《红细胞与贫血》PPT课件.ppt

基础血 液 学红细胞与贫血Erythrocyte&Anemia,夏 立病理生理学教研室,BLOOD,FunctionDeliver O2Remove metabolic wastesTransport hormonesProtection from blood loss-plateletsPrevent infection-antibodies and WBCMaintain temperature,pH,and fluid volume,At a Glance,Erythrocyte7.5m in dia,BiConcave（双凹状）Anucleate（无核）Cell Lack mitochondria(essentially no organelles)Hemoglobin（血红蛋白）transport respiratory gasesadult males 12-16 g/dladult women 11-15 g/dl,Objectives,recognizing the key components of Erythropoiesis(红细胞生成).understanding the general Structural&Functional features of red blood cells(RBCs).-Membrane of RBCs understanding the main Metabolic Pathways occurring in RBCs with reference to their relations to functions of RBCs.Recognizing changes occurring in Aging of RBCs.Identifying some of the main&common Diseases of RBCs as implication of defects of RBCs.,Blood Cell Production,1.Erythropoiesis,Proerythroblasts（原红细胞）,Basophilic erythroblast（早幼红细胞）,Polychromatophilic erythroblasts（中幼红细胞）,orthochromatic erythroblasts（晚幼红细胞）,Late Orthochromic normoblast（晚晚幼红细胞）,Reticulocyte（网织红细胞）(Ribosomal RNA stained with methylene blue),Reticulocyteno nucleusno organellesmany polyribosomeslarger than the mature RBCnot concaveNormally,25 billion cells,which is 1%of circulating blood,are reticulocytesIn severe anemia,many of these(3%)are released into the blood prematurely.,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,Too few RBCs leads to tissue hypoxia,Regulation of Erythropoiesis,1.Erythropoiesis,Hypoxia Inducible Factor(HIF),Regulation of Erythropoiesis,1.Erythropoiesis,Erythropoietin(EPO（促红细胞生成素）)34,000 Da,GlycoproteinReleased by the kidney in response to hypoxia(hemorrhage（出血）,hemolytic（溶血）,iron deficiency or high altitudes),Regulation of Erythropoiesis,1.Erythropoiesis,Regulation of Erythropoiesis,1.Erythropoiesis,Erythropoietin(EPO)Direct stimulus for erythropoiesisMore rapid maturation of committed bone marrow cellsIncreased circulating reticulocyte count in 12days,Regulation of Erythropoiesis,1.Erythropoiesis,Balance between RBC production and destruction depends onHormonal controls(Erythropoietin,EPO)Adequate supplies of Folic Acid(folate（叶酸）)Vitamin B12,cyanocobalamin（氰钴胺）Amino AcidsIronVitamin B6,pyridoxine（吡哆醇）Ascorbic Acid(Vitamin C),Regulation of Erythropoiesis,1.Erythropoiesis,1.Erythropoiesis(Disease),Aplastic Anemia(AA,再生障碍贫血),1.Erythropoiesis(Disease),The marrow biopsy section of a young adult with very severe aplastic anemia,A normal marrow biopsy section of a young adult.,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、HIV3、药物：氯霉素、噻氯匹定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,An immune attack of Tc cells targets hematopoietic stem and progenitor cells(CD34+cells)apoptosis hematopoietic failure,Aplastic Anemia(AA,再生障碍贫血),1.Erythropoiesis(Disease),Anemia of Chronic Renal Disease(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),Anemia of Chronic Renal Disease(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 Membrane,Flexibility to change shapeThe red cell must be able to change shape and squeeze through small capillaries.,2.Cell Membrane,The red cell membrane consists of a bipolar lipid layer supported by structural proteins.Protein,49%Lipid,42%Carbohydrate,8%Inorganic ion,1%Outermost layer:glycolipids,glycoproteins Central layer:cholesterol,phospholipids Inner layer:cytoskeleton(骨架蛋白)Spectrin（血影蛋白）Ankyrin（锚蛋白）,ProteinsIntegral 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 membranePeripheral 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 surfaceto maintain the biconcave shape of the red cellto strengthens the membrane against sheer force,2.Cell Membrane,ProteinsIntegral 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 membranePeripheral 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 surfaceto maintain the biconcave shape of the red cellto 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,Lipids60%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 of membrane phospholipids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),Carbohydratesare mostly found on the external surface of the red cell membrane.Monosaccharides（寡糖）are associated with specific blood group antigens,e.g.ABH and Lewis.,Producing blood group A antigen on the red cell of a group A individual.,2.Cell Membrane,Membrane Functioncellular deformability and membrane stabilitymembrane permeabilitymembrane antigenicity and immunologic functionreceptors,2.Cell Membrane,Membrane Functioncellular deformability and membrane stability structural characteristics-Biconcave shape is the contribute to gas transport huge surface area relative to volumeshorten the distance of gas exchange,2.Cell Membrane,Membrane Functionmembrane permeability,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,band 3 anion exchanger;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协同转运蛋白基底侧分子形式SK,small conductance potassium channel.小电导钾通道,2.Cell Membrane,Membrane Functionmembrane antigenicity and immunologic function,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 or carbohydrates.senescent cell antigen,SCA（老化抗原）,2.Cell Membrane,ANTIGENS ON RBC MEMBRANE,Membrane Functionmembrane antigenicity and immunologic function,2.Cell Membrane,Membrane Functionreceptors,hormone receptors：insulin，glucagonNeurotransmitter receptors：noradrenalineVirus receptors：flu.receptorothers：TfR，EPO receptor,2.Cell Membrane,2.Cell Membrane(disease),Hereditary Spherocytosis,Elliptocytosis（遗传性球形红细胞增多症，椭圆形红细胞增多症）,abnormal spectrin gene reduced spectrin synthesis or dysfunctional spectrin spherocytes or elliptocytes,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。,Hereditary Spherocytosis,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),the process of spherocytosis in hereditary spherocytosis,Hereditary Spherocytosis,Elliptocytosis,2.Cell Membrane(disease),The Congenital Dyserythropoietic Anemias（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),Lipids,PS exposure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PS exposure to trigger thrombosis,磷脂酰丝氨酸外翻可被巨噬细胞识别并吞噬PS exposure to be recognizedandphagocytized by macrophage,2.Cell Membrane(disease),Alteration in lipid composition can produce target cells or acanthocytes.,靶形红细胞,棘形红细胞,Lipids,2.Cell Membrane(disease),3.Cell Metabolism,metabolic changes in erythropoiesis,3.Cell Metabolism,3.Cell Metabolism,HAEMOGLOBIN 血红蛋白,Haemoglobin,MW 68,000Da 96%of the red blood cells dry weight 65%of haemoglobin synthesis occurs during the nucleated stages of RBC maturation and 35%occurs during the reticulocyte stage,HAEMOGLOBIN Structure,3.Cell Metabolism,HAEMOGLOBIN Function,3.Cell Metabolism,Iron atom in each heme can bind to one O2 moleculeEach Hb molecule can transport four O2Hemoglobin binds reversibly with oxygenO2 loading in the lungs Produces oxyhemoglobin（氧合血红蛋白）(ruby red)O2 unloading in the tissues Produces deoxyhemoglobin（脱氧血红蛋白）or reduced hemoglobin(dark red)CO2 loading in the tissues Produces carbaminohemoglobin（氨基甲酰血红蛋白）(carries 20%of CO2 in the blood),HAEMOGLOBIN Globin（珠蛋白）,3.Cell Metabolism,Hemoglobin Genes and Gene Products、,Mehta,A.B.,and A.V.Hoffbrand.2000.Haematology at a glance,Blackwell Science,Malden,Mass.,3.Cell Metabolism,Hemoglobin Genes and Gene Products,HAEMOGLOBIN Globin（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(95%)and HbA2(2.5-3.5%)are the main adult haemoglobins.,3.Cell Metabolism,Six Hb variants are normally formed.,HAEMOGLOBIN Globin（珠蛋白）,3.Cell Metabolism,Hemin can accelerate the synthesis珠蛋白的合成受血红素调节,HRI，Heme-regulated eIF2 kinase；eIF，eukaryote Initiation factor；eIF-2B，eIF-2B GDP-GTP exchange factor,HAEMOGLOBIN Globin（珠蛋白）,HAEMOGLOBIN HEME（血红素）,3.Cell Metabolism,HAEMOGLOBIN HEME（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 histidine residue and the other binds reversibly to oxygen.,3.Cell Metabolism,HAEMOGLOBIN HEME（血红素）,血红素合成的限速酶：ALA synthase，aminolevulinic acid合酶(-氨基-酮基戊酸合酶)辅酶：磷酸吡哆醛（Vit B6）,3.Cell Metabolism,Regulation of ALA Synthase（ALA合酶的调节）Level of enzyme synthesis（ALA合酶的表达水平）Enzyme synthesis,as well as its transport to the mitochondria,is inhibited by elevated levels of heme and hemin(the Fe3+oxidation product of heme)（过量的血红素高铁血红素抑制酶合成）Enzyme synthesis is upregulated by a large number of drugs including barbiturates,steroids(e.g.testosterone)and some oral contraceptives.（巴比妥类药物，类固醇，睾丸素，口服避孕药）Level of enzyme activity（ALA合酶的酶活性）Heme（血红素）and hemin（高铁血红素）inhibit ALA synthase activityRequires pyridoxal phosphate(Vitamin B6，磷酸吡哆醛)as a coenzyme,HAEMOGLOBIN HEME（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。,Chronic infections and inflammatory disorders cause chronic anaemia as a result of;1.slightly shortened red blood cell life span 2.sequestration of iron in inflammatory cells called macrophagesBoth procedures result in a decrease in the amount of iron available to make red blood cells.,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-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-Sickle cell anemia(镰状细胞贫血),3.Cell Metabolism(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。,Genetics of Sickle Cell Anemia,HEMOGLOBINOPATHY-Sickle cell anemia(镰状细胞贫血),3.Cell Metabolism(disease),Hemoglobin Electrophoresis,http:/themedicalbiochemistrypage.org/hemoglobin-myoglobin.html,Relative protein charge,Start(samples applied here),Anode(+),Cathode(-),HEMOGLOBINOPATHY-Sickle cell anemia,3.Cell Metabolism(disease),HEMOGLOBINOPATHY-Sickle cell anemia,3.Cell Metabolism(disease),Schema summarizing the pathophysiology of sickle cell anemia.K+,potassium;NO,nitric oxide;PS,phosphatidylserine;RBC,red blood cell;ROS,reactive oxygen species;TF,tissue factor;WBC,white blood cell;XO,xanthine oxidase.,HEMOGLOBINOPATHY-Sickle cell anemia,3.Cell Metabolism(disease),metabolic changes in erythropoiesis,3.Cell Metabolism,3.Cell Metabolism,Glycometabolism,Mature red cells no mitochondrial apparatus for oxidative metabolism-Red cells deliver oxygen,not consume itLimited Glucose as a source of energyGlycolysis generates ATP and 2,3-bisphosphoglycerate（2,3-二膦酸甘油酸，2,3-DPG）The pentose phosphate pathway produces NADPH Glutathione synthesis(谷胱甘肽合成)the antioxidant defense system,Energy required for:Maintenance of cation pumpsMaintenance of RBC integrity and deformabilityReduce oxidants in the systemMaintenance of HB in reduced stateMaintenance of reduced sulfhydryl groups in HB and other proteins,3.Cell Metabolism,Glycometabolism,Key Metabolic Pathways for the Erythrocyte,Glycolysis or Embden-Meyerhof pathway（糖酵解，恩-迈氏途径）Rapaport-Luebering Shunt（2,3-DPG支路，2，3二膦酸甘油酸支路）Hexose Monophosphate Shunt（磷酸戊糖途径，磷酸己糖支路）Methemoglobin reductase pathway（高铁血红蛋白还原酶途径）,3.Cell Metabolism,Key Metabolic Pathways for the Erythrocyte,Glycolysis or Embden-Meyerhof pathway糖酵解（恩-迈氏途径）,3.Cell Metabolism,Key Metabolic Pathways for the Erythrocyte,Glycolysis or Embden-Meyerhof pathway（糖酵解，恩-迈氏途径）Generates 90-95%of energy needed by RBCsGlucose is metabolized and generates two molecules of ATP(energy).Functions in the maintenance of RBC shape,flexibility and the cation pumps,3.Cell Metabolism,Key Metabolic Pathways for the Erythrocyte,Rapaport-Luebering Shunt（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,Key Metabolic Pathways for the Erythrocyte,3.Cell Metabolism,Rapaport-Luebering Shunt（2,3-DPG支路，2，3二膦酸甘油酸支路）,Key Metabolic Pathways for the Erythrocyte,3.Cell Metabolism,Rapaport-Luebering Shunt（2,3-DPG支路，2，3二膦酸甘油酸支路）,Key Metabolic Pathways for the Erythrocyte,Rapoport-Luebering Shunt（2,3-DPG支路，2，3二膦酸甘油酸支路）Allows the RBC to regulate oxygen transport during conditions of hypoxia or acid-base imbalance.Permits the accumulation of 2,3-DPG which is essential for maintaining normal oxygen tension,regulating hemoglobin affinity,3.Cell Metabolism,Key Metabolic Pathways for the Erythrocyte,3.Cell Metabolism,Hexose Monophosphate Shunt（磷酸戊糖途径，磷酸己糖支路）,Key Metabolic Pathways for the Erythrocyte,3.Cell Metabolism,Hexose Monophosphate Shunt（磷酸戊糖途径，磷酸己糖支路）,Key Metabolic Pathways for the Erythrocyte,3.Cell Metabolism,Hexose Monophosphate Shunt（磷酸戊糖途径，磷酸己糖支路）,Key Metabolic Pathways for the Erythrocyte,Metabolizes 5-10%of glucose.NADPH is end productProtects the RBC from oxidative injury.If the pathway is deficient,intracellular oxidants cant be neutralized,and then globin denatures and precipitates.The precipitates are referred to as Heinz bodies.Most common defect is deficiency of the enzyme glucose-6-phosphate dehydrogenase(G-6PD，葡萄糖-6-磷酸脱氢酶).,3.Cell Metabolism,Hexose Monophosphate Shunt（磷酸戊糖途径，磷酸己糖支路）,In red cells,there is a Met Hb reductase(高铁血红蛋白还原酶)which can use NADH to regenerate Hb,Key Metabolic Pathways for the Erythrocyte,Methemoglobin reductase pathway（高铁血红蛋白还原酶途径）,3.Cell Metabolism,Key Metabolic Pathways for the Erythrocyte,Maintains iron in the ferrous(Fe+)state.In the absence of the enzyme(methemoglob