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Chapter 11 I schemia-reperfusion injury

Chapter 11 I schemia-reperfusion injury. Zhao Mingyao BMC.ZZU. 1955, Sewell ligated coronary artery of dog, restore blood flow after deligation. What happened ?. Brief history. Simple phenomenon. Clinical ：. Shock , DIC Bypass surgery Fibrinolytic therapy

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Chapter 11 I schemia-reperfusion injury

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  1. Chapter 11 Ischemia-reperfusion injury Zhao Mingyao BMC.ZZU

  2. 1955,Sewell ligated coronary artery of dog, restore blood flow after deligation. What happened ? Brief history Simple phenomenon

  3. Clinical： Shock , DIC Bypass surgery Fibrinolytic therapy Cardiopulmonary operation Organ transplantation

  4. Concept of Ischemia-Reperfusion Injury The restoration of blood flow after transient ischemia may induce further reversible or irreversible cellular injury

  5. Features of IRI： 1. reversible  irreversible 2. Massive in organs 3.participating factors oxygen paradox calcium paradox pH paradox

  6. Perfusion fluid Perfusion fluid effect Normal O2 supply Without O2 O2 paradox Deteriorate injury with Ca2+ Ca2+paradox Without Ca2+ Correcting acidosis Acidosis pH paradox

  7. Section 1 Etiology of IRI 1. Duration of ischemia 2.Dependency on O2 supply 3.The condition of reperfusion: reperfusion pressure, speed, T, Na+, Ca2+, K+, Mg2+

  8. Effect of Ischemic time on perfusion arrhythmia of rat incidence rate Ischemic time

  9. Section 2 mechanism of IRI

  10. Part 1. Injury of free radicals

  11. Concept and Types of FR Free radicals are atoms or molecules with unpaired electrons in their outer orbital Non-lipid free radicals Lipid free radicals

  12. (1) Oxygen free radical（OFR) ---Induced by O2 Classification O·-2 OH· 1O2 Types Rective Oxygen Species (ROS) OFR H2O2 peroxynitrite

  13. (2) Lipid radicals types： L· LO· Alkoxyl LOO· Cl·、CH3 ·(Methane )、 NO ·

  14. 1. Generation of free radical 1) Initiation 2) Propagation 3) Degradation

  15. (1)Production and scavenging of OFR 1) Origin of O·-2： ①Mt ②Natural oxidation of some substances ③Enzyme catalysis ④Toxin acting on cell

  16. 2）Production process of OFR O2 + e O2 SOD O2+ 2e + 2H+ • H2O2 Cytaa3 O2 + 3 e + 3H+ HO +H2O H2O2 nse 2 H2O O2 + 4 e + 4H+ Single electron reduction Single electron reduction of O2

  17. O2－+ H2O2 O2 + OH +OH Haber-Weiss reaction(withoutFe2)  SLOW

  18. Fenton typeofHaber-Weiss reaction( with Fe3 ) O2－+ H2O2 O2 + OH +OH Fe2  Fast What significance ？？？

  19. 3）Scavenging of OFR Water-soluble Lipid-soluble ① Low molecule scavenger ② Enzymatic scavenger

  20. ①low molecule scavenger  *hydrofacies of intra- or extracell: Cysteine、Vit C、 Glutathione Cytosol ：NADPH *Cellular lipid： Vit E、 Vit A

  21. ②Enzymatic scavenger Superoxide dismutase (SOD) Catalase (CAT) Glutathione peroxidase (GSH-Px)

  22. Dismutation reaction Single electron reduction of O2 SOD • H2O2 + O2 2O2+ 2H+ H2O2 nse ?

  23. GSH-Px: containing selenium scavenging large biological molecule peroxide LOOH + 2GSH GSSG + LOH + H2O GSH-Px GSH reductase GSSG + NADPH + H+ 2GSH + NADP+

  24. (2) Mechanism of OFR ↑during IRI

  25. 1) Mitochondria pathway Single electron reduction of O2 ↑ Ca2+ enter Mt • O-2· ↑ hypoxia MnSOD 

  26. 2) Xanthine oxidase(XO) pathway↑ Xanthine oxidase (XO )10% xanthine dehydrogenase(XD) 90% Ca 2 + sensitive enzyme

  27. Ischemia: Hypoxathine↑↑ ATP degradation O2 Reperfusion: (1)Ca2+→protease xanthine + O·-2+ H2O2 XD XO （2）restore O2 O2 O·-2+ H2O2+ uric acid XO role in formation of OFR OH ·

  28. 3)Neutrophil pathway hexose bypass activation C3,LTB4 Activates NP Respiratory burst NADH(I) NADPH(II) NADH oxidase H+ + O-2·+H2O2 + O2 NADPH oxidase

  29. 4) Catecholamine autooxidation pathway Vanillylmandelic acid (VMA) Methyl transferase Adr • monoamine oxidase 80% during stress Renal excretion O2 -· adrenochrome

  30. (3) The detrimental effects of OFR to tissue 1）Lipid membrane 2）Protein: channel, pump, 3）Enzyme 4）Nuclear acid : DNA

  31. Membrane lipid peroxidation

  32. Biomacromolecle crosslinkage Protein ~ Lipid –pro ~ Two sulfur ~ Protein break -S-S- OH OH HO HO CH3-S- Lipid-lipid ~ O MDA released by oxidated fatty acid Amino acid oxidation fatty acid oxidation Malondialdehyde (MDA)

  33. DNA disruption and chromosome aberration induced by OH about 80% damage OH +2300 (hydroxyl)

  34. Part 2 Calcium overload

  35. 1. Ca 2+ transportation and distribution Ca 2+ Ca 2+ Ca2+ binding Pr Ca2+pump SR Ca 2+Channel Na + - Ca 2+ cotransportor Mt

  36. 2. Mechanism of ~ ① Na+ - Ca2+ exchange↑: H+-Na+ ↑; Na+ - Ca2+ ↑(forward mode reverse mode); PKC triggers ②ATP ↓: mitochondria damage, energy precursor ↓ ③Membrane permeability ↑ ④catecholamine ↑

  37. NE H+ Ca2+ α1 P1 Gq PLC Na+ DG IP3 PKC Ca2+ Ca2+ SR filament PKC activating Na+/Ca2+ exchanger indirectly

  38. 3. The detrimental effects ofCa2+overload to tissue (1) Activating Ca2+-activated protease (2) Defects in membrane permeability activating phospholipase A2 OFR (3) Hypercontracture and reperfusion arrhythmia cellular electrical action (4)Mitochondria damage

  39. Part 3. The endothelial injury and neutrophil activation

  40. 1.The role of neutrophil activated ①Swelling ②Adhesion ③Infiltration ④Release: arachidonic acid, PAF, lysosomal enzyme ⑤Respiratory burst ⑥Cell adhesion molecules(CAM): selectins, integrins, immunoglobulin superfamily

  41. 2. Mechanism of no-reflow phenomenon Vaso-endothelial damage Vaso-endothelial edema Occlusion of microvascular luman

  42. Rulo: 肉膜

  43. 3.NO and ONOO- production NO in VEC(eNOS), little, physiological NO in inflammatory cell(iNOS), rich, cytotoxic (Mt respiration, aconitase activity, DNA synthesis) and OONO- peroxynitrite

  44. Free radicals with a nitrogen center ① Nitric oxide(NO) O2 NOS L-arginine L-citrulline + NO NADPH NADP+

  45. ② Peroxynitrite, ONOO- NO+O2.- acidic NO2. + OH.+ H+ ONOO- H2O Killing bacterial & tumor

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