Emerging Therapeutic Targets and Therapies in Idiopathic Pulmonary Fibrosis

  • Vineela Parvathaneni
  • Snehal K. Shukla
  • Vivek GuptaEmail author
Part of the Molecular and Translational Medicine book series (MOLEMED)


The human respiratory system is primarily comprised of airways and lungs which work efficiently in sync to promote efficient gaseous exchange. While the tissues of the respiratory system, especially lungs, provide a vast surface area which is instrumental in efficient gaseous exchange and drug absorption, this attribute also inadvertently exposes the respiratory system to the outside environment and hence imposes higher potential for injury and infections. Any injury (including infections) to any of the components of the respiratory system will affect the primary function of the respiratory system, leading to respiratory disorders. One of the major classes of restrictive lung diseases is known as “interstitial lung disease (ILD),” which is comprised of more than 200 lung diseases, characterized by involvement of the lung interstitium. One of the primary disorders classified as ILD is idiopathic pulmonary fibrosis (IPF), a fatal disorder characterized by the continued decline in lung function. While the underlying disease mechanisms in IPF are mostly unknown, however, it is characterized by the progressive scarring of both lungs. This scarring results in alveolar epithelial cell injury, the formation of myofibroblast foci, and buildup of extracellular matrix in the lung parenchyma leading to scarring (thickening) of the lungs. Numerous clinical trials are still in progress to develop a medication to treat this disease. In this chapter, we summarize the state of the art of IPF therapies from preclinical animals through human clinical trials. We present evidence for the role of co-occurring disorders (i.e., gastroesophageal reflux disease, pulmonary hypertension, cardiovascular disease, osteoporosis, infectious agents, and other genetic factors) on the severity of the progression of human IPF disease. We then discuss the evolving therapeutic targets, including alveolar epithelial cell injury, WNT/beta-catenin signaling, MMPs, and how these related to the traditional therapies like corticosteroids and immunomodulators with new treatments including anticoagulants, antifibrotic agents, antioxidants, and beyond which hold promise for future therapies and understanding of the pathogenesis of IPF.


Therapy Lung Idiopathic pulmonary fibrosis Gastroesophageal reflux disease GERD Cardiovascular disease Osteoporosis Transforming growth factor-β (TGF-β) Matrix metalloproteinases (MMP) 


  1. 1.
    Celis EA. Lung anatomy: overview, gross anatomy, microscopic anatomy. 2017 [cited 2017 Dec 10]; Available from:
  2. 2.
    Barrett KE, Barman SM, Boitano S, Brooks HL. Introduction to pulmonary structure & mechanics. Ganong’s review of medical physiology, 25e. Access Pharmacy. McGraw-Hill Medical [Internet]. [cited 2017 Dec 10]. Available from:
  3. 3.
    Gerdin J. Health careers today – E-Book. Elsevier Health Sciences; 2013. 673 p.Google Scholar
  4. 4.
    Morton DA, Bo Foreman K, Albertine KH. Chapter 3. Lungs, The big picture: gross anatomy, AccessPharmacy. McGraw-Hill Medical [Internet]. [cited 2017 Dec 10]. Available from:
  5. 5.
    Vaidya B, Patel R, Muth A, Gupta V. Exploitation of novel molecular targets to treat idiopathic pulmonary fibrosis: a drug discovery perspective. Curr Med Chem. 2017;24(22):2439–58.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Chesnutt MS, Prendergast TJ. Pulmonary disease. Pathophysiology of disease: an introduction to clinical medicine, 7e. AccessPharmacy. McGraw-Hill Medical [Internet]. [cited 2017 Dec 10]. Available from:
  7. 7.
    American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165(2):277–304.CrossRefGoogle Scholar
  8. 8.
    Ryu JH, Moua T, Azadeh N, Baqir M, Yi ES. Current concepts and dilemmas in idiopathic interstitial pneumonias. F1000Res [Internet]. 2016;5. Available from:
  9. 9.
    Vancheri C. Common pathways in idiopathic pulmonary fibrosis and cancer. Eur Respir Rev. 2013;22(129):265–72.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Mujakperuo H, McGrath EE, Thickett DR. Co-trimoxazole for idiopathic pulmonary fibrosis: time for TIPAC-2? Thorax. 2013;68(2):123–4.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Wilson MS, Wynn TA. Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol. 2009;2(2):103–21.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    IPF and lung function – Lungs and you [Internet]. [cited 2017 Dec 10]. Available from:
  13. 13.
    Idiopathic pulmonary fibrosis (IPF) [Internet]. [cited 2017 Dec 10]. Available from:
  14. 14.
    What causes idiopathic pulmonary fibrosis? – NHLBI, NIH [Internet]. [cited 2017 Sep 21]. Available from:
  15. 15.
    Maher TM, Evans IC, Bottoms SE, Mercer PF, Thorley AJ, Nicholson AG, et al. Diminished prostaglandin E2 contributes to the apoptosis paradox in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2010;182(1):73–82.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Gharaee-Kermani M, Phan SH. Molecular mechanisms of and possible treatment strategies for idiopathic pulmonary fibrosis. Curr Pharm Des. 2005;11(30):3943–71.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Karampitsakos T, Woolard T, Bouros D, Tzouvelekis A. Toll-like receptors in the pathogenesis of pulmonary fibrosis. Eur J Pharmacol. 2017;808:35–43.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Martinez FJ, Collard HR, Pardo A, Raghu G, Richeldi L, Selman M, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Prim. 2017;3:17074.PubMedCrossRefGoogle Scholar
  19. 19.
    Agrawal A, Verma I, Shah V, Agarwal A, Sikachi RR. Cardiac manifestations of idiopathic pulmonary fibrosis. Intractable Rare Dis Res. 2016;5(2):70–5.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Scientists discover treatment target for pulmonary fibrosis [Internet]. [cited 2017 Dec 11]. Available from:
  21. 21.
    Turn CS, Lockey RF, Kolliputi N. Putting the brakes on age-related idiopathic pulmonary fibrosis: can Nox4 inhibitors suppress IPF? Exp Gerontol. 2015;63:81–2.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Raghu G, Craig Johnson W, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone. Am J Respir Crit Care Med. 1999;159(4):1061–9.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Thannickal VJ. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3(4):350–6.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Daccord C, Maher TM. Recent advances in understanding idiopathic pulmonary fibrosis. F1000Research. 2016;5.CrossRefGoogle Scholar
  25. 25.
    Idiopathic pulmonary fibrosis – rare disease quick facts [Internet]. Rare disease report. [cited 2017 Dec 10]. Available from:
  26. 26.
    Leslie KO. Idiopathic pulmonary fibrosis may be a disease of recurrent, tractional injury to the periphery of the aging lung: a unifying hypothesis regarding etiology and pathogenesis. Arch Pathol Lab Med. 2011;136(6):591–600.PubMedCrossRefGoogle Scholar
  27. 27.
    Who gets idiopathic pulmonary fibrosis? What are the causes? [Internet]. Idiopathic pulmonary fibrosis. [cited 2017 Dec 10]. Available from:
  28. 28.
    Atkins CP, Loke YK, Wilson AM. Outcomes in idiopathic pulmonary fibrosis: a meta-analysis from placebo controlled trials. Respir Med. 2014;108(2):376–87.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Idiopathic pulmonary fibrosis [Internet]. [cited 2017 Dec 11]. Available from: pneumonologiki kliniki/article/2478/idiopathis-pneymoniki-inosi.html.
  30. 30.
    Ley B, Collard HR. Epidemiology of idiopathic pulmonary fibrosis. Clin Epidemiol. 2013;5:483–92.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Fernández Pérez ER, Daniels CE, Schroeder DR, St Sauver J, Hartman TE, Bartholmai BJ, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest. 2010;137(1):129–37.PubMedCrossRefGoogle Scholar
  32. 32.
    Lai C-C, Wang C-Y, Lu H-M, Chen L, Teng N-C, Yan Y-H, et al. Idiopathic pulmonary fibrosis in Taiwan – a population-based study. Respir Med. 2012;106(11):1566–74.PubMedCrossRefGoogle Scholar
  33. 33.
    Mannino DM, Etzel RA, Parrish RG. Pulmonary fibrosis deaths in the United States, 1979–1991. An analysis of multiple-cause mortality data. Am J Respir Crit Care Med. 1996;153(5):1548–52.PubMedCrossRefGoogle Scholar
  34. 34.
    Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. 2015;46(3):795–806.PubMedCrossRefGoogle Scholar
  35. 35.
    Sgalla G, Biffi A, Richeldi L. Idiopathic pulmonary fibrosis: diagnosis, epidemiology and natural history. Respirology. 2016;21(3):427–37.PubMedCrossRefGoogle Scholar
  36. 36.
    Spagnolo P, Maher TM. Clinical trial research in focus: why do so many clinical trials fail in IPF? Lancet Respir Med. 2017;5(5):372–4.PubMedCrossRefGoogle Scholar
  37. 37.
    King TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011;378(9807):1949–61.PubMedCrossRefGoogle Scholar
  38. 38.
    Geiser T. Idiopathic pulmonary fibrosis-a disorder of alveolar wound repair? Swiss Med Wkly. 2003;133(29–30):405–11.PubMedGoogle Scholar
  39. 39.
    Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med. 2011;208(7):1339–50.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Xu S, Denton CP, Holmes A, Dashwood MR, Abraham DJ, Black CM. Endothelins: effect on matrix biosynthesis and proliferation in normal and scleroderma fibroblasts. J Cardiovasc Pharmacol. 1998;31(Suppl 1):S360–3.PubMedCrossRefGoogle Scholar
  41. 41.
    Selman M, Pardo A, Kaminski N. Idiopathic pulmonary fibrosis: aberrant recapitulation of developmental programs? PLoS Med. 2008;5(3):e62.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Bringardner BD, Baran CP, Eubank TD, Marsh CB. The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis. Antioxid Redox Signal. 2008;10(2):287–301.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Car BD, Meloni F, Luisetti M, Semenzato G, Gialdroni-Grassi G, Walz A. Elevated IL-8 and MCP-1 in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am J Respir Crit Care Med. 1994;149(3 Pt 1):655–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Ogushi F, Tani K, Maniwa K, Ichikawa W, Tada H, Kawano T, et al. Interleukin-8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis or idiopathic pulmonary fibrosis. J Med Investig. 1997;44(1–2):53–8.Google Scholar
  45. 45.
    Standiford TJ, Rolfe MR, Kunkel SL, Lynch JP 3rd, Becker FS, Orringer MB, et al. Altered production and regulation of monocyte chemoattractant protein-1 from pulmonary fibroblasts isolated from patients with idiopathic pulmonary fibrosis. Chest. 1993;103(2 Suppl):121S.PubMedCrossRefGoogle Scholar
  46. 46.
    Standiford TJ, Rolfe MW, Kunkel SL, Lynch JP, Burdick MD, Gilbert AR, et al. Macrophage inflammatory protein-1 alpha expression in interstitial lung disease. J Immunol. 1993;151(5):2852–63.PubMedGoogle Scholar
  47. 47.
    Magro CM, Waldman WJ, Knight DA, Allen JN, Nadasdy T, Frambach GE, et al. Idiopathic pulmonary fibrosis related to endothelial injury and antiendothelial cell antibodies. Hum Immunol. 2006;67(4–5):284–97.PubMedCrossRefGoogle Scholar
  48. 48.
    Marsh CB, Wewers MD, Tan LC, Rovin BH. Fc(gamma) receptor cross-linking induces peripheral blood mononuclear cell monocyte chemoattractant protein-1 expression: role of lymphocyte Fc(gamma)RIII. J Immunol. 1997;158(3):1078–84.PubMedGoogle Scholar
  49. 49.
    Marsh CB, Gadek JE, Kindt GC, Moore SA, Wewers MD. Monocyte Fc gamma receptor cross-linking induces IL-8 production. J Immunol. 1995;155(6):3161–7.PubMedGoogle Scholar
  50. 50.
    Knipe RS, Tager AM, Liao JK. The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev. 2015;67(1):103–17.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Morimoto K, Janssen WJ, Terada M. Defective efferocytosis by alveolar macrophages in IPF patients. Respir Med. 2012;106(12):1800–3.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol. 2005;166(5):1321–32.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Idiopathic pulmonary fibrosis etiology & risks – insights in IPF [Internet]. [cited 2017 Nov 21]. Available from:
  54. 54.
    Baumgartner KB, Samet JM, Coultas DB, Stidley CA, Hunt WC, Colby TV, et al. Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. Collab Cent Am J Epidemiol. 2000;152(4):307–15.CrossRefGoogle Scholar
  55. 55.
    Oh CK, Murray LA, Molfino NA. Smoking and idiopathic pulmonary fibrosis [Internet]. Pulmonary medicine. 2012 [cited 2018 May 14]. Available from:
  56. 56.
    García-Sancho Figueroa MC, Carrillo G, Pérez-Padilla R, Fernández-Plata MR, Buendía-Roldán I, Vargas MH, et al. Risk factors for idiopathic pulmonary fibrosis in a Mexican population. A case-control study. Respir Med. 2010;104(2):305–9.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Fujimoto H, Kobayashi T, Azuma A. Idiopathic pulmonary fibrosis: treatment and prognosis. Clin Med Insights Circ Respir Pulm Med. 2015;9s1:CCRPM.S23321.Google Scholar
  58. 58.
    Cerri S, Spagnolo P, Luppi F, Sgalla G, Richeldi L. Chapter 4 – Management of idiopathic pulmonary fibrosis. In: Interstitial lung disease [Internet]. Elsevier; 2018. [cited 2017 Sep 16]. p. 55–63. Available from:
  59. 59.
    Gnanapandithan K, Popkin JH, Devadoss R, Martin K. Gastroesophageal reflux and idiopathic pulmonary fibrosis: a long term relationship. Respir Med Case Rep. 2016;17:40–3.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Costabel U, Crestani B, Wells AU. Idiopathic pulmonary fibrosis: ERS Monograph. European Respiratory Society; 2016. 292 p.Google Scholar
  61. 61.
    Smith JS, Perez R, Gorbett D, Mueller J, Daniels CJ. Pulmonary hypertension idiopathic pulmonary fibrosis: a dastardly duo. Am J Med Sci. 2013;346(3):221–5.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Collum SD, Amione-Guerra J, Cruz-Solbes AS, DiFrancesco A, Hernandez AM, Hanmandlu A, et al. Pulmonary hypertension associated with idiopathic pulmonary fibrosis: current and future perspectives [Internet]. Can Respir J. 2017. [cited 2017 Dec 10]. Available from:
  63. 63.
    Dalleywater W, Powell HA, Hubbard RB, Navaratnam V. Risk factors for cardiovascular disease in people with idiopathic pulmonary fibrosis. Chest. 2015;147(1):150–6.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Hubbard RB, Smith C, Le Jeune I, Gribbin J, Fogarty AW. The association between idiopathic pulmonary fibrosis and vascular disease: a population-based study. Am J Respir Crit Care Med. 2008;178(12):1257–61.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Caffarelli C, Gonnelli S, Pitinca MDT, Francolini V, Fui A, Bargagli E, et al. Idiopathic pulmonary fibrosis a rare disease with severe bone fragility. Intern Emerg Med. 2016;11(8):1087–94.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Tanjore H, Cheng D-S, Degryse AL, Zoz DF, Abdolrasulnia R, Lawson WE, et al. Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress. J Biol Chem. 2015;290(6):3277.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Garcia CK. Idiopathic pulmonary fibrosis: update on genetic discoveries. Proc Am Thorac Soc. 2011;8(2):158–62.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Oh CK, Murray LA, Molfino NA. Smoking and idiopathic pulmonary fibrosis [Internet]. Pulm Med. 2012. [cited 2017 Nov 24]. Available from:
  69. 69.
    Kropski JA, Lawson WE, Young LR, Blackwell TS. Genetic studies provide clues on the pathogenesis of idiopathic pulmonary fibrosis. Dis Model Mech. 2013;6(1):9–17.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014;9:157–79.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Moore BB, Moore TA. Viruses in idiopathic pulmonary fibrosis. Etiol Exacerbation Ann Am Thorac Soc. 2015;12(Suppl 2):S186–92.Google Scholar
  72. 72.
    Yamazaki R, Nishiyama O, Sano H, Iwanaga T, Higashimoto Y, Kume H, et al. Clinical features and outcomes of IPF patients hospitalized for pulmonary infection: a Japanese cohort study. Maher TM, editor. Plos One. 2016;11(12):e0168164.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Jakab GJ. Sequential virus infections, bacterial superinfections, and Fibrogenesis. Am Rev Respir Dis. 1990;142(2):374–9.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Folcik VA, Garofalo M, Coleman J, Donegan JJ, Rabbani E, Suster S, et al. Idiopathic pulmonary fibrosis is strongly associated with productive infection by herpesvirus saimiri. Mod Pathol. 2014;27(6):851–62.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Jakab J, Sequential Virus G. Infections, bacterial superinfections, and fibrogenesis. Am Rev Respir Dis. 1990;142:374–9.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Molyneaux PL, Maher TM. The role of infection in the pathogenesis of idiopathic pulmonary fibrosis. Eur Respir Rev. 2013;22(129):376–81.PubMedCrossRefGoogle Scholar
  77. 77.
    Harrison NK. Pulmonary infection in Wegener’s granulomatosis and idiopathic pulmonary fibrosis. Thorax. 2009;64(8):647–9.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Idiopathic pulmonary fibrosis [Internet]. CRC Press. 2003. [cited 2018 May 14]. Available from:
  79. 79.
    Lynch JP. Idiopathic pulmonary fibrosis: CRC Press; 2003. 804 pGoogle Scholar
  80. 80.
    Pardo A, Selman M. Lung fibroblasts, aging, and idiopathic pulmonary fibrosis. Ann Am Thorac Soc. 2016;13(Supplement_5):S417–21.PubMedCrossRefGoogle Scholar
  81. 81.
    Leung J, Cho Y, Lockey RF, Kolliputi N. The role of aging in idiopathic pulmonary fibrosis. Lung. 2015;193(4):605–10.PubMedCrossRefGoogle Scholar
  82. 82.
    Sisson TH, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A, et al. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181(3):254–63.CrossRefGoogle Scholar
  83. 83.
    Camelo A, Dunmore R, Sleeman MA, Clarke DL. The epithelium in idiopathic pulmonary fibrosis: breaking the barrier. Front Pharmacol [Internet]. 2014;4. Available from:
  84. 84.
    Studer SM, Kaminski N. Towards systems biology of human pulmonary fibrosis. Proc Am Thorac Soc. 2007;4(1):85–91.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503–12.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Hodgson U, Pulkkinen V, Dixon M, Peyrard-Janvid M, Rehn M, Lahermo P, et al. ELMOD2 is a candidate gene for familial idiopathic pulmonary fibrosis. Am J Hum Genet. 2006;79(1):149–54.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Pulkkinen V, Bruce S, Rintahaka J, Hodgson U, Laitinen T, Alenius H, et al. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses. FASEB J. 2010;24(4):1167–77.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Kaur A, Mathai SK, Schwartz DA. Genetics in idiopathic pulmonary fibrosis pathogenesis, prognosis, and treatment. Front Med (Lausanne) [Internet]. 2017;4. Available from:
  89. 89.
    Zhang J, Xu D, Xu K, Wu B, Zheng M, Chen J, et al. HLA-A and HLA-B gene polymorphism and idiopathic pulmonary fibrosis in a Han Chinese population. Respir Med. 2012;106(10):1456–62.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Xue J, Gochuico BR, Alawad AS, Feghali-Bostwick CA, Noth I, Nathan SD, et al. The HLA class II Allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. PLoS One. 2011;6(2):e14715.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Wytrychowski K, Hans-Wytrychowska A, Nowakowska B. Familial idiopathic pulmonary fibrosis. In: Neurobiology of respiration [Internet]. Springer, Dordrecht; 2013 [cited 2017 Dec 10]. p. 363–7. (Advances in Experimental Medicine and Biology). Available from:
  92. 92.
    Cadigan KM. Wnt–β-catenin signaling. Curr Biol. 2008;18(20):R943–7.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Piersma B, Bank RA, Boersema M. Signaling in fibrosis: TGF-β, WNT, and YAP/TAZ converge. Front Med [Internet]. 2015. [cited 2017 Dec 11];2. Available from:
  94. 94.
    Königshoff M, Balsara N, Pfaff E-M, Kramer M, Chrobak I, Seeger W, et al. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One. 2008;3(5):e2142.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Chilosi M, Poletti V, Zamò A, Lestani M, Montagna L, Piccoli P, et al. Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol. 2003;162(5):1495–502.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A. 2002;99(9):6292–7.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Santangelo S, Scarlata S, Zito A, Chiurco D, Pedone C, Incalzi RA. Genetic background of idiopathic pulmonary fibrosis. Expert Rev Mol Diagn. 2013;13(4):389–406.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006;103(35):13180–5.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Treatment options [Internet]. [cited 2017 Dec 10]. Available from:
  101. 101.
    Behr J. Evidence-based treatment strategies in idiopathic pulmonary fibrosis. Eur Respir Rev. 2013;22(128):163–8.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Walter N. Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3(4):330–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Raghu G, Rochwerg B, Zhang Y, Garcia CAC, Azuma A, Behr J, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015;192(2):e3–19.PubMedCrossRefGoogle Scholar
  104. 104.
    Johnson MA, Kwan S, Snell NJ, Nunn AJ, Darbyshire JH, Turner-Warwick M. Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax. 1989;44(4):280–8.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Mapel DW, Samet JM, Coultas DB. Corticosteroids and the treatment of idiopathic pulmonary fibrosis: past, present, and future. Chest. 1996;110(4):1058–67.PubMedCrossRefGoogle Scholar
  106. 106.
    Gay SE, Kazerooni EA, Toews GB, Lynch JP, Gross BH, Cascade PN, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med. 1998;157(4 Pt 1):1063–72.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Carrington CB, Gaensler EA, Coutu RE, FitzGerald MX, Gupta RG. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med. 1978;298(15):801–9.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Michaelson JE, Aguayo SM, Roman J. Idiopathic pulmonary fibrosis: a practical approach for diagnosis and management. Chest. 2000;118(3):788–94.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Raghu G, Depaso WJ, Cain K, Hammar SP, Wetzel CE, Dreis DF, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis. 1991;144(2):291–6.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Lynch JP, McCune WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med. 1997;155(2):395–420.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Yasui H, Gabazza EC, Taguchi O, Risteli J, Risteli L, Wada H, et al. Decreased protein C activation is associated with abnormal collagen turnover in the Intraalveolar space of patients with interstitial lung disease. Clin Appl Thromb Hemost. 2000;6(4):202–5.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Hernández-Rodríguez NA, Cambrey AD, Harrison NK, Chambers RC, Gray AJ, Southcott AM, et al. Role of thrombin in pulmonary fibrosis. Lancet. 1995;346(8982):1071–3.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Lin C, von der Thüsen J, van der Poll T, Borensztajn K, Spek CA. Increased mortality during bleomycin-induced pulmonary fibrosis due to low endogenous activated protein C levels. Am J Respir Crit Care Med. 2015;192(10):1257–9.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Günther A, Lübke N, Ermert M, Schermuly RT, Weissmann N, Breithecker A, et al. Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits. Am J Respir Crit Care Med. 2003;168(11):1358–65.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest J. 2005;128(3):1475–82.CrossRefGoogle Scholar
  116. 116.
    Tomassetti S, Ruy JH, Gurioli C, Ravaglia C, Buccioli M, Tantalocco P, et al. The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice. Sarcoidosis Vasc Diffuse Lung Dis. 2013;30(2):121–7.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Entzian P, Schlaak M, Seitzer U, Bufe A, Acil Y, Zabel P. Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis. Lung. 1997;175(1):41–51.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Douglas WW, Ryu JH, Bjoraker JA, Schroeder DR, Myers JL, Tazelaar HD, et al. Colchicine versus prednisone as treatment of usual interstitial pneumonia. Mayo Clin Proc. 1997;72(3):201–9.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2000;161(4):1172–8.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Geismar LS, Hennessey S, Reiser KM, Last JA. D-Penicillamine prevents collagen accumulation in lungs of rats given bleomycin. Chest. 1986;89(3, Supplement):153S–4S.PubMedCrossRefGoogle Scholar
  121. 121.
    Ward WF, Shih-Hoellwarth A, Tuttle RD. Collagen accumulation in irradiated rat lung: modification by D-penicillamine. Radiology. 1983;146(2):533–7.PubMedCrossRefGoogle Scholar
  122. 122.
    Selman M, Carrillo G, Salas J, Padilla RP, Pérez-Chavira R, Sansores R, et al. Colchicine, D-Penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. Chest. 1998;114(2):507–12.PubMedCrossRefGoogle Scholar
  123. 123.
    Kolb M, Bonella F, Wollin L. Therapeutic targets in idiopathic pulmonary fibrosis. Respir Med. 2017;131:49–57.PubMedCrossRefGoogle Scholar
  124. 124.
    Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther. 1999;291(1):367–73.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Rasooli R, Pourgholamhosein F, Kamali Y, Nabipour F, Mandegary A. Combination therapy with pirfenidone plus prednisolone ameliorates paraquat-induced pulmonary fibrosis. Inflammation. 2017.Google Scholar
  126. 126.
    Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760–9.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):821–9.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Gurujeyalakshmi G, Giri SN. Molecular mechanisms of Antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-β and procollagen I and III gene expression. Exp Lung Res. 1995;21(5):791–808.PubMedCrossRefGoogle Scholar
  129. 129.
    Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 1999;341(17):1264–9.PubMedCrossRefGoogle Scholar
  130. 130.
    Okada T, Sugie I, Aisaka K. Effects of gamma-interferon on collagen and histamine content in bleomycin-induced lung fibrosis in rats. Lymphokine Cytokine Res. 1993;12(2):87–91.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Rafii R, Juarez MM, Albertson TE, Chan AL. A review of current and novel therapies for idiopathic pulmonary fibrosis. J Thorac Dis. 2013;5(1):48–73.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Piguet PF, Collart MA, Grau GE, Kapanci Y, Vassalli P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med. 1989;170(3):655–63.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Raghu G, Brown KK, Costabel U, Cottin V, du Bois RM, Lasky JA, et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am J Respir Crit Care Med. 2008;178(9):948–55.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Buchdunger E, O’Reilley T, Wood J. Pharmacology of imatinib (STI571). Eur J Cancer. 2002;38(Supplement 5):S28–36.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Daniels CE, Wilkes MC, Edens M, Kottom TJ, Murphy SJ, Limper AH, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis. J Clin Invest. 2004;114(9):1308–16.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Aono Y, Nishioka Y, Inayama M, Ugai M, Kishi J, Uehara H, et al. Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med. 2005;171(11):1279–85.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Azuma M, Nishioka Y, Aono Y, Inayama M, Makino H, Kishi J, et al. Role of α1-acid glycoprotein in therapeutic antifibrotic effects of imatinib with macrolides in mice. Am J Respir Crit Care Med. 2007;176(12):1243–50.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Myllärniemi M, Kaarteenaho R. Pharmacological treatment of idiopathic pulmonary fibrosis – preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine. Eur Clin Respir J [Internet]. 2015;2. Available from:
  139. 139.
    Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder DR. Imatinib treatment for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181(6):604–10.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Chaudhary NI, Roth GJ, Hilberg F, Müller-Quernheim J, Prasse A, Zissel G, et al. Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur Respir J. 2007;29(5):976–85.PubMedCrossRefGoogle Scholar
  141. 141.
    Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014;349(2):209–20.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079–87.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Tepede A, Yogaratnam D. Nintedanib for idiopathic pulmonary fibrosis. J Pharm Pract. 2017;897190017735242.Google Scholar
  144. 144.
    Meyer A, Buhl R, Magnussen H. The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis. Eur Respir J. 1994;7(3):431–6.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Zhang L, He Y-L, Li Q-Z, Hao X-H, Zhang Z-F, Yuan J-X, et al. N-acetylcysteine alleviated silica-induced lung fibrosis in rats by down-regulation of ROS and mitochondrial apoptosis signaling. Toxicol Mech Methods. 2014;24(3):212–9.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353(21):2229–42.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Network TIPFCR. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968–77.CrossRefGoogle Scholar
  148. 148.
    Wang Q, Zhu H, Zhou W-G, Guo X-C, Wu M-J, Xu Z-Y, et al. N-acetylcysteine-pretreated human embryonic mesenchymal stem cell administration protects against bleomycin-induced lung injury. Am J Med Sci. 2013;346(2):113–22.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Montes E, Ruiz V, Checa M, Maldonado V, Melendez-Zajgla J, Montaño M, et al. Renin is an angiotensin-independent profibrotic mediator: role in pulmonary fibrosis. Eur Respir J. 2012;39(1):141–8.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Ward WF, Molteni A, Ts’ao CH, Hinz JM. Captopril reduces collagen and mast cell accumulation in irradiated rat lung. Int J Radiat Oncol Biol Phys. 1990;19(6):1405–9.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Ward WF, Molteni A, Ts’ao C-H, Kim YT, Hinz JM. Radiation pneumotoxicity in rats: modification by inhibitors of angiotensin converting enzyme. Int J Radiat Oncol Biol Phys. 1992;22(3):623–5.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Marshall RP, Gohlke P, Chambers RC, Howell DC, Bottoms SE, Unger T, et al. Angiotensin II and the fibroproliferative response to acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2004;286(1):L156–64.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Nguyen L, Ward WF, Ts’ao C-H, Molteni A. Captopril inhibits proliferation of human lung fibroblasts in culture: a potential antifibrotic mechanism. Proc Soc Exp Biol Med. 1994;205(1):80–4.PubMedCrossRefGoogle Scholar
  154. 154.
    Uhal BD, Gidea C, Bargout R, Bifero A, Ibarra-Sunga O, Papp M, et al. Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. Am J Phys. 1998;275(5 Pt 1):L1013–7.Google Scholar
  155. 155.
    Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136.CrossRefGoogle Scholar
  156. 156.
    Molina-Molina M. Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin E2 synthesis. Thorax. 2006;61(7):604–10.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Couluris M, Kinder BW, Xu P, Gross-King M, Krischer J, Panos RJ. Treatment of idiopathic pulmonary fibrosis with losartan: a pilot project. Lung. 2012;190(5):523–7.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Losartan in treating patients with idiopathic pulmonary fibrosis – study results – [Internet]. [cited 2017 Dec 10]. Available from:
  159. 159.
    Uguccioni M, Pulsatelli L, Grigolo B, Facchini A, Fasano L, Cinti C, et al. Endothelin-1 in idiopathic pulmonary fibrosis. J Clin Pathol. 1995;48(4):330–4.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med. 1997;156(2 Pt 1):600–8.PubMedCrossRefGoogle Scholar
  161. 161.
    King TE, Behr J, Brown KK, du Bois RM, Lancaster L, de Andrade JA, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;177(1):75–81.PubMedCrossRefGoogle Scholar
  162. 162.
    King TE, Brown KK, Raghu G, du Bois RM, Lynch DA, Martinez F, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(1):92–9.PubMedCrossRefGoogle Scholar
  163. 163.
    Costabel U, Bonella F. Treatment of pulmonary fibrosis. New substances and new interventions. Internist (Berl). 2011;52(12):1422–8.CrossRefGoogle Scholar
  164. 164.
    Selman M, Ruiz V, Cabrera S, Segura L, Ramírez R, Barrios R, et al. TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? Am J Phys Lung Cell Mol Phys. 2000;279(3):L562–74.Google Scholar
  165. 165.
    Fujita M, Ye Q, Ouchi H, Harada E, Inoshima I, Kuwano K, et al. Doxycycline attenuated pulmonary fibrosis induced by bleomycin in mice. Antimicrob Agents Chemother. 2006;50(2):739–43.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Fujita H, Sakamoto N, Ishimatsu Y, Kakugawa T, Hara S, Hara A, et al. Effects of doxycycline on production of growth factors and matrix metalloproteinases in pulmonary fibrosis. Respiration. 2011;81(5):420–30.PubMedCrossRefGoogle Scholar
  167. 167.
    Mishra A, Bhattacharya P, Paul S, Paul R, Swarnakar S. An alternative therapy for idiopathic pulmonary fibrosis by doxycycline through matrix metalloproteinase inhibition. Lung India. 2011;28(3):174–9.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Bhattacharyya P, Nag S, Bardhan S, Acharya D, Paul R, Dey R, et al. The role of long-term doxycycline in patients of idiopathic pulmonaryfibrosis: the results of an open prospective trial. Lung India. 2009;26(3):81–5.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27(1):136–42.PubMedCrossRefGoogle Scholar
  170. 170.
    Lee JS. The role of gastroesophageal reflux and microaspiration in idiopathic pulmonary fibrosis. Clin Pulm Med. 2014;21(2):81–5.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Embarak S, Farag SE, Bihery AS, Ahmed AF, Yousef HY. Characteristics of gastro-esophageal reflux in patients with idiopathic pulmonary fibrosis. Egypt J Chest Dis Tuberc. 2015;64(2):505–11.CrossRefGoogle Scholar
  172. 172.
    Lee JS, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(12):1390–4.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Toonkel RL, Hare JM, Matthay MA, Glassberg MK. Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am J Respir Crit Care Med. 2013;188(2):133–40.CrossRefGoogle Scholar
  174. 174.
    Ortiz LA, DuTreil M, Fattman C, Pandey AC, Torres G, Go K, et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. PNAS. 2007;104(26):11002–7.PubMedCrossRefGoogle Scholar
  175. 175.
    Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, et al. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol. 2009;175(1):303–13.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH. Bone marrow–derived progenitor cells in pulmonary fibrosis. J Clin Invest. 2004;113(2):243–52.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Zhang C, Yin X, Zhang J, Ao Q, Gu Y, Liu Y. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe idiopathic pulmonary fibrosis: a case report. Exp Ther Med. 2017;13(5):1922–6.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Henderson WR, Chi EY, Ye X, Nguyen C, Tien Y-T, Zhou B, et al. Inhibition of Wnt/ -catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc Natl Acad Sci. 2010;107(32):14309–14.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Königshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, et al. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest. 2009;119(4):772–87.PubMedPubMedCentralGoogle Scholar
  180. 180.
    Kim TH, Kim S-H, Seo J-Y, Chung H, Kwak HJ, Lee S-K, et al. Blockade of the Wnt/β-catenin pathway attenuates bleomycin-induced pulmonary fibrosis. Tohoku J Exp Med. 2011;223(1):45–54.PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Yamada Y, Takanashi M, Sudo K, Ueda S, Ohno S, Kuroda M. Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis. PLoS One. 2017;12(2):e0171957.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Merlo CA, Weiss ES, Orens JB, Borja MC, Diener-West M, Conte JV, et al. Impact of U.S. lung allocation score on survival after lung transplantation. J Heart Lung Transplant. 2009;28(8):769–75.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Kistler KD, Nalysnyk L, Rotella P, Esser D. Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature. BMC Pulm Med. 2014;14:139.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Leuschner G, Stocker F, Veit T, Kneidinger N, Winter H, Schramm R, et al. Outcome of lung transplantation in idiopathic pulmonary fibrosis with previous anti-fibrotic therapy. J Heart Lung Transplant. 2017.Google Scholar
  185. 185.
    Fujimoto H, Kobayashi T, Azuma A. Idiopathic pulmonary fibrosis: treatment and prognosis. Clin Med Insights Circ Respir Pulm Med. 2016;9(Suppl 1):179–85.PubMedPubMedCentralGoogle Scholar
  186. 186.
    Nishiyama O, Kondoh Y, Kimura T, Kato K, Kataoka K, Ogawa T, et al. Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis. Respirology. 2008;13(3):394–9.PubMedCrossRefPubMedCentralGoogle Scholar
  187. 187.
    Swigris JJ, Brown KK, Make BJ, Wamboldt FS. Pulmonary rehabilitation in idiopathic pulmonary fibrosis: a call for continued investigation. Respir Med. 2008;102(12):1675–80.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    2312_Gross_Anatomy_of_the_Lungs.jpg (JPEG Image, 1280 × 880 pixels) – Scaled (80%) [Internet]. [cited 2017 Dec 18]. Available from:
  189. 189.
    Ipf_NIH.jpg (JPEG Image, 475 × 516 pixels) [Internet]. [cited 2017 Dec 18]. Available from:
  190. 190.
    Wu Y-S, Chen S-N. Apoptotic cell: linkage of inflammation and wound healing. Front Pharmacol [Internet]. 2014 [cited 2017 Dec 18];5. Available from:
  191. 191.
    Tanjore H, Lawson WE, Blackwell TS. Endoplasmic reticulum stress as a pro-fibrotic Stimulus. Biochim Biophys Acta. 2013;1832(7):940–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Vineela Parvathaneni
    • 1
  • Snehal K. Shukla
    • 1
  • Vivek Gupta
    • 1
    Email author
  1. 1.College of Pharmacy and Health SciencesSt. John’s UniversityQueensUSA

Personalised recommendations