1. Ischemia-reperfusion injury (IRI)

2. Introduction 1955, Sewel tied up coronary of dog ， loose suddenly ventricular fibrillation 。 Kane tied up left entricular branch of coronary of rat ECG no obvious change relieve deligation arrhythmic

3. 1972 Flore kidney IRI 1978 Modry lung IRI 1981 Greenberg intestine IRI

4. Concept: based on ischemia injury of tissue and organs restoration of blood flow after transient or ischemia further reversible or irreversible cell damage ischemia reperfusion injury （ IRI ） 。

5. pH paradox ischemia acidosis, disorder of function and metbolism on cell severe IRI pH paradox calcium paradox pre-perfuse rat heart with no calcium perfusion for 2min perfuse calcium perfusion, cell release enzyme myofibril over-constract, electron signals abnormal ， calcium paradox

6. Oxygen paradox Hypoxia liquid perfuse organ or culture without oxygen injury restore perfusion severe injury

7. Ⅰ. Cause of ischemia-reperfusion injur y and affecting factor coronary in spasm anti spasmotic thrombosis thrombolytic therapy 1. cause coronary by-pass operation on heart: no-reflow organ transplant

8. 2 ． Affecting factor small 5-10min: arrhythmia ⑴ ischemic animals 20-30min: ventricular time tremor big 20-40min: reversible injury animals 40-60min: irreversible injury diversity between small and big animal

9. Changes of ischemic perfuse: ATP 、 Ca 2 + 、 K +

10. ⑵ collateral ( 侧枝 ) circulation ： chronic ⑶ O 2 consumption rate [K + ], [Mg 2+ ] protection ⑷ electrolytes [Na + ], [Ca 2+ ] damage (5) condition of T, pressure,pH, Na +, Ca 2+ protection reperfusion T, pressure, Na +, Ca 2+ damage

11. Ⅱ. pathogenesis of ischemia-reperfusion injury 1. The role of free radical ⑴ kinds and concept of free radical free radical:

12. normal: O 2 +4e+4H + 2H 2 O O 2 → O - 2 H 2 O 2 OH H 2 O e - e - + 2H + e - + H + H2OH2O

13. oxygen free radical: O - 2 、 OH kinds of (active oxygen: 1 O 2 、 H 2 O 2 OH ) free radical lipid free radical: L 、 LO 、 LOO others: Cl 、 CH 3 、 NO

14. (2) mechanism of increase of oxygen free radical ① formation of oxygen free radical nature oxidation of Hb, Cyt C O 2 O ‾∙ 2 H 2 O 2 OH ∙ H 2 O H 2 O oxidation of enzyme : xanthine oxidase(XO) O ‾∙ 2 xanthine uric acid O 2 O ‾∙ 2 Mitochondria: O ‾∙ 2

15. normal : O 2 +4e+4H + → H 2 O+ATP abnormal :O 2 +e → O · - 2 +e +2H + → H 2 0 2 +e+H + → OH · +e+H + → H 2 0 Cyt P 450 O insert C—H C—OH O +2 H + H 2 O O ‾∙ 2 H 2 O 2

16. Produce of OH· SOD O · - 2 + O · - 2 +2H + H 2 O 2 +O 2 O · - 2 +H 2 O 2 OH · + OH · +O 2 Fenton Haber-Weiss ： SOD Fe 2+ Fe 3+ O · - 2 H 2 O 2 OH · + OH -

17. （ 2 ） lipid free radical concept ： types ： L ·, LO · LOO · （ 3 ） non- lipid free radical: NO· 、 ONOO - They are balance between produce and clearance

18. Haber-Weiss reaction(Fenton reaction ) OH ∙ Fe 3+ + O ‾∙ 2 Fe 2+ + O 2 H 2 O 2 Fe 3+ + OH - + OH ∙ O ‾∙ 2 + H 2 O 2 Fe 盐 O 2 + OH - + OH ∙ O ‾∙ 2 + OH ∙ 1 O 2 + OH - CI+ + H 2 O H 2 O + OCl - 1 O 2 OCl - + H 2 O 2 1 O 2 + Cl - + H 2 O photosensitive substance O 2 1 O 2 effects: WBC

19. 2O ‾∙ 2 + 2H + SOD H 2 O 2 + O 2 H 2 O 2 O 2 Other oxidase 2H + H 2 O 2 application disinfection

20. ② increase of oxygen free XD Xanthine oxidase (XO) : Ischemia ATP [Ca 2+ ] i xanthine xanthine dehydrogenase oxidase

21. Xanthine oxidase pathway ATP ADP AMP Adenine nucleoside Ca 2+ Hypoxanthine nucleoside Hypoxanthine xanthine+ O ‾∙ 2 +H 2 O O 2 Uricacid + O ‾∙ 2 +H 2 O Fe 2+ OH ∙ XD xo XO ischemia reperfusion

22. The effects of leucocyte reperfusion ： oxygen consumption of infiltrated WBC ↑ 70-90% O 2 NADPH +2O 2 2 O · - 2 +NADP + +H + NADH+O 2 +2H + H 2 O 2 +NAD + +H + NADPH 氧化酶 NADH 氧化酶

23. Phenomenon of increase in production of oxygen radicals 1.repiratory burst O ‾∙ 2 \ OH ∙ (oxygen burst) 2.hypoxia mitochondria repiratory chain O ‾∙ 2 Ca 2+

24. (3) damage action of free radical ① membrane lipid peroxidation cellular membrane permeability lipid peroxidation of membrane [Ca 2+ ] i calcium overload calcium overload

25. calcium overload lipid cross-linked calcium overload inhibition of Na + -pump and Ca 2+ -pump [Na + ] i, [Ca 2+ ] i membrane lipid phospholipase C PGs, LTs （花） peroxidation phospholipase D TXA 2 damage of mitochondria membrane ATP

27. ② inhibition of protein function enzymes ： stop heart beat IR GSH(blood) injury of protein channels: ③ destruction of nuclear acid DNA- DNA, DNA-protein :

28. (1) mechanism of calcium overload Ca 2+ input ① abnormal exchange of Na + /Ca 2+ ATP Na + -pump [Na + ] i exchange of Na +(out) /Ca 2+ (in) (convert) hypoxia exchange acidosis of Na +(in) /H +(out) [Na + ] i normal exchange of Na +(in) /Ca 2+(out) ，

29. ischemia catecholamine α 1 – receptor H + Ca 2+ Na + Ca 2+ IP 3 and DG PKC Ca 2+ Normal:βreceptor α1α1 Ca 2+ S R

30. catecholamine β – receptor [Ca 2+ ] i L Ca 2+ - channel Ca 2+ pre-apply anti-Ca 2+ drugs GOOD ② injury of biomembrane damage of cellular membrane normal glycocalyx Ca 2+ bridge Cellular membrane β Cellular membrane

31. No Ca 2+ glycocalyx reperfusion Ca 2+ glycocalyx Ca 2+ lipid break up PLA 2 Cellular membrane

32. Damage of mitochondria and sarcoplasmic Damage of mitochondria ATP Damage of Sarcopasmic Ca 2+ - ATPase calcium overload

33. (2) Damage mechanism of calcium overload ① phospholipase injury of cell membrane and cell organ ② output of Ca 2+ consumption of ATP ③ Ca 2+ + phosphate production of ATP deposition ④ [Ca 2+ ] i XO free radical ⑤ [Ca 2+ ] i

34. 3. role of leukocyte In 1984 ， Mullane found that conorary was obstructed 60min ， Engler ， Ischemia phospholipase LTs Congregate of leukocyte Expression of adhesion molecule Release inflammatory factor Production of free radical no-reflow

35. 5. Role of neutrophil : 1)Injury of microvessle microcirculation ： caliber contracte, dialate permability 2) Injury of cells

36. Ⅲ. Changes of function and metabolism 1. changes of heart in ischemia-reperfusion injury arrhythmia heart function cardiac output free radical energy calcium overload damage of mitochondria reperfusion sweep of ADP ， AMP produce ATP myocardial destruction of membrane structural rupture and dissolve of myofibril damage damage of mitochondrion

37. 2. changes of brain in ischemia-reperfusion injury ATP Na + -pump cellular edema Hypoxia of cells cellular acidosis Excitability transmitter inhibitive transmitter cAMP↑ cGMP↓ activate free fatty acid ↑ lipid peroxidation ↑

38. Hisconstructure Edema, necrosis 3. Others Colone, kidney

39. Ⅳ. Principles of prevention and treatment 1. restoring normal perfusion of tissue in time low temperature; low pressure; low flow; low natrium(sodium); low pH; low calcium

40. 2. improve the metabolism of the tissues ATP; cytochrome C; 3. sweep away free radical: VitE: lose e FR FR (lipid) VitC: clear OH ∙ (water) β-cartenoids: clear 1 O 2 GSH

41. （ 2 ） enzyme scavenger ： 2 O ‾∙ 2 +2H + H 2 O + O 2 H 2 O 2 H 2 O+ O 2 4. relieve of calcium overload Ca 2+ ion blok agent SOD CAT

42. 5. CoQ Inhibit L (lipid free radical) 2L+ CoQ 2LH+ CoQ protein enzyme inhibitor: ulinastatin