缺血再灌注损伤 (2)ppt课件

1、Ischemia-Reperfusion injuryIschemia 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 injuryIschemia-Reperfusion Thrombolytic therap

2、y, 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 ICUCellular change during Ischemia Altered mem

3、brane potential Altered ion distribution (+ intracellular Ca/Na) Cellular swelling Cytoskeletal disorgnization Increased hypoxanthine Decreased ATP Decreased phosphocreatinine Cellular acidosisCellular Effects of Ischemia Decreased ATP Intracellular accumulation of hypoxanthine Toxic reactive oxygen

4、 species (ROS) during reperfusionIschemia 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

5、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 A2 to f

6、orm arachidonic acid (thromboxane A2 and leukotriene B4) Increase leukocyte activation, chemotaxis, and leukocyteendothelial adherence after I-RRole of Complement I/R results in complement activation and the formation of several proinflammatory mediators that alter vascular homeostasis C3a, C5a, iC3

7、b, 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 mechanical ob

8、struction 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 Arrhythmias (VT,VF,i

9、dioV) 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 TherapyIschemic Preconditioning Exposure of

10、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 inhibiting leukocyte

11、 adherenceAntioxidant 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 SOD in cadave

12、ric renal transplantation equivocalAnticomplement 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 complement activat

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

14、 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 neutrophils Therapeu

15、tic 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 antagonist Leukocyte depletion/ FiltrationConclusion 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 th