
- 网络PDF下载
- Meta-XML下载
- BibTeX下载
- Endnote下载
- RefMan 下载
- NoteExpress下载
- NoteFirst下载
关联资源
相关文章
相关作者
相关机构
- 技术支持由北京北大方正电子有限公司提供 京ICP备09064830号-19
京公网安备11010802024621 - 本系统建议在Chrome、 IE9+ 以上版本浏览器阅读本站内容，360浏览器请切换至极速模式
- Cookies帮助我们提供服务并提供个性化体验。使用本网站，即表示您同意我们使用Cookies
