血液循环障碍英文课件：Ischemia-reperfusion injury 2009

1、Ischemia-Reperfusion InjuryJianzhong Sheng MD PhD,In 1955，Sewell et al., reported that ventricular fibrillation occurred in dogs when sudden return of blood flow to the coronary artery that was ligated,History,Myocardial reperfusion injury was first postulated in 1960 by Jennings et al. in their des

2、cription of the histologic features of reperfused ischemic canine myocardium.,The injury of ischemic cardiac muscles was more severe after reperfusion than before.,1967，Bulkley and Hutchins found that reflow of blood induced necrosis of cardiac myocytes after coronary artery bypass graft surgery. 19

3、81, Greenberg confirmed that reperfusion induced severe damage of the intestinal mucosal cells of cat after 3 hours of ischemia.,Clinic:,Shock, DIC microcirculation reperfusion Coronary reperfusion、artery bypass graft Restoration of blood supply in reimplantation of limb, transplantation of organs.,

4、The restoration of blood flow after transient ischemia may be associated with further reversible or irreversible cell damage, which is called ischemia-reperfusion injury or reperfusion injury.,What is ischemia-reperfusion injury?,In the definition of ischemia-reperfusion injury,3 Key points are: Isc

5、hemia for a long time Reestablishment of blood flow More severe injury,Characteristics of ischemia-reperfusion injury: 1. Reversible Irreversible injury 2. Having reported in heart, kidney, liver, lung, brain, intestine, skeletal muscles Calcium paradox Oxygen paradox pH paradox,Etiology of ischemia

6、-reperfusion injury,Cause Ischemia followed by reperfusion,Which factors are involved in reperfusion injury,Generally speaking, Duration of ischemia the longer period of ischemia, the more severe injury Severity of ischemia the more grievous ischemia, the more severe injury Speed of reperfusion the

7、faster reperfusion of blood, the more severe injury Ischemia preconditioning increasing tolerance to reperfusion injury,Why are more severe injury induced by reestablishment of blood flow after ischemia?,Vaso-endothelial edema ATP depletion decreased Na+-K+ pump function Na+ and water entering cell

8、endothelial edema Vaso-endothelial damage WBC adherence OFR (Oxygen Free Radical) increase and NO decrease Microvascular obstruction Squeeze of the coronary arteries induced by ischemic myocardium and by interstitial edema of myocardium Adherence, Aggregation and Activation of WBC,MICROVASCULAR DAMA

9、GENO-Reflow Phenomenon,Pathogenesis of ischemia-reperfusion injury,1. Injury of free radicals,(1) Free radical,Free radicalatoms, molecules or ions with unpaired electrons on an otherwise open shell configuration. These unpaired electrons are usually highly reactive, so radicals are likely to take p

10、art in chemical reactions. Oxygen free radical Lipid radical,(2) Oxygen free radical, OFR Types： the superoxide anion (O2-) the hydroxyl radical (OH ) singlet oxygen (1O2 ) hydrogen peroxide (H2O2),(3) Lipid free radicals： The interaction of oxygen free radicals with polyunsaturated fatty acids in t

11、he phospholipids of cell membrane leads to the formation of lipid free radicals. Types： Fatty acid radical (L) Lipid peroxide（LOO） (4) Others: Cl, CH3, NO,(5) Generation and elimination of oxygen free radicals,1) Origin of O-2： a. Mitochondria b. Oxidation of some chemicals in body. c. Catalysis by

12、enzymes d. Stimulation of cells with toxins,(6) Generation of OFR,O2 + e,O2 ,O2+ 2e + 2H+,H2O2,H2O2,O2 + 3 e + 3H+,HO + H2O,O2 + 4 e + 4H+,2 H2O,Cytaa3,SOD,SOD, Superoxide dismutase,Cytochrome aa3,Haber-Weiss reaction (without Fe3 ),O2 + H2O2 O2 + OH +OH,SLOW,hydroxyl radical; ferrum,Fenton-Haber-We

13、iss reaction,Fe3 O2 + H2O2 O2 + OH +OH,FAST,(6) Elimination of oxygen free radicals 1）Small MW scavenging agents,Dihydrocoenzyme II,Cysteine, Vit C, glutathione,Vit E、 Vit A,2）Enzymatic scavenging agents,Catalase (CAT),Peroxydase （H2O2）,Superoxide dismutase,MnSOD,CuZnSOD,(7) The mechanisms of increa

14、sed generation of oxygen free radicals during ischemia-reperfusion,1) Mitochondria pathway,Ca2+entering MT,O2+e,O-2,Hypoxia Mn-SOD ,Superoxide dismutase,2) Xanthine oxidase pathway,Ischemia:,ATP comsumption,Hypoxanthine ,Reperfusion:,(1) Ca2+ overload activating protein kinase,XO,(2) Restoration of

15、O2 supply,xanthine + O-2+ H2O2,O-2+ H2O2 +Uric acid,O2,O2,XD,OH ,Effect of XO on formation of OFR,3) Neutrophil pathway,NADH(I) NADPH(II),+ O2,NADPH oxidase,H+ + O-2+H2O2,NADH oxidase,C3, LTB4 (Complement C3 Leukotriene B4 ),Activating neutrophil,Hexose shunt activity,cellular respiration ,4) Catech

16、olamines ,Adr,Methyl transferase,vanillylmandelic acid (normal),Remove,Stress 80% O2,adrenochrome,O-2,monoamine oxidase,(8) Alterations induced by OFR,1) lipid peroxidation Alteration of membrane lipid Function inhibition of membrane proteins Enhance of arachidonic acid metabolism Blockage of ATP pr

17、oduction in mitochondria membrane,2) Injury of chromosome and nuclear acid,80% induced by OH,Attacking membrane structure such as mitochondria membrane interfering with energy metabolism Attacking DNA changing genetic information cell death Initiating lipid peroxidation increasing permeability of me

18、mbrane and inducing destruction of membrane cell death Destroying proteins decreased enzyme activity metabolic disorder,Destructive effects of OFR:,Calcium Overload Intracellular calcium concentration abnormally increases and leads to cell and tissue damages,How to maintain Intracellular calcium at

19、normal level? Ca2+ Pump on cell membrance Na+ - Ca2+ exchage pump Ca2+ Pump on mitochondrial membrane Ca2+ Pump on endoplasmic reticulum,2. Calcium overload,(1) Mechanisms of calcium overload,Disorder of Na+ -Ca2+ exchange Intracellular Na+, H+, NE- 1R- PLC-PKC Activation of Na+-H+ exchanger Cellula

20、r membrane injury permeability, membrane phospholipid degradation, OFR Injury of mitochondria Catecholamines-R,Why dose calcium overload occur during reperfusion Depleted energe Increased permeability of cellular membrance Increased intracellular sodium,(2) Alterations induced by calcium overload,Mi

21、tochondria functionATP production Activation of membrane phosphatidasemembrane damage Cardiac arrhythmia OFR Myofibril contracture, rupture, cell damage,What are effects of calcium overload Damage mitochondria ATP production decrease Cause myocardial injury contraction weakness promote OFR formation

22、 damage aggravation,3. The Role of Leukocyte,Blocking microvasculature in the region of reperfusion Adhering to microvascular endothelium through interaction between L-selectin on surface of WBC and ICAM-1 (cell adhesion molecules) on surface of endothelium Damaging tissues and cells in the region o

23、f reperfusion through releasing arachidonic acid (AA) TXA2 (thromboxane A ), lysosomal enzymes etc. And producing OFR in “respiratory burst”.,Accumulation of WBC,Vascular endothelial cells and neutrophil injury,1. Microvessel injury (1) no-reflow phenomenon (2) Change in blood flow, diameter and per

24、meability of vessel 2. Cell injury OFR, lysoome, cell factors Cell adhesion, accumulation, flow blockage vessel permeabilityedema,No reflow,Damaged endothelium NO decrease CAMs upregulation L-selectin ICAM-1 WBC ADHERENCE to ENDOTHELIUM Releasing OFR, TXA2, lysosomal enzymes Blocking blood flow Dama

25、ging tissues and cell,NO, nitric oxide; CAM, cell adhesion molecules; TXA2, thromboxane A2,OFR,Ca overload,endothelia- neutrophil,？,Alterations in metabolism and energy,Ca overload is common way of irreversible death of cells,Mechanisms of IRI,Excess oxygen Neutrophil Free radicals infiltration ISCH

26、EMIAREPERFUSION INJURY Microvascular damage Calcium overload Major mechanisms of ischemia- reperfusion injury,Alterations of metabolism and function during ischemia-reperfusion injury,Heart,1. Cardiac function-heart pump 2. Electrocardiogram-Reperfusion arrhythmia 3. Energy metabolism change in hear

27、t 4. Change in cardiac microstructure,Brain,1. Alterations of brain metabolism (energy, acidosis, FFA, transmitters) cAMP / cGMP PL 2. Abnormal electroencephalogram (EEG) (Slow wave, excitatory transmitters inhibitory transmitters) 3. Alterations in brain structure (edema, necrosis),Ischemia-reperfu

28、sion injury in other organs (intestine, kidney, bone),Excess oxygen Neutrophil Free radicals infiltration ISCHEMIAREPERFUSION INJURY Microvascular damage Calcium overload Major mechanisms of ischemia- reperfusion injury,1.Vasomotor Responses OFR Calcium Overload WBC Damaged endothelium NO, PGI2 release TXA2, ET release VASOCONSTRICTION Aggravating injury,OFR Calcium Overload WBC Damaged endothelium Vascular Sticking WBC Liable to form permeability platelets to endothelium thrombosis Edema Releasing OFR Blocking blood proteolytic enzymes flow Aggravating inju