Lung transplantation remains the only curative treatment for end-stage pulmonary disease. Lung ischemia–reperfusion injury (IRI) is a major contributor to primary allograft dysfunction and donor organ nonutilization. The alveolar macrophage is a key inflammatory mediator in IRI. Ex vivo lung perfusion (EVLP) has been investigated to rehabilitate lungs before transplant but has failed to provide significant improvements after IRI. We hypothesized that liquid ventilation (LV) could be utilized for ex vivo lung reconditioning in a rat IRI model. We compared EVLP with LV in an isolated ex vivo rat lung with an aqueous ventilant using quantitative physiological and immunological parameters. We observed improved physiological parameters and mechanical clearance of alveolar macrophages and cytokines halting the propagation of the inflammatory response in IRI. While the wide applicability to large animal or human transplantation have yet to be explored, these findings represent a method for lung reconditioning in the setting of significant IRI that could widen the lung organ donation pool and limit morbidity and mortality associated with ischemia-induced primary graft dysfunction.
Impact statement
Lung transplantation remains the only curative treatment for end-stage pulmonary disease. Ischemia–reperfusion injury (IRI) is a major contributor to primary allograft dysfunction and donor organ nonutilization. In this study, we report a novel method for ex vivo lung reconditioning after significant ischemic injury with improved, clinically relevant physiological parameters using liquid ventilation (LV). These improvements may result from mechanical clearance of alveolar macrophages and inflammatory cytokines, which blunt the propagation of IRI in addition to minimizing mechanical stress during the early reperfusion period. LV is a potential method for lung reconditioning that could widen the lung organ donation pool and make a positive clinical impact on patient outcomes.
Get full access to this article
View all access options for this article.
References
1.
YusenRD, EdwardsLB, DipchandAI, et al.The Registry of the International Society for Heart and Lung Transplantation: Thirty-third adult lung and heart-lung transplant report-2016; Focus theme: Primary diagnostic indications for transplant. J Heart Lung Transplant, 2016; 35(10):1170–1184; doi: 10.1016/j.healun.2016.09.001.
2.
DivithotawelaC, CypelM, MartinuT, et al.Long-term outcomes of lung transplant with ex vivo lung perfusion. JAMA Surg, 2019; 154(12):1143–1150; doi: 10.1001/jamasurg.2019.4079.
3.
CypelM, YeungJC, LiuM, et al.Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med, 2011; 364(15):1431–1440; doi: 10.1056/NEJMoa1014597.
4.
SteenS, SjobergT, PierreL, et al.Transplantation of lungs from a non-heart-beating donor. Lancet, 2001; 357(9259):825–829; doi: 10.1016/S0140-6736(00)04195-7.
5.
YeungJC, CypelM, MachucaTN, et al.Physiologic assessment of the ex vivo donor lung for transplantation. J Heart Lung Transplant, 2012; 31(10):1120–1126; doi: 10.1016/j.healun.2012.08.016.
6.
CypelM, LiuM, RubachaM, et al.Functional repair of human donor lungs by IL-10 gene therapy. Sci Transl Med, 2009; 1(4):4ra9; doi: 10.1126/scitranslmed.3000266.
7.
GalassoM, FeldJJ, WatanabeY, et al.Inactivating hepatitis C virus in donor lungs using light therapies during normothermic ex vivo lung perfusion. Nat Commun, 2019; 10(1):481; doi: 10.1038/s41467-018-08261-z.
8.
NelsonK, BobbaC, GhadialiS, et al.Animal models of ex vivo lung perfusion as a platform for transplantation research. World J Exp Med, 2014; 4(2):7–15; doi: 10.5493/wjem.v4.i2.7.
9.
KrishnadasanB, NaiduBV, ByrneK, et al.The role of proinflammatory cytokines in lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg, 2003; 125(2):261–272; doi: 10.1067/mtc.2003.16.
10.
NaiduBV, KrishnadasanB, FarivarAS, et al.Early activation of the alveolar macrophage is critical to the development of lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg, 2003; 126(1):200–207; doi: 10.1016/S0022-5223(03)00390-8.
11.
ChaoJ, WoodJG, BlancoVG, et al.The systemic inflammation of alveolar hypoxia is initiated by alveolar macrophage-borne mediator(s). Am J Respir Cell Mol Biol, 2009; 41(5):573–582; doi: 10.1165/rcmb.2008-0417OC.
12.
EppingerMJ, JonesML, DeebGM, et al.Pattern of injury and the role of neutrophils in reperfusion injury of rat lung. J Surg Res, 1995; 58(6):713–718; doi: 10.1006/jsre.1995.1112.
13.
Van RooijenN, SandersA. Liposome mediated depletion of macrophages: Mechanism of action, preparation of liposomes and applications. J Immunol Methods, 1994; 174(1–2):83–93; doi: 10.1016/0022-1759(94)90012-4.
14.
DangSC, JiangDL, ChenM, et al.Clodronate-containing liposomes attenuate lung injury in rats with severe acute pancreatitis. J Zhejiang Univ Sci B, 2010; 11(11):828–835; doi: 10.1631/jzus.B1000044.
15.
van RooijenN, HendrikxE. Liposomes for specific depletion of macrophages from organs and tissues. Methods Mol Biol, 2010; 605:189–203; doi: 10.1007/978-1-60327-360-2_13.
TawficQA, KausalyaR. Liquid ventilation. Oman Med J, 2011; 26(1):4–9; doi: 10.5001/omj.2011.02.
18.
GreenspanJS, WolfsonMR, RubensteinSD, et al.Liquid ventilation of human preterm neonates. J Pediatr, 1990; 117(1 Pt 1):106–111; doi: 10.1016/S0022-3476(05)82457-6.
19.
ClarkLCJr., GollanF. Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure. Science, 1966; 152(3730):1755–1756; doi: 10.1126/science.152.3730.1755.
20.
GaugerPG, PranikoffT, SchreinerRJ, et al.Initial experience with partial liquid ventilation in pediatric patients with the acute respiratory distress syndrome. Crit Care Med, 1996; 24(1):16–22; doi: 10.1097/00003246-199601000-00006.
21.
HirschlRB, PranikoffT, GaugerP, et al.Liquid ventilation in adults, children, and full-term neonates. Lancet, 1995; 346(8984):1201–1202; doi: 10.1016/s0140-6736(95)92903-7.
22.
HirschlRB, ParentA, TooleyR, et al.Liquid ventilation improves pulmonary function, gas exchange, and lung injury in a model of respiratory failure. Ann Surg, 1995; 221(1):79–88; doi: 10.1097/00000658-199501000-00010.
23.
KohlhauerM, BerdeauxA, KerberRE, et al.Liquid ventilation for the induction of ultrafast hypothermia in resuscitation sciences: A review. Ther Hypothermia Temp Manag, 2016; 6(2):63–70; doi: 10.1089/ther.2015.0024.
24.
NakajimaD, LiuM, OhsumiA, et al.Lung lavage and surfactant replacement during ex vivo lung perfusion for treatment of gastric acid aspiration-induced donor lung injury. J Heart Lung Transplant, 2017; 36(5):577–585; doi: 10.1016/j.healun.2016.11.010.
25.
LoeheF, MuellerC, BittmannI, et al.Influence of long-term preservation with endobronchially administered perfluorodecalin on pulmonary graft function. Transplantation, 2000; 70(10):1417–1424; doi: 10.1097/00007890-200011270-00004.
26.
LowensteinE, LincolnJC, ModellJH, et al.Preservation of excised canine lungs by ventilation with liquid fluorocarbon. Fed Proc, 1970; 29(5):1775–1777.
27.
YoshidaS, SekineY, ShinozukaN, et al.The efficacy of partial liquid ventilation in lung protection during hypotension and cardiac arrest: Preliminary study of lung transplantation using non-heart-beating donors. J Heart Lung Transplant, 2005; 24(6):723–729; doi: 10.1016/j.healun.2004.03.019.
28.
AndradeCF, MartinsLK, ToniettoTA, et al.Partial liquid ventilation with perfluorodecalin following unilateral canine lung allotransplantation in non-heart-beating donors. J Heart Lung Transplant, 2004; 23(2):242–251; doi: 10.1016/S1053-2498(03)00105-0.
29.
ItanoH, AoeM, IchibaS, et al.Partial liquid ventilation for acute allograft dysfunction after canine lung transplantation. Ann Thorac Surg, 1999; 67(2):332–339; doi: 10.1016/s0003-4975(98)01136-9.
30.
GilpinSE, GuyetteJP, GonzalezG, et al.Perfusion decellularization of human and porcine lungs: Bringing the matrix to clinical scale. J Heart Lung Transplant, 2014; 33(3):298–308; doi: 10.1016/j.healun.2013.10.030.
31.
OttHC, ClippingerB, ConradC, et al.Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med, 2010; 16(8):927–933; doi: 10.1038/nm.2193.
32.
CypelM, RubachaM, YeungJ, et al.Normothermic ex vivo perfusion prevents lung injury compared to extended cold preservation for transplantation. Am J Transplant, 2009; 9(10):2262–2269; doi: 10.1111/j.1600–6143.2009.02775.x.
33.
BassaniGA, LonatiC, BrambillaD, et al.Ex pvivo lung erfusion in the rat: Detailed procedure and videos. PLoS One, 2016; 11(12):e0167898; doi: 10.1371/journal.pone.0167898.
34.
ValenzaF, SibillaS, PorroGA, et al.An improved in vivo rat model for the study of mechanical ventilatory support effects on organs distal to the lung. Crit Care Med, 2000; 28(11):3697–3704; doi: 10.1097/00003246-200011000-00027.
35.
DinarelloCA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood, 2011; 117(14):3720–3732; doi: 10.1182/blood-2010-07-273417.
36.
ChangDM, HsuK, DingYA, et al.Interleukin-1 in ischemia-reperfusion acute lung injury. Am J Respir Crit Care Med, 1997; 156(4 Pt 1):1230–1234; doi: 10.1164/ajrccm.156.4.9702095.
37.
HoyerFF, NaxerovaK, SchlossMJ, et al.Tissue-specific macrophage responses to remote injury impact the outcome of subsequent local immune challenge. Immunity, 2019; 51(5):899–914 e897; doi: 10.1016/j.immuni.2019.10.010.
38.
CarrMW, RothSJ, LutherE, et al.Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A, 1994; 91(9):3652–3656; doi: 10.1073/pnas.91.9.3652.
39.
ChiuS, BharatA. Role of monocytes and macrophages in regulating immune response following lung transplantation. Curr Opin Organ Transplant, 2016; 21(3):239–245; doi: 10.1097/MOT.0000000000000313.
