Advertisement

Physiologic and Epigenetic Changes with Pulmonary Vascular Injury After Lung Transplantation

  • Steven Kenneth HuangEmail author
  • Roberto G. Carbone
  • Giovanni Bottino
Chapter

Abstract

Despite advances in donor procurement, storage, and surgical reimplantation techniques, the development of ischemia-reperfusion injury in the first 48–72 h after transplantation remains a significant cause of morbidity and mortality. With more severe forms of injury, primary graft dysfunction can occur. Risk factors for vascular injury include the condition of the donor, duration of cold ischemia time, and factors associated with the recipient and management posttransplantation. The pathophysiology of ischemia-reperfusion injury is complex and involves the dysregulation of energy metabolism and accompanying apoptosis, oxidative stress with reactive oxygen species, and endothelial barrier dysfunction. The release of cytokines and bioactive lipid mediators also plays an important role in the process. Further recruitment of neutrophils and T cells contribute to further damage. Although evidence for epigenetic changes occurring after reperfusion injury is sparse, the physiologic alterations after transplantation provides an environment for epigenetic changes to occur in a fashion similar to that observed in many other forms of lung disease such as pulmonary fibrosis, asthma, and chronic obstructive lung disease. Strategies to limit ischemia-reperfusion include use of formulated preservation solutions, limitation of cold ischemia time, and use of ex vivo lung perfusion strategies. Although treatment remains largely supportive, therapies that target certain pathophysiologic pathways have achieved particular interest.

Keywords

Ischemia-reperfusion injury Primary graft dysfunction Reimplantation injury Bronchiolitis obliterans Ex vivo lung perfusion Reactive oxygen species Oxidative stress Epigenetics DNA methylation Histone modification 

Abbreviations

ARDS

Acute respiratory distress syndrome

BOS

Bronchiolitis obliterans syndrome

COPD

Chronic obstructive pulmonary disease

DNMT

DNA methyltransferase

ECMO

Extracorporeal membrane oxygenation

EVLP

Ex vivo lung perfusion

HIF

Hypoxia-inducible factor

IFN

Interferon

IL

Interleukin

miRNA

MicroRNA

NET

Neutrophil extracellular trap

NO

Nitric oxide

PAF

Platelet-activating factor

PGD

Primary graft dysfunction

ROS

Reactive oxygen species

TET

Ten-eleven translocation

TLR

Toll-like receptor

TNF

Tumor necrosis factor

References

  1. 1.
    Christie JD, Sager JS, Kimmel SE, Ahya VN, Gaughan C, Blumenthal NP, Kotloff RM. Impact of primary graft failure on outcomes following lung transplantation. Chest. 2005;127:161–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Arcasoy SM, Fisher A, Hachem RR, Scavuzzo M, Ware LB, ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part V: predictors and outcomes. J Heart Lung Transplant. 2005;24:1483–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Christie JD, Carby M, Bag R, Corris P, Hertz M, Weill D, ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2005;24:1454–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Lee JC, Christie JD. Primary graft dysfunction. Proc Am Thorac Soc. 2009;6:39–46.PubMedCrossRefGoogle Scholar
  5. 5.
    Daud SA, Yusen RD, Meyers BF, Chakinala MM, Walter MJ, Aloush AA, Patterson GA, Trulock EP, Hachem RR. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2007;75:507–13.CrossRefGoogle Scholar
  6. 6.
    de Perrot M, Bonser RS, Dark J, Kelly RF, McGiffin D, Menza R, Pajaro O, Schueler S, Verleden GM, ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part III: donor-related risk factors and markers. J Heart Lung Transplant. 2005;24:1460–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Whitson BA, Nath DS, Johnson AC, Walker AR, Prekker ME, Radosevich DM, Herrington CS, Dahlberg PS. Risk factors for primary graft dysfunction after lung transplantation. J Thorac Cardiovasc Surg. 2006;131:73–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Christie JD, Kotloff RM, Pochettino A, Arcasoy SM, Rosengard BR, Landis JR, Kimmel SE. Clinical risk factors for primary graft failure following lung transplantation. Chest. 2003;124:1232–41.PubMedCrossRefGoogle Scholar
  9. 9.
    Oto T, Excell L, Griffiths AP, Levvey BJ, Snell GI. The implications of pulmonary embolism in a multiorgan donor for subsequent pulmonary, renal, and cardiac transplantation. J Heart Lung Transplant. 2008;27:78–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Diamond JM, Lee JC, Kawut SM, Shah RJ, Localio AR, Bellamy SL, Lederer DJ, Cantu E, Kohl BA, Lama VN, Bhorade SM, Crespo M, Demissie E, Sonett J, Wille K, Orens J, Shah AS, Weinacker A, Arcasoy S, Shah PD, Wilkes DS, Ware LB, Palmer SM, Christie JD, Lung Transplant Outcomes Group. Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med. 2013;187:527–34.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kaneda H, Waddell TK, de Perrot M, Bai XH, Gutierrez C, Arenovich T, Chaparro C, Liu M, Keshavjee S. Pre-implantation multiple cytokine mRNA expression analysis of donor lung grafts predicts survival after lung transplantation in humans. Am J Transplant. 2006;6:544–51.PubMedCrossRefGoogle Scholar
  12. 12.
    Pasque MK. Standardizing thoracic organ procurement for transplantation. J Thorac Cardiovasc Surg. 2010;139:13–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Fiser SM, Kron IL, Long SM, Kaza AK, Kern JA, Cassada DC, Jones DR, Robbins MC, Tribble CG. Influence of graft ischemic time on outcomes following lung transplantation. J Heart Lung Transplant. 2001;20:1291–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Novick RJ, Bennett LE, Meyer DM, Hosenpud JD. Influence of graft ischemic time and donor age on survival after lung transplantation. J Heart Lung Transplant. 1999;18:425–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Thabut G, Mal H, Cerrina J, Dartevelle P, Dromer C, Velly JF, Stern M, Loirat P, Leseche G, Bertocchi M, Mornex JF, Haloun A, Despins P, Pison C, Blin D, Reynaud-Gaubert M. Graft ischemic time and outcome of lung transplantation: a multicenter analysis. Am J Respir Crit Care Med. 2005;171:786–91.PubMedCrossRefGoogle Scholar
  16. 16.
    Yeung JC, Krueger T, Yasufuku K, de Perrot M, Pierre AF, Waddell TK, Singer LG, Keshavjee S, Cypel M. Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study. Lancet Respir Med. 2017;5:119–24.PubMedCrossRefGoogle Scholar
  17. 17.
    de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med. 2003;167:490–511.PubMedCrossRefGoogle Scholar
  18. 18.
    Ware LB, Golden JA, Finkbeiner WE, Matthay MA. Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation. Am J Respir Crit Care Med. 1999;159:980–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Clavien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts. An overview and synthesis of current studies. Transplantation. 1992;53:957–78.PubMedCrossRefGoogle Scholar
  20. 20.
    Fischer S, Maclean AA, Liu M, Cardella JA, Slutsky AS, Suga M, Moreira JF, Keshavjee S. Dynamic changes in apoptotic and necrotic cell death correlate with severity of ischemia-reperfusion injury in lung transplantation. Am J Respir Crit Care Med. 2000;162:1932–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Fang A, Studer S, Kawut SM, Ahya VN, Lee J, Wille K, Lama V, Ware L, Orens J, Weinacker A, Palmer SM, Crespo M, Lederer DJ, Deutschman CS, Kohl BA, Bellamy S, Demissie E, Christie JD, Lung Transplant Outcomes Group. Elevated pulmonary artery pressure is a risk factor for primary graft dysfunction following lung transplantation for idiopathic pulmonary fibrosis. Chest. 2011;139:782–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Barr ML, Kawut SM, Whelan TP, Girgis R, Bottcher H, Sonett J, Vigneswaran W, Follette DM, Corris PA, ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part IV: recipient-related risk factors and markers. J Heart Lung Transplant. 2005;24:1468–82.PubMedCrossRefGoogle Scholar
  23. 23.
    Dudek SM, Garcia JG. Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol (1985). 2001;91:1487–500.CrossRefGoogle Scholar
  24. 24.
    Zhao YD, Peng J, Granton E, Lin K, Lu C, Wu L, Machuca T, Waddell TK, Keshavjee S, de Perrot M. Pulmonary vascular changes 22 years after single lung transplantation for pulmonary arterial hypertension: a case report with molecular and pathological analysis. Pulm Circ. 2015;5:739–43.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Bando K, Keenan RJ, Paradis IL, Konishi H, Komatsu K, Hardesty RL, Griffith BP. Impact of pulmonary hypertension on outcome after single-lung transplantation. Ann Thorac Surg. 1994;58:1336–42.PubMedCrossRefGoogle Scholar
  26. 26.
    Conte JV, Borja MJ, Patel CB, Yang SC, Jhaveri RM, Orens JB. Lung transplantation for primary and secondary pulmonary hypertension. Ann Thorac Surg. 2001;72:1673–9, discussion 1679–80PubMedCrossRefGoogle Scholar
  27. 27.
    Huerd SS, Hodges TN, Grover FL, Mault JR, Mitchell MB, Campbell DN, Aziz S, Chetham P, Torres F, Zamora MR. Secondary pulmonary hypertension does not adversely affect outcome after single lung transplantation. J Thorac Cardiovasc Surg. 2000;119:458–65.PubMedCrossRefGoogle Scholar
  28. 28.
    Julliard WA, Meyer KC, De Oliveira NC, Osaki S, Cornwell RC, Sonetti DA, Maloney JD. The presence or severity of pulmonary hypertension does not affect outcomes for single-lung transplantation. Thorax. 2016;71:478–80.PubMedCrossRefGoogle Scholar
  29. 29.
    Aeba R, Griffith BP, Kormos RL, Armitage JM, Gasior TA, Fuhrman CR, Yousem SA, Hardesty RL. Effect of cardiopulmonary bypass on early graft dysfunction in clinical lung transplantation. Ann Thorac Surg. 1994;57:715–22.PubMedCrossRefGoogle Scholar
  30. 30.
    Triantafillou AN, Pasque MK, Huddleston CB, Pond CG, Cerza RF, Forstot RM, Cooper JD, Patterson GA, Lappas DG. Predictors, frequency, and indications for cardiopulmonary bypass during lung transplantation in adults. Ann Thorac Surg. 1994;57:1248–51.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Stammberger U, Gaspert A, Hillinger S, Vogt P, Odermatt B, Weder W, Schmid RA. Apoptosis induced by ischemia and reperfusion in experimental lung transplantation. Ann Thorac Surg. 2000;69:1532–6.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Shoji T, Omasa M, Nakamura T, Yoshimura T, Yoshida H, Ikeyama K, Fukuse T, Wada H. Mild hypothermia ameliorates lung ischemia reperfusion injury in an ex vivo rat lung model. Eur Surg Res. 2005;37:348–53.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Gielis JF, Boulet GA, Briede JJ, Horemans T, Debergh T, Kusse M, Cos P, Van Schil PE. Longitudinal quantification of radical bursts during pulmonary ischaemia and reperfusion. Eur J Cardiothorac Surg. 2015;48:622–9.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Chatterjee S, Nieman GF, Christie JD, Fisher AB. Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol. 2014;307:L668–80.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Gilmont RR, Dardano A, Engle JS, Adamson BS, Welsh MJ, Li T, Remick DG, Smith DJ Jr, Rees RS. TNF-alpha potentiates oxidant and reperfusion-induced endothelial cell injury. J Surg Res. 1996;61:175–82.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Mallavia B, Liu F, Sheppard D, Looney MR. Inhibiting integrin alphavbeta5 reduces ischemia-reperfusion injury in an orthotopic lung transplant model in mice. Am J Transplant. 2016;16:1306–11.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Stone ML, Sharma AK, Zhao Y, Charles EJ, Huerter ME, Johnston WF, Kron IL, Lynch KR, Laubach VE. Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol. 2015;308:L1245–52.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Zhao X, Jin Y, Li H, Wang Z, Zhang W, Feng C. Hypoxia-inducible factor 1 alpha contributes to pulmonary vascular dysfunction in lung ischemia-reperfusion injury. Int J Clin Exp Pathol. 2014;7:3081–8.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Ge H, Zhu H, Xu N, Zhang D, Ou J, Wang G, Fang X, Zhou J, Song Y, Bai C. Increased lung ischemia-reperfusion injury in aquaporin 1-null mice is mediated via decreased hypoxia-inducible factor 2alpha stability. Am J Respir Cell Mol Biol. 2016;54:882–91.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Balakrishna S, Song W, Achanta S, Doran SF, Liu B, Kaelberer MM, Yu Z, Sui A, Cheung M, Leishman E, Eidam HS, Ye G, Willette RN, Thorneloe KS, Bradshaw HB, Matalon S, Jordt SE. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2014;307:L158–72.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ivey CL, Williams FM, Collins PD, Jose PJ, Williams TJ. Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit. Evidence for a role for C5a and interleukin-8. J Clin Invest. 1995;95:2720–8.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Compeau CG, Ma J, DeCampos KN, Waddell TK, Brisseau GF, Slutsky AS, Rotstein OD. In situ ischemia and hypoxia enhance alveolar macrophage tissue factor expression. Am J Respir Cell Mol Biol. 1994;11:446–55.PubMedCrossRefGoogle Scholar
  43. 43.
    Pinsky DJ, Liao H, Lawson CA, Yan SF, Chen J, Carmeliet P, Loskutoff DJ, Stern DM. Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest. 1998;102:919–28.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Ogawa S, Gerlach H, Esposito C, Pasagian-Macaulay A, Brett J, Stern D. Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium. Increased monolayer permeability and induction of procoagulant properties. J Clin Invest. 1990;85:1090–8.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Krishnadasan B, Naidu BV, Byrne K, Fraga C, Verrier ED, Mulligan MS. The role of proinflammatory cytokines in lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2003;125:261–72.PubMedCrossRefGoogle Scholar
  46. 46.
    Ng CS, Wan S, Arifi AA, Yim AP. Inflammatory response to pulmonary ischemia-reperfusion injury. Surg Today. 2006;36:205–14.PubMedCrossRefGoogle Scholar
  47. 47.
    De Perrot M, Sekine Y, Fischer S, Waddell TK, McRae K, Liu M, Wigle DA, Keshavjee S. Interleukin-8 release during early reperfusion predicts graft function in human lung transplantation. Am J Respir Crit Care Med. 2002;165:211–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Lan Q, Mercurius KO, Davies PF. Stimulation of transcription factors NF kappa B and AP1 in endothelial cells subjected to shear stress. Biochem Biophys Res Commun. 1994;201:950–6.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    den Hengst WA, Gielis JF, Lin JY, Van Schil PE, De Windt LJ, Moens AL. Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process. Am J Physiol Heart Circ Physiol. 2010;299:H1283–99.CrossRefGoogle Scholar
  50. 50.
    Arbibe L, Koumanov K, Vial D, Rougeot C, Faure G, Havet N, Longacre S, Vargaftig BB, Bereziat G, Voelker DR, Wolf C, Touqui L. Generation of lyso-phospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2 and inhibited by a direct surfactant protein A-phospholipase A2 protein interaction. J Clin Invest. 1998;102:1152–60.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Nagase T, Ishii S, Kume K, Uozumi N, Izumi T, Ouchi Y, Shimizu T. Platelet-activating factor mediates acid-induced lung injury in genetically engineered mice. J Clin Invest. 1999;104:1071–6.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kawahara K, Tagawa T, Takahashi T, Akamine S, Nakamura A, Yamamoto S, Muraoka S, Tomita M. The effect of the platelet-activating factor inhibitor TCV-309 on reperfusion injury in a canine model of ischemic lung. Transplantation. 1993;55:1438–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Stammberger U, Carboni GL, Hillinger S, Schneiter D, Weder W, Schmid RA. Combined treatment with endothelin- and PAF-antagonists reduces posttransplant lung ischemia/reperfusion injury. J Heart Lung Transplant. 1999;18:862–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Shennib H, Serrick C, Saleh D, Adoumie R, Stewart DJ, Giaid A. Alterations in bronchoalveolar lavage and plasma endothelin-1 levels early after lung transplantation. Transplantation. 1995;59:994–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Taghavi S, Abraham D, Riml P, Paulus P, Schafer R, Klepetko W, Aharinejad S. Co-expression of endothelin-1 and vascular endothelial growth factor mediates increased vascular permeability in lung grafts before reperfusion. J Heart Lung Transplant. 2002;21:600–3.PubMedCrossRefGoogle Scholar
  56. 56.
    Fiser SM, Tribble CG, Long SM, Kaza AK, Cope JT, Laubach VE, Kern JA, Kron IL. Lung transplant reperfusion injury involves pulmonary macrophages and circulating leukocytes in a biphasic response. J Thorac Cardiovasc Surg. 2001;121:1069–75.PubMedCrossRefGoogle Scholar
  57. 57.
    Naidu BV, Krishnadasan B, Farivar AS, Woolley SM, Thomas R, Van Rooijen N, Verrier ED, Mulligan MS. Early activation of the alveolar macrophage is critical to the development of lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2003;126:200–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Welbourn CR, Goldman G, Paterson IS, Valeri CR, Shepro D, Hechtman HB. Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil. Br J Surg. 1991;78:651–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Adoumie R, Serrick C, Giaid A, Shennib H. Early cellular events in the lung allograft. Ann Thorac Surg. 1992;54:1071–6, discussion 1076–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10:826–37.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Merry HE, Phelan P, Doak MR, Zhao M, Hwang B, Mulligan MS. Role of toll-like receptor-4 in lung ischemia-reperfusion injury. Ann Thorac Surg. 2015;99:1193–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Zanotti G, Casiraghi M, Abano JB, Tatreau JR, Sevala M, Berlin H, Smyth S, Funkhouser WK, Burridge K, Randell SH, Egan TM. Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema. Am J Physiol Lung Cell Mol Physiol. 2009;297:L52–63.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Zhao M, Fernandez LG, Doctor A, Sharma AK, Zarbock A, Tribble CG, Kron IL, Laubach VE. Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol. 2006;291:L1018–26.PubMedCrossRefGoogle Scholar
  64. 64.
    Moore TM, Khimenko P, Adkins WK, Miyasaka M, Taylor AE. Adhesion molecules contribute to ischemia and reperfusion-induced injury in the isolated rat lung. J Appl Physiol (1985). 1995;78:2245–52.CrossRefGoogle Scholar
  65. 65.
    Sayah DM, Mallavia B, Liu F, Ortiz-Munoz G, Caudrillier A, DerHovanessian A, Ross DJ, Lynch JP III, Saggar R, Ardehali A, Lung Transplant Outcomes Group, Ware LB, Christie JD, Belperio JA, Looney MR. Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med 2015;191:455–63.Google Scholar
  66. 66.
    Sharma AK, LaPar DJ, Stone ML, Zhao Y, Mehta CK, Kron IL, Laubach VE. NOX2 activation of natural killer T cells is blocked by the adenosine A2A receptor to inhibit lung ischemia-reperfusion injury. Am J Respir Crit Care Med. 2016;193:988–99.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    de Perrot M, Young K, Imai Y, Liu M, Waddell TK, Fischer S, Zhang L, Keshavjee S. Recipient T cells mediate reperfusion injury after lung transplantation in the rat. J Immunol. 2003;171:4995–5002.PubMedCrossRefGoogle Scholar
  68. 68.
    Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–22.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008;9:465–76.PubMedCrossRefGoogle Scholar
  70. 70.
    Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, Ji H, Potash JB, Sabunciyan S, Feinberg AP. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009;41:178–86.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Hellman A, Chess A. Gene body-specific methylation on the active X chromosome. Science. 2007;315:1141–3.PubMedCrossRefGoogle Scholar
  72. 72.
    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012;13:97–109.PubMedCrossRefGoogle Scholar
  74. 74.
    Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–80.PubMedCrossRefGoogle Scholar
  75. 75.
    Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.PubMedCrossRefGoogle Scholar
  76. 76.
    Rabinovich EI, Kapetanaki MG, Steinfeld I, Gibson KF, Pandit KV, Yu G, Yakhini Z, Kaminski N. Global methylation patterns in idiopathic pulmonary fibrosis. PLoS One. 2012;7:e33770.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Sanders YY, Ambalavanan N, Halloran B, Zhang X, Liu H, Crossman DK, Bray M, Zhang K, Thannickal VJ, Hagood JS. Altered DNA methylation profile in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186:525–35.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Sanders YY, Pardo A, Selman M, Nuovo GJ, Tollefsbol TO, Siegal GP, Hagood JS. Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2008;39:610–8.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Huang SK, Fisher AS, Scruggs AM, White ES, Hogaboam CM, Richardson BC, Peters-Golden M. Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice. Am J Pathol. 2010;177:2245–55.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Cisneros J, Hagood J, Checa M, Ortiz-Quintero B, Negreros M, Herrera I, Ramos C, Pardo A, Selman M. Hypermethylation-mediated silencing of p14(ARF) in fibroblasts from idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012;303:L295–303.PubMedCrossRefGoogle Scholar
  81. 81.
    Huang SK, Scruggs AM, McEachin RC, White ES, Peters-Golden M. Lung fibroblasts from patients with idiopathic pulmonary fibrosis exhibit genome-wide differences in DNA methylation compared to fibroblasts from nonfibrotic lung. PLoS One. 2014;9:e107055.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Coward WR, Watts K, Feghali-Bostwick CA, Knox A, Pang L. Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis. Mol Cell Biol. 2009;29:4325–39.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Coward WR, Watts K, Feghali-Bostwick CA, Jenkin G, Pang L. Repression of IP-10 by interactions between histone deacetylation and hypermethylation in idiopathic pulmonary fibrosis. Mol Cell Biol. 2010;30:2874–86.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Huang SK, Scruggs AM, Donaghy J, Horowitz JC, Zaslona Z, Przybranowski S, White ES, Peters-Golden M. Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts. Cell Death Dis. 2013;4:e621.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Dakhlallah D, Batte K, Wang Y, Cantemir-Stone CZ, Yan P, Nuovo G, Mikhail A, Hitchcock CL, Wright VP, Nana-Sinkam SP, Piper MG, Marsh CB. Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2013;187:397–405.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, Thannickal VJ, Cardoso WV, Lu J. miR-29 is a major regulator of genes associated with pulmonary fibrosis. Am J Respir Cell Mol Biol. 2011;45:287–94.PubMedCrossRefGoogle Scholar
  87. 87.
    Yang S, Cui H, Xie N, Icyuz M, Banerjee S, Antony VB, Abraham E, Thannickal VJ, Liu G. miR-145 regulates myofibroblast differentiation and lung fibrosis. FASEB J. 2013;27:2382–91.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Pottier N, Maurin T, Chevalier B, Puissegur MP, Lebrigand K, Robbe-Sermesant K, Bertero T, Lino Cardenas CL, Courcot E, Rios G, Fourre S, Lo-Guidice JM, Marcet B, Cardinaud B, Barbry P, Mari B. Identification of keratinocyte growth factor as a target of microRNA-155 in lung fibroblasts: implication in epithelial-mesenchymal interactions. PLoS One. 2009;4:e6718.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lino Cardenas CL, Henaoui IS, Courcot E, Roderburg C, Cauffiez C, Aubert S, Copin MC, Wallaert B, Glowacki F, Dewaeles E, Milosevic J, Maurizio J, Tedrow J, Marcet B, Lo-Guidice JM, Kaminski N, Barbry P, Luedde T, Perrais M, Mari B, Pottier N. miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1. PLoS Genet. 2013;9:e1003291.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Yang S, Banerjee S, de Freitas A, Sanders YY, Ding Q, Matalon S, Thannickal VJ, Abraham E, Liu G. Participation of miR-200 in pulmonary fibrosis. Am J Pathol. 2012;180:484–93.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Sun H, Chen J, Qian W, Kang J, Wang J, Jiang L, Qiao L, Chen W, Zhang J. Integrated long non-coding RNA analyses identify novel regulators of epithelial-mesenchymal transition in the mouse model of pulmonary fibrosis. J Cell Mol Med. 2016;20:1234–46.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Li M, Riddle SR, Frid MG, El Kasmi KC, McKinsey TA, Sokol RJ, Strassheim D, Meyrick B, Yeager ME, Flockton AR, McKeon BA, Lemon DD, Horn TR, Anwar A, Barajas C, Stenmark KR. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol. 2011;187:2711–22.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Xu XF, Ma XL, Shen Z, Wu XL, Cheng F, Du LZ. Epigenetic regulation of the endothelial nitric oxide synthase gene in persistent pulmonary hypertension of the newborn rat. J Hypertens. 2010;28:2227–35.PubMedCrossRefGoogle Scholar
  94. 94.
    Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thebaud B, Husain AN, Cipriani N, Rehman J. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121:2661–71.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Guo L, Yang Y, Liu J, Wang L, Li J, Wang Y, Liu Y, Gu S, Gan H, Cai J, Yuan JX, Wang J, Wang C. Differentially expressed plasma microRNAs and the potential regulatory function of Let-7b in chronic thromboembolic pulmonary hypertension. PLoS One. 2014;9:e101055.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Wang L, Guo LJ, Liu J, Wang W, Yuan JX, Zhao L, Wang J, Wang C. MicroRNA expression profile of pulmonary artery smooth muscle cells and the effect of let-7d in chronic thromboembolic pulmonary hypertension. Pulm Circ. 2013;3:654–64.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, MacDonald RA, Greig JA, Robertson KE, Masson R, Denby L, Dempsie Y, Long L, Morrell NW, Baker AH. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30:716–23.PubMedCrossRefGoogle Scholar
  98. 98.
    Courboulin A, Paulin R, Giguere NJ, Saksouk N, Perreault T, Meloche J, Paquet ER, Biardel S, Provencher S, Cote J, Simard MJ, Bonnet S. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011;208:535–48.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Xu Z, Sharma M, Gelman A, Hachem R, Mohanakumar T. Significant role for microRNA-21 affecting toll-like receptor pathway in primary graft dysfunction after human lung transplantation. J Heart Lung Transplant. 2017;36(3):331–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A, Hayashi S, Adcock IM, Hogg JC, Barnes PJ. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. 2005;352:1967–76.PubMedCrossRefGoogle Scholar
  101. 101.
    Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ, Adcock IM. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression. J Exp Med. 2006;203:7–13.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Karmaus W, Ziyab AH, Everson T, Holloway JW. Epigenetic mechanisms and models in the origins of asthma. Curr Opin Allergy Clin Immunol. 2013;13:63–9.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Yang IV, Pedersen BS, Liu A, O’Connor GT, Teach SJ, Kattan M, Misiak RT, Gruchalla R, Steinbach SF, Szefler SJ, Gill MA, Calatroni A, David G, Hennessy CE, Davidson EJ, Zhang W, Gergen P, Togias A, Busse WW, Schwartz DA. DNA methylation and childhood asthma in the inner city. J Allergy Clin Immunol. 2015;136:69–80.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Liu H, Zhou Y, Boggs SE, Belinsky SA, Liu J. Cigarette smoke induces demethylation of prometastatic oncogene synuclein-gamma in lung cancer cells by downregulation of DNMT3B. Oncogene. 2007;26:5900–10.PubMedCrossRefGoogle Scholar
  105. 105.
    Parker MD, Chambers PA, Lodge JP, Pratt JR. Ischemia- reperfusion injury and its influence on the epigenetic modification of the donor kidney genome. Transplantation. 2008;86:1818–23.PubMedCrossRefGoogle Scholar
  106. 106.
    Mehta TK, Hoque MO, Ugarte R, Rahman MH, Kraus E, Montgomery R, Melancon K, Sidransky D, Rabb H. Quantitative detection of promoter hypermethylation as a biomarker of acute kidney injury during transplantation. Transplant Proc. 2006;38:3420–6.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Huang N, Tan L, Xue Z, Cang J, Wang H. Reduction of DNA hydroxymethylation in the mouse kidney insulted by ischemia reperfusion. Biochem Biophys Res Commun. 2012;422:697–702.PubMedCrossRefGoogle Scholar
  108. 108.
    Watson CJ, Collier P, Tea I, Neary R, Watson JA, Robinson C, Phelan D, Ledwidge MT, McDonald KM, McCann A, Sharaf O, Baugh JA. Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum Mol Genet. 2014;23:2176–88.PubMedCrossRefGoogle Scholar
  109. 109.
    Franco R, Schoneveld O, Georgakilas AG, Panayiotidis MI. Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett. 2008;266:6–11.PubMedCrossRefGoogle Scholar
  110. 110.
    Wilson CB, Rowell E, Sekimata M. Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol. 2009;9:91–105.PubMedCrossRefGoogle Scholar
  111. 111.
    Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, Reid SP, Levy DE, Bromberg JS. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182:259–73.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Zaslona Z, Scruggs AM, Peters-Golden M, Huang SK. Protein kinase A inhibition of macrophage maturation is accompanied by an increase in DNA methylation of the colony-stimulating factor 1 receptor gene. Immunology. 2016;149:225–37.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Masson E, Stern M, Chabod J, Thevenin C, Gonin F, Rebibou JM, Tiberghien P. Hyperacute rejection after lung transplantation caused by undetected low-titer anti-HLA antibodies. J Heart Lung Transplant. 2007;26:642–5.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Pierre AF, DeCampos KN, Liu M, Edwards V, Cutz E, Slutsky AS, Keshavjee SH. Rapid reperfusion causes stress failure in ischemic rat lungs. J Thorac Cardiovasc Surg. 1998;116:932–42.PubMedCrossRefGoogle Scholar
  115. 115.
    Clark SC, Sudarshan C, Khanna R, Roughan J, Flecknell PA, Dark JH. Controlled reperfusion and pentoxifylline modulate reperfusion injury after single lung transplantation. J Thorac Cardiovasc Surg. 1998;115:1335–41.PubMedCrossRefGoogle Scholar
  116. 116.
    Halldorsson AO, Kronon MT, Allen BS, Rahman S, Wang T. Lowering reperfusion pressure reduces the injury after pulmonary ischemia. Ann Thorac Surg. 2000;69:198–203, discussion 204.PubMedCrossRefGoogle Scholar
  117. 117.
    Botha P, Jeyakanthan M, Rao JN, Fisher AJ, Prabhu M, Dark JH, Clark SC. Inhaled nitric oxide for modulation of ischemia-reperfusion injury in lung transplantation. J Heart Lung Transplant. 2007;26:1199–205.PubMedCrossRefGoogle Scholar
  118. 118.
    Chiang CH, Wu K, Yu CP, Yan HC, Perng WC, Wu CP. Hypothermia and prostaglandin E(1) produce synergistic attenuation of ischemia-reperfusion lung injury. Am J Respir Crit Care Med. 1999;160:1319–23.PubMedCrossRefGoogle Scholar
  119. 119.
    Shargall Y, Guenther G, Ahya VN, Ardehali A, Singhal A, Keshavjee S, ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part VI: treatment. J Heart Lung Transplant. 2005;24:1489–500.PubMedCrossRefGoogle Scholar
  120. 120.
    Kemming GI, Merkel MJ, Schallerer A, Habler OP, Kleen MS, Haller M, Briegel J, Vogelmeier C, Furst H, Reichart B, Zwissler B. Inhaled nitric oxide (NO) for the treatment of early allograft failure after lung transplantation. Munich Lung Transplant Group. Intensive Care Med. 1998;24:1173–80.PubMedCrossRefGoogle Scholar
  121. 121.
    Fischer S, Bohn D, Rycus P, Pierre AF, de Perrot M, Waddell TK, Keshavjee S. Extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: analysis of the Extracorporeal Life Support Organization (ELSO) registry. J Heart Lung Transplant. 2007;26:472–7.PubMedCrossRefGoogle Scholar
  122. 122.
    Kermeen FD, McNeil KD, Fraser JF, McCarthy J, Ziegenfuss MD, Mullany D, Dunning J, Hopkins PM. Resolution of severe ischemia-reperfusion injury post-lung transplantation after administration of endobronchial surfactant. J Heart Lung Transplant. 2007;26:850–6.PubMedCrossRefGoogle Scholar
  123. 123.
    Wittwer T, Grote M, Oppelt P, Franke U, Schaefers HJ, Wahlers T. Impact of PAF antagonist BN 52021 (Ginkolide B) on post-ischemic graft function in clinical lung transplantation. J Heart Lung Transplant. 2001;20:358–63.PubMedCrossRefGoogle Scholar
  124. 124.
    Keshavjee S, Davis RD, Zamora MR, de Perrot M, Patterson GA. A randomized, placebo-controlled trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human beings. J Thorac Cardiovasc Surg. 2005;129:423–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Forgiarini LF, Forgiarini LA Jr, da Rosa DP, Silva MB, Mariano R, Paludo Ade O, Andrade CF. N-acetylcysteine administration confers lung protection in different phases of lung ischaemia-reperfusion injury. Interact Cardiovasc Thorac Surg. 2014;19:894–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Zhu C, Bilali A, Georgieva GS, Kurata S, Mitaka C, Imai T. Salvage of nonischemic control lung from injury by unilateral ischemic lung with apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, in isolated perfused rat lung. Transl Res. 2008;152:273–82.PubMedCrossRefGoogle Scholar
  127. 127.
    Lu W, Si YI, Ding J, Chen X, Zhang X, Dong Z, Fu W. Mesenchymal stem cells attenuate acute ischemia-reperfusion injury in a rat model. Exp Ther Med. 2015;10:2131–7.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Tian W, Liu Y, Zhang B, Dai X, Li G, Li X, Zhang Z, Du C, Wang H. Infusion of mesenchymal stem cells protects lung transplants from cold ischemia-reperfusion injury in mice. Lung. 2015;193:85–95.PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2018

Authors and Affiliations

  • Steven Kenneth Huang
    • 1
    Email author
  • Roberto G. Carbone
    • 2
  • Giovanni Bottino
    • 3
  1. 1.Department of Pulmonary and Critical Care MedicineUniversity of MichiganAnn ArborUSA
  2. 2.Department of Internal MedicineUniversity of GenoaGenoaItaly
  3. 3.Department of MedicineUniversity of Genoa—DIMIGenoaItaly

Personalised recommendations