血红蛋白氧亲和力在临床应用的研究进展
摘要
人体内氧的运输主要依赖红细胞内血红蛋白与氧的结合和解离,血红蛋白与氧结合的能力即血红蛋白氧亲和力是血红蛋白的重要特征之一。氧亲和力通过血红蛋白氧饱和度为50%时的氧分压(P_(50))表征。所以,P_(50)反映出人体的氧摄入和组织细胞的氧获取的能力,其改变受多种因素影响,包括体内H+浓度、二氧化碳分压(PCO_2)、温度、2,3-二磷酸甘油酸(2,3-DPG)等变构效应剂及多种药物。P_(50)的检测和调节在输血和潜在的疾病诊断及治疗等临床应用方面具有巨大的研究空间和潜力。
引文
1 Mairb?url H,Weber R E.Oxygen transport by hemoglobin[J].Compr Physiol,2012,2(2):1463-1489.
2朱大年,王庭槐.生理学[M].第8版.北京:人民卫生出版社,2013:170-176.
3 Brunori M.Variations on the theme:allosteric control in hemoglobin[J].FEBS J,2014,281(2):633-43.
4 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.
5 Li Q,Ma H,Zhang Y,et al.Study on oxidation stability and oxygen affinity of hemoglobin during storage[J].Artif Organs,2018,42(12):1185-1195.
6 Malte H,Lykkeboe G.The Bohr/Haldane effect:A model based uncovering of the full extent of its impact on O2 delivery to and CO2 removal from tissues[J].J Appl Physiol(1985),2018,125(3):916-922.
7 Li C,Li X,Liu J,et al.Investigation of the differences between the Tibetan and Han populations in the hemoglobinoxygen affinity of red blood cells and in the adaptation to highaltitude environments[J].Hematology,2018,23(5):309-313.
8 Gladwin M T,Kim-Shapiro D B.The functional nitrite reductase activity of the heme-globins[J].Blood,2008,112(7):2636-2647.
9 Nakagawa A,Lui F E,Wassaf D,et al.Identification of a small molecule that increases hemoglobin oxygen affinity and reduces SS erythrocyte sickling[J].ACS Chem Biol,2014,9(10):2318-2325.
10 Gell D A.Structure and function of haemoglobins[J].Blood Cells Mol Dis,2018,70:13-42.
11 Helms C C,Gladwin M T,Kim-Shapiro D B.Erythrocytes and Vascular Function:Oxygen and Nitric Oxide[J].Front Physiol,2018,9:125.
12 García-Roa M,Del CVM,Bobes A M,et al.Red blood cell storage time and transfusion:current practice,concerns and future perspectives[J].Blood Transfus,2017,15(3):222-231.
13 Li Y,Xiong Y,Wang R,et al.Blood banking-induced alteration of red blood cell oxygen release ability[J].Blood Transfus,2016,14(2):238-244.
14 Srinivasan A J,Kausch K,Inglut C,et al.Estimation of Achievable Oxygen Consumption Following Transfusion With Rejuvenated Red Blood Cells[J].Semin Thorac Cardiovasc Surg,2018,30(2):134-141.
15 Aujla H,Woniak M,Kumar T,et al.Rejuvenation of allogenic red cells:benefits and risks[J].Vox Sang,2018,113(6):509-529.
16 Wo niak M J,Qureshi S,Sullo N,et al.A comparison of red cell rejuvenation versus mechanical washing for the prevention of transfusion-associated organ Injury in Swine[J].Anesthesiology,2018,128(2):375-385.
17 Avellan-Hietanen H,Aittomaki J,Ekroos H,et al.Decreased oxygen saturation as a result of haemoglobin Titusville[J].Clin Respir J,2008,2(4):242-244.
18 Oliveira J L,Coon L M,Frederick L A,et al.Genotypephenotype correlation of hereditary erythrocytosis mutations,a single center experience[J].Am J Hematol,2018.
19 Orvain C,Joly P,Pissard S,et al.Diagnostic approach to hemoglobins with high oxygen affinity:experience from France and Belgium and review of the literature[J].Ann Biol Clin(Paris),2017,75(1):39-51.
20 Mangin O.High oxygen affinity hemoglobins[J].Rev Med Interne,2017,38(2):106-112.
21 Metcalf B,Chuang C,Dufu K,et al.Discovery of GBT440,an orally bioavailable R-state stabilizer of sickle cell hemoglobin[J].ACS Med Chem Lett,2017,8(3):321-326.
22 Bourgeaux V,Hequet O,Campion Y,et al.Inositol hexaphosphate-loaded red blood cells prevent in vitro sickling[J].Transfusion,2010,50(10):2176-2184.
23 Bourgeaux V,Aufradet E,Campion Y,et al.Efficacy of homologous inositol hexaphosphate-loaded red blood cells in sickle transgenic mice[J].Br J Haematol,2012,157(3):357-369.
24 Safo M K,Kato G J.Therapeutic strategies to alter the oxygen affinity of sickle hemoglobin[J].Hematol Oncol Clin North Am,2014,28(2):217-231.
25 Kassa T,Strader M B,Nakagawa A,et al.TargetingβCys93 in hemoglobin S with an antisickling agent possessing dual allosteric and antioxidant effects[J].Metallomics,2017,9(9):1260-1270.
26 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.
27 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 JHaematol,2016,175(1):141-153.
28 Dufu K,Oksenberg D.GBT440 reverses sickling of sickled red blood cells under hypoxic conditions in vitro[J].Hematol Rep,2018,10(2):7419.
29 Dufu K,Patel M,Oksenberg D,et al.GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions[J].Clin Hemorheol Microcirc,2018,70(1):95-105.
30 Estepp J H.Voxelotor(GBT440),a first-in-class hemoglobin oxygen-affinity modulator,has promising and reassuring preclinical and clinical data[J].Am J Hematol,2018,93(3):326-329.
31 Dufu K,Yalcin O,ESY A,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.
32 Geng X,Dufu K,Hutchaleelaha A,et al.Increased hemoglobin-oxygen affinity ameliorates bleomycin-induced hypoxemia and pulmonary fibrosis[J].Physiol Rep,2016,4(17):e12965.
33 Putz N D,Shaver C M,Dufu K,et al.GBT1118,a compound that increases the oxygen affinity of hemoglobin,improves survival in murine hypoxic acute lung injury[J].JAppl Physiol(1985),2018,124(4):899-905.
34 Stücker O,Vicaut E,Villereal M C,et al.Coronary response to large decreases of hemoglobin-O2 affinity in isolated rat heart[J].Am J Physiol,1985,249(6 Pt 2):H1224-H1227.
35 Teisseire B,Ropars C,Villeréal M C,et al.Long-term physiological effects of enhanced O2 release by inositol hexaphosphate-loaded erythrocytes[J].Proc Natl Acad Sci U SA,1987,84(19):6894-6898.
36 Deleuze P H,Bailleul C,Shiiya N,et al.Enhanced O2transportation during cardiopulmonary bypass in piglets by the use of inositol hexaphosphate loaded red blood cells[J].Int JArtif Organs,1992,15(4):239-242.
37 Huang F,Nojiri H,Shimizu T,et al.Beneficial effect of transfusion with low-affinity red blood cells in endotoxemia[J].Transfusion,2005,45(11):1785-1790.
38 Watanabe T,Takeda T,Omiya S,et al.Reduction in hemoglobin-oxygen affinity results in the improvement of exercise capacity in mice with chronic heart failure[J].J Am Coll Cardiol,2008,52(9):779-786.
39 Dhar R,Zazulia A R,Derdeyn C P,et al.RBC transfusion improves cerebral oxygen delivery in subarachnoid hemorrhage[J].Crit Care Med,2017,45(4):653-659.
40 Sihn G,Walter T,Klein J C,et al.Anti-angiogenic properties of myo-inositol trispyrophosphate in ovo and growth reduction of implanted glioma[J].FEBS Lett,2007,581(5):962-966.
41 Raykov Z,Grekova S P,Bour G,et al.Myo-inositol trispyrophosphate-mediated hypoxia reversion controls pancreatic cancer in rodents and enhances gemcitabine efficacy[J].Int J Cancer,2014,134(11):2572-2582.
42 Derbal-Wolfrom L,Pencreach E,Saandi T,et al.Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2[J].Oncogene,2013,32(36):4313-4318.
43 Limani P,Linecker M,Kachaylo E,et al.Antihypoxic potentiation of standard therapy for experimental colorectal liver metastasis through myo-inositol trispyrophosphate[J].Clin Cancer Res,2016,22(23):5887-5897.
44 Aprahamian M,Bour G,Akladios C Y,et al.Myo-inositol trisPyrophosphate treatment leads to HIF-1αsuppression and eradication of early hepatoma tumors in rats[J].Chembiochem,2011,12(5):777-783.
45 Chen WR,Yu Y,Zulfajri M,et al.Phthalide derivatives from angelica sinensis decrease hemoglobin oxygen affinity:Anew allosteric-modulating mechanism and potential use as 2,3-BPG functional substitutes[J].Sci Rep,2017,7(1):5504.
46 McKoy M,Allen K,Richards A,et al.Effect of cilostazol on the p50 of the oxygen-hemoglobin dissociation curve[J].Int J Angiol,2015,24(1):67-70.
47 Khandelwal S R,Randad R S,Lin P S,et al.Enhanced oxygenation in vivo by allosteric inhibitors of hemoglobin saturation[J].Am J Physiol,1993,265(4 Pt2):H1450-H1453.
48 Kunert M P,Liard J F,Abraham D J,et al.Low-affinity hemoglobin increases tissue PO2 and decreases arteriolar diameter and flow in the rat cremaster muscle[J].Microvasc Res,1996,52(1):58-68.
49 Woods J A,Storey C J,Babcock E E,et al.Right-shifting the oxyhemoglobin dissociation curve with RSR13:effects on high-energy phosphates and myocardial recovery after low-flow ischemia[J].J Cardiovasc Pharmacol,1998,31(3):359-63.
50 Kilgore K S,Shwartz C F,Gallagher M A,et al.RSR13,a synthetic allosteric modifier of hemoglobin,improves myocardial recovery following hypothermic cardiopulmonary bypass[J].Circulation,1999,100(19 Suppl):II351-II356.
51 Weiss R G,Mejia M A,Kass D A,et al.Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin-oxygen affinity[J].J Clin Invest,1999,103(5):739-746.
52 Kleinberg L,Grossman S A,Piantadosi S,et al.Phase I trial to determine the safety,pharmacodynamics,and pharmacokinetics of RSR13,a novel radioenhancer,in newly diagnosed glioblastoma multiforme[J].J Clin Oncol,1999,17(8):2593-2603.
53 Miyake M,Grinberg O Y,Hou H,et al.The effect of RSR13,a synthetic allosteric modifier of hemoglobin,on brain tissue pO2(measured by EPR oximetry)following severe hemorrhagic shock in rats[J].Adv Exp Med Biol,2003,530:319-329.
54 Suh J H,Stea B,Nabid A,et al.Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases[J].J Clin Oncol,2006,24(1):106-114.
55 Fylaktakidou K C,Lehn J M,Greferath R,et al.Inositol tripyrophosphate:a new membrane permeant allosteric effector of haemoglobin[J].Bioorg Med Chem Lett,2005,15(6):1605-1608.
56 Kieda C,Greferath R,Crola dSC,et al.Suppression of hypoxia-induced HIF-1alpha and of angiogenesis in endothelial cells by myo-inositol trispyrophosphate-treated erythrocytes[J].Proc Natl Acad Sci U S A,2006,103(42):15576-15581.
2朱大年,王庭槐.生理学[M].第8版.北京:人民卫生出版社,2013:170-176.
3 Brunori M.Variations on the theme:allosteric control in hemoglobin[J].FEBS J,2014,281(2):633-43.
4 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.
5 Li Q,Ma H,Zhang Y,et al.Study on oxidation stability and oxygen affinity of hemoglobin during storage[J].Artif Organs,2018,42(12):1185-1195.
6 Malte H,Lykkeboe G.The Bohr/Haldane effect:A model based uncovering of the full extent of its impact on O2 delivery to and CO2 removal from tissues[J].J Appl Physiol(1985),2018,125(3):916-922.
7 Li C,Li X,Liu J,et al.Investigation of the differences between the Tibetan and Han populations in the hemoglobinoxygen affinity of red blood cells and in the adaptation to highaltitude environments[J].Hematology,2018,23(5):309-313.
8 Gladwin M T,Kim-Shapiro D B.The functional nitrite reductase activity of the heme-globins[J].Blood,2008,112(7):2636-2647.
9 Nakagawa A,Lui F E,Wassaf D,et al.Identification of a small molecule that increases hemoglobin oxygen affinity and reduces SS erythrocyte sickling[J].ACS Chem Biol,2014,9(10):2318-2325.
10 Gell D A.Structure and function of haemoglobins[J].Blood Cells Mol Dis,2018,70:13-42.
11 Helms C C,Gladwin M T,Kim-Shapiro D B.Erythrocytes and Vascular Function:Oxygen and Nitric Oxide[J].Front Physiol,2018,9:125.
12 García-Roa M,Del CVM,Bobes A M,et al.Red blood cell storage time and transfusion:current practice,concerns and future perspectives[J].Blood Transfus,2017,15(3):222-231.
13 Li Y,Xiong Y,Wang R,et al.Blood banking-induced alteration of red blood cell oxygen release ability[J].Blood Transfus,2016,14(2):238-244.
14 Srinivasan A J,Kausch K,Inglut C,et al.Estimation of Achievable Oxygen Consumption Following Transfusion With Rejuvenated Red Blood Cells[J].Semin Thorac Cardiovasc Surg,2018,30(2):134-141.
15 Aujla H,Woniak M,Kumar T,et al.Rejuvenation of allogenic red cells:benefits and risks[J].Vox Sang,2018,113(6):509-529.
16 Wo niak M J,Qureshi S,Sullo N,et al.A comparison of red cell rejuvenation versus mechanical washing for the prevention of transfusion-associated organ Injury in Swine[J].Anesthesiology,2018,128(2):375-385.
17 Avellan-Hietanen H,Aittomaki J,Ekroos H,et al.Decreased oxygen saturation as a result of haemoglobin Titusville[J].Clin Respir J,2008,2(4):242-244.
18 Oliveira J L,Coon L M,Frederick L A,et al.Genotypephenotype correlation of hereditary erythrocytosis mutations,a single center experience[J].Am J Hematol,2018.
19 Orvain C,Joly P,Pissard S,et al.Diagnostic approach to hemoglobins with high oxygen affinity:experience from France and Belgium and review of the literature[J].Ann Biol Clin(Paris),2017,75(1):39-51.
20 Mangin O.High oxygen affinity hemoglobins[J].Rev Med Interne,2017,38(2):106-112.
21 Metcalf B,Chuang C,Dufu K,et al.Discovery of GBT440,an orally bioavailable R-state stabilizer of sickle cell hemoglobin[J].ACS Med Chem Lett,2017,8(3):321-326.
22 Bourgeaux V,Hequet O,Campion Y,et al.Inositol hexaphosphate-loaded red blood cells prevent in vitro sickling[J].Transfusion,2010,50(10):2176-2184.
23 Bourgeaux V,Aufradet E,Campion Y,et al.Efficacy of homologous inositol hexaphosphate-loaded red blood cells in sickle transgenic mice[J].Br J Haematol,2012,157(3):357-369.
24 Safo M K,Kato G J.Therapeutic strategies to alter the oxygen affinity of sickle hemoglobin[J].Hematol Oncol Clin North Am,2014,28(2):217-231.
25 Kassa T,Strader M B,Nakagawa A,et al.TargetingβCys93 in hemoglobin S with an antisickling agent possessing dual allosteric and antioxidant effects[J].Metallomics,2017,9(9):1260-1270.
26 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.
27 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 JHaematol,2016,175(1):141-153.
28 Dufu K,Oksenberg D.GBT440 reverses sickling of sickled red blood cells under hypoxic conditions in vitro[J].Hematol Rep,2018,10(2):7419.
29 Dufu K,Patel M,Oksenberg D,et al.GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions[J].Clin Hemorheol Microcirc,2018,70(1):95-105.
30 Estepp J H.Voxelotor(GBT440),a first-in-class hemoglobin oxygen-affinity modulator,has promising and reassuring preclinical and clinical data[J].Am J Hematol,2018,93(3):326-329.
31 Dufu K,Yalcin O,ESY A,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.
32 Geng X,Dufu K,Hutchaleelaha A,et al.Increased hemoglobin-oxygen affinity ameliorates bleomycin-induced hypoxemia and pulmonary fibrosis[J].Physiol Rep,2016,4(17):e12965.
33 Putz N D,Shaver C M,Dufu K,et al.GBT1118,a compound that increases the oxygen affinity of hemoglobin,improves survival in murine hypoxic acute lung injury[J].JAppl Physiol(1985),2018,124(4):899-905.
34 Stücker O,Vicaut E,Villereal M C,et al.Coronary response to large decreases of hemoglobin-O2 affinity in isolated rat heart[J].Am J Physiol,1985,249(6 Pt 2):H1224-H1227.
35 Teisseire B,Ropars C,Villeréal M C,et al.Long-term physiological effects of enhanced O2 release by inositol hexaphosphate-loaded erythrocytes[J].Proc Natl Acad Sci U SA,1987,84(19):6894-6898.
36 Deleuze P H,Bailleul C,Shiiya N,et al.Enhanced O2transportation during cardiopulmonary bypass in piglets by the use of inositol hexaphosphate loaded red blood cells[J].Int JArtif Organs,1992,15(4):239-242.
37 Huang F,Nojiri H,Shimizu T,et al.Beneficial effect of transfusion with low-affinity red blood cells in endotoxemia[J].Transfusion,2005,45(11):1785-1790.
38 Watanabe T,Takeda T,Omiya S,et al.Reduction in hemoglobin-oxygen affinity results in the improvement of exercise capacity in mice with chronic heart failure[J].J Am Coll Cardiol,2008,52(9):779-786.
39 Dhar R,Zazulia A R,Derdeyn C P,et al.RBC transfusion improves cerebral oxygen delivery in subarachnoid hemorrhage[J].Crit Care Med,2017,45(4):653-659.
40 Sihn G,Walter T,Klein J C,et al.Anti-angiogenic properties of myo-inositol trispyrophosphate in ovo and growth reduction of implanted glioma[J].FEBS Lett,2007,581(5):962-966.
41 Raykov Z,Grekova S P,Bour G,et al.Myo-inositol trispyrophosphate-mediated hypoxia reversion controls pancreatic cancer in rodents and enhances gemcitabine efficacy[J].Int J Cancer,2014,134(11):2572-2582.
42 Derbal-Wolfrom L,Pencreach E,Saandi T,et al.Increasing the oxygen load by treatment with myo-inositol trispyrophosphate reduces growth of colon cancer and modulates the intestine homeobox gene Cdx2[J].Oncogene,2013,32(36):4313-4318.
43 Limani P,Linecker M,Kachaylo E,et al.Antihypoxic potentiation of standard therapy for experimental colorectal liver metastasis through myo-inositol trispyrophosphate[J].Clin Cancer Res,2016,22(23):5887-5897.
44 Aprahamian M,Bour G,Akladios C Y,et al.Myo-inositol trisPyrophosphate treatment leads to HIF-1αsuppression and eradication of early hepatoma tumors in rats[J].Chembiochem,2011,12(5):777-783.
45 Chen WR,Yu Y,Zulfajri M,et al.Phthalide derivatives from angelica sinensis decrease hemoglobin oxygen affinity:Anew allosteric-modulating mechanism and potential use as 2,3-BPG functional substitutes[J].Sci Rep,2017,7(1):5504.
46 McKoy M,Allen K,Richards A,et al.Effect of cilostazol on the p50 of the oxygen-hemoglobin dissociation curve[J].Int J Angiol,2015,24(1):67-70.
47 Khandelwal S R,Randad R S,Lin P S,et al.Enhanced oxygenation in vivo by allosteric inhibitors of hemoglobin saturation[J].Am J Physiol,1993,265(4 Pt2):H1450-H1453.
48 Kunert M P,Liard J F,Abraham D J,et al.Low-affinity hemoglobin increases tissue PO2 and decreases arteriolar diameter and flow in the rat cremaster muscle[J].Microvasc Res,1996,52(1):58-68.
49 Woods J A,Storey C J,Babcock E E,et al.Right-shifting the oxyhemoglobin dissociation curve with RSR13:effects on high-energy phosphates and myocardial recovery after low-flow ischemia[J].J Cardiovasc Pharmacol,1998,31(3):359-63.
50 Kilgore K S,Shwartz C F,Gallagher M A,et al.RSR13,a synthetic allosteric modifier of hemoglobin,improves myocardial recovery following hypothermic cardiopulmonary bypass[J].Circulation,1999,100(19 Suppl):II351-II356.
51 Weiss R G,Mejia M A,Kass D A,et al.Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin-oxygen affinity[J].J Clin Invest,1999,103(5):739-746.
52 Kleinberg L,Grossman S A,Piantadosi S,et al.Phase I trial to determine the safety,pharmacodynamics,and pharmacokinetics of RSR13,a novel radioenhancer,in newly diagnosed glioblastoma multiforme[J].J Clin Oncol,1999,17(8):2593-2603.
53 Miyake M,Grinberg O Y,Hou H,et al.The effect of RSR13,a synthetic allosteric modifier of hemoglobin,on brain tissue pO2(measured by EPR oximetry)following severe hemorrhagic shock in rats[J].Adv Exp Med Biol,2003,530:319-329.
54 Suh J H,Stea B,Nabid A,et al.Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases[J].J Clin Oncol,2006,24(1):106-114.
55 Fylaktakidou K C,Lehn J M,Greferath R,et al.Inositol tripyrophosphate:a new membrane permeant allosteric effector of haemoglobin[J].Bioorg Med Chem Lett,2005,15(6):1605-1608.
56 Kieda C,Greferath R,Crola dSC,et al.Suppression of hypoxia-induced HIF-1alpha and of angiogenesis in endothelial cells by myo-inositol trispyrophosphate-treated erythrocytes[J].Proc Natl Acad Sci U S A,2006,103(42):15576-15581.