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1、BLOOD Plasma-55% Formed elements-45% Buffy coat-3%)arereleased intothebloodprematurely. 1. Erythropoiesis 骨髓红系定向细胞增殖及其最重要受体的理论模型 EPO：促红细胞生成素；GM-CSF：粒-巨核细胞集落刺激因子；IL3：白介素3； Transferrin:转铁蛋白；Fibronectin:纤连蛋白 1. Erythropoiesis ToofewRBCsleadstotissuehypoxia Regulation of Erythropoiesis 1. Erythropoiesis
2、 Kidney (and liver to a smaller extent) releases ERYTHROPOIETIN. Erythropoietin stimulates red bone marrow. Enhanced erythropoiesis increases RBC count. O2- carrying ability of blood increases. Homeostasis: Normal blood oxygen levels Stimulus: Hypoxia (low blood O2- carrying ability) due to Decrease
3、d RBC count Decreased amount of hemoglobin Decreased availability of O2 1 2 3 4 5 IMBALANCE IMBALANCE HypoxiaInducibleFactor(HIF) Regulation of Erythropoiesis 1. Erythropoiesis Erythropoietin(EPO（促红细胞生成素） ) 34,000Da,Glycoprotein Releasedbythekidneyinresponseto hypoxia(hemorrhage（出血）, hemolytic（溶血）,i
4、rondeficiencyor highaltitudes) Regulation of Erythropoiesis 1. Erythropoiesis Regulation of Erythropoiesis 1. Erythropoiesis Erythropoietin(EPO) Directstimulusfor erythropoiesis Morerapidmaturationof committedbonemarrow cells Increasedcirculating reticulocytecountin1 2days Regulation of Erythropoies
5、is 1. Erythropoiesis BalancebetweenRBCproductionanddestructiondependson Hormonalcontrols(Erythropoietin,EPO) Adequatesuppliesof FolicAcid(folate（叶酸）) VitaminB12,cyanocobalamin（氰钴胺） AminoAcids Iron VitaminB6,pyridoxine（吡哆醇） AscorbicAcid(VitaminC) Regulation of Erythropoiesis 1. Erythropoiesis 1. Eryt
6、hropoiesis (Disease) AplasticAnemia(AA,再生障碍贫血) 1. Erythropoiesis (Disease) Themarrowbiopsysectionofayoung adultwithverysevereaplasticanemia Anormalmarrowbiopsysection ofayoungadult. 获得性再生障碍性贫血是一种血液中红细胞、中性粒细胞、单核细胞和 血小板减少，而骨髓组织被脂肪组织代替、造血祖细胞几乎缺如的临床 综合征。 病因： 1、毒性物质：苯、有机磷 2、病毒感染：EB、肝炎病毒、HIV 3、药物：氯霉素、噻氯匹定
7、 4、自身免疫病：红斑狼疮 5、妊娠 共同发病途径： 细胞毒T细胞自身反应 AnimmuneattackofTccells targetshematopoieticstem andprogenitorcells(CD34+ cells)apoptosis hematopoieticfailure AplasticAnemia(AA,再生障碍贫血) 1. Erythropoiesis (Disease) AnemiaofChronicRenalDisease(慢性肾脏疾病的贫血) 病变的肾脏产生EPO减少是贫血的主要原因 毒性代谢产物的累积导致红细胞寿命缩短、骨髓抑制 并发炎症或营养不良可加重贫
8、血 慢性肾脏疾病患者血细胞比容与内生肌酐清除 率的关系。 尿毒症患者的循环血EPO水平下降 正常个体和单纯贫血患者 有肾的尿毒症患者 无肾的尿毒症患者 1. Erythropoiesis (Disease) AnemiaofChronicRenalDisease(慢性肾脏疾病的贫血) A.外周血涂片 慢性肾脏疾病没有特征性的红细胞改变。偶见红细胞 碎片，靶形红细胞，棘形红细胞等异常红细胞形态。 B.外周血涂片 溶血尿毒症综合征。大量的破碎红细胞是溶血尿毒症综 合征的典型表现。红细胞大小不一和少量球形红细胞。 1. Erythropoiesis (Disease) 2. Cell Membran
9、e Flexibilitytochangeshape The red cell must be able to change shape and squeeze through small capillaries. Sphingomyelin(SM鞘磷脂) Phosphatidylcholine(PC磷脂酰胆碱) Phosphatidylethanolamine(PE磷脂酰乙醇胺) Phosphatidylserine(PS磷脂酰丝氨酸) 2. Cell Membrane Theredcellmembraneconsistsofa bipolarlipidlayersupportedbystr
10、uctural proteins. Protein,49% Lipid,42% Carbohydrate,8% Inorganicion,1% Outermostlayer: glycolipids,glycoproteins Centrallayer: cholesterol,phospholipids Innerlayer: cytoskeleton(骨架蛋白) Spectrin（血影蛋白） Ankyrin（锚蛋白） Proteins Integral proteins (I， 内在蛋白) Band 3（区带3蛋白，阴离子交换蛋白） Glycophorin （血型糖蛋白） are impo
11、rtant for the active transport of solutes across the membrane Peripheral Proteins (P， 周围蛋白) Spectrin （血影蛋白） Actin（肌动蛋白） Ankyrin（锚蛋白） Band 4 （区带4蛋白） membrane skeleton on the inner surface to maintain the biconcave shape of the red cell to strengthens the membrane against sheer force 2. Cell Membrane
12、Proteins Integral proteins (I， 内在蛋白) Band 3（区带3蛋白，阴离子交换蛋白） Glycophorin （血型糖蛋白） are important for the active transport of solutes across the membrane Peripheral Proteins (P， 周围蛋白) Spectrin （血影蛋白） Actin（肌动蛋白） Ankyrin（锚蛋白） Band 4 （区带4蛋白） membrane skeleton on the inner surface to maintain the biconcave
13、shape of the red cell to strengthens the membrane against sheer force Proteins in the red cell membrane can be solubilised by a detergent called sodium dodecyl sulphate (SDS) and then be separated according to their size using polyacrylamide gel- electrophoresis (SDS-PAGE). 2. Cell Membrane Lipids 6
14、0% phospholipid （磷脂） 30% neutral lipids (mainly cholesterol（胆固醇）) 10% glycolipids（糖脂） The phospho- and glyco-lipids are structural with polar groups (hydrophilic) on the external and internal surfaces of the cell. Non-polar groups (hydrophobic) form a barrier at the centre of the membrane. Asymmetry
15、ofmembranephospholipids 膜磷脂的非对称分布 2. Cell Membrane Sphingomyelin(SM鞘磷脂) Phosphatidylcholine(PC磷脂酰胆碱) Phosphatidylethanolamine(PE磷脂酰乙醇胺 ) Phosphatidylserine(PS磷脂酰丝氨酸) Carbohydrates are mostly found on the external surface of the red cell membrane. Monosaccharides （寡糖）are associated with specific bloo
16、d group antigens, e.g. ABH and Lewis. A gene product (A transferase) Gal GlcGal GlcNAc Red cell membrane Type 2 precursor Note: 14 linkage band 3 1 23 4 Fuc 1 23 4 GalNAc Donor nucleotide (UDP-GalNAc) Acceptor sugar (Galactose) Specific 13 linkage Producing blood group A antigen on the red cell of a
17、 group A individual. 2. Cell Membrane MembraneFunction 1. cellulardeformabilityandmembranestability 2. membranepermeability 3. membraneantigenicityandimmunologicfunction 4. receptors 2. Cell Membrane MembraneFunction 1. cellulardeformabilityandmembranestability structuralcharacteristics-Biconcavesha
18、peisthecontributetogas transport hugesurfacearearelativetovolume shortenthedistanceofgasexchange 2. Cell Membrane MembraneFunction 2. membranepermeability 2. Cell Membrane 红细胞膜的通透性，人红细胞主要的离子转运途径 AE1,band3anionexchanger;带3阴离子运转蛋白（高丰度跨膜糖蛋白， 转运Cl-水通道蛋白 KCC1,氯化物-阳离子协同转运蛋白家族KCl协同转运系统 NKCC2,Na-K-Cl协同转运蛋白基
19、底侧分子形式 SK,smallconductancepotassiumchannel.小电导钾通道 2. Cell Membrane MembraneFunction 3. membraneantigenicityandimmunologicfunction Blood group antigens are associated with the red cell membrane and are either integral to its structure or are adsorbed onto it from the plasma. They are made of proteins
20、 or carbohydrates. senescent cell antigen, SCA（老化抗原） 2. Cell Membrane ANTIGENSONRBCMEMBRANE MembraneFunction 3. membraneantigenicityandimmunologicfunction 2. Cell Membrane MembraneFunction 4. receptors hormonereceptors：insulin，glucagon Neurotransmitterreceptors：noradrenaline Virusreceptors：flu.recep
21、tor others：TfR，EPOreceptor 2. Cell Membrane 2. Cell Membrane (disease) HereditarySpherocytosis,Elliptocytosis （遗传性球形红细胞增多症，椭圆形红细胞增多症） abnormalspectringene reducedspectrinsynthesisordysfunctionalspectrin spherocytesorelliptocytes 遗传性球形红细胞增多症是一种以外周血涂片成熟红细胞呈球形、网织 红细胞增多和脾脏肿大为特征的先天性溶血性贫血。红细胞在通过脾脏 微循环时，由于
22、细胞膜丢失和膜面积缩小而呈球形样改变并伴有变形可 塑性降低。失去变形能力的红细胞在脾脏被破坏最终导致贫血。 HereditarySpherocytosis,Elliptocytosis （遗传性球形红细胞增多症，椭圆形红细胞增多症） 遗传性球形红细胞增多症病理生理学。 HS主要缺陷为细胞膜丢失，膜面积减少，表面积减少， 导致细胞球形变，变形能力减弱。 2. Cell Membrane (disease) theprocessofspherocytosisinhereditaryspherocytosis HereditarySpherocytosis,Elliptocytosis reduce
23、dspectrin synthesis dysfunctional spectrin abnormalspectrin gene Spectrinmalfunction withinerythrocyte membrane Erythrocytesare exposedtohighsheer forceswithinthe microcirculation Cytoskeletonfunction impaired;cellloses abilitytodeform Spherocyte:asmall, morerigid,spherical erythrocyteresults Cellsa
24、reeitherdestroyed withinthemicrocirculation ordetectedandremoved bythereticuloendothelial system ofthespleenHaemolysis; prematureredcell deathoccurs causinganaemia 2. Cell Membrane (disease) TheCongenitalDyserythropoieticAnemias（CDA） 先天性红细胞生成异常性贫血 先天性红细胞生成异常性贫血（CDA）是指一类罕见的，以红系无效造血，多 核红细胞和组织内铁蓄积为特征的遗
25、传性难治性贫血。可分为、型。 先天性红细胞生成异常性贫 血（CDA）型中 带3蛋白-N-乙酰乳糖聚糖链 合成不足， 而鞘磷脂表现为过度糖基 化。 2. Cell Membrane (disease) LipidsPSexposure 磷脂酰丝氨酸外翻 磷脂酰丝氨酸外翻可启动凝血活化途径 PSexposuretotriggerthrombosis 磷脂酰丝氨酸外翻可被巨噬细胞 识别并吞噬 PSexposuretobe recognizedandphagocytizedby macrophage 2. Cell Membrane (disease) Alterationinlipidcomposi
26、tioncanproducetargetcellsoracanthocytes. 靶形红细胞棘形红细胞 Lipids 2. Cell Membrane (disease) 3. Cell Metabolism metabolic changes in erythropoiesis metabolic capability normoblast reticulocyte mature erythrocyte Multiplication capacity DNA synthesize RNA synthesize RNA existence Protein synthesize Heme syn
27、thesize Lipoid synthesize Tricarboxylic acid cycle Oxidative phosphorylation THE EMBDEN-MEYERHOF PATHWAY (EMP) Pentose-phosphate shunt pathway 3. Cell Metabolism 3. Cell Metabolism HAEMOGLOBIN血红蛋白 Haemoglobin,MW68,000Da 96%oftheredbloodcellsdryweight 65% of haemoglobin synthesis occurs during the nu
28、cleatedstagesofRBCmaturationand 35%occursduringthereticulocytestage Heme group (a) Hemoglobin consists of globin珠蛋白 (two alpha and two beta polypeptide chains) and four heme血红素 groups. (b) Iron-containing heme pigment (a protoporphyrin ring （原卟啉环） plus ferrous iron (Fe2+) a Globin chains b Globin ch
29、ains HAEMOGLOBINStructure 3. Cell Metabolism HAEMOGLOBINFunction 3. Cell Metabolism Ironatomineachhemecanbindto oneO2molecule EachHbmoleculecantransportfourO2 Hemoglobinbindsreversiblywithoxygen O2loadinginthelungs Producesoxyhemoglobin（氧合血红蛋白）(rubyred) O2unloadinginthetissues Producesdeoxyhemoglobi
30、n（脱氧血红蛋白） orreducedhemoglobin(darkred) CO2loadinginthetissues Producescarbaminohemoglobin（氨基甲酰血红蛋白） (carries20%ofCO2intheblood) HAEMOGLOBINGlobin（珠蛋白） 3. Cell Metabolism HemoglobinGenesandGeneProducts 、 Mehta, A. B., and A. V. Hoffbrand.2000.Haematologyataglance,BlackwellScience,Malden,Mass. HbF:2an
31、d2 HbA1:2and2 HbA2:2and2 HbE:2and2 Yolk sacLiverSpleenBone marrow 3. Cell Metabolism HemoglobinGenesandGeneProducts HAEMOGLOBINGlobin（珠蛋白） Embryonic haemoglobins include Gower 1, Gower 2 and Hb Portland. HbF is the predominant haemoglobin of fetal life (65-95%). Adults have only trace amounts of HbF
32、 (95%) and HbA2 (2.5-3.5%) are the main adult haemoglobins. 3. Cell Metabolism Six Hb variants are normally formed. HAEMOGLOBINGlobin（珠蛋白） 3. Cell Metabolism Hemincanacceleratethesynthesis 珠蛋白的合成受血红素调节 HRI，Heme-regulated eIF2kinase； eIF，eukaryoteInitiation factor； eIF-2B，eIF-2BGDP-GTP exchangefactor
33、 HAEMOGLOBINGlobin（珠蛋白） (卟啉) （吡咯环）（次甲基） HAEMOGLOBINHEME（血红素） 3. Cell Metabolism HAEMOGLOBINHEME（血红素） 3. Cell Metabolism HEME consists of four pyrrole rings （吡咯环）with a central iron atom linked to the four nitrogen atoms. The iron atom has two further binding sites, one of which is bound to a globin
34、histidine residue and the other binds reversibly to oxygen. 3. Cell Metabolism HAEMOGLOBINHEME（血红素） 血红素合成的限速酶： ALAsynthase， aminolevulinic acid合酶 (-氨基-酮基戊酸合酶) 辅酶： 磷酸吡哆醛（Vit B6） 3. Cell Metabolism RegulationofALASynthase（ALA合酶的调节） Levelofenzymesynthesis（ALA合酶的表达水平） Enzymesynthesis,aswellasitstranspor
35、ttothemitochondria,isinhibited byelevatedlevelsofhemeandhemin(theFe3+oxidationproductof heme)（过量的血红素高铁血红素抑制酶合成） Enzymesynthesisisupregulatedbyalargenumberofdrugsincluding barbiturates,steroids(e.g.testosterone)andsomeoralcontraceptives.（ 巴比妥类药物，类固醇，睾丸素，口服避孕药） Levelofenzymeactivity（ALA合酶的酶活性） Heme（血红
36、素）andhemin（高铁血红素）inhibitALAsynthaseactivity Requirespyridoxalphosphate(VitaminB6，磷酸吡哆醛)asacoenzyme HAEMOGLOBINHEME（血红素） 3. Cell Metabolism (disease) PORPHYRIAS 卟啉症 卟啉病是由于血红素生物合成途径中酶缺陷导致反应过程中间代谢产物过量生成 与蓄积，并引发神经系统症状和（或）关照性皮肤症状等疾患 血红素生物合成途径中 各种酶与中间代谢产物 ，以及与酶缺乏相对应 的卟啉病类型。 Iron Protoporphyrin Globin Haem
37、 Haemo globin Thalassaemia Irondeficiency Chronic inflammation Malignancy Chronicinfectionsand inflammatorydisorders causechronicanaemiaasa resultof; 1.slightlyshortenedred bloodcelllifespan 2.sequestrationofironin inflammatorycellscalled macrophages Bothproceduresresultina decreaseintheamountof iro
38、navailabletomakered bloodcells. 3. Cell Metabolism (disease) HEMOGLOBINOPATHY血红蛋白病 血红蛋白病是全球最常见的遗传性红细胞疾病。 是指珠蛋白生成障碍贫血（珠蛋白合成不足）和 异常血红蛋白病（珠蛋白一级结构中氨基酸突变）， 以地中海贫血和镰状细胞综合征为主。 可导致中度到重度贫血。 3. Cell Metabolism (disease) 地中海贫血以一条或多条珠蛋白链合成缺陷的遗传性疾病。 包括和-地中海贫血。由于珠蛋白链合成的不平衡，导致 无效红细胞生成，溶血和不同程度的贫血。 HEMOGLOBINOPATHY-
39、Thalassemias（地中海贫血） 3. Cell Metabolism (disease) HEMOGLOBINOPATHY-Thalassemias（地中海贫血） 地中海贫血， 过多的 链形成 4分子（HBH） （可溶） -地中海贫血， 过多的链（不可 溶）致红细胞损伤 ，造成重度贫血。 3. Cell Metabolism (disease) HEMOGLOBINOPATHY-Thalassemias（地中海贫血） 3. Cell Metabolism (disease) HEMOGLOBINOPATHY-Sicklecellanemia(镰状细胞贫血) 3. Cell Metabo
40、lism (disease) 镰状细胞综合征是-珠蛋白链第6位氨基酸谷氨酸被缬氨酸所替代，导致血红蛋白 分子脱氧时变得不可溶，形成HBS多聚体，改变了红细胞的正常结构，使红细胞 呈僵硬，并由双凹圆盘状变为镰刀形。这类红细胞变形能力差，易破损溶血，导 致血管阻塞、组织缺氧、损伤、坏死。 GeneticsofSickleCellAnemia HEMOGLOBINOPATHY-Sicklecellanemia(镰状细胞贫血) 3. Cell Metabolism (disease) HemoglobinElectrophoresis themedicalbiochemistrypage.org/he
41、moglobin-myoglobin.html Homozygous HbS Normal neonate Normal adult HbSC Heterozygous HbS Relative protein charge Start (samples applied here) Anode (+) Cathode (-) HEMOGLOBINOPATHY-Sicklecellanemia 3. Cell Metabolism (disease) HEMOGLOBINOPATHY-Sicklecellanemia 3. Cell Metabolism (disease) Schemasumm
42、arizingthepathophysiologyofsicklecellanemia.K+,potassium;NO,nitric oxide;PS,phosphatidylserine;RBC,redbloodcell;ROS,reactiveoxygenspecies;TF,tissue factor;WBC,whitebloodcell;XO,xanthineoxidase. HEMOGLOBINOPATHY-Sicklecellanemia 3. Cell Metabolism (disease) metabolic changes in erythropoiesis metabol
43、ic capability normoblast reticulocyte mature erythrocyte Multiplication capacity DNA synthesize RNA synthesize RNA existence Protein synthesize Heme synthesize Lipoid synthesize Tricarboxylic acid cycle Oxidative phosphorylation THE EMBDEN-MEYERHOF PATHWAY (EMP) Pentose-phosphate shunt pathway 3. Ce
44、ll Metabolism 3. Cell Metabolism Glycometabolism Matureredcells nomitochondrialapparatusforoxidativemetabolism -Redcellsdeliveroxygen,notconsumeit Limited Glucoseasasourceofenergy GlycolysisgeneratesATPand2,3-bisphosphoglycerate （2,3-二膦酸甘油酸，2,3-DPG） ThepentosephosphatepathwayproducesNADPH Glutathion
45、esynthesis(谷胱甘肽合成)theantioxidantdefensesystem Energyrequiredfor: Maintenanceofcationpumps MaintenanceofRBCintegrityanddeformability Reduceoxidantsinthesystem MaintenanceofHBinreducedstate MaintenanceofreducedsulfhydrylgroupsinHB andotherproteins 3. Cell Metabolism Glycometabolism KeyMetabolicPathway
46、sfortheErythrocyte GlycolysisorEmbden-Meyerhofpathway （糖酵解，恩-迈氏途径） Rapaport-LueberingShunt （2,3-DPG支路，2，3二膦酸甘油酸支路） HexoseMonophosphateShunt （磷酸戊糖途径，磷酸己糖支路） Methemoglobinreductasepathway （高铁血红蛋白还原酶途径） 3. Cell Metabolism KeyMetabolicPathwaysfortheErythrocyte Glycolysisor Embden- Meyerhof pathway 糖酵解 （
47、恩-迈氏途径 ） 3. Cell Metabolism KeyMetabolicPathwaysfortheErythrocyte GlycolysisorEmbden-Meyerhofpathway （糖酵解，恩-迈氏途径） Generates90-95%ofenergyneededbyRBCs Glucoseismetabolizedandgeneratestwo moleculesofATP(energy). FunctionsinthemaintenanceofRBCshape, flexibilityandthecationpumps 3. Cell Metabolism KeyMe
48、tabolicPathwaysfortheErythrocyte Rapaport-LueberingShunt（2,3-DPG支路，2，3二膦酸甘油酸支路） 3. Cell Metabolism 1,3-二膦酸甘油酸 二膦酸甘油酸变位酶 3膦酸甘油酸 2，3-二膦酸甘油酸 PO2(mmHg) Hbsaturation(100%) 50 50 CO2 pH 2,3-DPG CO2 pH 2,3-DPG KeyMetabolicPathwaysfortheErythrocyte 3. Cell Metabolism Rapaport-LueberingShunt（2,3-DPG支路，2，3二膦酸
49、甘油酸支路） KeyMetabolicPathwaysfortheErythrocyte 3. Cell Metabolism mfi.ku.dk/PPaulev/chapter8/images/8-3.jpg Rapaport-LueberingShunt（2,3-DPG支路，2，3二膦酸甘油酸支路） KeyMetabolicPathwaysfortheErythrocyte Rapoport-LueberingShunt （2,3-DPG支路，2，3二膦酸甘油酸支路） AllowstheRBCtoregulateoxygentransportduring conditionsofhypox
50、iaoracid-baseimbalance. Permitstheaccumulationof2,3-DPGwhichis essentialformaintainingnormaloxygentension, regulatinghemoglobinaffinity 3. Cell Metabolism KeyMetabolicPathwaysfortheErythrocyte 3. Cell Metabolism HexoseMonophosphateShunt（磷酸戊糖途径，磷酸己糖支路） KeyMetabolicPathwaysfortheErythrocyte 3. Cell Me