IRI缺血再灌注损伤-病理生理学课件.ppt

1、缺缺 血再血再 灌灌 注注 损损 伤伤Ischemia-reperfusion injuryIschemia-reperfusion injuryDepartment of Department of PathophysiologyPathophysiology Case studyCase study 患者患者,男，男，5858岁，上午岁，上午8 8时，起床后感到胸闷，时，起床后感到胸闷，30min30min后后突感心胸前区剧烈绞痛，突感心胸前区剧烈绞痛，9 9时入急诊病房。时入急诊病房。体查体查：血压：血压75/50mmHg75/50mmHg，意识淡漠，心率意识淡漠，心率6565次次/mi

2、n/min，律，律 齐。心电图示齐。心电图示度房室传导阻滞。度房室传导阻滞。冠状动脉造影冠状动脉造影：右冠状动脉上段：右冠状动脉上段85%85%狭窄，中段狭窄，中段78%78%狭窄。狭窄。入院治疗：入院治疗：立即给予阿托品、多巴胺、低分子右旋糖酐等立即给予阿托品、多巴胺、低分子右旋糖酐等进行进行扩冠扩冠治疗。上午治疗。上午1010时静脉点滴时静脉点滴尿激酶尿激酶。10:3010:30分患分患者出现阵发性心室颤动（室颤），立即给予除颤，到下者出现阵发性心室颤动（室颤），立即给予除颤，到下午午1313时反复发生室性心动过速、室颤，共计时反复发生室性心动过速、室颤，共计6 6次。到下次。到下午午16

3、16时，经给予利多卡因、小剂量异丙肾上腺素后心律时，经给予利多卡因、小剂量异丙肾上腺素后心律转为窦性，血压平稳，意识清楚。转为窦性，血压平稳，意识清楚。QuestionQuestion为什么在溶栓后出现严重的心律失常为什么在溶栓后出现严重的心律失常?ContentsContentsIntroductioIntroduction nCauses and conditions of IRICauses and conditions of IRIMechanisms of IRIMechanisms of IRIMetabolic and functional alterationsMetaboli

4、c and functional alterationsPrevention and treatment principlePrevention and treatment principleAnimal experimentAnimal experimentl Ischemia-reperfusion injury was first described in Ischemia-reperfusion injury was first described in heart,Sewell,1955 heart,Sewell,1955Animal experimentAnimal experim

5、entlThe concept of ischemia-reperfusion injury was The concept of ischemia-reperfusion injury was proposed by Jennings for the first time in 1960 proposed by Jennings for the first time in 1960 lCerebralCerebral ischemia-reperfusion injury,Ames,1968 ischemia-reperfusion injury,Ames,1968lRenal Renal

6、ischemia-reperfusion injury,ischemia-reperfusion injury,Flore,Flore,19721972llung lung ischemia-reperfusion injury,ischemia-reperfusion injury,ModryModry,1978,1978lintestine intestine ischemia-reperfusion injury,Greenberg,1981ischemia-reperfusion injury,Greenberg,1981 Animal experimentAnimal experim

7、ent Organ transplantationOrgan transplantation(器官移植器官移植)Shock Shock ThrombolysisThrombolysis（溶栓治疗）（溶栓治疗）Cardiac bypass surgery Cardiac bypass surgery(冠脉搭桥术冠脉搭桥术)PTCA(percutaneousPTCA(percutaneous transluminaltransluminal coronary angioplasty)coronary angioplasty)Clinic ClinicConcept of IRIConcept of

8、 IRIblood reperfusion sometimes induces or blood reperfusion sometimes induces or aggravates the further reversible even irreversibleaggravates the further reversible even irreversible cell damage,especially for a prolonged ischemia.cell damage,especially for a prolonged ischemia.在缺血基础上恢复血流后在缺血基础上恢复

9、血流后组织损伤反而组织损伤反而加重，甚至发生不可逆性损伤的现象加重，甚至发生不可逆性损伤的现象。IRI IRI 特特 点点特特 点点可逆损伤可逆损伤 不不可逆损伤可逆损伤具有器官具有器官 普遍性普遍性Causes and Conditions of IRICauses and Conditions of IRICauses:Causes:先缺血先缺血（ischemiaischemia），），后复灌后复灌（reperfusionreperfusion）全身循环障碍后恢复血液供应全身循环障碍后恢复血液供应(shockshock)组织器官缺血后血流恢复组织器官缺血后血流恢复(organ transp

10、lantation)organ transplantation)某些新的医疗技术的应用某些新的医疗技术的应用 (thrombolyticthrombolytic therapy,PTCA,cardiac therapy,PTCA,cardiac bypass surgery bypass surgery)1 12 23 34 4Duration of Duration of IschemiaIschemia(缺血时间缺血时间)Collateral Collateral CirculationCirculation(侧枝循环侧枝循环)Dependency Dependency on oxygen

11、 on oxygen SupplySupply(需氧程度需氧程度)Condition of Condition of ReperfusionReperfusion(再灌注条件再灌注条件)Causes and conditions of IRICauses and conditions of IRIConditions:Conditions:1Free radicalsFree radicals(自由基自由基)2Calcium Calcium overloadoverload(钙超载钙超载)3NeutrophilsNeutrophils activationactivation(白细胞激活白细胞

12、激活)Mechanisms of IRIMechanisms of IRI再再 灌灌 注注 损损 伤伤 的的“三三 剑剑 客客”Definition and categories of FRDefinition and categories of FR(概念、分类概念、分类)Generation of FRGeneration of FR（代（代 谢）谢）Source of FR during IRISource of FR during IRI（增多的机制）（增多的机制）Alterations induced by FRAlterations induced by FR（损伤的机制）（损伤的

13、机制）自由基自由基(free radicalfree radical)的概念的概念外外 层层 电电 子子 轨轨 道道 上上 含含 有有 单单 个个 不不 配配 对对 电电 子子 的的 原原 子、原子、原 子子 团团 和和 分分 子子 的的 总总 称。称。Free radicalFree radical are a highly reactive group of atoms,molecules or radicals,which carry unpaired are a highly reactive group of atoms,molecules or radicals,which car

14、ry unpaired electron in outer orbital electron in outer orbital）化学性质活泼化学性质活泼氧化性强氧化性强半衰期短半衰期短Half-life of Half-life of some rsome reactive eactive s speciespeciesR Reactiveeactive species speciesHalf-life Half-life (s)(s)PhysiolPhysiol conc.conc.(mol/lmol/l)Hydroxyl radical(OHHydroxyl radical(OH)1010

15、-9-9Singlet oxygen (Singlet oxygen (1 1O O2 2)1010-5-5Peroxynitrite anion(ONOOPeroxynitrite anion(ONOO-)0 0.05 105 1.0 0Nitric oxide(NONitric oxide(NO)1-101-101010-9-9Hydrogen peroxide(HHydrogen peroxide(H2 2O O2 2)s spontpontan.hours/an.hours/daysdays(accelerated by accelerated by enzymeenzymes s)1

16、010-9-9 -10-10-7 7Superoxide anion(OSuperoxide anion(O2 2)s spontpontan.hours/an.hours/daysdays(by SOD by SOD accelaccel.to to 1010-6-6)1010-1212 -10-10-1111categoriescategories分分 类类其他其他氧自由氧自由基基Oxygen free Oxygen free radicalsradicals脂性自由基脂性自由基Lipid radicalsLipid radicalsO O2 2mitochrondrimitochrond

17、ria a9899%12%超氧阴离子超氧阴离子 O O2 2过氧化氢过氧化氢 H H2 2O O2 2羟自由基羟自由基 OHOHATPATPSODSODH H2 2O O2 2谷胱甘肽过氧化物酶（谷胱甘肽过氧化物酶（GSH-PXGSH-PX）过氧化氢酶（过氧化氢酶（CATCAT）髓过氧化物酶（髓过氧化物酶（MPOMPO）清清除除Generation of FRGeneration of FRSource of FR during IRISource of FR during IRIXanthineXanthine oxidaseoxidase pathway pathway(黄嘌呤氧化酶形成增

18、多黄嘌呤氧化酶形成增多)NeutrophilsNeutrophils pathway pathway(中性粒细胞呼吸爆发中性粒细胞呼吸爆发)Mitochondria pathwayMitochondria pathway(线粒体功能受损线粒体功能受损)Catecholamine auto-oxidation pathwayCatecholamine auto-oxidation pathway(儿茶酚胺自身氧化儿茶酚胺自身氧化)XanthineXanthine oxidaseoxidase pathway pathwayATPATP降解降解ADP AMPADP AMP腺苷肌酐腺苷肌酐次黄嘌呤次

19、黄嘌呤细胞内钙超载细胞内钙超载钙依赖性蛋白水解酶钙依赖性蛋白水解酶黄嘌呤脱氢酶（黄嘌呤脱氢酶（XDXD）黄嘌呤氧化酶（黄嘌呤氧化酶（XOXO）黄嘌呤黄嘌呤尿酸尿酸脱电子脱电子O O2 2接受电子接受电子OFROFR损伤组织损伤组织10%10%组织缺血组织缺血+NeutrophilsNeutrophils pathway pathwayNADPHNADPH oxidaseoxidaseNADPHNADPHNADPNADP+Respiration burstRespiration burstMitochondria pathwayMitochondria pathwayMitochondria p

20、athwayMitochondria pathwayCatecholamine auto-oxidation pathwayCatecholamine auto-oxidation pathwayischemiaischemiaCAsCAs调节作用调节作用氧化产物氧化产物OFROFRreperfusionreperfusionO O2 2+Alterations induced by FRAlterations induced by FRAlterations induced by FRAlterations induced by FREnhanced lipid Enhanced lipid

21、 peroxidationperoxidation of membrane of membrane膜脂质过氧化增强膜脂质过氧化增强Protein denaturalizationProtein denaturalization蛋白质功能抑制蛋白质功能抑制DNA disruption and chromosome aberrationDNA disruption and chromosome aberration核酸及染色体破坏核酸及染色体破坏IRIIRI自自 由由 基基 对对 膜膜 的的 损损 伤伤正常血细胞正常血细胞自由基损伤自由基损伤严重自由基损伤严重自由基损伤-SHHS-SHHS-CHC

22、H3 3-S-S-磷脂磷脂穿膜糖穿膜糖蛋白蛋白膜表面蛋白膜表面蛋白正正 常常 细细 胞胞 膜膜 结结 构构 示示 意意 图图OHOHOOHOOHOHOHHOOHOOOHOHHOOHOOOHOHHOHOHOOHOOOHOHHOHOOHOHCH3-S-CH3-S-O O-S-S-S-S-蛋白质蛋白质断裂断裂蛋白质蛋白质-蛋白质蛋白质交联交联二硫交联二硫交联脂质脂质-蛋白蛋白质交联质交联氨基酸氨基酸氧化氧化从氧化的脂肪酸从氧化的脂肪酸释出的释出的丙二醛丙二醛脂质脂质-脂脂质交联质交联脂肪酸脂肪酸氧化氧化Enhanced lipid Enhanced lipid peroxidationperoxid

23、ation of membrane of membrane Destruction of the normal membrane structureDestruction of the normal membrane structure(膜结构破坏膜结构破坏)Alter the normal function of blood vesselsAlter the normal function of blood vessels(改变血管的功能改变血管的功能)Promote the generation of FRPromote the generation of FR(促进自由基生成促进自由基生

24、成)Generation of ATPGeneration of ATP (ATP(ATP生成减少生成减少)Protein denaturalizationProtein denaturalization 蛋白质断裂蛋白质断裂蛋白质蛋白质-蛋白质交联蛋白质交联-S-S-S-S-CHCH3 3-S-S-O O二硫交联二硫交联氨基酸氧化氨基酸氧化OHOHHOHOOHOHHOHO蛋白质蛋白质-脂质交联脂质交联 蛋白质变性、酶的活性丧失蛋白质变性、酶的活性丧失 受体、离子通道功能障碍受体、离子通道功能障碍自自 由由 基基DNA disruption and chromosome aberrationD

25、NA disruption and chromosome aberration80%80%由由OHOH所致所致Concept of Concept of calcium overloadcalcium overloadThe phenomenon of cellular structure damage and The phenomenon of cellular structure damage and dysfunction which caused by intracellular calciumdysfunction which caused by intracellular calc

26、ium increasing abnormally is increasing abnormally is termed”calciumtermed”calcium overload”overload”细细 胞胞 内内 钙钙 含含 量量 异异 常常 增增 多，多，并并 导导 致致 细细 胞胞 结结 构构 损损 伤伤 和和 功功 能、代能、代 谢谢 障障 碍碍 的的 现现 象。象。MitoMitoSRSRCaCa2+2+细细 胞胞 内内 外外 钙钙 分分 布布50%50%（1010-3-3mol/Lmol/L）（1010-7-7mol/Lmol/L）1%1%5%5%14%14%30%30%Mit

27、oMitoSRSRCaCa2+2+钙钙泵泵CaCa2+2+3Na3Na+NaNa+-Ca-Ca2+2+交换体交换体Mechanism of calcium overloadMechanism of calcium overload1.1.Disorder of Na Disorder of Na+/Ca/Ca2+2+exchange exchange (Na (Na+-Ca-Ca2+2+交交 换换 异异 常常)3.3.Membrane permeability damageMembrane permeability damage (生生 物物 膜膜 损损 伤伤)2.Activation of

28、Protein 2.Activation of Protein kinasekinase C C (蛋蛋 白白 激激 酶酶 C C 激激 活活)钙超载时进入细胞的主要途径钙超载时进入细胞的主要途径 正常：正常：3 3个个NaNa+1 1个个CaCa2+2+可进行双向转运可进行双向转运 CaCa2+2+3Na3Na+K K+NaNa+NaNa+-Ca-Ca2+2+交换异常交换异常NaNa+-Ca-Ca2+2+交换异常交换异常细细 胞胞 内内 高高 NaNa+直直 接接 激激 活活K K+NaNa+3Na3Na+CaCa2+2+ATPATPNaNa+CaCa2+2+ischemiareperfus

29、ionNaNa+-Ca-Ca2+2+交换异常交换异常细细 胞胞 内内 高高 H H+间间 接接 激激 活活H H+NaNa+H H+H H+3Na3Na+CaCa2+2+NaNa+K K+ischemiareperfusionH H+NaNa+Ca2+H H+NaNa+3Na3Na+CaCa2+2+PKCPKCCaCa2+2+CaCa2+2+肌浆网肌浆网1GPGPPLCPLCPIPPIP2 2DGDGIPIP3 3去甲肾上腺素去甲肾上腺素1 1Ca2+蛋白激酶蛋白激酶C(PKC)C(PKC)激活激活u 细细 胞胞 膜膜 通通 透透 性性 增增 加加 u 线线 粒粒 体体 和和 肌肌 浆浆 网网

30、 膜膜 损损 伤伤生生 物物 膜膜 损损 伤伤MitoMitoSRSRCaCa2+2+钙钙泵泵NaNa+-Ca-Ca2+2+交换体交换体CaCa2+2+3Na3Na+MitoMitoXD XOXD XO蛋白酶蛋白酶OFROFR核酶核酶CaCa2+2+磷脂酶磷脂酶CaCa2+2+CaCa2+2+钙超载是细胞不可逆死亡的共同通路！钙超载是细胞不可逆死亡的共同通路！钙超载引起钙超载引起IRIIRI的机制的机制NeutrophilsNeutrophils activation activation黏附分子黏附分子趋化因子趋化因子白细胞白细胞内皮细胞内皮细胞白白 细细 胞胞 增增 多多 机机 制制Neu

31、trophilsNeutrophils activation activation微血管通透性微血管通透性粒细胞游出损伤细胞粒细胞游出损伤细胞血液流变学改变血液流变学改变白细胞粘附聚白细胞粘附聚集、血流缓慢集、血流缓慢微血管口径的改变微血管口径的改变内皮细胞肿胀内皮细胞肿胀缩血管物质缩血管物质扩血管物质扩血管物质白细胞介导的损伤机制白细胞介导的损伤机制无复流现象无复流现象(no-reflow phenomenon)(no-reflow phenomenon)SummarySummaryFRFRCaCa2+2+overload overloadneutrophilsneutrophilsMeta

32、bolic and functional alterationsMetabolic and functional alterationsIschemia-reperfusionIschemia-reperfusionIntestineIntestineLungLungBrainBrainHeartHeartLiverLiverAlteration of metabolism and functionAlteration of metabolism and functionMyocardial ischemia-reperfusion injuryMyocardial ischemia-repe

33、rfusion injury心功能心功能变化变化 心肌能心肌能量代谢量代谢变化变化 心肌超心肌超微结构微结构变化变化u 心心 肌肌 舒舒 缩缩 功功 能能u 再再 灌灌 注注 性性 心心 律律 失失 常常心心 功功 能能 变变 化化1.1.心心 肌肌 舒舒 缩缩 功功 能能：静静 止止 张张 力力 VEDPVEDP 发发 展展 张张 力力 VPSPVPSP，dp/dtdp/dtmaxmax心肌顿抑（心肌顿抑（myocardial stunningmyocardial stunning）迟呆心肌迟呆心肌 指心肌短时间缺血后恢复再灌流一段时间内心肌指心肌短时间缺血后恢复再灌流一段时间内心肌出现的出

34、现的可逆性可逆性收缩功能降低，常需数小时或数天才收缩功能降低，常需数小时或数天才可恢复正常功能的现象可恢复正常功能的现象.条条 件：件：u 再灌区必须存在有功能上可以恢复的心肌细胞再灌区必须存在有功能上可以恢复的心肌细胞u 缺血时间缺血时间u 缺血心肌的数量、缺血程度、再灌注恢复速度缺血心肌的数量、缺血程度、再灌注恢复速度Characteristics:Characteristics:ventricular tachycardia and fibrillationventricular tachycardia and fibrillation2.2.再灌注性心律失常再灌注性心律失常(Reper

35、fusion arrhythmias)(Reperfusion arrhythmias)Ischemia-reperfusion injury in heartIschemia-reperfusion injury in heart正正 常常 延延 迟迟 后后 除除 极极（再灌注性心律失常）（再灌注性心律失常）Principles of Prevention and TreatmentPrinciples of Prevention and Treatment 控制再灌注条件控制再灌注条件清除自由基清除自由基减轻钙超载减轻钙超载改善缺血组织代谢改善缺血组织代谢Lower Lower conce

36、ntration concentration of calciumof calcium and sodium and sodiumLower Lower pressurepressureLower Lower flowflow speed speedLower Lower temperaturetemperatureLower Lower pHpHRelieve reperfusion Relieve reperfusion injuryinjuryControl the reperfusion conditionsControl the reperfusion conditionsenzym

37、esenzymesScavengers of Scavengers of free radicalsfree radicalsNon-enzyme Non-enzyme substancessubstancesenzymesenzymesCATCAT(catalasecatalase)SODSOD(superoxidesuperoxide dismutasedismutase)GSH-GSH-PxPx(glutathione(glutathione peroxidaseperoxidase)l 2O2+2H+H2O2+O2l 2H2O2 H2O+O2l H2O2+2GSH 2H2O+O2CAT

38、CATGSH-GSH-PxPxSODSODMnSODMnSODCuZnSODCuZnSOD霍金与霍金与CuZnCuZn-SOD-SOD突变所致的脊髓侧索硬化症突变所致的脊髓侧索硬化症Non-enzyme Non-enzyme substancessubstancesVitamin CVitamin CallopurinolallopurinolVitamin EVitamin EDMSODMSO(dimethyldimethyl sulfoxidesulfoxide)-caritinoidcaritinoidglutathioneglutathioneCell Cell protectorsp

39、rotectorsThe The energy energy suppleme-suppleme-ntationntationPreconditPrecondit-ioning-ioningABCRequirement of this chapterRequirement of this chapterl掌握掌握缺血缺血-再灌注损伤、钙超载、无复流现象概念；再灌注损伤、钙超载、无复流现象概念；IRIIRI的的三大重要发生机制；自由基清除剂。三大重要发生机制；自由基清除剂。l熟悉熟悉缺血缺血-再灌注损伤的原因及条件再灌注损伤的原因及条件。l了解了解脏器缺血脏器缺血-再灌注损伤的变化；防治病生基础

40、。再灌注损伤的变化；防治病生基础。急性中风溶栓手术前后急性中风溶栓手术前后Coronary artery bypass grafting(CABG)Coronary artery bypass grafting(CABG)冠冠 状状 动动 脉脉 搭搭 桥桥 术术 1967,Favaloro1967,Favaloro 1995,Benetti1995,Benetti ClintonClinton Yeltsin Yeltsin PTCAPTCA(percutaneouspercutaneous transluminaltransluminal coronary angioplasty)coron

41、ary angioplasty)Place a devicePlace a device经皮冠状动脉成形术经皮冠状动脉成形术u 缺血时间过短或过长都不易发生再灌注损伤。缺血时间过短或过长都不易发生再灌注损伤。u 不同动物、不同器官再灌注损伤所需的缺血时间不同。不同动物、不同器官再灌注损伤所需的缺血时间不同。动物：小动物较短，而大动物和人类较长动物：小动物较短，而大动物和人类较长 大鼠在体心大鼠在体心IRIR时缺血时间对时缺血时间对IRIIRI的影响的影响缺血时间缺血时间(min)(min)再灌注再灌注时间时间(min)(min)N N心律心律不齐不齐(%)(%)异位异位节律节律(%)(%)室颤

42、室颤(%)(%)死亡率死亡率(%)(%)2 2101010100 00 00 05 510102121808038.138.147.647.625.825.810101010101060604040404010.010.01515101011119 99.09.00 0器官器官IRIIRI与缺血时间与缺血时间animalanimalhumanhumanheartheart40403030liver liver 45453030brain brain 3030intestine intestine 6060kidney kidney 6060skeletal muscles skeletal m

43、uscles 4h4h再再 灌灌 注注 的的 条条 件件低温、低压、低温、低压、低低pHpH、低钠、低钙低钠、低钙 -减轻减轻IRIIRI252550mmHg50mmHg高温、高压、高高温、高压、高PHPH、高钠、高钙、高钠、高钙 -加重加重IRIIRI120mmHg120mmHg活性氧活性氧(ROS)(ROS)H H2 2O O2 2singlet oxygen(singlet oxygen(1 1O O2 2)氧自由基氧自由基(Oxygen free radicalsOxygen free radicals,OFROFR）：）：由氧诱发的自由基。由氧诱发的自由基。OFROFRSuperox

44、ideSuperoxide anion radical anion radical(O(O2 2)hydroxyl radical hydroxyl radical(OH(OH)由氧形成，并在分子由氧形成，并在分子组成上含有氧的一类组成上含有氧的一类化学性质非常活泼的化学性质非常活泼的物质。物质。O O2 2+2e+2H+2e+2H+O O2 2 +OHOH脂性自由基（脂性自由基（Lipid radicalsLipid radicals）：）：氧自由基与氧自由基与多价多价不饱不饱和脂肪酸作用后生成的中间和脂肪酸作用后生成的中间代谢代谢产物产物。烷自由基（烷自由基（L L）烷氧自由基（烷氧自由基

45、（LOLO）烷过氧自由基（烷过氧自由基（LOOLOO）脂性自由基脂性自由基p 氯自由基氯自由基(Chlorine radicals,Chlorine radicals,Cl Clp 甲基自由基甲基自由基(Methyl radicals,Methyl radicals,CHCH3 3p 一氧化氮自由基一氧化氮自由基(nitric oxide(nitric oxide radicals,NOradicals,NONONO和和ONOOONOO-产生产生O O2 2H H2 2O O2 2OHOHH H2 2O OO O2 2e e-e e-+2H+2H+e e-+H+H+e e-+H+H+H H2 2O O活活 性性 氧氧 生生 成成 反反 应应 式式SODSOD歧化歧化HaberHaber-Weiss -Weiss 反反 应应SLOWO O2 2.+H +H2 2O O2 2 O O2 2 +OH +OH-+OH+OHFenton Fenton 型型 HaberHaber Weiss Weiss 反反 应应FeFe2 2 O O2 2.+H +H2 2O O2 2 O O2 2 +OH +OH-+OH+OHFASTis the most active and strong OFRis the most active and strong OFR.OHOH