Skip to main content
SpringerLink
Log in

Pharmacologic Treatment of IPF

  • Chapter
  • First Online:
Idiopathic Pulmonary Fibrosis

Part of the book series: Respiratory Medicine ((RM))

Abstract

The pathogenetic mechanisms leading to lung fibrosis in idiopathic pulmonary fibrosis (IPF) are mostly unknown. The old paradigm of inflammation has been substantially replaced by hypotheses of dysregulated wound healing with an excessive production of extracellular matrix. The lack of a complete comprehension of pathological mechanisms and the development of new hypotheses has led to a change in pharmacological approaches over the last two decades. The International Consensus Statement on IPF Diagnosis and Treatment published in 2000 established a standardized definition of IPF for the first time. This statement suggested possible benefit with a treatment regimen consisting of prednisone, azathioprine, or cyclophosphamide. However, the subsequent guideline published in 2011 stated that the use of aggressive immunosuppressive and cytotoxic treatment regimens has largely failed to reduce the death rate in patients with IPF. The 2015 American Thoracic Society (ATS)/European Respiratory Society (ERS)/ Japanese Respiratory Society (JRS)/Latin American Thoracic Society (ALAT) clinical practice guideline that updated the 2011 guideline formulated a conditional recommendation for the use of either pirfenidone or nintedanib. This recommendation was based upon a new pathogenetic model where aberrant reparative mechanisms and fibrotic processes play a pivotal role in IPF pathogenesis. For the first time, an IPF-specific therapy was recommended, and new standards for therapy were established. The antifibrotic drugs, pirfenidone and nintedanib, can slow disease progression but have failed to arrest or reverse the disease course, which is probably related to the pathological heterogeneity of IPF. Many molecular pathways have been identified and could be potential targets for novel agents. The challenge of the next decade will be to develop targeted therapies against specific pathways. The aim of this chapter is to examine the evolution of IPF treatment during the last two decades, evaluate past treatments and the reasons why they were ineffective, present current approaches to disease management, and identify ongoing clinical trials with novel investigational drugs that target putative pathogenetic mechanisms of disease. Finally, current and potential strategies to treat and prevent acute exacerbations of IPF are reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med [Internet]. 2011;183(6):788–824. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21471066.

  2. Raghu G, Rochwerg B, Zhang Y, 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 [Internet]. 2015 [cited 2017 May 29];192(2):e3–e19. https://doi.org/10.1164/rccm.201506-1063ST.

    Article  PubMed  Google Scholar 

  3. Idiopathic pulmonary fibrosis: diagnosis and treatment. Am J Respir Crit Care Med. [Internet] 2000 [cited 2017 May 28];161(2):646–664. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10673212.

  4. McAnulty RJ, Laurent GJ. Pathogenesis of lung fibrosis and potential new therapeutic strategies. Exp Nephrol [Internet]. [cited 2017 May 28]3(2):96–107. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7773645

  5. Mapel DW, Samet JM, Coultas DB. Corticosteroids and the treatment of idiopathic pulmonary fibrosis. Past, present, and future. Chest [Internet]. 1996 [cited 2017 May 28];110(4):1058–67. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8874268.

  6. B.T. SOCIETY and S.O. COMMITTEE. The diagnosis, assessment and treatment of diffuse parenchymal lung disease in adults. Introduction. Thorax [Internet] 1999 [cited 2017 May 28];54 Suppl 1:S1–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11006787.

    Article  PubMed Central  Google Scholar 

  7. Hanson D, Winterbauer RH, Kirtland SH, Wu R. Changes in pulmonary function test results after 1 year of therapy as predictors of survival in patients with idiopathic pulmonary fibrosis. Chest [Internet]. 1995 [cited 2017 May 28];108(2):305–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7634857.

    Article  CAS  PubMed  Google Scholar 

  8. Richeldi L, Davies HRHR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. [Internet] 2003 [cited 2017 May 28];(3):CD002880. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12917934.

  9. Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: clinical features and their influence on survival. Thorax [Internet]. 1980 [cited 2017 May 28];35(3):171–80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7385089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med [Internet]. 2000 [cited 2017 Jun 12];161(4 I):1172–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10764308.

    Article  CAS  PubMed  Google Scholar 

  11. Raghu G, Depaso WJ, Cain K, 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 [Internet]. 1991 [cited 2017 May 29];144(2):291–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1859050.

    Article  CAS  PubMed  Google Scholar 

  12. Flaherty KR, Toews GB, Lynch JP, et al. Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med [Internet]. 2001 [cited 2017 May 29];110(4):278–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11239846.

  13. Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: response to corticosteroid treatment and its effect on survival. Thorax [Internet]. 1980 [cited 2017 May 29];35(8):593–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7444826.

  14. Shah NR, Noble P, Jackson RM, et al. A critical assessment of treatment options for idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffus lung Dis Off J WASOG [Internet]. 2005 [cited 2017 May 29];22(3):167–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16315778.

  15. 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 [Internet]. 1989 [cited 2017 May 29];44(4):280–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2669218.

  16. Zisman DA, Lynch JP 3rd, Toews GB, Kazerooni EA, Flint A, Martinez FJ. Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids. Chest [Internet]. 2000 [cited 2017 May 29];117(6):1619–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10858393.

    Article  CAS  PubMed  Google Scholar 

  17. Baughman RP, Lower EE. Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis. Chest [Internet]. 1992 [cited 2017 May 29];102(4):1090–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1395749.

  18. Collard HR, Ryu JH, Douglas WW, et al. Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest [Internet]. 2004 [cited 2017 May 29];125(6):2169–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15189938.

  19. Lynch JP, McCune WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med [Internet]. 1997 [cited 2017 May 28];155(2):395–420. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9032171.

    Article  PubMed  Google Scholar 

  20. Zhang L, Zhu Y, Luo W, Xi P, Yan Y. The protective effect of colchicine on bleomycin-induced pulmonary fibrosis in rats. Chin Med Sci J Chung-kuo i hsueh k’o hsueh tsa chih [Internet]. 1992 [cited 2017 May 29];7(1):58–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1384784.

  21. Rennard SI, Bitterman PB, Ozaki T, Rom WN, Crystal RG. Colchicine suppresses the release of fibroblast growth factors from alveolar macrophages in vitro. The basis of a possible therapeutic approach of the fibrotic disorders. Am Rev Respir Dis [Internet]. 1988 [cited 2017 May 29];137(1):181–5. https://doi.org/10.1164/ajrccm/137.1.181.

    Article  CAS  PubMed  Google Scholar 

  22. Douglas WW, Ryu JH, Swensen SJ, et al. Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. A randomized prospective study. Members of the Lung Study Group. Am J Respir Crit Care Med [Internet]. 1998 [cited 2017 May 29];158(1):220–5. https://doi.org/10.1164/ajrccm.158.1.9709089.

    Article  CAS  PubMed  Google Scholar 

  23. Selman M, Carrillo G, Salas J, et al. Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. Chest [Internet]. 1998 [cited 2017 May 29];114(2):507–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9726738.

    Article  CAS  PubMed  Google Scholar 

  24. Peters SG, McDougall JC, Douglas WW, Coles DT, DeRemee RA. Colchicine in the treatment of pulmonary fibrosis. Chest [Internet]. 1993 [cited 2017 May 29];103(1):101–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8417861.

  25. Addrizzo-Harris DJ, Harkin TJ, Tchou-Wong KM, et al. Mechanisms of colchicine effect in the treatment of asbestosis and idiopathic pulmonary fibrosis. Lung [Internet]. 2002 [cited 2017 May 29];180(2):61–72. https://doi.org/10.1007/s004080000083.

    Article  CAS  PubMed  Google Scholar 

  26. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med [Internet]. 2005 [cited 2017 May 29];353(21):2229–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16306520

    Article  CAS  PubMed  Google Scholar 

  27. Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N -acetylcysteine for pulmonary fibrosis. N Engl J Med [Internet]. 2012 [cited 2017 Jun 12];366(21):1968–77. https://doi.org/10.1056/NEJMoa1113354.

  28. Montuschi P, Ciabattoni G, Paredi P, et al. 8-Isoprostane as a biomarker of oxidative stress in interstitial lung diseases. Am J Respir Crit Care Med [Internet]. 1998 [cited 2017 Jun 13];158(5 PART I):1524–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9817703.

    Article  CAS  PubMed  Google Scholar 

  29. Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med [Internet]. 1997 [cited 2017 May 29];156(6):1897–901. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9412572.

    Article  CAS  PubMed  Google Scholar 

  30. The Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med [Internet]. 2014 [cited 2017 Jun 13];370(22):2093–101. https://doi.org/10.1056/NEJMoa1401739.

  31. Homma S, Azuma A, Taniguchi H, et al. Efficacy of inhaled N-acetylcysteine monotherapy in patients with early stage idiopathic pulmonary fibrosis. Respirology [Internet]. 2012 [cited 2017 Jun 13];17(3):467–77. https://doi.org/10.1111/j.1440-1843.2012.02132.x.

    Article  PubMed  Google Scholar 

  32. Noth I, Zhang Y, Ma S-F, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med [Internet]. 2013 [cited 2017 Jun 12];1(4):309–17. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24429156.

  33. Oldham JM, Ma S-F, Martinez FJ, et al. TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med [Internet]. 2015 [cited 2017 Jun 12];192(12):1475–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26331942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Narayanan AS, Whithey J, Souza A, Raghu G. Effect of gamma-interferon on collagen synthesis by normal and fibrotic human lung fibroblasts. Chest [Internet]. 1992 [cited 2017 May 18];101(5):1326–31. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1582292.

  35. Prior C, Haslam PL. In vivo levels and in vitro production of interferon-gamma in fibrosing interstitial lung diseases. Clin Exp Immunol [Internet]. 1992 [cited 2017 May 17];88(2):280–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1572093.

    Article  Google Scholar 

  36. Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block L-H. 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 [Internet]. 1999 [cited 2017 May 17];341(17):1264–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10528036.

    Article  CAS  PubMed  Google Scholar 

  37. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med [Internet]. 2004 [cited 2017 May 17];350(2):125–33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14711911.

    Article  CAS  PubMed  Google Scholar 

  38. King TE, Albera C, Bradford WZ, et al. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet [Internet]. 2009 [cited 2017 May 18];374(9685):222–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19570573.

    Article  CAS  Google Scholar 

  39. Spagnolo P, Giovane C Del, Luppi F, et al. Non-steroid agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. [Internet] 2010 [cited 2017 May 18];(9):CD003134. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20824834.

  40. Crooks MG, Hart SP. Coagulation and anticoagulation in idiopathic pulmonary fibrosis. Eur Respir Rev [Internet]. 2015;24(137):392–9. Available from: http://err.ersjournals.com/content/24/137/392.

    Article  PubMed  Google Scholar 

  41. Navaratnam V, Fogarty AW, McKeever T, et al. Presence of a prothrombotic state in people with idiopathic pulmonary fibrosis: a population-based case–control study. Thorax [Internet]. 2014 [cited 2017 May 18];69(3):207–15. https://doi.org/10.1136/thoraxjnl-2013-203740.

    Article  PubMed  Google Scholar 

  42. Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest [Internet]. 2005 [cited 2017 May 19];128(3):1475–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16162746.

    Article  CAS  PubMed  Google Scholar 

  43. Noth I, Anstrom KJ, Calvert SB, et al. A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med [Internet]. 2012 [cited 2017 May 19];186(1):88–95. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22561965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kreuter M, Wijsenbeek MS, Vasakova M, et al. Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis. Eur Respir J [Internet]. 2016 [cited 2017 May 19];47(6):1776–84. https://doi.org/10.1183/13993003.01482-2016.

    Article  PubMed  Google Scholar 

  45. Shea BS, Probst CK, Brazee PL, et al. Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis. JCI Insight. [Internet] 2017 [cited 2017 May 19];2(9). Available from: http://www.ncbi.nlm.nih.gov/pubmed/28469072.

  46. Schuliga M, Jaffar J, Berhan A, et al. Annexin A2 contributes to lung injury and fibrosis by augmenting factor Xa fibrogenic activity. Am J Phys Lung Cell Mol Phys [Internet]. 2017 [cited 2017 May 19];312(5):L772–82. https://doi.org/10.1152/ajplung.00553.2016.

    Article  PubMed  Google Scholar 

  47. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet [Internet]. 2002 [cited 2017 May 19];360(9337):895–900. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12354470.

    Article  CAS  Google Scholar 

  48. Milara J, Escrivá J, Ortiz JL, et al. Vascular effects of sildenafil in patients with pulmonary fibrosis and pulmonary hypertension: an ex vivo/in vitro study. Eur Respir J [Internet]. 2016 [cited 2017 May 20];47(6):1737–49. https://doi.org/10.1183/13993003.01259-2015.

    Article  CAS  PubMed  Google Scholar 

  49. Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med [Internet]. 2010 [cited 2017 May 19];363(7):620–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20484178.

  50. Han MK, Bach DS, Hagan PG, et al. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest [Internet]. 2013 [cited 2017 May 20];143(6):1699–708. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0012369213604018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jackson RM, Glassberg MK, Ramos CF, Bejarano PA, Butrous G, Gómez-Marín O. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung [Internet]. 2010 [cited 2017 May 19];188(2):115–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20012639.

  52. Rochwerg B, Neupane B, Zhang Y, et al. Treatment of idiopathic pulmonary fibrosis: a network meta-analysis. 2016 [cited 2017 May 18];14(1):18. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26843176

  53. Fonseca C, Abraham D, Renzoni EA. Endothelin in pulmonary fibrosis. Am J Respir Cell Mol Biol [Internet]. 2011 [cited 2017 May 21];44(1):1–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20448055.

    Article  CAS  PubMed  Google Scholar 

  54. 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 [Internet]. 1997 [cited 2017 May 21];156(2 I):600–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9279246.

    Article  CAS  PubMed  Google Scholar 

  55. King TE, Behr J, Brown KK, et al. BUILD-1: a randomized placebo-controlled trial of Bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med [Internet]. 2008 [cited 2017 May 21];177(1):75–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17901413.

  56. King TE, Brown KK, Raghu G, et al. BUILD-3: a randomized, controlled trial of Bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med [Internet]. 2011 [cited 2017 May 21];184(1):92–9. https://doi.org/10.1164/rccm.201011-1874OC.

    Article  PubMed  Google Scholar 

  57. Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J, MUSIC Study Group. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J [Internet]. 2013 [cited 2017 May 21];42(6):1622–32. https://doi.org/10.1183/09031936.00104612.

    Article  CAS  PubMed  Google Scholar 

  58. Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with Ambrisentan. Ann Intern Med [Internet]. 2013 [cited 2017 May 21];158(9):641. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23648946.

    Article  PubMed  Google Scholar 

  59. Daniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest [Internet]. 2004 [cited 2017 May 22];114(9):1308–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15520863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Daniels CE, Lasky JA, Limper AH, et al. Imatinib treatment for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med [Internet]. 2010 [cited 2017 May 22];181(6):604–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20007927.

    Article  CAS  PubMed  Google Scholar 

  61. Hilberg O, Simonsen U, du Bois R, Bendstrup E. Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis. Clin Respir J [Internet]. 2012 [cited 2017 Jul 20];6(3):131–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22697264.

    Article  CAS  PubMed  Google Scholar 

  62. Conte E, Gili E, Fagone E, Fruciano M, Iemmolo M, Vancheri C. Effect of pirfenidone on proliferation, TGF-β-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts. Eur J Pharm Sci [Internet]. 2014 [cited 2017 Jul 20];58:13–9. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0928098714000840.

    Article  CAS  PubMed  Google Scholar 

  63. Kakugawa T, Mukae H, Hayashi T, et al. Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. Eur Respir J [Internet]. 2004 [cited 2017 Jul 20];24(1):57–65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15293605.

    Article  CAS  PubMed  Google Scholar 

  64. Misra HP, Rabideau C. Pirfenidone inhibits NADPH-dependent microsomal lipid peroxidation and scavenges hydroxyl radicals. Mol Cell Biochem [Internet]. 2000 [cited 2017 Jul 20];204(1–2):119–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10718632.

  65. Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study. Am J Respir Crit Care Med [Internet]. 1999 [cited 2017 Jul 20];159(4 Pt 1):1061–9. https://doi.org/10.1164/ajrccm.159.4.9805017.

    Article  CAS  PubMed  Google Scholar 

  66. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med [Internet]. 2005 [cited 2017 Feb 4];171(9):1040–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15665326.

  67. Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J [Internet]. 2010 [cited 2017 Feb 4];35(4):821–9. https://doi.org/10.1183/09031936.00005209.

    Article  PubMed  CAS  Google Scholar 

  68. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet [Internet]. 2011 [cited 2017 Jul 20];377(9779):1760–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21571362.

  69. King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med [Internet]. 2014;370(22):2083–92. https://doi.org/10.1056/NEJMoa1402582.

    Article  PubMed  CAS  Google Scholar 

  70. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J [Internet]. 2016 [cited 2017 Jul 20];47(1):243–53. https://doi.org/10.1183/13993003.00026-2015.

    Article  PubMed  CAS  Google Scholar 

  71. Nathan SD, Albera C, Bradford WZ, et al. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med [Internet]. 2017 [cited 2017 Jul 20];5(1):33–41. Available from: http://linkinghub.elsevier.com/retrieve/pii/S2213260016303265.

    Article  CAS  PubMed  Google Scholar 

  72. Costabel U, Albera C, Bradford WZ, et al. Analysis of lung function and survival in RECAP: an open-label extension study of pirfenidone in patients with idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffus lung Dis Off J WASOG [Internet]. 2014 [cited 2017 Jul 20];31(3):198–205. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25363219.

  73. Koschel D, Cottin V, Skold M, et al. Pirfenidone post-authorization safety registry (PASSPORT) – interim analysis of IPF treatment. Eur Respir J [Internet]. 2014 [cited 2017 Jul 20];44(Suppl 58):1904. Available from: http://erj.ersjournals.com/content/44/Suppl_58/1904.

  74. Lancaster L, Albera C, Bradford WZ, et al. Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials. BMJ Open Respir Res [Internet]. 2016 [cited 2017 Jul 20];3(1):e000105. https://doi.org/10.1136/bmjresp-2015-000105.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res [Internet]. 2008 [cited 2017 Jul 20];68(12):4774–82. https://doi.org/10.1158/0008-5472.CAN-07-6307.

    Article  CAS  PubMed  Google Scholar 

  76. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med [Internet]. 2011 [cited 2017 Feb 4];365(12):1079–87. https://doi.org/10.1056/NEJMoa1103690.

    Article  CAS  PubMed  Google Scholar 

  77. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med [Internet]. 2014 [cited 2017 Feb 4];370(22):2071–82. https://doi.org/10.1056/NEJMoa1402584.

    Article  PubMed  CAS  Google Scholar 

  78. Corte T, Bonella F, Crestani B, et al. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir Res [Internet]. 2015;16(1):116. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26400368.

  79. Richeldi L, Cottin V, Flaherty KR, et al. Design of the INPULSIS™ trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med [Internet]. 2014 [cited 2017 Jul 20];108(7):1023–30. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0954611114001565.

    Article  PubMed  Google Scholar 

  80. Richeldi L, Cottin V, du Bois RM, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS?? Trials. Respir Med. 2015;113:74–9.

    Article  Google Scholar 

  81. Kolb M, Richeldi L, Behr J, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax [Internet]. 2017 [cited 2017 Jul 20];72(4):340–6. https://doi.org/10.1136/thoraxjnl-2016-208710.

    Article  PubMed  Google Scholar 

  82. Costabel U, Inoue Y, Richeldi L, et al. Efficacy of Nintedanib in idiopathic pulmonary fibrosis across Prespecified subgroups in INPULSIS. Am J Respir Crit Care Med [Internet]. 2016 [cited 2017 Jul 20];193(2):178–85. Available from: http://static.thoracic.org/podcast/AJRCCM-interviews/rccm-201503-0562OC.mp3.

    Article  CAS  PubMed  Google Scholar 

  83. Wuyts WA, Kolb M, Stowasser S, Stansen W, Huggins JT, Raghu G. First data on efficacy and safety of Nintedanib in patients with idiopathic pulmonary fibrosis and forced vital capacity of ≤50% of predicted value. Lung [Internet]. 2016 [cited 2017 Jul 20];194(5):739–43. https://doi.org/10.1007/s00408-016-9912-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Loveman E, Copley VR, Scott DA, Colquitt JL, Clegg AJ, O’Reilly KMA. Comparing new treatments for idiopathic pulmonary fibrosis – a network meta-analysis. BMC Pulm Med [Internet]. 2015 [cited 2017 Jul 20];15(1):37. https://doi.org/10.1186/s12890-015-0034-y.

  85. Canestaro WJ, Forrester SH, Raghu G, Ho L, Devine BE. Drug treatment of idiopathic pulmonary fibrosis systematic review and network meta-analysis. Chest. 2016;149(3):756–66.

    Article  PubMed  Google Scholar 

  86. Linden PA, Gilbert RJ, Yeap BY, et al. Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg [Internet]. 2006 [cited 2017 Jul 20];131(2):438–46. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0022522305017514.

    Article  PubMed  Google Scholar 

  87. Hoppo T, Jarido V, Pennathur A, et al. Antireflux surgery preserves lung function in patients with gastroesophageal reflux disease and end-stage lung disease before and after lung transplantation. Arch Surg [Internet]. 2011 [cited 2017 Jul 20];146(9):1041–7. https://doi.org/10.1001/archsurg.2011.216.

    Article  PubMed  Google Scholar 

  88. Raghu G, Morrow E, Collins BF, et al. Laparoscopic anti-reflux surgery for idiopathic pulmonary fibrosis at a single centre. Eur Respir J [Internet]. 2016 [cited 2017 Jul 20];48(3):826–32. https://doi.org/10.1183/13993003.00488-2016.

    Article  PubMed  Google Scholar 

  89. Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med [Internet]. 2011 [cited 2017 Jul 20];184(12):1390–4. https://doi.org/10.1164/rccm.201101-0138OC.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Lee JS, Collard HR, Anstrom KJ, et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med. 2013;1(5):369–76.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Ghebremariam YT, Cooke JP, Gerhart W, et al. Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. J Transl Med [Internet]. 2015 [cited 2017 Jul 20];13(1):249. Available from: http://www.translational-medicine.com/content/13/1/249.

  92. Lee CM, Lee DH, Ahn BK, et al. Protective effect of proton pump inhibitor for survival in patients with gastroesophageal reflux disease and idiopathic pulmonary fibrosis. J Neurogastroenterol Motil [Internet]. 2016 [cited 2017 Jul 20];22(3):444–51. Available from: http://www.jnmjournal.org/journal/view.html?doi=10.5056/jnm15192

    Article  PubMed  PubMed Central  Google Scholar 

  93. Liu B, Su F, Xu N, Qu T, Li M, Ju Y. Chronic use of anti-reflux therapy improves survival of patients with pulmonary fibrosis. Int J Clin Exp Med [Internet]. 2017 [cited 2017 Jul 20];10(3):5805–10. Available from: www.ijcem.com.

  94. Kreuter M, Wuyts W, Renzoni E, Koschel D, Maher TM, Kolb M, Weycker D, Spagnolo P, Kirchgaessler KU, Herth FJ, Costabel U. Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis. Lancet Respir Med. 2016;4(5):381–9. https://doi.org/10.1016/S2213-2600(16)00067-9.

    Article  CAS  PubMed  Google Scholar 

  95. Johannson KA, Strâmbu I, Ravaglia C, et al. Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers? Lancet Respir Med [Internet]. 2017 [cited 2017 Jul 24];5(7):591–8. Available from: http://linkinghub.elsevier.com/retrieve/pii/S2213260017302199.

  96. Magnini D, Montemurro G, Iovene B, et al. Idiopathic pulmonary fibrosis: molecular endotypes of fibrosis stratifying existing and emerging therapies. Respiration [Internet]. 2017 [cited 2017 Aug 2];93(6):379–95. https://doi.org/10.1159/000475780.

    Article  CAS  PubMed  Google Scholar 

  97. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet [Internet]. 2017 [cited 2017 Aug 2];389(10082):1941–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28365056.

  98. Lehtonen ST, Veijola A, Karvonen H, et al. Pirfenidone and nintedanib modulate properties of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis. Respir Res [Internet]. 2016;17(1):14. Available from: http://apps.webofknowledge.com.

  99. Ogura T, Taniguchi H, Azuma A, et al. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J [Internet]. 2015;45(5):1382–92. Available from: http://erj.ersjournals.com/content/45/5/1382.

    Article  PubMed  CAS  Google Scholar 

  100. Jia G, Chandriani S, Abbas AR, et al. CXCL14 is a candidate biomarker for Hedgehog signalling in idiopathic pulmonary fibrosis. Thorax. [Internet] 2017 [cited 2017 Jul 20];thoraxjnl-2015-207682. Available from: http://thorax.bmj.com/lookup/doi/10.1136/thoraxjnl-2015-207682.

  101. Leask A, Parapuram SK, Shi-Wen X, Abraham DJ. Connective tissue growth factor (CTGF, CCN2) gene regulation: a potent clinical bio-marker of fibroproliferative disease? J Cell Commun Signal [Internet]. 2009 [cited 2017 Jul 20];3(2):89–94. https://doi.org/10.1007/s12079-009-0037-7.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Murray LA, Argentieri RL, Farrell FX, et al. Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGF$β$1, IL-13 and CCL2. Int J Biochem Cell Biol [Internet]. 2008;40(10):2174–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18395486.

    Article  CAS  Google Scholar 

  103. Bonniaud P, Martin G, Margetts PJ, et al. Connective tissue growth factor is crucial to inducing a profibrotic environment in “fibrosis-resistant” BALB/c mouse lungs. Am J Respir Cell Mol Biol [Internet]. 2004;31(5):510–6. Available from: http://www.atsjournals.org/doi/abs/10.1165/rcmb.2004-0158OC.

    Article  CAS  PubMed  Google Scholar 

  104. Wang X, Wu G, Gou L, et al. A novel single-chain-Fv antibody against connective tissue growth factor attenuates bleomycin-induced pulmonary fibrosis in mice. Respirology [Internet]. 2011 [cited 2017 Jul 20];16(3):500–7. https://doi.org/10.1111/j.1440-1843.2011.01938.x.

    Article  PubMed  Google Scholar 

  105. Bonniaud P, Kolb M, Galt T, et al. Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis. J Immunol [Internet]. 2004;173(3):2099–108. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15265946.

    Article  CAS  PubMed  Google Scholar 

  106. Allen JT, Knight RA, Bloor CA, Spiteri MA. Enhanced insulin-like growth factor binding protein–related protein 2 (connective tissue growth factor) expression in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am J Respir Cell Mol Biol [Internet]. 1999;21(6):693–700. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10572066.

    Article  CAS  PubMed  Google Scholar 

  107. Leduc M, Tremblay M, Grouix B, et al. PBI-4050, a novel first-in-class anti-fibrotic compound, inhibits CTGF and collagen I production in human alveolar epithelial cells and fibroblasts, and reduces lung fibrosis in the bleomycin-induced lung fibrosis model. Am J Respir Crit Care Med. [Internet] 2014;189(A1998). https://doi.org/10.1164/ajrccm-conference.2014.189.1_MeetingAbstracts.A1998,

  108. Goodwin A, Jenkins G. Role of integrin-mediated TGF$β$ activation in the pathogenesis of pulmonary fibrosis. Biochem Soc Trans [Internet]. 2009;37(4):849–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19614606.

    Article  CAS  PubMed  Google Scholar 

  109. Saini G, Porte J, Weinreb PH, et al. $α$v$β$6 integrin may be a potential prognostic biomarker in interstitial lung disease. Eur Respir J [Internet]. 2015;46(2):486–94. https://doi.org/10.1183/09031936.00210414.

    Article  PubMed  Google Scholar 

  110. Horan GS, Wood S, Ona V, et al. Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med [Internet]. 2008 [cited 2017 Jul 24];177(1):56–65. https://doi.org/10.1164/rccm.200706-805OC.

    Article  CAS  PubMed  Google Scholar 

  111. Vancheri C. Common pathways in idiopathic pulmonary fibrosis and cancer. Eur Respir Rev [Internet]. 2013 [cited 2017 Jul 24];22(129):265–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23997054.

    Article  PubMed  Google Scholar 

  112. Conte E, Gili E, Fruciano M, et al. PI3K p110γ overexpression in idiopathic pulmonary fibrosis lung tissue and fibroblast cells: in vitro effects of its inhibition. Lab Investig [Internet]. 2013 [cited 2017 Jul 24];93(5):566–76. https://doi.org/10.1038/labinvest.2013.6.

    Article  CAS  PubMed  Google Scholar 

  113. Conte E, Fruciano M, Fagone E, et al. Inhibition of PI3K prevents the proliferation and differentiation of human lung fibroblasts into myofibroblasts: the role of class I P110 isoforms. PLoS One [Internet]. 2011 [cited 2017 Jul 24];6(10):e24663. https://doi.org/10.1371/journal.pone.0024663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mercer PF, Woodcock H V, Eley JD, et al. Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF. Thorax. [Internet] 2016;thoraxjnl--2015--207429--. Available from: http://thorax.bmj.com/content/early/2016/04/21/thoraxjnl-2015-207429?papetoc.

  115. Jin X, Dai H, Ding K, Xu X, Pang B, Wang C. Rapamycin attenuates bleomycin-induced pulmonary fibrosis in rats and the expression of metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in lung tissue. Chin Med J [Internet]. 2014 [cited 2017 Jul 24];127(7):1304–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24709185.

  116. Street CA, Bryan BA. Rho kinase proteins – pleiotropic modulators of cell survival and apoptosis. Anticancer Res [Internet]. 2011;31(11):3645–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22110183.

  117. Le T-TT, Karmouty-Quintana H, Melicoff E, et al. Blockade of IL-6 trans signaling attenuates pulmonary fibrosis. J Immunol [Internet]. 2014 [cited 2017 Jul 24];193(7):3755–68. https://doi.org/10.4049/jimmunol.1302470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A [Internet]. 2014;111(47):16814–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25385601.

    Article  CAS  Google Scholar 

  119. Funke M, Zhao Z, Xu Y, Chun J, Tager AM. The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol [Internet]. 2012 [cited 2017 Jul 24];46(3):355–64. https://doi.org/10.1165/rcmb.2010-0155OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Neidlinger NA, Larkin SK, Bhagat A, Victorino GP, Kuypers FA. Hydrolysis of phosphatidylserine-exposing red blood cells by secretory phospholipase A2 generates lysophosphatidic acid and results in vascular dysfunction. J Biol Chem [Internet]. 2006;281(2):775–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16278219.

    Article  PubMed  CAS  Google Scholar 

  121. Tager AM, LaCamera P, Shea BS, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med [Internet]. 2008;14(1):45–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18066075.

    Article  PubMed  CAS  Google Scholar 

  122. Oikonomou N, Mouratis M-A, Tzouvelekis A, et al. Pulmonary Autotaxin expression contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol [Internet]. 2012;47(5):566–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22744859.

    Article  PubMed  CAS  Google Scholar 

  123. Watterson KR, Lanning DA, Diegelmann RF, Spiegel S. Regulation of fibroblast functions by lysophospholipid mediators: potential roles in wound healing. Wound Repair Regen [Internet]. 2007;15(5):607–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17971005.

    Article  PubMed  Google Scholar 

  124. Swaney J, Chapman C, Correa L, et al. A novel, orally active LPA 1 receptor antagonist inhibits lung fibrosis in the mouse bleomycin modelb ph. Br J Pharmacol. 2010;160:1699–713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wygrecka M, Zakrzewicz D, Taborski B, et al. TGF-β1 induces tissue factor expression in human lung fibroblasts in a PI3K/JNK/Akt-dependent and AP-1-dependent manner. Am J Respir Cell Mol Biol [Internet]. 2012 [cited 2017 Jul 24];47(5):614–27. https://doi.org/10.1165/rcmb.2012-0097OC.

    Article  CAS  PubMed  Google Scholar 

  126. Cui Y, Osorio JC, Risquez C, et al. Transforming growth factor-β1 downregulates vascular endothelial growth factor-D expression in human lung fibroblasts via the Jun NH2-terminal kinase signaling pathway. Mol Med [Internet]. 2014 [cited 2017 Jul 24];20(1):120–34. Available from: http://www.molmed.org/content/pdfstore/13_123_Cui.pdf.

  127. Königshoff M, Rojas M. Galectin-3: the bridge over troubled waters. Am J Respir Crit Care Med [Internet]. 2012;185(5):473–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22383566.

    Article  PubMed  Google Scholar 

  128. Mackinnon AC, Gibbons MA, Farnworth SL, et al. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med [Internet]. 2012 [cited 2017 Jul 24];185(5):537–46. Available from: http://www.atsjournals.org/doi/abs/10.1164/rccm.201106-0965OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hinz B. Mechanical aspects of lung fibrosis: a spotlight on the myofibroblast. Proc Am Thorac Soc [Internet]. 2012 [cited 2017 Jul 24];9(3):137–47. https://doi.org/10.1513/pats.201202-017AW.

    Article  CAS  PubMed  Google Scholar 

  130. Barry-Hamilton V, Spangler R, Marshall D, Scott McCauley HMR, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Carol Wai CAG, Velayo AC, Jorgensen B, Biermann D, Tsai D, Jennifer Green SZ-E, et al. Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment. Nat Med [Internet]. 2010;16(9):1009–17. Available from: http://www.nature.com/doifinder/10.1038/nm.2208.

    Article  CAS  PubMed  Google Scholar 

  131. Raghu G, Brown KK, Collard HR, et al. Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med [Internet]. 2017 [cited 2017 Jul 24];5(1):22–32. Available from: http://linkinghub.elsevier.com/retrieve/pii/S2213260016304210.

    Article  CAS  PubMed  Google Scholar 

  132. Peters-Golden M, Henderson WR. Leukotrienes. N Engl J Med [Internet]. 2007 [cited 2017 Jul 24];357(18):1841–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17978293.

    Article  CAS  PubMed  Google Scholar 

  133. Wilborn J, Bailie M, Coffey M, Burdick M, Strieter R, Peters-Golden M. Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis. J Clin Invest [Internet]. 1996 [cited 2017 Jul 24];97(8):1827–36. Available from: http://www.jci.org/articles/view/118612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Izumo T, Kondo M, Nagai A. Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis. Eur Respir J [Internet]. 2009 [cited 2017 Jul 24];34(6):1444–51. https://doi.org/10.1183/09031936.00143708.

    Article  CAS  PubMed  Google Scholar 

  135. May RD, Fung M. Strategies targeting the IL-4/IL-13 axes in disease. Cytokine [Internet]. 2015 [cited 2017 Jul 24];75(1):89–116. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1043466615002045.

    Article  CAS  PubMed  Google Scholar 

  136. Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med [Internet]. 2001 [cited 2017 Jul 24];194(6):809–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11560996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Park SW, Ahn MH, Jang HK, et al. Interleukin-13 and its receptors in idiopathic interstitial pneumonia: clinical implications for lung function. J Korean Med Sci [Internet]. 2009 [cited 2017 Jul 24];24(4):614–20. Available from: https://synapse.koreamed.org/DOIx.php?id=10.3346/jkms.2009.24.4.614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Batra V, Musani AI, Hastie AT, et al. Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-beta1, TGF-beta2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on alpha-smooth muscle actin and collagen III synthesis by primary human lu. Clin Exp Allergy [Internet]. 2004 [cited 2017 Jul 24];34(3):437–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15005738.

  139. Darrell P, David R, Wang M, Ronkainen Sanna D, Crawford Jeff R, Travis Elizabeth L, Gomer RH. Reduction of bleomycin-induced pulmonary fibrosis by serum amyloid P. J Immunol. 2007;27(6):316–24.

    Google Scholar 

  140. Murray LA, Rosada R, Moreira AP, et al. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages. PLoS One. 2010;5(3).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Duffield JS, Lupher ML. PRM-151 (recombinant human serum amyloid P/pentraxin 2) for the treatment of fibrosis. Drug News Perspect [Internet]. 2010 [cited 2017 Jul 24];23(5):305–15. Available from: http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml:summary_pr?p_JournalId=3&p_RefId=1444206&p_IsPs=N.

  142. Dillingh MR, van den Blink B, Moerland M, et al. Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis. Pulm Pharmacol Ther [Internet]. 2013 [cited 2017 Jul 24];26(6):672–6. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1094553913000540.

    Article  CAS  Google Scholar 

  143. Burlingham WJ, Love RB, Jankowska-Gan E, et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest [Internet]. 2007 [cited 2017 Jul 24];117(11):3498–506. https://doi.org/10.1172/JCI28031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Vittal R, Mickler EA, Fisher AJ, et al. Type V collagen induced tolerance suppresses collagen deposition, TGF-?? And associated transcripts in pulmonary fibrosis. PLoS One [Internet]. 2013 [cited 2017 Jul 24];8(10):e76451. https://doi.org/10.1371/journal.pone.0076451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wilkes DS, Chew T, Flaherty KR, et al. Oral immunotherapy with type v collagen in idiopathic pulmonary fibrosis. Eur Respir J [Internet]. 2015 [cited 2017 Jul 24];45(5):1393–402. https://doi.org/10.1183/09031936.00105314.

    Article  CAS  PubMed  Google Scholar 

  146. Feghali-Bostwick CA, Tsai CG, Valentine VG, et al. Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. J Immunol [Internet]. 2007 [cited 2017 Jul 24];179(4):2592–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17675522.

    Article  CAS  PubMed  Google Scholar 

  147. Yilmaz O, Oztay F, Kayalar O. Dasatinib attenuated bleomycin-induced pulmonary fibrosis in mice. Growth Factors [Internet]. 2015 [cited 2017 Jul 24];33(5–6):366–75. https://doi.org/10.3109/08977194.2015.1109511.

    Article  CAS  PubMed  Google Scholar 

  148. Cruz FF, Horta LFB, De Albuquerque Maia L, et al. Dasatinib reduces lung inflammation and fibrosis in acute experimental silicosis. PLoS One [Internet]. 2016 [cited 2017 Jul 24];11(1):e0147005. https://doi.org/10.1371/journal.pone.0147005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Molyneaux PL, Maher TM. The role of infection in the pathogenesis of idiopathic pulmonary fibrosis. Eur Respir Rev [Internet]. 2013 [cited 2017 Feb 4];22(129):376–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23997064.

    Article  PubMed  Google Scholar 

  150. Yonemaru M, Kasuga I, Kusumoto H, et al. Elevation of antibodies to cytomegalovirus and other herpes viruses in pulmonary fibrosis. Eur Respir J [Internet]. 1997;10(9):2040–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9311499.

  151. Manika K, Alexiou-Daniel S, Papakosta D, et al. Epstein-Barr virus DNA in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis [Internet]. 2007 [cited 2017 Jul 24];24(2):134–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18496984.

  152. Egan JJ, Adamali HI, Lok SS, Stewart JP, Woodcock AA. Ganciclovir antiviral therapy in advanced idiopathic pulmonary fibrosis: an open pilot study. Pulm Med [Internet]. 2011 [cited 2017 Jul 24];2011:240805. Available from: http://www.hindawi.com/journals/pm/2011/240805/.

  153. Molyneaux PL, Cox MJ, Willis-Owen SAG, et al. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2014;190(8):906–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Han MK, Zhou Y, Murray S, et al. Lung microbiome and disease progression in idiopathic pulmonary fibrosis: an analysis of the COMET study. Lancet Respir Med [Internet]. 2014 [cited 2017 Feb 4];2(7):548–56. Available from: http://www.thelancet.com/article/S2213260014700694/fulltext.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Shulgina L, Cahn AP, Chilvers ER, et al. Treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole: a randomised controlled trial. Thorax [Internet]. 2013 [cited 2017 May 28];68(9):155–62. https://doi.org/10.1136/thoraxjnl-2012-202403.

    Article  PubMed  Google Scholar 

  156. Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med [Internet]. 2016 [cited 2017 Feb 4];194(3):265–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27299520.

  157. Agarwal R, Jindal SK. Acute exacerbation of idiopathic pulmonary fibrosis: a systematic review. Eur J Intern Med [Internet]. 2008 [cited 2017 May 28];19(4):227–35. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0953620507003500.

    Article  PubMed  Google Scholar 

  158. Papiris SA, Manali ED, Kolilekas L, Triantafillidou C, Tsangaris I, Kagouridis K. Steroids in idiopathic pulmonary fibrosis acute exacerbation: defenders or killers? Am J Respir Crit Care Med [Internet]. 2012 [cited 2017 May 19];185(5):587–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22383571.

  159. Kondoh Y, Taniguchi H, Kawabata Y, Yokoi T, Suzuki K, Takagi K. Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest [Internet]. 1993 [cited 2017 May 28];103(6):1808–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8404104.

  160. Song JW, Hong S-B, Lim C-M, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J [Internet]. 2011;37(2):356–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20595144.

    Article  PubMed  Google Scholar 

  161. Tajima S, Oshikawa K, Tominaga S, Sugiyama Y. The increase in serum soluble ST2 protein upon acute exacerbation of idiopathic pulmonary fibrosis. Chest [Internet]. 2003 [cited 2017 May 28];124(4):1206–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14555548.

  162. Juarez MM, Chan AL, Norris AG, Morrissey BM, Albertson TE. Acute exacerbation of idiopathic pulmonary fibrosis-a review of current and novel pharmacotherapies. J Thorac Dis. 2015;7(3):499–519.

    PubMed  PubMed Central  Google Scholar 

  163. Ding J, Chen Z, Feng K. Procalcitonin-guided antibiotic use in acute exacerbations of idiopathic pulmonary fibrosis. Int J Med Sci. 2013;10(7):903–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Anderson R, Grabow G, Oosthuizen R, Theron A, Van Rensburg AJ. Effects of sulfamethoxazole and trimethoprim on human neutrophil and lymphocyte functions in vitro: in vivo effects of co-trimoxazole. Antimicrob Agents Chemother [Internet]. 1980 [cited 2017 May 28];17(3):322–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7425598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev [Internet]. 2010 [cited 2017 May 28];23(3):590–615. https://doi.org/10.1128/CMR.00078-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Oda K, Yatera K, Fujino Y, et al. Efficacy of concurrent treatments in idiopathic pulmonary fibrosis patients with a rapid progression of respiratory failure: an analysis of a national administrative database in Japan. BMC Pulm Med [Internet]. 2016 [cited 2017 May 28];16(1):91. https://doi.org/10.1186/s12890-016-0253-x.

  167. Eickelberg O, Pansky A, Koehler E, et al. Molecular mechanisms of TGF-(beta) antagonism by interferon (gamma) and cyclosporine A in lung fibroblasts. FASEB J [Internet]. 2001 [cited 2017 May 29];15(3):797–806. https://doi.org/10.1096/fj.00-0233com.

    Article  CAS  PubMed  Google Scholar 

  168. Homma S, Sakamoto S, Kawabata M, et al. Cyclosporin treatment in steroid-resistant and acutely exacerbated interstitial pneumonia. Intern Med [Internet]. 2005 [cited 2017 May 29];44(11):1144–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16357451.

    Article  CAS  PubMed  Google Scholar 

  169. Sakamoto S, Homma S, Miyamoto A, Kurosaki A, Fujii T, Yoshimura K. Cyclosporin A in the treatment of acute exacerbation of idiopathic pulmonary fibrosis. Intern Med [Internet]. 2010 [cited 2017 May 29];49(2):109–15. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20075573.

    Article  CAS  PubMed  Google Scholar 

  170. Inase N, Sawada M, Ohtani Y, et al. Cyclosporin A followed by the treatment of acute exacerbation of idiopathic pulmonary fibrosis with corticosteroid. Intern Med [Internet]. 2003 [cited 2017 May 29];42(7):565–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12879947.

    Article  CAS  PubMed  Google Scholar 

  171. Nagano J, Iyonaga K, Kawamura K, et al. Use of tacrolimus, a potent antifibrotic agent, in bleomycin-induced lung fibrosis. Eur Respir J [Internet]. 2006 [cited 2017 May 29];27(3):460–9. https://doi.org/10.1183/09031936.06.00070705.

    Article  CAS  PubMed  Google Scholar 

  172. Kino T, Hatanaka H, Miyata S, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) [Internet]. 1987 [cited 2017 May 29];40(9):1256–65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2445722.

  173. Horita N, Akahane M, Okada Y, et al. Tacrolimus and steroid treatment for acute exacerbation of idiopathic pulmonary fibrosis. Intern Med [Internet]. 2011 [cited 2017 May 29];50(3):189–95. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21297319.

    Article  CAS  PubMed  Google Scholar 

  174. Nannini C, West CP, Erwin PJ, Matteson EL. Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies. Arthritis Res Ther [Internet]. 2008 [cited 2017 May 29];10(5):R124. Available from: http://arthritis-research.biomedcentral.com/articles/10.1186/ar2534.

    Article  CAS  Google Scholar 

  175. ovelli L, Ruggiero R, De Giacomi F, et al. Corticosteroid and cyclophosphamide in acute exacerbation of idiopathic pulmonary fibrosis: a single center experience and literature review. Sarcoidosis Vasc Diffus lung Dis Off J WASOG [Internet]. 2016 [cited 2017 May 29];33(4):385–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28079851.

  176. Mendoza-Milla C, Valero Jiménez A, Rangel C, et al. Dehydroepiandrosterone has strong antifibrotic effects and is decreased in idiopathic pulmonary fibrosis. Eur Respir J [Internet]. 2013;42:1309–21. Available from: http://ow.ly/nD9sz.

    Article  PubMed  CAS  Google Scholar 

  177. Morawiec E, Tillie-Leblond I, Pansini V, Salleron J, Remy-Jardin M, Wallaert B. Exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses. Eur Respir J [Internet]. 2011 [cited 2017 May 29];38(6):1487–9. Available from: http://erj.ersjournals.com/content/38/6/1487.short.

    Article  CAS  PubMed  Google Scholar 

  178. Donahoe M, Valentine VG, Chien N, Gibson KF, Raval JS, Saul M, et al. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. PLoS ONE. 2015;10(6):e0127771. https://doi.org/10.1371/journal.pone.0127771.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Tsushima K, Yamaguchi K, Kono Y, et al. Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: a proof of concept study. Pulm Pharmacol Ther [Internet]. 2014 [cited 2017 May 30];29(2):233–40. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1094553914000467.

    Article  CAS  Google Scholar 

  180. Isshiki T, Sakamoto S, Kinoshita A, Sugino K, Kurosaki A, Homma S. Recombinant human soluble thrombomodulin treatment for acute exacerbation of idiopathic pulmonary fibrosis: a retrospective study. Respiration. 2015;89:201–7. https://doi.org/10.1159/000369828.

    Article  CAS  PubMed  Google Scholar 

  181. Kataoka K, Taniguchi H, Kondoh Y, et al. Recombinant human thrombomodulin in acute exacerbation of idiopathic pulmonary fibrosis. Chest [Internet]. 2015 [cited 2017 May 30];148(2):436–43. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0012369215503401.

    Article  PubMed  Google Scholar 

  182. Mitaka C, Tomita M. Polymyxin B-immobilized fiber column hemoperfusion therapy for septic shock. Shock [Internet]. 2011 [cited 2017 May 30];36(4):332–8. Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00024382-201110000-00003.

    Article  CAS  PubMed  Google Scholar 

  183. Cruz DN, Perazella MA, Bellomo R, et al. Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review. Crit Care [Internet]. 2007 [cited 2017 May 30];11(2):R47. Available from: http://ccforum.biomedcentral.com/articles/10.1186/cc5780.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Enomoto N, Mikamo M, Oyama Y, et al. Treatment of acute exacerbation of idiopathic pulmonary fibrosis with direct hemoperfusion using a polymyxin B-immobilized fiber column improves survival. BMC Pulm Med [Internet]. 2015 [cited 2017 May 30];15(1):15. https://doi.org/10.1186/s12890-015-0004-4.

  185. Abe S, Azuma A, Mukae H, et al. Polymyxin B-immobilized fiber column (PMX) treatment for idiopathic pulmonary fibrosis with acute exacerbation: a multicenter retrospective analysis. Intern Med [Internet]. 2012 [cited 2017 May 30];51(12):1487–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22728479.

    Article  CAS  PubMed  Google Scholar 

  186. Tachibana K, Inoue Y, Nishiyama A, et al. Polymyxin-B hemoperfusion for acute exacerbation of idiopathic pulmonary fibrosis: serum IL-7 as a prognostic marker. Sarcoidosis Vasc Diffus lung Dis Off J WASOG [Internet]. 2011 [cited 2017 May 30];28(2):113–22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22117502.

  187. Maher TM, Whyte MKB, Hoyles RK, et al. Development of a consensus statement for the definition, diagnosis, and treatment of acute exacerbations of idiopathic pulmonary fibrosis using the Delphi technique. Adv Ther [Internet]. 2015 [cited 2017 May 19];32(10):929–43. https://doi.org/10.1007/s12325-015-0249-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pulmonary Medicine, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy

    Andrea Smargiassi, Giuliana Pasciuto, Emanuele Giovanni Conte, Mariarita Andreani, Roberta Marra & Luca Richeldi

Authors
  1. Andrea Smargiassi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuliana Pasciuto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emanuele Giovanni Conte
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariarita Andreani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roberta Marra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luca Richeldi
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Internal Medicine, Section of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine & Public Health, Madison, WI, USA

    Keith C. Meyer

  2. Advanced Lung Disease and Lung Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA

    Steven D. Nathan

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Smargiassi, A., Pasciuto, G., Conte, E.G., Andreani, M., Marra, R., Richeldi, L. (2019). Pharmacologic Treatment of IPF. In: Meyer, K., Nathan, S. (eds) Idiopathic Pulmonary Fibrosis. Respiratory Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-99975-3_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-99975-3_13

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-99974-6

  • Online ISBN: 978-3-319-99975-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation