1、肺再灌注损伤肺再灌注损伤ReferencesnIschemia-Reperfusion-induced Lung Injury Am J Respir Crit Care Med,2003 nReduced Neutrophil Infiltration Protects Against Lung Reperfusion Injury After Transplantation Ann Thorac Surg 19992肺再灌注损伤ContentsnIntroductionnDonor lung assessmentnEffect of cold ischemic storagenOxidat
2、ive stressnSodium pump inactivationnIntracellular calcium overloadnIron releasenCell deathnConsequences of ischemia&reperfusionnUpregulation of molecules on cell surface membranenRelease of proinflammatory mediatorsnLeukocyte activationnStrategies to prevent lung dysfunctionnMethod of lung preservat
3、ion and reperfusionnClinical evidence in prevention and treatment of lung reperfusion injurynFuture StrategiesnTake home message3肺再灌注损伤IntroductionnNon-specific alveolar damage,lung edema,and hypoxemia occurring within 72 hours after lung transplantationnRemains a significant cause of morbidity and
4、mortality after lung transplantation4肺再灌注损伤Donor Lung AssessmentnParameters:donor hx,ABG,CXR,bronchoscopy findings,PE of the lungnStrict contraindications：bil.infiltrates on CXR,persistent pus at bronchoscopy,signs of bronchaspirationnBrain stem death:upregulated IL-8;significantly correlate w/prima
5、ry graft failure after reperfusion 5肺再灌注损伤Donor Lung Assessment6肺再灌注损伤Donor Lung Assessment7肺再灌注损伤Effect of Cold Ischemic StoragenOxidative stressnSodium pump inactivationnIntracellular calcium overloadnIron releasenCell death8肺再灌注损伤Oxidative StressnFormation of ROS:superoxide anion、hydrogen peroxid
6、e、hydroxyl radical nCell injury produced by lipid peroxidationnIschemia-reperfusionanoxia-reoxygenation in most organ transplantationnLung to be considered differentlynEndothelium:one of the predominant sources of oxidants during nonhypoxic lung ischemia 9肺再灌注损伤Oxidative Stress10肺再灌注损伤Sodium Pump In
7、activationnSodium(Na/K-ATPase)pump:important to preserve proper intracellular electrolyte conc.and to maintain adequate clearance of alveolar fluidnHypothermic storage results in loss of function,then cell swellingnPreservation at 10 superior than at 4nResume better if preserved w/extracellular-type
8、 preservation solution(low K,high Na)11肺再灌注损伤Intracellular Calcium OverloadnHypothermic storage alters calcium metabolism by release of calcium from intracellular depots and by pathologic influx through the plasma membranenElevated cytosolic Ca enhance the conversion of xanthine dehydrogenase to xan
9、thine oxidase,potentiate the damaging effect of free radicals on mitochondrianProtective effect of verapamil,nifedipine and diltiazem12肺再灌注损伤Iron ReleasenEssential element,highly toxic under pathophysiologic or stress conditionsnFenton reaction:reactive hydroxyl radicalnIncreased injury observed in
10、iron-supplemented tissue nProtection by iron chelator,deferoxamine13肺再灌注损伤Iron Release14肺再灌注损伤Consequences of Ischemia&ReperfusionnUpregulation of molecules on cell surface membranenRelease of proinflammatory mediatorsnLeukocyte activation15肺再灌注损伤Upregulation of Molecules on Cell Surface MembranenAd
11、hesion moleculesnSelectins、Ig superfamily、integrinsnUpregulated during ischemia,blockade of adhesion molecules while reperfusion can reduce reperfusion injurynProthrombotic&antifibinolytic factors nHypoxia develop procoagulant properties,contribute to microvascular thrombosis、impede return of blood
12、flow after reperfusion16肺再灌注损伤Release of Proinflammatory MediatorsnCytokinesnIL-8:rapidly increased after reperfusion;negatively correlated w/lung functionnIL-10:age of donor inversely correlated w/;anti-inflammatory cytokine;lungs from older donor might be more susceptible to ischemia-reperfusion i
13、njury nLipidsnPhospholipase A2,induces the production of platelet-activating factor,an potent mediator of inflammation,which activates leukocytes,stimulates platelet aggregation,induces the release of cytokines and expression of cell adhesion molecules17肺再灌注损伤Leukocyte ActivationnBiphasic patternnEa
14、rly phase:depends primarily on donor characteristicsnDelayed phase:occurs over the ensuing 24 hrs,depends primarily on recipient factors19肺再灌注损伤Strategies to Prevent Lung DysfunctionnMethod of lung preservation and reperfusionnClinical evidence in prevention and treatment of lung reperfusion injuryn
15、Future Strategies20肺再灌注损伤Method of Lung Preservation and ReperfusionnLung preservation solutionnIntracellular-type:Euro-Collins、University of WinsconsinnExtracellular-type:LPD、CelsiornLPD the only specifically developed for lung preservationnLPD-glucose:the preservation solution of choice for lung t
16、ransplantation currently 21肺再灌注损伤Composition of Preservation Solutions22肺再灌注损伤Method of Lung Preservation and ReperfusionnVolume,pressure,and temperature of flush solutionsnHigh perfusate vol.given at high flow rate(60 ml/kg given in 4 min):better cooling of lungs&better lung function after reperfus
17、ionnFlushing pressure of 10 to 15 mmHg associated w/complete flushing of the pulmonary vascular beds,and better lung function after reperfusionnHypothermic recommended 23肺再灌注损伤Method of Lung Preservation and ReperfusionnInflation,oxygenation,and storage temperaturenPreservation improved when inflate
18、d w/O2nExpansion w/O2 during ischemic period:nMaintain some aerobic metabolismnPreserves integrity of surfactantnPreserves epithelial fluid transportnInflation during storage should be limited to 50%of total lung capacity to avoid barotrauma 24肺再灌注损伤Clinical Evidence in Prevention and Treatment of L
19、ung Reperfusion InjurynNitric OxidenDecreased after ischemia and reperfusionnInhaled NO clinically useful to treat ischemia-reperfusion injury nThe role in preventing ischemia-reperfusion injury remains controversial nProstaglandinsnPGE1:vasodilator properties,better distribution of preservation sol
20、ution25肺再灌注损伤Clinical Evidence in Prevention and Treatment of Lung Reperfusion InjurynComplement inhibitionnSoluble complement receptor-1:14/29 v.s 6/30 nAntagonist of platelet-activating factornBetter alveolar-arterial O2 gradient and CXRnEncourage larger multi-center trials26肺再灌注损伤Clinical Evidenc
21、e in Prevention and Treatment of Lung Reperfusion InjurynSurfactant therapynSurfactant dysfunction occurs during ischemia-reperfusion injurynExogenous surfactant therapy improve lung function,enhance immediate recovery27肺再灌注损伤Future StrategiesnHeme oxygenase pathwaynPreconditioningnGene therapy28肺再灌
22、注损伤Heme Oxygenase PathwaynHeme oxygenase:catalyze the conversion of heme into biliverdin,CO,and free ironnHeme oxygenase-1 provide potent cytoprotective effects nHeme oxygenase-1 deficient mice and humans exhibit increased susceptibility to oxidative stress nFuture studies required 29肺再灌注损伤Precondit
23、ioningnTissues exposed to one insult can develop tolerance to a subsequent injurynBiological adaptationnShort periods of ischemia(ischemic preconditioning)、increased temperature(hyperthermic preconditioning)、administration of pharmacologic agents(chemical preconditioning)nMechanism not well understo
24、odnIschemic preconditioning:effective clinically in hepatic resection、CABG;remains unproven in clinical lung transplantation 30肺再灌注损伤Gene TherapynTransfection of the donor lung through transtracheal route using a 2nd-generation adenoviral vectornTransfection of the gene coding for anti-inflammatory
25、cytokine,human IL-10,reduced ischemia-reperfusion injury,improves lung function in a rat single lung transplant modelnHuman lung protection by gene therapy may soon be possible31肺再灌注损伤Take Home MessagenDonor lung assessmentnEffect of cold ischemic storagenOxidative stressnSodium pump inactivationnIn
26、tracellular calcium overloadnIron releasenCell deathnConsequences of ischemia&reperfusionnUp-regulation of molecules on cell surface membranenRelease of pro-inflammatory mediatorsnLeukocyte activationnStrategies to prevent lung dysfunctionnMethod of lung preservation and reperfusionnClinical evidence in prevention and treatment of lung reperfusion injurynFuture StrategiesnOne of the major challenges will be to improve the number of donor lungs available for transplantation 32肺再灌注损伤Thanks for Your Attention33肺再灌注损伤
