Lung ischemia reperfusion injury (LIRI) is a pathologic process occurring when oxygen supply to the lung has been compromised followed by a period of reperfusion. The disruption of oxygen supply can occur either via limited blood flow or decreased ventilation termed anoxic ischemia and ventilated ischemia, respectively. When reperfusion occurs, blood flow and oxygen are reintroduced to the ischemic lung parenchyma, facilitating a toxic environment through the creation of reactive oxygen species, activation of the immune and coagulation systems, endothelial dysfunction, and apoptotic cell death. This review will focus on the mechanisms of LIRI, the current supportive treatments used, and the many therapies currently under research for prevention and treatment of LIRI.
FrazierAAGalvinJRFranksTJRosado-De-ChristensonML. From the archives of the AFIP: pulmonary vasculature: hypertension and infarction. Radiographics. 2000;20:491-524.
2.
den HengstWAGielisJFLinJYVan SchilPEDe WindtLJMoensAL: Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process. Am J Physiol Heart Circ Physiol. 2010;299:H1283-H1299.
3.
BabikerMAObeidHAAshongEF. Acute reversible pulmonary ischemia. A cause of the acute chest syndrome in sickle cell disease. Clin Pediatr (Phila). 1985;24:716-718.
4.
TempletonAWGarrottoLJ. Acquired extracardiac causes of pulmonary ischemia. Dis Chest. 1967;51:166-171.
5.
ApostolakisEFilosKSKoletsisEDougenisD. Lung dysfunction following cardiopulmonary bypass. J Card Surg. 2010;25:47-55.
6.
GoudarziBMBonvinoS. Critical care issues in lung and heart transplantation. Crit Care Clin. 2003;19:209-231.
7.
EltzschigHKEckleT. Ischemia and reperfusion—from mechanism to translation. Nat Med. 2011;17:1391-1401.
8.
ChenGYNunezG. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10:826-837.
9.
LandWG. Emerging role of innate immunity in organ transplantation: part I: evolution of innate immunity and oxidative allograft injury. Transplant Rev (Orlando). 2012;26:60-72.
10.
CavassaniKAIshiiMWenH, et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med. 2008;205:2609-2621.
KuhlickeJFrickJSMorote-GarciaJCRosenbergerPEltzschigHK. Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PLoS One. 2007;2:e1364.
13.
BenDFYuXYJiGY, et al. TLR4 mediates lung injury and inflammation in intestinal ischemia-reperfusion. J Surg Res. 2012;174:326-333.
14.
HotchkissRSStrasserAMcDunnJESwansonPE. Cell death. N Engl J Med. 2009;361:1570-1583.
15.
LepperPMBalsR. On the edge: targeting Toll-like receptor 2 in ischemia/reperfusion injury. Circ Cardiovasc Interv. 2012;5:146-149.
16.
IyerSSPulskensWPSadlerJJ, et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A. 2008;106:20388-20393.
17.
GrenzAHomannDEltzschigHK. Extracellular adenosine: a safety signal that dampens hypoxia-induced inflammation during ischemia. Antioxid Redox Signal. 2011;15:2221-2234.
18.
KreiselDSugimotoSTietjensJ, et al. Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis. J Clin Invest. 2011;121:265-276.
19.
LieszASuri-PayerEVeltkampC, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15:192-199.
20.
IadecolaCAnratherJ. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17:796-808.
21.
PacherPSzaboC. Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. Am J Pathol. 2008;173:2-13.
22.
WoodKCGladwinMT. The hydrogen highway to reperfusion therapy. Nat Med. 2007;13:673-674.
23.
ChiangCHPaiHILiuSL. Ventilator-induced lung injury (VILI) promotes ischemia/reperfusion lung injury (I/R) and NF-kappaB antibody attenuates both injuries. Resuscitation. 2008;79:147-154.
24.
KohmotoJNakaoAStolzDB, et al. Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant. 2007;7:2279-2290.
25.
WolfPSMerryHEFarivarASMcCourtieASMulliganMS. Stress-activated protein kinase inhibition to ameliorate lung ischemia reperfusion injury. J Thorac Cardiovasc Surg. 2008;135:656-665.
26.
KanzlerHBarratFJHesselEMCoffmanRL. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med. 2007;13:552-559.
27.
ShichitaTSugiyamaYOoboshiH, et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15:946-950.
28.
ElvingtonAAtkinsonCKulikL, et al. Pathogenic natural antibodies propagate cerebral injury following ischemic stroke in mice. J Immunol. 2012;188:1460-1468.
29.
KulikLFlemingSDMoratzC, et al. Pathogenic natural antibodies recognizing annexin IV are required to develop intestinal ischemia-reperfusion injury. J Immunol. 2009;182:5363-5373.
30.
DiepenhorstGMvan GulikTMHackCE. Complement-mediated ischemia-reperfusion injury: lessons learned from animal and clinical studies. Ann Surg. 2009;249:889-899.
31.
RicklinDHajishengallisGYangKLambrisJD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785-797.
32.
ArmstrongPWGrangerCBAdamsPX, et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. JAMA. 2007;297:43-51.
33.
FattouchKBiancoGSpezialeG, et al. Beneficial effects of C1 esterase inhibitor in ST-elevation myocardial infarction in patients who underwent surgical reperfusion: a randomised double-blind study. Eur J Cardiothorac Surg. 2007;32:326-332.
34.
LazarHLBokeschPMvan LentaF, et al. Soluble human complement receptor 1 limits ischemic damage in cardiac surgery patients at high risk requiring cardiopulmonary bypass. Circulation. 2004;110:II274-II279.
35.
MoserMNieswandtBUssarSPozgajovaMFasslerR. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med. 2008;14:325-330.
AtarDPetzelbauerPSchwitterJ, et al. Effect of intravenous FX06 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction results of the F.I.R.E. (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury) trial. J Am Coll Cardiol. 2009;53:720-729.
41.
EltzschigHKCollardCD. Vascular ischaemia and reperfusion injury. Br Med Bull. 2004;70:71-86.
42.
BrighamKL. Role of free radicals in lung injury. Chest. 1986;89:859-863.
43.
de PerrotMLiuMWaddellTKKeshavjeeS. Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med. 2003;167:490-511.
44.
KennedyTPRaoNVHopkinsCPenningtonLTolleyEHoidalJR. Role of reactive oxygen species in reperfusion injury of the rabbit lung. J Clin Invest. 1989;83:1326-1335.
45.
McCordJM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985;312:159-163.
46.
RyrfeldtABannenbergGMoldeusP. Free radicals and lung disease. Br Med Bull. 1993;49:588-603.
47.
OvechkinAVLominadzeDSedorisKCRobinsonTWTyagiSCRobertsAM. Lung ischemia-reperfusion injury: implications of oxidative stress and platelet-arteriolar wall interactions. Arch Physiol Biochem. 2007;113:1-12.
48.
Al-MehdiABZhaoGDodiaC, et al. Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K+. Circ Res. 1998;83:730-737.
49.
AdkinsWKTaylorAE. Role of xanthine oxidase and neutrophils in ischemia-reperfusion injury in rabbit lung. J Appl Physiol. 1990;69:2012-2018.
50.
HendersonLMChappellJBJonesOT. Superoxide generation by the electrogenic NADPH oxidase of human neutrophils is limited by the movement of a compensating charge. Biochem J. 1988;255:285-290.
51.
CrossCEHalliwellBBorishET, et al. Oxygen radicals and human disease. Ann Intern Med. 1987;107:526-545.
52.
AllisonRCKyleJAdkinsWKPrasadVRMcCordJMTaylorAE. Effect of ischemia reperfusion or hypoxia reoxygenation on lung vascular permeability and resistance. J Appl Physiol. 1990;69:597-603.
KinnulaVLSarnestoAHeikkilaLToivonenHMattilaSRaivioKO. Assessment of xanthine oxidase in human lung and lung transplantation. Eur Respir J. 1997;10:676-680.
58.
FisherAB. Reactive oxygen species and cell signaling with lung ischemia. Undersea Hyperb Med. 2004;31:97-103.
59.
ZuluetaJJYuFSHertigIAThannickalVJHassounPM. Release of hydrogen peroxide in response to hypoxia-reoxygenation: role of an NAD(P)H oxidase-like enzyme in endothelial cell plasma membrane. Am J Respir Cell Mol Biol. 1995;12:41-49.
60.
BabiorBM. The NADPH oxidase of endothelial cells. IUBMB Life. 2000;50:267-269.
61.
DoddOJPearseDB. Effect of the NADPH oxidase inhibitor apocynin on ischemia-reperfusion lung injury. Am J Physiol Heart Circ Physiol. 2000;279:H303-H312.
62.
ZhangQMatsuzakiIChatterjeeSFisherAB. Activation of endothelial NADPH oxidase during normoxic lung ischemia is KATP channel dependent. Am J Physiol Lung Cell Mol Physiol. 2005;289:L954-L961.
63.
FisherABAl-MehdiABManevichY. Shear stress and endothelial cell activation. Crit Care Med. 2002;30:S192-S197.
64.
Dodd-oJMWelshLESalazarJD, et al. Effect of NADPH oxidase inhibition on cardiopulmonary bypass-induced lung injury. Am J Physiol Heart Circ Physiol. 2004;287: H927-H936.
65.
HartCM. Nitric oxide in adult lung disease. Chest. 1999;115: 1407-1417.
66.
NaiduBVKrishnadasanBFarivarAS, et al. Early activation of the alveolar macrophage is critical to the development of lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2003;126:200-207.
67.
MooreTMKhimenkoPLWilsonPSTaylorAE. Role of nitric oxide in lung ischemia and reperfusion injury. Am J Physiol. 1996;271:H1970-H1977.
68.
IschiropoulosHAl-MehdiABFisherAB. Reactive species in ischemic rat lung injury: contribution of peroxynitrite. Am J Physiol. 1995;269:L158-L164.
69.
EppingerMJWardPAJonesMLBollingSFDeebGM. Disparate effects of nitric oxide on lung ischemia-reperfusion injury. Ann Thorac Surg. 1995;60:1169-1175.
70.
LeeJCChristieJD. Primary graft dysfunction. Proc Am Thorac Soc. 2009;6:39-46.
71.
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342: 1301-1308.
72.
ShargallYGuentherGAhyaVNArdehaliASinghalAKeshavjeeS. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part VI: treatment. J Heart Lung Transplant. 2005;24:1489-1500.
73.
ArmstrongRAJonesRLWilsonNH. Mechanism of the inhibition of platelet aggregation produced by prostaglandin F2 alpha. Prostaglandins. 1985;29:601-610.
74.
GasparriRIJannisNCFlamengWJLerutTEVan RaemdonckDE. Ischemic preconditioning enhances donor lung preservation in the rabbit. Eur J Cardiothorac Surg. 1999;16:639-646.
75.
FeatherstoneRLChambersDJKellyFJ. Ischemic preconditioning enhances recovery of isolated rat lungs after hypothermic preservation. Ann Thorac Surg. 2000;69: 237-242.
76.
FriedrichISpillnerJLuEX, et al. Ischemic pre-conditioning of 5 minutes but not of 10 minutes improves lung function after warm ischemia in a canine model. J Heart Lung Transplant. 2001;20:985-995.
77.
JavadpourMKellyCJChenGStokesKLeahyABouchier-HayesDJ. Thermotolerance induces heat shock protein 72 expression and protects against ischaemia-reperfusion-induced lung injury. Br J Surg. 1998;85:943-946.
78.
LuhSPKuoPHKuoTF, et al. Effects of thermal preconditioning on the ischemia-reperfusion-induced acute lung injury in minipigs. Shock. 2007;28:615-622.
79.
HirataTFukuseTIshikawaS, et al. “Chemical preconditioning” by 3-nitropropionate reduces ischemia-reperfusion injury in cardiac-arrested rat lungs. Transplantation. 2001;71: 352-359.
80.
SchutteHWitzenrathMMayerKRosseauSSeegerWGrimmingerF. Short-term “preconditioning” with inhaled nitric oxide protects rabbit lungs against ischemia-reperfusion injury. Transplantation. 2001;72:1363-1370.
81.
BenjaminIJMcMillanDR. Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. Circ Res. 1998;83:117-132.
82.
XuanYTTangXLBanerjeeS, et al. Nuclear factor-kappaB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res. 1999;84: 1095-1109.
83.
FukuseTHirataTOmasaMWadaH. Effect of adenosine triphosphate-sensitive potassium channel openers on lung preservation. Am J Respir Crit Care Med. 2002;165: 1511-1515.
84.
NeelyCFKeithIM. A1 adenosine receptor antagonists block ischemia-reperfusion injury of the lung. Am J Physiol. 1995;268:L1036-L1046.
85.
TavareANTsakokT. Does prophylactic inhaled nitric oxide reduce morbidity and mortality after lung transplantation?Interact Cardiovasc Thorac Surg. 2011;13:516-520.
86.
MeadeMOGrantonJTMatte-MartynA, et al. A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. Am J Respir Crit Care Med. 2003;167:1483-1489.
87.
ArdehaliALaksHLevineM, et al. A prospective trial of inhaled nitric oxide in clinical lung transplantation. Transplantation. 2001;72:112-115.
88.
PerrinGRochAMicheletP, et al. Inhaled nitric oxide does not prevent pulmonary edema after lung transplantation measured by lung water content: a randomized clinical study. Chest. 2006;129:1024-1030.
89.
OhsawaIIshikawaMTakahashiK, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688-694.
90.
XieKYuYHuangY, et al. Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and apoptosis. Shock. 2012;37:548-555.
91.
MaoYFZhengXFCaiJM, et al. Hydrogen-rich saline reduces lung injury induced by intestinal ischemia/reperfusion in rats. Biochem Biophys Res Commun. 2009;381:602-605.
92.
HuangCSKawamuraTToyodaYNakaoA. Recent advances in hydrogen research as a therapeutic medical gas. Free Radic Res. 2010;44:971-982.
93.
WagnerFAsfarPCalziaERadermacherPSzaboC. Bench-to-Bedside Review: Hydrogen sulfide—the third gaseous transmitter: applications for critical care. Crit Care. 2009;13:213.
94.
BlackstoneEMorrisonMRothMB. H2S induces a suspended animation-like state in mice. Science. 2005; 308:518.
95.
BlackstoneERothMB. Suspended animation-like state protects mice from lethal hypoxia. Shock. 2007;27:370-372.
96.
RothMBNystulT. Buying time in suspended animation. Sci Am. 2005;292:48-55.
97.
FuZLiuXGengBFangLTangC. Hydrogen sulfide protects rat lung from ischemia-reperfusion injury. Life Sci. 2008;82:1196-1202.
98.
ChinBYJiangGWegielB, et al. Hypoxia-inducible factor 1alpha stabilization by carbon monoxide results in cytoprotective preconditioning. Proc Natl Acad Sci U S A. 2007;104:5109-5114.
99.
RyterSWChoiAM. Therapeutic applications of carbon monoxide in lung disease. Curr Opin Pharmacol. 2006;6:257-262.
100.
MayrFBSpielALeitnerJ, et al. Effects of carbon monoxide inhalation during experimental endotoxemia in humans. Am J Respir Crit Care Med. 2005;171:354-360.
101.
KnudsenLBoxlerLMuhlfeldC, et al. Lung preservation in experimental ischemia/reperfusion injury and lung transplantation: a comparison of natural and synthetic surfactants. J Heart Lung Transplant. 2012;31:85-93.
MuhlfeldCBeckerLBussingerC, et al. Exogenous surfactant in ischemia/reperfusion: effects on endogenous surfactant pools. J Heart Lung Transplant. 2010;29:327-334.
104.
OchsMNenadicIFehrenbachA, et al. Ultrastructural alterations in intraalveolar surfactant subtypes after experimental ischemia and reperfusion. Am J Respir Crit Care Med. 1999;160:718-724.
105.
NovickRJMacDonaldJVeldhuizenRA, et al. Evaluation of surfactant treatment strategies after prolonged graft storage in lung transplantation. Am J Respir Crit Care Med. 2996;154:98-104.
106.
HausenBRohdeRHewittCW, et al. Exogenous surfactant treatment before and after sixteen hours of ischemia in experimental lung transplantation. J Thorac Cardiovasc Surg. 1997;113:1050-1058.
107.
StruberMHirtSWCremerJHarringerWHaverichA. Surfactant replacement in reperfusion injury after clinical lung transplantation. Intensive Care Med. 1999;25:862-864.
108.
KermeenFDMcNeilKDFraserJF, et al. Resolution of severe ischemia-reperfusion injury post-lung transplantation after administration of endobronchial surfactant. J Heart Lung Transplant. 2007;26:850-856.
109.
van PutteBPCobelensPMvanderKaaijN, et al. Exogenous surfactant attenuation of ischemia-reperfusion injury in the lung through alteration of inflammatory and apoptotic factors. J Thorac Cardiovasc Surg. 2009;137:824-828.
110.
de PerrotMFischerSLiuM, et al. Prostaglandin E1 protects lung transplants from ischemia-reperfusion injury: a shift from pro- to anti-inflammatory cytokines. Transplantation. 2001;72:1505-1512.
111.
AoeMTrachiotisGDOkabayashiK, et al. Administration of prostaglandin E1 after lung transplantation improves early graft function. Ann Thorac Surg. 1994;58:655-661.
112.
Della RoccaGCocciaCPompeiLCostaMGDi MarcoPPietropaoliP: Inhaled aerosolized prostaglandin E1, pulmonary hemodynamics, and oxygenation during lung transplantation. Minerva Anestesiol. 2008;74:627-633.
113.
LockingerASchutteHWalmrathDSeegerWGrimmingerF. Protection against gas exchange abnormalities by pre-aerosolized PGE1, iloprost and nitroprusside in lung ischemia-reperfusion. Transplantation. 2001;71:185-193.
114.
ThomSR. Hyperbaric oxygen: its mechanisms and efficacy. Plast Reconstr Surg. 2011;127(suppl 1):131S-141S.
115.
TibblesPMEdelsbergJS. Hyperbaric-oxygen therapy. N Engl J Med. 1996;334:1642-1648.
116.
BurasJ. Basic mechanisms of hyperbaric oxygen in the treatment of ischemia-reperfusion injury. Int Anesthesiol Clin. 2000;38:91-109.
117.
ZamboniWAWongHPStephensonLL. Effect of hyperbaric oxygen on neutrophil concentration and pulmonary sequestration in reperfusion injury. Arch Surg. 1996;131:756-760.
118.
KeshavjeeSDavisRDZamoraMRde PerrotMPattersonGA. A randomized, placebo-controlled trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human beings. J Thorac Cardiovasc Surg. 2005;129:423-428.
119.
KrishnadasanBNaiduBVByrneKFragaCVerrierEDMulliganMS. The role of proinflammatory cytokines in lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2003;125:261-272.
120.
BogoyevitchMAArthurPG. Inhibitors of c-Jun N-terminal kinases: JuNK no more?Biochim Biophys Acta. 2008;1784: 76-93.
121.
IshiiMSuzukiYTakeshitaK, et al. Inhibition of c-Jun NH2-terminal kinase activity improves ischemia/reperfusion injury in rat lungs. J Immunol. 2004;172: 2569-2577.
122.
ChimaRSHakePWPirainoGMangeshkarPDenenbergAZingarelliB. Ciglitazone ameliorates lung inflammation by modulating the inhibitor kappaB protein kinase/nuclear factor-kappaB pathway after hemorrhagic shock. Crit Care Med. 2008;36:2849-2857.
123.
ItoKShimadaJKatoD, et al. Protective effects of preischemic treatment with pioglitazone, a peroxisome proliferator-activated receptor-gamma ligand, on lung ischemia-reperfusion injury in rats. Eur J Cardiothorac Surg. 2004;25:530-536.
124.
GeudensNWuytsWARegaFR, et al. N-acetyl cysteine attenuates the inflammatory response in warm ischemic pig lungs. J Surg Res. 2008;146:177-183.
125.
InciIZhaiWArniSHillingerSVogtPWederW. N-acetylcysteine attenuates lung ischemia-reperfusion injury after lung transplantation. Ann Thorac Surg. 2007;84: 240-246.
