缺血再灌注损伤Ischemia-Reperfusion injury.ppt

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1、缺血再灌注损伤Ischemia-Reperfusion injury Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望IschemiaAnesthesiologist:MI,peripheral vascular insufficiency,stroke,and hypovolemic shockRestoration of blood flow to an ischemic organ is essential to prevent irreversible ce

2、llular injuryReperfusion may augment tissue injuryIschemia-ReperfusionThrombolytic therapy,organ transplantation,coronary angioplasty,aortic cross-clamping,or cardiopulmonary bypassSevere:systemic inflammatory response syndrome(SISS)or multiple organ dysfunction syndrome(MODS)Account for 3040%of the

3、 mortality in tertiary referral ICUCellular change during IschemiaAltered membrane potentialAltered ion distribution(+intracellular Ca/Na)Cellular swellingCytoskeletal disorgnizationIncreased hypoxanthineDecreased ATPDecreased phosphocreatinine Cellular acidosisCellular Effects of IschemiaDecreased

4、ATPIntracellular accumulation of hypoxanthineToxic reactive oxygen species(ROS)during reperfusionIschemia at EndotheliumExpress certain proinflammatory gene products(leukocyte adhesion molecules,cytokines)bioactive agents(endothelin,thromboxane A2)Repressing other“protective”gene products(constituti

5、ve nitric oxide synthase,thrombomodulin)and bioactive agents(prostacyclin,nitric oxide).Role of Reactive Oxygen SpeciesIncluding(O2),(OH),(HOCl),(H2O2),and nitric oxidederived peroxynitriteDirectly damage cellular membranes by lipid peroxidation.Stimulate leukocyte activation and chemotaxis by activ

6、ating plasma membrane phospholipase A2 to form arachidonic acid(thromboxane A2 and leukotriene B4)Increase leukocyte activation,chemotaxis,and leukocyteendothelial adherence after I-RRole of ComplementI/R results in complement activation and the formation of several proinflammatory mediators that al

7、ter vascular homeostasisC3a,C5a,iC3b,C5b9Most potent is C5acomplement may compromise blood flow to an ischemic organ by altering vascular homeostasis and increasing leukocyteendothelial adherence.Role of LeukocytesI/R results in leukocyte activation,chemotaxis,leukocyteendothelial cell adhesion,and

8、transmigrationmechanical obstructionactivated leukocytes release toxic ROS,proteases,and elastases,resulting in increased microvascular permeability,edema,thrombosis,and parenchymal cell death Manifestations of I/R injuryVascular Injury and the“No Reflow”PhenomenonMyocardial StunningReperfusion Arrh

9、ythmias(VT,VF,idioV)CNS/GI I/R injuryMultiorgan Dysfunction Syndromerisk factors:hypercholesterolemia,hypertension,or diabetes and so on Therapeutic Strategies To Prevent I-R InjuryIschemic PreconditioningAntioxidant TherapyAnticomplement TherapyAntileukocyte TherapyIschemic PreconditioningExposure

10、of tissues to brief periods of ischemia protects them from the harmful effects of prolonged I-Rcoronary artery bypass graftingreduce liver injury undergoing hepatic resectionIncreases cellular adenosine production and confer protection by augmenting cellular energy stores and/or inhibiting leukocyte

11、 adherenceAntioxidant Therapysuperoxide dismutase,catalase,mannitol,allopurinol,vitamin E,N-acetylcysteine,iron chelating compounds,angiotensin-converting enzyme inhibitors,or calcium channel antagonistshuman recombinant superoxide dismutase in patients with hemorrhagic shockSOD in cadaveric renal t

12、ransplantationequivocalAnticomplement TherapyC3 convertase inhibitorSoluble complement receptor 1 decrease infarct size by 44%in a rat model of myocardial I-R.“Humanized,”recombinant,single-chain antibody specific for human C5(h5G1.1-scFv)significantly attenuate complement activation,leukocyte activ

13、ation,myocardial injury,blood loss,and cognitive dysfunction in humans undergoing coronary artery bypass graft surgery with cardiopulmonary bypassAntileukocyte Therapyinhibition of inflammatory mediator release or receptor engagement,leukocyte adhesion molecule synthesis,or leukocyteendothelial adhe

14、sionLeukocyte depletion/FiltrationSoluble interleukin-1 receptor antagonists,antitumor necrosis factor antibodies,or platelet activation factorleukotriene B4 antagonistsAspirin-triggered lipoxins prevent chemotaxis,adhesion,and transmigration of neutrophils Therapeutic strategies to attenuate I/R in

15、juryControlled,graded reperfusionIschemic preconditioningAspirin-triggered lipoxin analogs Antioxidant:SOD,iron chelating compounds,mannitol,allopurinol,vitamin E,N-acetylcysteineAnticomplement Therapy:anti-C5(h5G1.1-scFv)Calcium antagonistLeukocyte depletion/FiltrationConclusionTreatment of I-R inj

16、ury is also confounded by the fact that inhibition of I-Rassociated inflammation might disrupt protective physiologic responses or result in immunosuppression.timely reperfusion of the ischemic area at risk remains the cornerstone of clinical practice,therapeutic strategies such as ischemic preconditioning,controlled reperfusion,and antioxidant,complement,or neutrophil therapy may significantly prevent or limit I-R injury in humans.Thanks for your attention!