Please wait a minute...
浙江大学学报（医学版）
J Zhejiang Univ (Med Sci)  2019, Vol. 48 Issue (6): 674-681    DOI: 10.3785/j.issn.1008-9292.2019.12.13
    
Research progress on mechanism in adaptation of hemoglobin to plateau hypoxia
LI Xue1,2(),LI Wenbin2(),FENG Shilan1,*(),WANG Rong1,2,*()
1. School of Pharmacy, Lanzhou University, Lanzhou 730000, China
2. Key Laboratory of the Plateau Medicine, the 940 th Hospital of PLA Joint Logistics Support Force, Lanzhou 730050, China
Download: HTML( 8 )   PDF(3449KB)
Export: BibTeX | EndNote (RIS)      

Abstract  

Low oxygen partial pressure is the main cause of acute mountain sickness.Hemoglobin plays a crucial physiological role in the binding, utilization, transportation and release of oxygen in the body. To increase the capacity of oxygen binding of hemoglobin or the capacity of oxygen supply in tissues can help alleviate altitude sickness. However, increasing hemoglobin content has certain limitations. Using techniques from molecular biology, researchers are looking for endogenous or exogenous substances that can regulate the conformation of hemoglobin to increase oxygen uptake in the alveoli, or the availability of alveolar oxygen in the tissues. At present, the research on allosteric modulators to improve the affinity of hemoglobin has made some progress, and research on applying this mechanism to plateau hypoxia is also underway. This article reviews the relationship between hemoglobin and hypoxia, the structure of hemoglobin and the role of various allosteric modulators in hypoxia, which would provide information for finding new substances regulating the conformation of hemoglobin.

Key words： Hemoglobins      Altitude      Altitude sickness      Hypoxia/physiopathology      Adaptation, physiological      Allosteric regulation      Review     
Received: 15 October 2019      Published: 19 January 2020
CLC:  R594.3  
Corresponding Authors: FENG Shilan,WANG Rong     E-mail: lixue18@lzu.edu.cn;yfcs2002@163.com;fengshl@lzu.edu.cn;wangrong-69@163.com
Service
E-mail this article
Add to my bookshelf
Add to citation manager
E-mail Alert
RSS
Articles by authors
LI Xue
LI Wenbin
FENG Shilan
WANG Rong
Cite this article:

LI Xue,LI Wenbin,FENG Shilan,WANG Rong. Research progress on mechanism in adaptation of hemoglobin to plateau hypoxia. J Zhejiang Univ (Med Sci), 2019, 48(6): 674-681.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2019.12.13     OR     http://www.zjujournals.com/med/Y2019/V48/I6/674


血红蛋白在高原低氧适应中的机制研究进展

低氧分压是造成急性高山病的主要原因。机体中血红蛋白在氧的结合、利用、运输、释放中起着重要作用，增加血红蛋白的氧气结合量或者在组织中的供氧量有助于缓解高原病。但增加血红蛋白含量有一定的局限性，研究人员利用分子生物学的技术，寻找可调节血红蛋白构象的内源性或外源性物质，提高肺泡中的摄氧量或肺泡氧在组织中的利用率。目前有关变构调节剂改善血红蛋白亲和力的研究已取得一定进展，将这一机制运用到高原低氧的研究也正在展开。本文从血红蛋白与高原低氧的关系入手，阐述了血红蛋白的结构以及各种变构调节剂在低氧中发挥的作用，希望为寻找新的调节血红蛋白构象的物质提供理论依据。


关键词： 血红蛋白类,  高海拔,  高原病,  低氧/病理生理学,  适应, 生理学,  别构调节,  综述 
指标 平原移居者 高原世居者
藏族人 埃塞俄比亚人 安第斯人
血红蛋白 增加 较低 同0海拔处 随年龄增长而增加，与海拔相关
血氧饱和度 随海拔升高而降低 较低 同0海拔处 较低
通气量 增加 高静息通气量 高于0海拔处 低静息通气量
Tab 1 Differences in hemoglobin, oxygen saturation and ventilation between plain settlers and plateau settlers
Fig 1 Spatial structure of human deoxyhemoglobin and oxyhemoglobin
Fig 2 A schematic diagram of the release of oxygen from hemoglobin in tissues
Fig 3 Binding site of human hemoglobin to 2, 3-diphosphoglycerate
[1]   B?RTSCH P , SWENSON E R . Clinical practice:acute high-altitude illnesses[J]. N Engl J Med, 2013, 368 (24): 2294- 2302
doi: 10.1056/NEJMcp1214870
[2]   王积福, 郭志坚, 黄慧群 et al. 急进高原不同时间人体血红蛋白与高原反应相关性[J]. 青海医学院学报, 2010, 31 (3): 184- 186
WANG Jifu , GUO Zhijian , HUANG Huiqun et al. Correlation between hemoglobin and mountain response after rapidly ascended to highlands in different reriods[J]. Journal of Qinghai Medical College, 2010, 31 (3): 184- 186
doi: 10.3969/j.issn.1006-8252.2010.03.010
[3]   WEST J B . High-altitude medicine[J]. Lancet Respir Med, 2015, 3 (1): 12- 13
doi: 10.1016/S2213-2600(14)70238-3
[4]   STORZ J F , MORIYAMA H . Mechanisms of hemoglobin adaptation to high altitude hypoxia[J]. High Alt Med Biol, 2008, 9 (2): 148- 157
doi: 10.1089/ham.2007.1079
[5]   ZHANG D D , LI S H . Optical dating of Tibetan human hand-and footprints:An implication for the palaeoenvironment of the last glaciation of the Tibetan Plateau[J]. Geophys Res Lett, 2002, 29 (5): 16-1- 16-3
doi: 10.1029/2001GL013749
[6]   HOCHACHKA P W . Mechanism and evolution of hypoxia-tolerance in humans[J]. J Exp Biol, 1998, 201 (Pt 8): 1243- 1254
[7]   董宏彬, 洪欣, 尹昭云 . 血红蛋白与高原低氧适应[J]. 国外医学卫生学分册, 2004, 31 (4): 220- 223
DONG Hongbin , HONG Xin , Yin Zhaoyun . The adaptation of hemoglobin and plateau hypoxia[J]. Foreign Medical Sciences (Section of Hygiene), 2004, 31 (4): 220- 223
[8]   BEALL C M . Detecting natural selection in high-altitude human populations[J]. Respir Physiol Neurobiol, 2007, 158 (2-3): 161- 171
doi: 10.1016/j.resp.2007.05.013
[9]   BEALL C M , DECKER M J , BRITTENHAM G M et al. An Ethiopian pattern of human adaptation to high-altitude hypoxia[J]. Proc Natl Acad Sci U S A, 2002, 99 (26): 17215- 17218
doi: 10.1073/pnas.252649199
[10]   WANG B, ZHANG Y B, ZHANG F, et al. On the origin of Tibetans and their genetic basis in adapting high-altitude environments[J/OL]. PLoS One, 2011, 6(2): e17002.
[11]   李玉红 . 高原环境下藏汉族之间肺通气功能和血红蛋白比较[J]. 临床肺科杂志, 2014, 19 (10): 1785- 1787
LI Yuhong . Comparison of pulmonary ventilation function and hemoglobin between Tibetans and Hans at high altitude[J]. Journal of Clinical Pulmonary Medicine, 2014, 19 (10): 1785- 1787
[12]   GONGGALANZ I, LABASANGZH U, BJERTNESS E, et al. Acute mountain sickness, arterial oxygen saturation and heart rate among Tibetan students who reascend to Lhasa after 7 years at low altitude: a prospective cohort study[J/OL]. BMJ Open, 2017, 7(7): e016460.
[13]   贺启莲, 格日力, 李占强 et al. 高原适应遗传学缺氧诱导因子通路相关基因及其药理学研究进展[J]. 药学学报, 2019, 54 (4): 611- 619
HE Qilian , GE Rili , LI Zhanqiang et al. Hypoxia inducing factor related genetic adaptation in high-altitude and pharmacological modulation[J]. Acta Pharmaceutica Sinica, 2019, 54 (4): 611- 619
[14]   RISSO A , FABBRO D , DAMANTE G et al. Expression of fetal hemoglobin in adult humans exposed to high altitude hypoxia[J]. Blood Cells Mol Dis, 2012, 48 (3): 147- 153
[15]   BEALL C M . High-altitude adaptations[J]. Lancet, 2003, 362 s14- s15
doi: 10.1016/S0140-6736(03)15058-1
[16]   LEAF D E , GOLDFARB D S . Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness[J]. J Appl Physiol (1985), 2007, 102 (4): 1313- 1322
doi: 10.1152/japplphysiol.01572.2005
[17]   易元月, 刘宝, 官立彬 et al. 模拟高原不同时间缺氧暴露对大鼠红细胞结构与功能的影响[J]. 中国病理生理杂志, 2018, 34 (1): 130- 135
YI Yuanyue , LIU Bao , GUAN Libin et al. Effects of hypoxia exposure for different time on structure and function of red blood cells in rats[J]. Chinese Journal of Pathophysiology, 2018, 34 (1): 130- 135
doi: 10.3969/j.issn.1000-4718.2018.01.022
[18]   LIU C , LIU B , ZHANG E L et al. Elevated pentose phosphate pathway is involved in the recovery of hypoxia-induced erythrocytosis[J]. Mol Med Rep, 2017, 16 (6): 9441- 9448
doi: 10.3892/mmr.2017.7801
[19]   格日力, 佘海茹, 陈秋红 et al. 高原红细胞增多症患者红细胞二磷酸甘油酸和氧亲和力变化的探讨[J]. 中国应用生理学杂志, 1995, 11 (3): 205- 208
GE Rili , SHE Hairu , CHEN Qiuhong et al. Study on the changes of erythrocyte diphosphate glycerate and oxygen affinity in patients with high altitude polycythemia[J]. Chinese Journal of Applied Physiology, 1995, 11 (3): 205- 208
[20]   AKUNOV A , SYDYKOV A , TOKTASH T et al. Hemoglobin changes after long-term intermittent work at high altitude[J]. Front Physiol, 2018, 9 1552
doi: 10.3389/fphys.2018.01552
[21]   LENFANT C , TORRANCE J , ENGLISH E et al. Effect of altitude on oxygen binding by hemoglobin and on organic phosphate levels[J]. J Clin Invest, 1968, 47 (12): 2652- 2656
doi: 10.1172/JCI105948
[22]   赵玲莉, 耿慧, 邓丽君 et al. EPO的临床研究进展[J]. 青海医药杂志, 2011, 41 (3): 74- 77
ZHAO Lingli , GENG Hui , DENG Lijun et al. The progress in clinical research of EPO[J]. Qinghai Medical Journal, 2011, 41 (3): 74- 77
[23]   MAIRB?URL H , WEBER R E . Oxygen transport by hemoglobin[J]. Compr Physiol, 2012, 2 (2): 1463- 1489
[24]   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
[25]   GOW A J , STAMLER J S . Reactions between nitric oxide and haemoglobin under physiological conditions[J]. Nature, 1998, 391 (6663): 169- 173
doi: 10.1038/34402
[26]   BALABAN D Y , DUFFIN J , PREISS D et al. The in-vivo oxyhaemoglobin dissociation curve at sea level and high altitude[J]. Respir Physiol Neurobiol, 2013, 186 (1): 45- 52
doi: 10.1016/j.resp.2012.12.011
[27]   张倩, 官立彬, 白志川 et al. 血红蛋白与高原习服适应的研究进展[J]. 重庆医学, 2014, 43 (6): 753- 755, 757
ZHANG Qian , GUAN Libin , BAI Zhichuan et al. Advances in research on hemoglobin and altitude adaptation[J]. Chongqing Medicine, 2014, 43 (6): 753- 755, 757
doi: 10.3969/j.issn.1671-8348.2014.06.046
[28]   官立彬, 李晓栩, 崔宇 et al. 血红蛋白变构剂及其抗缺氧效应的研究进展[J]. 西南国防医药, 2017, 27 (11): 1244- 1246
GUAN Libin , LI Xiaoxu , CUI Yu et al. Research progress of hemoglobin allosteric agent and its anti-hypoxia effect[J]. Medical Journal of National Defending Forces in Southwest China, 2017, 27 (11): 1244- 1246
doi: 10.3969/j.issn.1004-0188.2017.11.041
[29]   BAUER C , SCHR?DER E . Carbamino compounds of haemoglobin in human adult and foetal blood[J]. J Physiol, 1972, 227 (2): 457- 471
doi: 10.1113/jphysiol.1972.sp010042
[30]   SUN K , ZHANG Y , D'ALESSANDRO A et al. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia[J]. Nat Commun, 2016, 7 12086
doi: 10.1038/ncomms12086
[31]   POMPONI M , BERTONATI C , FUGLEI E et al. 2, 3-DPG-Hb complex:a hypothesis for an asymmetric binding[J]. Biophys Chem, 2000, 84 (3): 253- 260
[32]   LIU H , ZHANG Y , WU H et al. Beneficial role of erythrocyte adenosine A2B receptor-mediated AMP-activated protein kinase activation in high-altitude hypoxia[J]. Circulation, 2016, 134 (5): 405- 421
doi: 10.1161/CIRCULATIONAHA.116.021311
[33]   YALCIN O , CABRALES P . Increased hemoglobin O2 affinity protects during acute hypoxia[J]. Am J Physiol Heart Circ Physiol, 2012, 303 (3): H271- H281
doi: 10.1152/ajpheart.00078.2012
[34]   官立彬, 李晓栩, 李锦松 et al. 5-羟甲基糠醛对模拟高原大鼠血红蛋白氧结合特性及游泳耐力和空间记忆能力的影响[J]. 第三军医大学学报, 2015, 37 (15): 1561- 1565
GUAN Libin , LI Xiaoxu , LI Jinsong et al. Effect of 5-HMF on hemoglobin-oxygen affinity, swimming endurance and spatial memory ability of rats in high altitude simulated environment[J]. Journal of Third Military Medical University, 2015, 37 (15): 1561- 1565
[35]   CHEN W R , YU Y , ZULFAJRI M et al. Phthalide derivatives from angelica sinensis decrease hemoglobin oxygen affinity:a new allosteric-modulating mechanism and potential use as 2, 3-BPG functional substitutes[J]. Sci Rep, 2017, 7 (1): 5504
doi: 10.1038/s41598-017-04554-3
[36]   乔瑞峰, 汪明慧, 解旭东 et al. 外源性二磷酸果糖在脑组织损伤中的保护作用[J]. 医学综述, 2019, 25 (6): 1099- 1104
QIAO Ruifeng , WANG Minghui , JIE Xudong et al. Effect of exogenous fructose 1, 6-diphosphate on neuroprotection[J]. Medical Recapitulate, 2019, 25 (6): 1099- 1104
doi: 10.3969/j.issn.1006-2084.2019.06.011
[37]   SUN K , ZHANG Y , BOGDANOV M V et al. Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity[J]. Blood, 2015, 125 (10): 1643- 1652
doi: 10.1182/blood-2014-08-595751
[38]   OKSENBERG D , DUFU K , PATEL M P et al. 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, 175 (1): 141- 153
doi: 10.1111/bjh.14214
[39]   DUFU K , YALCIN O , AO-IEONG E et al. GBT1118, a potent allosteric modifier of hemoglobin O2 affinity, increases tolerance to severe hypoxia in mice[J]. Am J Physiol Heart Circ Physiol, 2017, 313 (2): H381- H391
doi: 10.1152/ajpheart.00772.2016
[40]   NAKAGAWA A , FERRARI M , SCHLEIFER G et al. A triazole disulfide compound increases the affinity of hemoglobin for oxygen and reduces the sickling of human sickle cells[J]. Mol Pharm, 2018, 15 (5): 1954- 1963
doi: 10.1021/acs.molpharmaceut.8b00108
[41]   马林, 魏志强, 黄爱民 et al. 丙三醇对水溶液中血红蛋白构象的影响——荧光猝灭和动态光散射研究[J]. 化学学报, 2009, 67 (14): 1566- 1572
MA Lin , WEI Zhiqiang , HUANG Aimin et al. Influence of glycerol on the conformation of hemoglobin in aqueous solutions:a study of fluorescence quenching and dynamic light scattering[J]. Acta Chimica Sinica, 2009, 67 (14): 1566- 1572
doi: 10.3321/j.issn:0567-7351.2009.14.006
[1] DU Xiaotian, OUYANG Hongwei. Correlation between histone methylation level and pathological development of osteoarthritis[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 682-687.
[2] YUAN Xuechun,XIANG Dawei,MIN Qiong,DING Yidan,ZHAO Anpeng,WANG Rong. Effects of acute hypoxia on expression of pregnane X receptor in liver tissues of rats exposed to high altitude[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 603-608.
[3] DING Yidan,LI Wenbin,WANG Rong,ZHANG Jianchun. Research progress on the effects of plateau hypoxia on blood-brain barrier structure and drug permeability[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 668-673.
[4] KONG Limin, LU Jingyi, ZHU Huajian, ZHANG Jiankang. Research progress on selective immunoproteasome inhibitors[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 688-694.
[5] XU Jiajun,SHU Qiang. Application of 3D printing techniques in treatment of congenital heart disease[J]. J Zhejiang Univ (Med Sci), 2019, 48(5): 573-579.
[6] ZHANG Junhao,JIN Jinghua,YANG Wei. Autophagy regulates the function of vascular smooth muscle cells in the formation and rupture of intracranial aneurysms[J]. J Zhejiang Univ (Med Sci), 2019, 48(5): 552-559.
[7] CHEN Dianyu,QI Ming. Research progress on uniparental disomy in cancer[J]. J Zhejiang Univ (Med Sci), 2019, 48(5): 560-566.
[8] LIN Jing,CHEN Zhimin. Research progress on early identification of severe adenovirus pneumonia in children[J]. J Zhejiang Univ (Med Sci), 2019, 48(5): 567-572.
[9] HUANG Shumin,ZHAO Zhengyan. Advances in newborn screening and immune system reconstitution of severe combined immunodeficiency[J]. J Zhejiang Univ (Med Sci), 2019, 48(4): 351-357.
[10] CHEN Guangjie,WANG Xiaohao,TANG Daxing. Progress on evaluation, diagnosis and management of disorders of sex development[J]. J Zhejiang Univ (Med Sci), 2019, 48(4): 358-366.
[11] ZHANG Jianmin. Advances in surgical treatment of ischemic cerebrovascular disease[J]. J Zhejiang Univ (Med Sci), 2019, 48(3): 233-240.
[12] WU Yuxing, ZHANG Shihong, CHEN Zhong. The roles of habenula and related neural circuits in neuropsychiatric diseases[J]. J Zhejiang Univ (Med Sci), 2019, 48(3): 310-317.
[13] ZHANG Yunzhu, ZHU Chunpeng, LU Xinliang. Advances in serum biomarkers for early diagnosis of gastric cancer[J]. J Zhejiang Univ (Med Sci), 2019, 48(3): 326-333.
[14] ZHU Ziling, TAN Jing, DENG Hong. Nucleus translocation of membrane/cytoplasm proteins in tumor cells[J]. J Zhejiang Univ (Med Sci), 2019, 48(3): 318-325.
[15] Baboo Kalianee Devi,CHEN Zhengyun,ZHANG Xinmei. Progress on medical treatment in the management of adenomyosis[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 142-147.