09 ir injury
•Download as PPT, PDF•
5 likes•1,261 views
patholophysiology of injury Pathophysiology（病理生理学） Pathology uploaded by prabesh 杰诗
Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Similar to 09 ir injury
Similar to 09 ir injury (20)
More from Prabesh Raj Jamkatel
More from Prabesh Raj Jamkatel (20)
Recently uploaded
Recently uploaded (20)
09 ir injury
- 1. Dept. of PathologyDept. of Pathology Medical CollegeMedical College Hunan Normal UniversityHunan Normal University (( 湖南 范大学医学院病理学教研室师湖南 范大学医学院病理学教研室师 )) 1 Chapter 9Chapter 9 Ischemia-Reperfusion InjuryIschemia-Reperfusion Injury （缺血（缺血 -- 再灌注 ）损伤再灌注 ）损伤
- 2. 22 Ischemia-Reperfusion InjuryIschemia-Reperfusion Injury a.a. IntroductionIntroduction b.b. EtiologyEtiology c.c. PathogenesisPathogenesis d.d. Alterations of Metabolism andAlterations of Metabolism and FunctionFunction e.e. Pathophysiological Basis ofPathophysiological Basis of Prevention and TreatmentPrevention and Treatment
- 3. Ischemia Concept Injury More injury Reperfusion “A paradox” After prolonged ischemia, reestablishment of blood flow (reperfusion) does not relieve ischemic injury; On the contrary, it aggravates the tissue injury.
- 4. Oxygen Paradox Low O2 Perfusion Tissue injury O2-containing fluid Tissue injury ↑ Perfusion Paradoxes During IR Injury
- 5. Calcium Paradox Ca2+ -free fluid Perfusion Tissue injury Ca2+ -containing fluid Tissue injury ↑ Perfusion Paradoxes During IR Injury
- 6. pH Paradox Acidosis Tissue injury Correction of Acidosis Tissue injury ↑ Perfusion Paradoxes During IR Injury
- 7. 1955 Sewell1955 Sewell Ligation of dog coronary artery → restoreLigation of dog coronary artery → restore blood flow → ventricular fibrillation → deathblood flow → ventricular fibrillation → death 1960 Jennings1960 Jennings Myocardial IRIMyocardial IRI (first to name IRI) 1968 Ames1968 Ames Brain IRIBrain IRI 1972 Flore1972 Flore Kidney IRIKidney IRI 1978 Modry Lung IRI1978 Modry Lung IRI 1981 Greenberg Intestine IRI1981 Greenberg Intestine IRI History of Ischemia-Reperfusion Injury (IRI) Research
- 8. 88 Ischemia-Reperfusion InjuryIschemia-Reperfusion Injury a.a. IntroductionIntroduction b.b. EtiologyEtiology c.c. PathogenesisPathogenesis d.d. Alterations of Metabolism andAlterations of Metabolism and FunctionFunction e.e. Pathophysiological Basis ofPathophysiological Basis of Prevention and TreatmentPrevention and Treatment
- 9. Coronary Artery Bypass Graft (CABG) Percutaneous Transluminal Coronary Angioplasty (PTCA) Shock resuscitation (fluid infusion) Organ transplantation Thrombolytic therapy Etiology Ischemia followed by reperfusion
- 10. CABG (Coronary Artery Bypass Graft ) Favaloro(1967) Benetti (1995) 10
- 11. PTCA （ Percutaneous Transluminal Coronary Angioplasty ） Balloon Stent 11
- 12. Factors Influencing IR Injury a.a. Duration of ischemiaDuration of ischemia b.b. Collateral circulationCollateral circulation c.c. Dependency on oxygen supplyDependency on oxygen supply d.d. Condition of reperfusionCondition of reperfusion 12
- 13. Effect of Duration of Ischemia on IRI Ischemia time (min) Reperfusion time (min) Ventricular tachycardia (%) Ventricula r fibrillation (%) Mortality (%) 2 10 0 0 0 5 10 47.6 47.6 25.8 10 10 30.0 40.0 10.0 15 10 9.0 0 0
- 14. 1414 Ischemia-Reperfusion InjuryIschemia-Reperfusion Injury a.a. IntroductionIntroduction b.b. EtiologyEtiology c.c. PathogenesisPathogenesis d.d. Alterations of Metabolism andAlterations of Metabolism and FunctionFunction e.e. Pathophysiological Basis ofPathophysiological Basis of Prevention and TreatmentPrevention and Treatment
- 15. Pathogenesis of IR Injury a.a. Role of OFR/ROSRole of OFR/ROS b.b. Calcium overloadCalcium overload c.c. Activation of neutrophilsActivation of neutrophils
- 16. Free Radicals Highly reactive group of atoms, molecules or radicals, which carry unpaired electron in the outer orbit. Free radicals that contain oxygen. Properties of free radicalsProperties of free radicals Chemically activeChemically active Highly oxidativeHighly oxidative Short half-lifeShort half-life Oxygen Free Radicals (OFR)
- 17. Reactive Oxygen Species (ROS) A group of chemically reactive molecules containing oxygen. Oxygen free radicals: O2 ., OH ., LO . Non-free radicals: 1 O2 , H2O2 Classification of ROS
- 18. Free Radicals Oxygen Free Radicals Reactive Oxygen Species Non-Free Radicals (Oxygen- containing) Non-Oxygen Free Radicals O2 . OH . LO . 1 O2 H2O2 OONO- L . Cl . CH3 . The Relationship Between Free radicals and Reactive Oxygen Species
- 19. RReactive specieseactive species Half-lifeHalf-lifeHalf-lifeHalf-life Hydroxyl radical (Hydroxyl radical (•• OH)OH) Alcoxyl radical (ROAlcoxyl radical (RO•• )) Singlet oxygen (Singlet oxygen (11 OO22)) Peroxynitrite anion (ONOOPeroxynitrite anion (ONOO-- )) Peroxyl radical (ROOPeroxyl radical (ROO•• )) Nitric oxide (Nitric oxide (•• NO)NO) Hydrogen peroxide (HHydrogen peroxide (H22OO22)) Superoxide anion (OSuperoxide anion (O22 •• )) 1010-9-9 ss 1010-6-6 ss 1010-5-5 ss 00..05 – 105 – 1..00 ss 77 ss 1 – 101 – 10 ss hours/hours/daysdays hours/hours/daysdays 19 Half-life ofHalf-life of Some ROSSome ROS
- 20. Mechanism of OFR Increase During IR InjuryMechanism of OFR Increase During IR Injury a.a. Increased OFR productionIncreased OFR production b.b. Decreased OFR clearanceDecreased OFR clearance Role of ORF/ROS Injurious Effects of OFRInjurious Effects of OFR
- 21. 21 Generation of OFR a.a. Xanthine oxidase pathwayXanthine oxidase pathway b.b. Neutrophils pathwayNeutrophils pathway c.c. Mitochondria pathwayMitochondria pathway
- 22. Xanthine Oxidase Pathway Xanthine dehydrogenase Xanthine oxidase (XO) ATP↓ Ischemia [Ca2++ ]i↑ ATP ADP AMP HypoxanthineXanthineO2 . _ H2O2 + + O2 Reperfusion Uric acidO2 . _ +H2O2 + XOO2 OH. Ca2++ -dependent proteinase Adenosine
- 23. 23 Generation of OFR a.a. Xanthine oxidase pathwayXanthine oxidase pathway b.b. Neutrophils pathwayNeutrophils pathway c.c. Mitochondria pathwayMitochondria pathway
- 24. OFROFR Respiratory burstRespiratory burst （呼吸爆（呼吸爆 ）发）发 Activation of neutrophilsActivation of neutrophils IschemiaIschemia Neutrophils Pathway Oxygen consumptionOxygen consumption↑↑ ReperfusionReperfusion OO22 ↑↑ Chemoattractants (CChemoattractants (C33,, LTBLTB44)) Kill pathogenKill pathogen Damage tissueDamage tissue
- 25. OO22 HH22OO22 HOClHOCl NADPHNADPH oxidaseoxidase NADPHNADPH MPOMPO MPOMPO ((myeloperoxidasemyeloperoxidase)) NADPNADP++ •• OHOH •• NONO OO22 •• OONOOONO--•• OHOH Respiratory burst Respiratory burst Also called oxidative burst, is the rapid release of OFRAlso called oxidative burst, is the rapid release of OFR from WBCs (neutrophils).from WBCs (neutrophils). 25
- 26. 26 Generation of OFR a.a. Xanthine oxidase pathwayXanthine oxidase pathway b.b. Neutrophils pathwayNeutrophils pathway c.c. Mitochondria pathwayMitochondria pathway
- 27. Generation of Endogenous OFR O2（ 98% ） 4e _ +4H + 2H2O + ATP Cytochrome oxydase e _ O2 e _ +2H + H2O2 OH. e _ +H + H2O e _ +H + H2O （ 1-2% ） _ SOD O2 . FeFe 33 ++
- 28. Ischemia Mitochondria Pathway Ca2+ entering mito ATP↓ OO22 .. __ ↑↑e _ Reperfusion O2 OO22 + O2（ 98% ） 4e _ +4H + 2H2O Cytochrome oxydase e _ O2 e _ +2H + H2O2 OH. e _ +H + H2O e _ +H + H2O_ O2 . × (2%)
- 29. Mechanism of OFR Increase During IR InjuryMechanism of OFR Increase During IR Injury a.a. Increased OFR productionIncreased OFR production b.b. Decreased OFR clearanceDecreased OFR clearance Role of ORF/ROS Injurious Effects of OFRInjurious Effects of OFR
- 30. 30 Clearance of OFR a.a. Enzymatic clearanceEnzymatic clearance SOD (Superoxide dismutase)SOD (Superoxide dismutase) CAT (Catalase)CAT (Catalase) b.b. Non-enzymatic clearanceNon-enzymatic clearance
- 31. Enzymatic Clearance of OFR e _ O2 e _ +2H + H2O2 e _ +H + （ 1-2% ） _ O2 . H2O + O2 SOD CAT Mn-SOD CuZn-SOD Amyotrophic lateral sclerosis (ALS) Mutation Stephen Hawking
- 32. 32 Clearance of OFR a.a. Enzymatic clearanceEnzymatic clearance b.b. Non-enzymatic clearanceNon-enzymatic clearance
- 33. Non-enzymatic OFR scavengersNon-enzymatic OFR scavengers Vitamins (Vit C, Vit E)Vitamins (Vit C, Vit E) CeruloplasminCeruloplasmin Dimethyl sulfoxide (DMSO)Dimethyl sulfoxide (DMSO) AllopurinolAllopurinol Glutathione (GSH)Glutathione (GSH) H2O2 + 2GSH 2H2O+ GSSG
- 34. Mechanism of OFR Increase During IR InjuryMechanism of OFR Increase During IR Injury a.a. Increased OFR productionIncreased OFR production b.b. Decreased OFR clearanceDecreased OFR clearance Role of ORF/ROS Injurious Effects of OFRInjurious Effects of OFR
- 35. Injurious Effects of OFR
- 37. Cell membrane damage Destruction of membrane structure Increased permeability Membrane protein function ↓ Organelle membrane damage Lysosome Destruction of membrane → release of lysosomal enzymes → autocytolysis Mitochondrion Swelling → Mito dysfunction → ATP ↓ Sarcoplasmic reticulum (SR) SR uptake of Ca2+ ↓ → Ca2+ overload Consequences of Lipid Damage
- 40. Pathogenesis of IR Injury a.a. Role of ORF/ROSRole of ORF/ROS b.b. Calcium overloadCalcium overload c.c. Activation of neutrophilsActivation of neutrophils
- 41. Calcium Overload During IR, the concentration of cytosolic CaDuring IR, the concentration of cytosolic Ca2+2+ increases obviously, causing cell damage andincreases obviously, causing cell damage and dysfunction. This phenomenon is called “Calciumdysfunction. This phenomenon is called “Calcium Overload”.Overload”.
- 42. Mechanisms of Calcium Overload NaNa++ -Ca-Ca2+2+ exchanger dysfunctionexchanger dysfunction Damage in cell membraneDamage in cell membrane Damage in organelle (Mito or SR) membraneDamage in organelle (Mito or SR) membrane Na+ -Ca2+ Exchanger Ca2+ Pump Ca2+ [Ca2+ ]e ： 10-3 M [Ca2+ ]i ： 10-7 M Ca2+ channel Mito SR Ca2+ Na + Ca 2+ Ca 2+ SR: Sarcoplasmic reticulum
- 43. Ischemia → ATP↓→ Na+ -K+ ATPase↓→ [Na+ ]i↑→ Activate Na+ -Ca2+ exchanger K+ Na+ 3Na+ Ca2+ ATP↓ Na+ ↑ Ca2+ ↑ Mechanism of Na+ -Ca2+ Exchanger Dysfunction
- 44. Mito SR IRI [Ca2+ ]i ↑ OFR ↑ Proteinase Destruction Membrane Cytoskeleton Nuclease Chr Damage Na+ -Ca2+ ExchangerCa 2+ Na + Mito dysfunction Mito oxidation ↓ Consequences of Calcium Overload
- 45. Pathogenesis of IR Injury a.a. Role of ORF/ROSRole of ORF/ROS b.b. Calcium overloadCalcium overload c.c. Activation of neutrophilsActivation of neutrophils
- 46. IR injuryIR injury Activation of Neutrophils Chemokines (LTs, PAF, Kinin) Adhesion molecules ↑↑ (integrin, ICAM-1)(integrin, ICAM-1) Activation of Neutrophils Granzymes (elastase, collagenase) OFR Cytokines
- 47. Ischemia injury Reperfusion injury Reperfusion Free Radicals Ca2+ overload Neutrophils Summary of Pathogenesis of IR Injury
- 48. 4848 Ischemia-Reperfusion InjuryIschemia-Reperfusion Injury a.a. OverviewOverview b.b. EtiologyEtiology c.c. PathogenesisPathogenesis d.d. Alterations of Metabolism andAlterations of Metabolism and FunctionFunction e.e. Pathophysiological Basis ofPathophysiological Basis of Prevention and TreatmentPrevention and Treatment
- 49. OO22 ••-- HH22OO22 HOClHOCl •• OOHH GutGut Heart &Heart & vesselsvessels Lungs &Lungs & airwaysairways Brain &Brain & nervesnerves 49 IR Injury to Important OrgansIR Injury to Important Organs
- 50. ArrhythmiaArrhythmia Ventricular fibrillationVentricular fibrillation Ventricular TachycardiaVentricular Tachycardia Myocardial dysfunctionMyocardial dysfunction COCO ↓↓ Myocardial stunningMyocardial stunning Reversible reduction of the function of heartReversible reduction of the function of heart contraction after reperfusion.contraction after reperfusion. Restored after a few hours or days.Restored after a few hours or days. Myocardial IR Injury
- 51. 5151 Ischemia-Reperfusion InjuryIschemia-Reperfusion Injury a.a. IntroductionIntroduction b.b. EtiologyEtiology c.c. PathogenesisPathogenesis d.d. Alterations of Metabolism andAlterations of Metabolism and FunctionFunction e.e. Pathophysiological Basis ofPathophysiological Basis of Prevention and TreatmentPrevention and Treatment
- 52. Reduce ischemia Control reperfusion conditions Scavenge OFR Relieve Ca2+ overload Improve metabolism - Energy supplementation - Cell protectors Prevention and Treatment of IR Injury
- 53. Lower pressureLower pressure Lower flow speedLower flow speed Lower temperatureLower temperature Lower pHLower pH Lower CaLower Ca2+2+ and Naand Na++ ↓↓ OFR and edemaOFR and edema ↓↓ CaCa2+2+ overloadoverload ↓↓ metabolism →↓ energymetabolism →↓ energy consumptionconsumption Control Reperfusion ConditionsControl Reperfusion Conditions
- 54. NS: Normal saline SOD: Superoxide dismutase DMSO: Dimethyl sulfoxide Verap: Verapamil (Calcium antagonist) Treatment of IR-induced Myocardial Injury IncidenceofIncidenceof VentricularFibrillationVentricularFibrillation
Editor's Notes
- http://v.qihuang99.com/player/1777.html?1777-0-16
- During ischemia, ROS generation is reduced. However, during reperfusion, ROS production is greatly increased (one of the major mechanisms of IR injury).
- CABG: 冠状动脉旁路搭桥术 PTCA: 经皮冠状动脉扩张术
- CABG: 冠状动脉旁路搭桥术
- PTCA: 经皮腔内冠状动脉成型术 用球囊或支架 (stent: stand, support)。 1977 first case in the world.
- Abundance in collateral circulation (侧枝循环), not easy for IR injury.
- ROS, 活性氧簇 1O2，singlet oxygen (单线态氧)
- ONOO-: 过氧亚硝基阴离子
- The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, NCX, or exchange protein) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca2+). The NCX removes a single calcium ion in exchange for the import of three sodium ions.[1] The exchanger exists in many different cell types and animal species.[2] The NCX is considered one of the most important cellular mechanisms for removing Ca2+.[2] Should be intracellular calcium.
- LBT4 increase is because of breakdown of membrane lipid leading to increase of AA.
- Usually it denotes the release of these chemicals from immune cells, e.g., neutrophils and monocytes, as they come into contact with different bacteria or fungi. Two enzymes are involved, NADPH oxidase and MPO. It plays an important role in immune response. OONO-: Peroxynitrite anion. Hypochlorous acid (NaOCl or CaOCl) is used as bleach or disinfectant.
- O2-: superoxide anion; OH-: hydroxyl radical. O2. is the basis for production of other OFR; OH. is the most active and potent endogenous OFR. Catalase (CAT) makes H2O2 to become H2O and O2.
- Mn (Manganese) (锰) [‘mæŋɡəniːz] (not to confuse with Mg (Magnesium)（镁） [mæɡ’niːziəm] ). Cu (Copper) ['kɑːpər] Hawking (physicist and cosmologist from U of Cambridge) suffers from a rare early-onset, slow-progressing form of amyotrophic lateral sclerosis (ALS,肌萎缩性脊髓侧索硬化征), also known as motor neuron disease or Lou Gehrig's disease, that has gradually paralysed him over the decades.[20] He now communicates using a single cheek muscle attached to a speech-generating device. Hawking married twice and has three children.全身关节不能活动，不能说话。
- Allopurinol inhibit the transformation from xanthine dehydrogenase to xanthine oxidase. Reaction of GSH to GSSG requires GSH-Px (glutathione peroxidase).
- Lipids, proteins, and DNA can be oxidized.
- Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism. It most often affects polyunsaturated fatty acids, because they contain multiple double bonds in between which lie methylene bridges (-CH2-) that possess especially reactive hydrogens. As with any radical reaction, the reaction consists of three major steps: initiation, propagation, and termination.
- DNA breakage, crosslinking will occur. 80% of DNA OFR damage is caused by .OH. Lead to gene mutation.
- Calcium overload (a pathological process) does not equal to calcium increase. Two types of calcium channel: VOCC: Voltage-operated Ca2+ channel; ROCC: Receptor-operated Ca2+ channel. Mito contains 500-fold more calcium than cytosol. Intracellular IP3 increases, calcium is released from ER to the cytoplasm. Na-Ca exchanger is not a pump, does not need energy. It depends on Na-Ca concentration. (exchange of Na vs. Ca at 3:1). This [Ca2+]e：10-3 ~ 10-2M; [Ca2+]i：10-8 ~10-7M
- Calcium overload (a pathological process) does not equal to calcium increase. Two types of calcium channel: VOCC: Voltage-operated Ca2+ channel; ROCC: Receptor-operated Ca2+ channel. Mito contains 500-fold more calcium than cytosol. Intracellular IP3 increases, calcium is released from ER to the cytoplasm. Na-Ca exchanger is not a pump, does not need energy. It depends on Na-Ca concentration. (exchange of Na vs. Ca at 3:1). This [Ca2+]e：10-3 ~ 10-2M; [Ca2+]i：10-8 ~10-7M
- Formation of Calcium Phosphate precipitation → Mito oxidation↓ Increased OFR production is because blocking Mito oxidation. (1-2 single electron reduction increases producing more OFR).
- Stunning (心肌顿抑) is a protective mechanism, leading to decreased oxygen consumption.
- Cell protectors: metallothionein, taurate (牛磺酸)
- Lower pH to decrease the difference between extracellular and intracellular [H+], reducing Na-Ca exchange. Lower Na will reduce the activation of Na-Ca exchanger.