缺血再灌注损伤IschemiaReperfusion injury.ppt
Ischemia-Reperfusion injury,Ischemia,Anesthesiologist:MI,peripheral vascular insufficiency,stroke,and hypovolemic shockRestoration of blood flow to an ischemic organ is essential to prevent irreversible cellular injuryReperfusion may augment tissue injury,Ischemia-Reperfusion,Thrombolytic 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 mortality in tertiary referral ICU,Cellular change during Ischemia,Altered membrane potentialAltered ion distribution(+intracellular Ca/Na)Cellular swellingCytoskeletal disorgnizationIncreased hypoxanthineDecreased ATPDecreased phosphocreatinine Cellular acidosis,Cellular Effects of Ischemia,Decreased ATPIntracellular accumulation of hypoxanthineToxic reactive oxygen species(ROS)during reperfusion,Ischemia at Endothelium,Express certain proinflammatory gene products(leukocyte adhesion molecules,cytokines)bioactive agents(endothelin,thromboxane A2)Repressing other“protective”gene products(constitutive nitric oxide synthase,thrombomodulin)and bioactive agents(prostacyclin,nitric oxide).,Role of Reactive Oxygen Species,Including(O2),(OH),(HOCl),(H2O2),and nitric oxidederived peroxynitriteDirectly damage cellular membranes by lipid peroxidation.Stimulate leukocyte activation and chemotaxis by activating plasma membrane phospholipase A2 to form arachidonic acid(thromboxane A2 and leukotriene B4)Increase leukocyte activation,chemotaxis,and leukocyteendothelial adherence after I-R,Role of Complement,I/R results in complement activation and the formation of several proinflammatory mediators that alter 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 Leukocytes,I/R results in leukocyte activation,chemotaxis,leukocyteendothelial cell adhesion,and transmigrationmechanical obstructionactivated leukocytes release toxic ROS,proteases,and elastases,resulting in increased microvascular permeability,edema,thrombosis,and parenchymal cell death,Manifestations of I/R injury,Vascular Injury and the“No Reflow”PhenomenonMyocardial StunningReperfusion Arrhythmias(VT,VF,idioV)CNS/GI I/R injuryMultiorgan Dysfunction Syndromerisk factors:hypercholesterolemia,hypertension,or diabetes and so on,Therapeutic Strategies To Prevent I-R Injury,Ischemic PreconditioningAntioxidant TherapyAnticomplement TherapyAntileukocyte Therapy,Ischemic Preconditioning,Exposure 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 adherence,Antioxidant Therapy,superoxide 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 transplantationequivocal,Anticomplement Therapy,C3 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 activation,myocardial injury,blood loss,and cognitive dysfunction in humans undergoing coronary artery bypass graft surgery with cardiopulmonary bypass,Antileukocyte Therapy,inhibition of inflammatory mediator release or receptor engagement,leukocyte adhesion molecule synthesis,or leukocyteendothelial adhesionLeukocyte 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 injury,Controlled,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/Filtration,Conclusion,Treatment of I-R injury 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!,
