Mechanisms of Fibrogenesis in Post-transplant Bronchiolitis Obliterans

  • Anish Wadhwa
  • Vibha N. LamaEmail author
Part of the Respiratory Medicine book series (RM, volume 8)


Bronchiolitis obliterans (BO) post-lung transplant is a fibroproliferative disease of the small airways. Among all fibrotic diseases, BO is unique in that we have the opportunity to follow the evolution of airway remodeling and fibrosis via serial lung samplings. Although there is a definite role of immune and nonimmune injury in the pathogenesis of this disease, the physiological impairment in BO is related to fibrogenesis. Hence, understanding the pathogenesis of fibroproliferation in BO is critical for identifying targets for future therapeutic interventions and the timing of such therapy. This review updates the understanding of the cellular and molecular participants in fibrotic remodeling of the lung allograft.


Bronchiolitis obliterans Fibrosis Mesenchymal cell Collagen Remodeling Lung transplant Fibroproliferation Myofibroblast Fibrogenesis Mesenchymal stem cell 


  1. 1.
    Yousem SA, Suncan SR, Ohori NP, Sonmez-Alpan E. Architectural remodeling of lung allografts in acute and chronic rejection. Arch Pathol Lab Med. 1992;116:1175–80.PubMedGoogle Scholar
  2. 2.
    Burke CM, Theodore J, Dawkins KD, Yousem SA, Blank N, Billingham ME, et al. Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation. Chest. 1984;86:824–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Stewart S, Fishbein MC, Snell GI, Berry GJ, Boehler A, Burke MM, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant. 2007;26:1229–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Davis WA, Finlen Copeland CA, Todd JL, Snyder LD, Martissa JA, Palmer SM. Spirometrically significant acute rejection increases the risk for BOS and death after lung transplantation. Am J Transplant. 2012;12:745–52.PubMedCrossRefGoogle Scholar
  5. 5.
    Burton CM, Iversen M, Carlsen J, Mortensen J, Andersen CB, Steinbruchel D, et al. Acute cellular rejection is a risk factor for bronchiolitis obliterans syndrome independent of post-transplant baseline FEV1. J Heart Lung Transplant. 2009;28:888–93.PubMedCrossRefGoogle Scholar
  6. 6.
    Hachem RR, Khalifah AP, Chakinala MM, Yusen RD, Aloush AA, Mohanakumar T, et al. The significance of a single episode of minimal acute rejection after lung transplantation. Transplantation. 2005;80:1406–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Khalifah AP, Hachem RR, Chakinala MM, Yusen RD, Aloush A, Patterson GA, et al. Minimal acute rejection after lung transplantation: a risk for bronchiolitis obliterans syndrome. Am J Transplant. 2005;5:2022–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Heng D, Sharples LD, McNeil K, Stewart S, Wreghitt T, Wallwork J. Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors. J Heart Lung Transplant. 1998;17:1255–63.PubMedGoogle Scholar
  9. 9.
    Scott AI, Sharples LD, Stewart S. Bronchiolitis obliterans syndrome: risk factors and therapeutic strategies. Drugs. 2005;65:761–71.PubMedCrossRefGoogle Scholar
  10. 10.
    Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant. 2002;21:271–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Husain AN, Siddiqui MT, Holmes EW, Chandrasekhar AJ, McCabe M, Radvany R, et al. Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 1999;159:829–33.PubMedCrossRefGoogle Scholar
  12. 12.
    Fukami N, Ramachandran S, Takenaka M, Weber J, Subramanian V, Mohanakumar T. An obligatory role for lung infiltrating B cells in the immunopathogenesis of obliterative airway disease induced by antibodies to MHC class I molecules. Am J Transplant. 2012;12:867–76.PubMedCrossRefGoogle Scholar
  13. 13.
    Jaramillo A, Fernandez FG, Kuo EY, Trulock EP, Patterson GA, Mohanakumar T. Immune mechanisms in the pathogenesis of bronchiolitis obliterans syndrome after lung transplantation. Pediatr Transplant. 2005;9:84–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Srinivasan M, Flynn R, Price A, Ranger A, Browning JL, Taylor PA, et al. Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood. 2012;119:1570–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Xue J, Zhu X, George MP, Myerburg MM, Stoner MW, Pilewski JW, et al. A human-mouse chimeric model of obliterative bronchiolitis after lung transplantation. Am J Pathol. 2011;179:745–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Burlingham WJ, Love RB, Jankowska-Gan E, Haynes LD, Xu Q, Bobadilla JL, et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007;117:3498–506.PubMedCrossRefGoogle Scholar
  17. 17.
    Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res. 1999;250:273–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Lama VN, Harada H, Badri LN, Flint A, Hogaboam CM, McKenzie A, et al. Obligatory role for interleukin-13 in obstructive lesion development in airway allografts. Am J Pathol. 2006;169:47–60.PubMedCrossRefGoogle Scholar
  19. 19.
    Gilpin SE, Lung KC, Sato M, Singer LG, Keshavjee S, Waddell TK. Altered progenitor cell and cytokine profiles in bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2012;31:222–8.PubMedCrossRefGoogle Scholar
  20. 20.
    LaPar DJ, Burdick MD, Emaminia A, Harris DA, Strieter BA, Liu L, et al. Circulating fibrocytes correlate with bronchiolitis obliterans syndrome development after lung transplantation: a novel clinical biomarker. Ann Thorac Surg. 2011;92:470–7; discussion 477.Google Scholar
  21. 21.
    Lama VN, Phan SH. The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond. Proc Am Thorac Soc. 2006;3:373–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Brocker V, Langer F, Fellous TG, Mengel M, Brittan M, Bredt M, et al. Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants. Am J Respir Crit Care Med. 2006;173:1276–82.PubMedCrossRefGoogle Scholar
  23. 23.
    Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, et al. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest. 2007;117:989–96.PubMedCrossRefGoogle Scholar
  24. 24.
    Walker N, Badri L, Wettlaufer S, Flint A, Sajjan U, Krebsbach PH, et al. Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts. Am J Pathol. 2011;178:2461–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Badri L, Murray S, Liu LX, Walker NM, Flint A, Wadhwa A, et al. Mesenchymal stromal cells in bronchoalveolar lavage as predictors of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2011;183:1062–70.PubMedCrossRefGoogle Scholar
  26. 26.
    Salama M, Jaksch P, Andrukhova O, Taghavi S, Klepetko W, Aharinejad S. Endothelin-1 is a useful biomarker for early detection of bronchiolitis obliterans in lung transplant recipients. J Thorac Cardiovasc Surg. 2010;140:1422–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Salama M, Andrukhova O, Jaksch P, Taghavi S, Kelpetko W, Dekan G, et al. Endothelin-1 governs proliferation and migration of bronchoalveolar lavage-derived lung mesenchymal stem cells in bronchiolitis obliterans syndrome. Transplantation. 2011;92:155–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Badri L, Lama VN. Lysophosphatidic acid induces migration of human lung-resident mesenchymal stem cells through the beta-catenin pathway. Stem Cells. 2012;30(9):2010–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Andersson-Sjoland A, Thiman L, Nihlberg K, Hallgren O, Rolandsson S, Skog I, et al. Fibroblast phenotypes and their activity are changed in the wound healing process after lung transplantation. J Heart Lung Transplant. 2011;30:945–54.PubMedGoogle Scholar
  30. 30.
    Walker NM, Badri LN, Wadhwa A, Wettlaufer S, Peters-Golden M, Lama VN. Prostaglandin E2 as an inhibitory modulator of fibrogenesis in human lung allografts. Am J Respir Crit Care Med. 2012;185:77–84.PubMedCrossRefGoogle Scholar
  31. 31.
    Elssner A, Jaumann F, Dobmann S, Behr J, Schwaiblmair M, Reichenspurner H, et al. Elevated levels of interleukin-8 and transforming growth factor-beta in bronchoalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells. Munich Lung Transplant Group. Transplantation. 2000;70:362–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Magnan A, Mege JL, Escallier JC, Brisse J, Capo C, Reynaud M, et al. Balance between alveolar macrophage IL-6 and TGF-beta in lung-transplant recipients. Marseille and Montreal Lung Transplantation Group. Am J Respir Crit Care Med. 1996;153:1431–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Hertz MI, Henke CA, Nakhleh RE, Harmon KR, Marinelli WA, Fox JM, et al. Obliterative bronchiolitis after lung transplantation: a fibroproliferative disorder associated with platelet-derived growth factor. Proc Natl Acad Sci U S A. 1992;89:10385–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Charpin JM, Stern M, Grenet D, Israel-Biet D. Insulinlike growth factor-1 in lung transplants with obliterative bronchiolitis. Am J Respir Crit Care Med. 2000;161:1991–8.PubMedCrossRefGoogle Scholar
  35. 35.
    DiGiovine B, Lynch III JP, Martinez FJ, Flint A, Whyte RI, Iannettoni MD, et al. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8. J Immunol. 1996;157:4194–202.PubMedGoogle Scholar
  36. 36.
    Hardison MT, Galin FS, Calderon CE, Djekic UV, Parker SB, Wille KM, et al. The presence of a matrix-derived neutrophil chemoattractant in bronchiolitis obliterans syndrome after lung transplantation. J Immunol. 2009;182:4423–31.PubMedCrossRefGoogle Scholar
  37. 37.
    Devouassoux G, Drouet C, Pin I, Brambilla C, Brambilla E, Colle PE, et al. Alveolar neutrophilia is a predictor for the bronchiolitis obliterans syndrome, and increases with degree of severity. Transpl Immunol. 2002;10:303–10.PubMedCrossRefGoogle Scholar
  38. 38.
    Neurohr C, Huppmann P, Samweber B, Leuschner S, Zimmermann G, Leuchte H, et al. Prognostic value of bronchoalveolar lavage neutrophilia in stable lung transplant recipients. J Heart Lung Transplant. 2009;28:468–74.PubMedCrossRefGoogle Scholar
  39. 39.
    Riise GC, Williams A, Kjellstrom C, Schersten H, Andersson BA, Kelly FJ. Bronchiolitis obliterans syndrome in lung transplant recipients is associated with increased neutrophil activity and decreased antioxidant status in the lung. Eur Respir J. 1998;12:82–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Zheng L, Walters EH, Ward C, Wang N, Orsida B, Whitford H, et al. Airway neutrophilia in stable and bronchiolitis obliterans syndrome patients following lung transplantation. Thorax. 2000;55:53–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Zheng L, Whitford HM, Orsida B, Levvey BJ, Bailey M, Walters EH, et al. The dynamics and associations of airway neutrophilia post lung transplantation. Am J Transplant. 2006;6:599–608.PubMedCrossRefGoogle Scholar
  42. 42.
    Bharat A, Kuo E, Steward N, Aloush A, Hachem R, Trulock EP, et al. Immunological link between primary graft dysfunction and chronic lung allograft rejection. Ann Thorac Surg. 2008;86:189–95; discussion 196–7.Google Scholar
  43. 43.
    Blocher S, Wilker S, Sucke J, Pfeil U, Dietrich H, Weimer R, et al. Acute rejection of experimental lung allografts: characterization of intravascular mononuclear leukocytes. Clin Immunol. 2007;124:98–108.PubMedCrossRefGoogle Scholar
  44. 44.
    Geudens N, Vanaudenaerde BM, Neyrinck AP, Van De Wauwer C, Vos R, Verleden GM, et al. The importance of lymphocytes in lung ischemia-reperfusion injury. Transplant Proc. 2007;39:2659–62.PubMedCrossRefGoogle Scholar
  45. 45.
    Hodge G, Hodge S, Chambers D, Reynolds PN, Holmes M. Acute lung transplant rejection is associated with localized increase in T-cell IFNgamma and TNFalpha proinflammatory cytokines in the airways. Transplantation. 2007;84:1452–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Rizzo M, SivaSai KS, Smith MA, Trulock EP, Lynch JP, Patterson GA, et al. Increased expression of inflammatory cytokines and adhesion molecules by alveolar macrophages of human lung allograft recipients with acute rejection: decline with resolution of rejection. J Heart Lung Transplant. 2000;19:858–65.PubMedCrossRefGoogle Scholar
  47. 47.
    Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB, et al. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol. 2008;181:4389–96.PubMedGoogle Scholar
  48. 48.
    Adams BF, Berry GJ, Huang X, Shorthouse R, Brazelton T, Morris RE. Immunosuppressive therapies for the prevention and treatment of obliterative airway disease in heterotopic rat trachea allografts. Transplantation. 2000;69:2260–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Adams BF, Brazelton T, Berry GJ, Morris RE. The role of respiratory epithelium in a rat model of obliterative airway disease. Transplantation. 2000;69:661–4.PubMedCrossRefGoogle Scholar
  50. 50.
    Ikonen TS, Brazelton TR, Berry GJ, Shorthouse RS, Morris RE. Epithelial re-growth is associated with inhibition of obliterative airway disease in orthotopic tracheal allografts in non-immunosuppressed rats. Transplantation. 2000;70:857–63.PubMedCrossRefGoogle Scholar
  51. 51.
    Glanville AR, Tazelaar HD, Theodore J, Imoto E, Rouse RV, Baldwin JC, et al. The distribution of MHC class I and II antigens on bronchial epithelium. Am Rev Respir Dis. 1989;139:330–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Taylor PM, Rose ML, Yacoub MH. Expression of MHC antigens in normal human lungs and transplanted lungs with obliterative bronchiolitis. Transplantation. 1989;48:506–10.PubMedCrossRefGoogle Scholar
  53. 53.
    Reznik SI, Jaramillo A, Zhang L, Patterson GA, Cooper JD, Mohanakumar T. Anti-HLA antibody binding to HLA class I molecules induces proliferation of airway epithelial cells: a potential mechanism for bronchiolitis obliterans syndrome. J Thorac Cardiovasc Surg. 2000;119:39–45.PubMedCrossRefGoogle Scholar
  54. 54.
    Mauck KA, Hosenpud JD. The bronchial epithelium: a potential allogeneic target for chronic rejection after lung transplantation. J Heart Lung Transplant. 1996;15:709–14.PubMedGoogle Scholar
  55. 55.
    Jaramillo A, Naziruddin B, Zhang L, Reznik SI, Smith MA, Aloush AA, et al. Activation of human airway epithelial cells by non-HLA antibodies developed after lung transplantation: a potential etiological factor for bronchiolitis obliterans syndrome. Transplantation. 2001;71:966–76.PubMedCrossRefGoogle Scholar
  56. 56.
    Goers TA, Ramachandran S, Aloush A, Trulock E, Patterson GA, Mohanakumar T. De novo production of k-alpha1 tubulin-specific antibodies: role in chronic lung allograft rejection. J Immunol. 2008;180:4487–94.PubMedGoogle Scholar
  57. 57.
    Keenan RJ, Lega ME, Dummer JS, Paradis IL, Dauber JH, Rabinowich H, et al. Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation. Transplantation. 1991;51:433–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Reichenspurner H, Girgis RE, Robbins RC, Conte JV, Nair RV, Valentine V, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. Ann Thorac Surg. 1995;60:1845–53.PubMedCrossRefGoogle Scholar
  59. 59.
    Sharples LD, Tamm M, McNeil K, Higenbottam TW, Stewart S, Wallwork J. Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation—early risk factors. Transplantation. 1996;61:560–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Hodge S, Holmes M, Banerjee B, Musk M, Kicic A, Waterer G, et al. Posttransplant bronchiolitis obliterans syndrome is associated with bronchial epithelial to mesenchymal transition. Am J Transplant. 2009;9:727–33.PubMedCrossRefGoogle Scholar
  61. 61.
    Hertz MI, Jessurun J, King MB, Savik SK, Murray JJ. Reproduction of the obliterative bronchiolitis lesion after heterotopic transplantation of mouse airways. Am J Pathol. 1993;142:1945–51.PubMedGoogle Scholar
  62. 62.
    Cao H, Lan Q, Shi Q, Zhou X, Liu G, Liu J, et al. Anti-IL-23 antibody blockade of IL-23/IL-17 pathway attenuates airway obliteration in rat orthotopic tracheal transplantation. Int Immunopharmacol. 2011;11:569–75.PubMedCrossRefGoogle Scholar
  63. 63.
    Deuse T, Schrepfer S, Reichenspurner H, Hoyt G, Fischbein MP, Robbins RC, et al. Techniques for experimental heterotopic and orthotopic tracheal transplantations—when to use which model? Transpl Immunol. 2007;17:255–61.PubMedCrossRefGoogle Scholar
  64. 64.
    Sato M, Hirayama S, Hwang DM, Lara-Guerra H, Wagnetz D, Waddell TK, et al. The role of intrapulmonary de novo lymphoid tissue in obliterative bronchiolitis after lung transplantation. J Immunol. 2009;182:7307–16.PubMedCrossRefGoogle Scholar
  65. 65.
    Sato M, Hirayama S, Lara-Guerra H, Anraku M, Waddell TK, Liu M, et al. MMP-dependent migration of extrapulmonary myofibroblast progenitors contributing to posttransplant airway fibrosis in the lung. Am J Transplant. 2009;9:1027–36.PubMedCrossRefGoogle Scholar
  66. 66.
    Sato M, Liu M, Anraku M, Ogura T, D’Cruz G, Alman BA, et al. Allograft airway fibrosis in the pulmonary milieu: a disorder of tissue remodeling. Am J Transplant. 2008;8:517–28.PubMedCrossRefGoogle Scholar
  67. 67.
    Asimacopoulos PJ, Molokhia FA, Pegg CA, Norman JC. Lung transplantation in the rat. Transplant Proc. 1971;3:583–5.PubMedGoogle Scholar
  68. 68.
    Zhai W, Ge J, Inci I, Hillinger S, Markus C, Korom S, et al. Simplified rat lung transplantation by using a modified cuff technique. J Invest Surg. 2008;21:33–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Matsumura Y, Marchevsky A, Zuo XJ, Kass RM, Matloff JM, Jordan SC. Assessment of pathological changes associated with chronic allograft rejection and tolerance in two experimental models of rat lung transplantation. Transplantation. 1995;59:1509–17.PubMedGoogle Scholar
  70. 70.
    Jungraithmayr WM, Korom S, Hillinger S, Weder W. A mouse model of orthotopic, single-lung transplantation. J Thorac Cardiovasc Surg. 2009;137:486–91.PubMedCrossRefGoogle Scholar
  71. 71.
    Okazaki M, Krupnick AS, Kornfeld CG, Lai JM, Ritter JH, Richardson SB, et al. A mouse model of orthotopic vascularized aerated lung transplantation. Am J Transplant. 2007;7:1672–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Suzuki H, Fan L, Wilkes DS. Development of obliterative bronchiolitis in a murine model of orthotopic lung transplantation. J Vis Exp. 2012;(65). pii: 3947.Google Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Pulmonary and Critical Care MedicineUniversity of Michigan Health SystemAnn ArborUSA
  2. 2.Department of Internal MedicineUniversity of MichiganAnn ArborUSA

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