Lung Reperfusion Injury After TransplantationReferencesnIschemia-Reperfusion-induced Lung Injury Am J Respir Crit Care Med,2003 nReduced Neutrophil Infiltration Protects Against Lung Reperfusion Injury After Transplantation Ann Thorac Surg 1999ContentsnIntroductionnDonor lung assessmentnEffect of cold ischemic storagenOxidative stressnSodium pump inactivationnIntracellular calcium overloadnIron releasenCell deathnConsequences of ischemia significantly correlate w/ primary graft failure after reperfusion Donor Lung AssessmentDonor Lung AssessmentEffect of Cold Ischemic StoragenOxidative stressnSodium pump inactivationnIntracellular calcium overloadnIron releasenCell deathOxidative StressnFormation of ROS: superoxide anion、hydrogen peroxide、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 Oxidative StressSodium Pump InactivationnSodium (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 preservation solution (low K, high Na)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 xanthine oxidase, potentiate the damaging effect of free radicals on mitochondrianProtective effect of verapamil, nifedipine and diltiazemIron ReleasenEssential element, highly toxic under pathophysiologic or stress conditionsnFenton reaction: reactive hydroxyl radicalnIncreased injury observed in iron- supplemented tissue nProtection by iron chelator, deferoxamineIron ReleaseConsequences of Ischemia 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 injury 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 moleculesRelease of Proinflammatory MediatorsnComplementnActivation may lead to cellular injurynSmooth m. contraction, increased vascular permeability, degranulation of phagocytic cells, mast cells, and basophilsnComplement receptor-1: natural complement antagonist; inhibiting C3 3 isoformsnEndothelin-1: the production of cytokines, retention of neutrophils in the lungnEndothelin-1 receptor antagonist: lung function improvedLeukocyte ActivationnBiphasic patternnEarly phase: depends primarily on donor characteristicsnDelayed phase: occurs over the ensuing 24 hrs, depends primarily on recipient factorsStrategies to Prevent Lung DysfunctionnMethod of lung preservation and reperfusionnClinical evidence in prevention and treatment of lung reperfusion injurynFuture StrategiesMethod 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 transplantation currently Composition of Preservation SolutionsMethod 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 remains unproven in clinical lung transplantation Gene TherapynTransfection of the donor lung through transtracheal route using a 2nd-generation adenoviral vectornTransfection of the gene coding for anti- inflammatory 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 possibleTake Home MessagenDonor lung assessmentnEffect of cold ischemic storagenOxidative stressnSodium pump inactivationnIntracellular 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 ava