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1、Ischemia-Reperfusion injury,Ischemia,Anesthesiologist: MI, peripheral vascular insufficiency, stroke, and hypovolemic shock Restoration of blood flow to an ischemic organ is essential to prevent irreversible cellular injury Reperfusion may augment tissue injury,Ischemia-Reperfusion,Thrombolytic ther
2、apy, organ transplantation, coronary angioplasty, aortic cross-clamping, or cardiopulmonary bypass Severe: 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
3、membrane potential Altered ion distribution (+ intracellular Ca/Na) Cellular swelling Cytoskeletal disorgnization Increased hypoxanthine Decreased ATP Decreased phosphocreatinine Cellular acidosis,Cellular Effects of Ischemia,Decreased ATP Intracellular accumulation of hypoxanthine Toxic reactive ox
4、ygen 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 bioa
5、ctive agents ( prostacyclin, nitric oxide).,Role of Reactive Oxygen Species,Including (O2), (OH), (HOCl), (H2O2), and nitric oxidederived peroxynitrite Directly damage cellular membranes by lipid peroxidation. Stimulate leukocyte activation and chemotaxis by activating plasma membrane phospholipase
6、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 homeostasis C3a,
7、C5a, iC3b, C5b9 Most potent is C5a complement 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 transmigration mech
8、anical obstruction activated 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” Phenomenon Myocardial Stunning Reperfusion Arrhythmia
9、s (VT,VF,idioV) CNS /GI I/R injury Multiorgan Dysfunction Syndrome risk factors: hypercholesterolemia, hypertension, or diabetes and so on,Therapeutic Strategies To Prevent I-R Injury,Ischemic Preconditioning Antioxidant Therapy Anticomplement Therapy Antileukocyte Therapy,Ischemic Preconditioning,E
10、xposure of tissues to brief periods of ischemia protects them from the harmful effects of prolonged I-R coronary artery bypass grafting reduce liver injury undergoing hepatic resection Increases cellular adenosine production and confer protection by augmenting cellular energy stores and/or inhibitin
11、g leukocyte adherence,Antioxidant Therapy,superoxide dismutase, catalase, mannitol, allopurinol, vitamin E, N-acetylcysteine, iron chelating compounds, angiotensin-converting enzyme inhibitors, or calcium channel antagonists human recombinant superoxide dismutase in patients with hemorrhagic shock S
12、OD in cadaveric renal transplantation equivocal,Anticomplement Therapy,C3 convertase inhibitor Soluble 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 comp
13、lement 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 molecul
14、e synthesis, or leukocyteendothelial adhesion Leukocyte depletion/ Filtration Soluble interleukin-1 receptor antagonists, antitumor necrosis factor antibodies, or platelet activation factorleukotriene B4 antagonists Aspirin-triggered lipoxins prevent chemotaxis, adhesion, and transmigration of neutr
15、ophils,Therapeutic strategies to attenuate I/R injury,Controlled, graded reperfusion Ischemic preconditioning Aspirin-triggered lipoxin analogs Antioxidant: SOD, iron chelating compounds, mannitol, allopurinol, vitamin E, N-acetylcysteine Anticomplement Therapy: anti-C5(h5G1.1-scFv) Calcium antagoni
16、st Leukocyte 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!,