Skip to main content
SpringerLink
Log in

The Role of TGF-β in Radiation and Chemotherapy Induced Pulmonary Fibrosis: Inhibition of TGF-β as a Novel Therapeutic Strategy

  • Chapter
Transforming Growth Factor-β in Cancer Therapy, Volume I

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 1625 Accesses

Abstract

Pulmonary fibrosis is a life-threatening side effect of cancer therapy, affecting 1–10% of patients receiving chemotherapy or thoracic radiation. Chemo- and radiation therapy may induce either an early phase acute pneumonitis or a late phase fibrotic process, or both. The acute phase can sometimes be treated effectively with corticosteroids, however, steroids are rarely effective in treating fibrosing disease and alternative therapies have proven elusive. recent animal and human clinical data implicate the cytokine TGF-β as a key regulator of fibrosis. TGF-β promotes differentiation of fibroblasts to myofibroblasts, as well as fibroblast and myofibroblast proliferation and production of collagen, resulting in accumulation of fibrotic scar tissue and loss of lung function. It is proposed that interfering with TGF-β expression and/or signaling may be clinically useful strategies to block the progression of lung fibrosis. Several strategies in various stages of investigation, from the laboratory to phase III clinical trials, are discussed. These strategies fall into two general classes; direct inhibition of TGF-β itself (via soluble TGF-β decoy receptors, TGF-β antibodies, decorin, RNA interference, and the latency associated peptide) and interference with the downstream signaling cascades initiated by TGF-β (interferon-γ, pirfenidone, imatinib mesylate, and peroxisome proliferator activated receptor-γ[PPAR-γ]agonists). Concerns in implementing anti-TGF-β therapies in pulmonary fibrosis patients include possible systemic effects of inhibiting TGF-β, as well as possible effects on the underlying tumor of local or systemic inhibition of TGF-β.

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 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med 1994;150:967–972.

    CAS  PubMed  Google Scholar 

  2. Strieter RM. Mechanisms of pulmonary fibrosis: conference summary. Chest 2001;120:77S–85S.

    Article  CAS  PubMed  Google Scholar 

  3. Sime PJ, O’Reilly KM. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol 2001;99:308–319.

    Article  CAS  PubMed  Google Scholar 

  4. Gross NJ. Pulmonary effects of radiation therapy. Ann Intern Med 1977;86:81–92.

    CAS  PubMed  Google Scholar 

  5. Abratt RP, Morgan GW, Silvestri G, Willcox P. Pulmonary complications of radiation therapy. Clin Chest Med 2004;25:167–177.

    Article  PubMed  Google Scholar 

  6. Abid SH, Malhotra V, Perry MC. Radiation-induced and chemotherapy-induced pulmonary injury. Curr Opin Oncol 2001;13:242–248.

    Article  CAS  PubMed  Google Scholar 

  7. Ohe Y, Yamamoto S, Suzuki K, et al. Risk factors of treatment-related death in chemotherapy and thoracic radiotherapy for lung cancer. Eur J Cancer 2001;37:54–63.

    Article  CAS  PubMed  Google Scholar 

  8. Movsas B, Raffin TA, Epstein AH, Link CJ, Jr. Pulmonary radiation injury. Chest 1997;111:1061–1076.

    Article  CAS  PubMed  Google Scholar 

  9. Roach M 3rd, Gandara DR, Yuo HS, et al. Radiation pneumonitis, following combined modality therapy for lung cancer: analysis of prognostic factors. J Clin Oncol 1995;13:2606–2612.

    PubMed  Google Scholar 

  10. Mehta V. Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: pulmonary function, prediction, and prevention. Int J Radiat Oncol Biol Phys 2005;63:5–24.

    PubMed  Google Scholar 

  11. Byhardt RW, Martin L, Pajak TF, Shin KH, Emami B, Cox JD. The influence of field size and other treatment factors on pulmonary toxicity following hyperfractionated irradiation for inoperable non-small cell lung cancer (NSCLC)—analysis of a Radiation Therapy Oncology Group (RTOG) protocol. Int J Radiat Oncol Biol Phys 1993;27:537–544.

    CAS  PubMed  Google Scholar 

  12. Libshitz HI, Southard ME. Complications of radiation therapy: the thorax. Semin Roentgenol 1974;9:41–49.

    Article  CAS  PubMed  Google Scholar 

  13. Keane TJ, Van Dyk J, Rider WD. Idiopathic interstitial pneumonia following bone marrow transplantation: the relationship with total body irradiation. Int J Radiat Oncol Biol Phys 1981;7:1365–1370.

    CAS  PubMed  Google Scholar 

  14. Mah K, Van Dyk J, Keane T, Poon PY Acute radiation-induced pulmonary damage: a clinical study on the response to fractionated radiation therapy. Int J Radiat Oncol Biol Phys 1987;13:179–188.

    CAS  PubMed  Google Scholar 

  15. Mah K, Keane TJ, Van Dyk J, Braban LE, Poon PY, Hao Y. Quantitative effect of combined chemotherapy and fractionated radiotherapy on the incidence of radiation-induced lung damage: a prospective clinical study. Int J Radiat Oncol Biol Phys 1994;28:563–574.

    CAS  PubMed  Google Scholar 

  16. Koc M, Polat P, Suma S. Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Radiother Oncol 2002;64:171–175.

    Article  CAS  PubMed  Google Scholar 

  17. Bese NS, Umay C, Yildirim S, et al. The effects of tamoxifen on radiation-induced pulmonary fibrosis in Wistar albino rats: results of an experimental study. Breast 2006;15:456–460.

    Article  PubMed  Google Scholar 

  18. Freid JR, Goldberg H. Post-irradiation changes in the lung and thorax. Am J Roentgenol 1940;43: 877–895.

    Google Scholar 

  19. Morgan GW, Breit SN. Radiation and the lung: a reevaluation of the mechanisms mediating pulmonary injury. Int J Radiat Oncol Biol Phys 1995;31:361–369.

    CAS  PubMed  Google Scholar 

  20. Roberts CM, Foulcher E, Zaunders JJ, et al. Radiation pneumonitis: a possible lymphocyte-mediated hypersensitivity reaction. Ann Intern Med 1993;118:696–700.

    CAS  PubMed  Google Scholar 

  21. Abratt, RP, Morgan GW. Lung toxicity following chest irradiation in patients with lung cancer. Lung Cancer 2002;35:103–109.

    Article  PubMed  Google Scholar 

  22. Gibson PG, Bryant DH, Morgan GW, et al. Radiation-induced lung injury: a hypersensitivity pneumonitis? Ann Intern Med 1988;109:288–291.

    CAS  PubMed  Google Scholar 

  23. De Jaeger K, Seppenwoolde Y, Kampinga HH, Boersma LJ, Belderbos JS, Lebesque JV. Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1378–1387.

    Article  PubMed  CAS  Google Scholar 

  24. Anscher MS, Marks LB, Shafman TD, et al. Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy. Int J Radiat Oncol Biol Phys 2003;56:988–995.

    Article  PubMed  Google Scholar 

  25. Barthelemy-Brichant N, Bosquee L, Cataldo D, et al. Increased IL-6 and TGF-beta1 concentrations in bronchoalveolar lavage fluid associated with thoracic radiotherapy. Int J Radiat Oncol Biol Phys 2004;58:758–767.

    CAS  PubMed  Google Scholar 

  26. Novakova-Jiresova A, Van Gameren MM, Coppes RP, Kampinga HH, Groen HJ. Transforming growth factor-beta plasma dynamics and post-irradiation lung injury in lung cancer patients. Radiother Oncol 2004;71:183–189.

    Article  CAS  PubMed  Google Scholar 

  27. Vujaskovic Z, Groen HJ. TGF-beta, radiation-induced pulmonary injury and lung cancer. Int J Radiat Biol 2000;76:511–516.

    Article  CAS  PubMed  Google Scholar 

  28. Anscher MS, Kong FM, Jirtle RL. The relevance of transforming growth factor beta 1 in pulmonary injury after radiation therapy. Lung Cancer 1998;19:109–120.

    Article  CAS  PubMed  Google Scholar 

  29. Twohig KJ, Matthay RA. Pulmonary effects of cytotoxic agents other than bleomycin. Clin Chest Med 1990;11:31–54.

    CAS  PubMed  Google Scholar 

  30. Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clin Chest Med 1990;11:1–20.

    CAS  PubMed  Google Scholar 

  31. Blum RH, Carter SK, Agre K. A clinical review of bleomycin—a new antineoplastic agent. Cancer 1973;31:903–914.

    Article  CAS  PubMed  Google Scholar 

  32. Douglas MJ, Coppin CM. Bleomycin and subsequent anaesthesia: a retrospective study at Vancouver General Hospital. Can Anaesth Soc J 1980;27:449–452.

    Article  CAS  PubMed  Google Scholar 

  33. Gilson AJ, Sahn SA. Reactivation of bleomycin lung toxicity following oxygen administration. A second response to corticosteroids. Chest 1985;88:304–306.

    Article  CAS  PubMed  Google Scholar 

  34. Goldiner PL, Carlon GC, Cvitkovic E, Schweizer O, Howland WS. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J 1978;1:1664–1667.

    Article  CAS  PubMed  Google Scholar 

  35. Goldiner PL, Schweizer O. The hazards of anesthesia and surgery in bleomycin-treated patients. Semin Oncol 1979;6:121–124.

    CAS  PubMed  Google Scholar 

  36. Samuels ML, Johnson DE, Holoye PY, Lanzotti VJ. Large-dose bleomycin therapy and pulmonary toxicity. A possible role of prior radiotherapy. JAMA 1976;235:1117–1120.

    Article  CAS  PubMed  Google Scholar 

  37. Einhorn L, Krause M, Hornback N, Furnas B. Enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer. Cancer 1976;37:2414–2416.

    Article  CAS  PubMed  Google Scholar 

  38. Nygaard K, Smith-Erichsen N, Hatlevoll R, Refsum SB. Pulmonary complications after bleomycin, irradiation and surgery for esophageal cancer. Cancer 1978;41:17–22.

    Article  CAS  PubMed  Google Scholar 

  39. Hakkinen PJ, Whiteley JW, Witschi HR. Hyperoxia, but not thoracic X-irradiation, potentiates bleomycin-and cyclophosphamide-induced lung damage in mice. Am Rev Respir Dis 1982;126: 281–285.

    CAS  PubMed  Google Scholar 

  40. Alliot C, Tabuteau S, Desablens B, Aubry P, Andrejak M. Fatal pulmonary fibrosis after a low cumulated dose of bleomycin: role of alpha1-antitrypsin deficiency? Am J Hematol 1999;62:198–199.

    Article  CAS  PubMed  Google Scholar 

  41. Rabinowits M, Souhami L, Gil RA, Andrade CA, Paiva HC. Increased pulmonary toxicity with bleomycin and cisplatin chemotherapy combinations. Am J Clin Oncol 1990;13:132–138.

    Article  CAS  PubMed  Google Scholar 

  42. McLeod BF, Lawrence HJ, Smith DW, Vogt PJ, Gandara DR. Fatal bleomycin toxicity from a low cumulative dose in a patient with renal insufficiency. Cancer 1987;60:2617–2620.

    Article  CAS  PubMed  Google Scholar 

  43. Bauer KA, Skarin AT, Balikian JP, Garnick MB, Rosenthal DS, Canellos GP. Pulmonary complications associated with combination chemotherapy programs containing bleomycin. Am J Med 1983;74:557–563.

    Article  CAS  PubMed  Google Scholar 

  44. Skarin AT, Rosenthal DS, Moloney WC, Frei E 3rd. Combination chemotherapy of advanced non-Hodgkin lymphoma with bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP). Blood 1977;49:759–770.

    CAS  PubMed  Google Scholar 

  45. Van Barneveld PW, Sleijfer DT, van der Mark TW, et al. Natural course of bleomycin-induced pneumonitis. A follow-up study. Am Rev Respir Dis 1987;135:48–51.

    PubMed  Google Scholar 

  46. White DA, Stover DE. Severe bleomycin-induced pneumonitis. Clinical features and response to corticosteroids. Chest 1984;86:723–728.

    Article  CAS  PubMed  Google Scholar 

  47. Brown WG, Hasan FM, Barbee RA. Reversibility of severe bleomycin-induced pneumonitis. JAMA 1978;239:2012–2014.

    Article  CAS  PubMed  Google Scholar 

  48. Bedrossian CW, Luna MA, Mackay B, Lichtiger B. Ultrastructure of pulmonary bleomycin toxicity. Cancer 1973;32:44–51.

    Article  CAS  PubMed  Google Scholar 

  49. Jones AW. Bleomycin lung damage: the pathology and nature of the lesion. Br J Dis Chest 1978;72:321–326.

    CAS  PubMed  Google Scholar 

  50. Luna MA, Bedrossian CW, Lichtiger B, Salem PA. Interstitial pneumonitis associated with bleomycin therapy. Am J Clin Pathol 1972;58:501–510.

    CAS  PubMed  Google Scholar 

  51. Yagoda A, Mukherji B, Young C, et al. Bleomycin, an antitumor antibiotic. Clinical experience in 274 patients. Ann Intern Med 1972;77:861–870.

    CAS  PubMed  Google Scholar 

  52. Inoue A, Kunitoh H, Sekine I, Sumi M, Tokuuye K, Saijo N. Radiation pneumonitis in lung cancer patients: a retrospective study of risk factors and the long-term prognosis Int J Radiat Oncol Biol Phys 2001;49:649–655.

    CAS  PubMed  Google Scholar 

  53. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998;352:257–263.

    Google Scholar 

  54. Vaughan MB, Howard EW, Tomasek JJ. Transforming growth factor-beta1 promotes the morphological and functional differentiation of the myofibroblast. Exp Cell Res 2000;257:180–189.

    Article  CAS  PubMed  Google Scholar 

  55. Phan SH. The myofibroblast in pulmonary fibrosis. Chest 2002;122:286S–289S.

    Article  PubMed  Google Scholar 

  56. White ES, Lazar MH, Thannickal VJ. Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis. J Pathol 2003;201:343–354.

    Article  CAS  PubMed  Google Scholar 

  57. Chambers RC, Leoni P, Kaminski N, Laurent GJ, Heller RA. Global expression profiling of fibroblast responses to transforming growth factor-beta1 reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching. Am J Pathol 2003;162:533–546.

    CAS  PubMed  Google Scholar 

  58. Pardo A, Selman M. Molecular mechanisms of pulmonary fibrosis. Front Biosci 2002;7:d1743–d1761.

    Article  CAS  PubMed  Google Scholar 

  59. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136–151.

    CAS  PubMed  Google Scholar 

  60. Rodemann HP, Bamberg M. Cellular basis of radiation-induced fibrosis. Radiother Oncol 1995;35:83–90.

    Article  CAS  PubMed  Google Scholar 

  61. Kuhn C, McDonald JA. The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. Am J Pathol 1991;138:1257–1265.

    CAS  PubMed  Google Scholar 

  62. Hu B, Wu Z, Phan SH. Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. Am J Respir Cell Mol Biol 2003;29:397–404.

    Article  CAS  PubMed  Google Scholar 

  63. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993;122:103–111.

    Article  CAS  PubMed  Google Scholar 

  64. Zhang HY, Phan SH. Inhibition of myofibroblast apoptosis by transforming growth factor beta(1). Am J Respir Cell Mol Biol 1999;21:658–665.

    CAS  PubMed  Google Scholar 

  65. Coker RK, Laurent GJ, Shahzeidi S, et al. Transforming growth factors-beta 1,-beta 2, and-beta 3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis. Am J Pathol 1997;150:981–991.

    CAS  PubMed  Google Scholar 

  66. Selman M, Ruiz V, Cabrera S, et al. TIMP-1,-2,-3, and-4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? Am J Physiol Lung Cell Mol Physiol 2000;279:L562–L574.

    CAS  PubMed  Google Scholar 

  67. Ramos C, Montano M, Garcia-Alvarez J, et al. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. Am J Respir Cell Mol Biol 2001;24:591–598.

    CAS  PubMed  Google Scholar 

  68. Yamamoto T, Eckes B, Krieg T. Bleomycin increases steady-state levels of type I collagen, fibronectin and decorin mRNAs in human skin fibroblasts. Arch Dermatol Res 2000;292:556–561.

    Article  CAS  PubMed  Google Scholar 

  69. Yamamoto T, Katayama I, Nishioka K. Fibroblast proliferation by bleomycin stimulated peripheral blood mononuclear cell factors. J Rheumatol 1999;26:609–615.

    CAS  PubMed  Google Scholar 

  70. Rube CE, Uthe D, Schmid KW, et al. Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation. Int J Radiat Oncol Biol Phys 2000;47:1033–1042.

    CAS  PubMed  Google Scholar 

  71. Phan SH, Kunkel SL. Lung cytokine production in bleomycin-induced pulmonary fibrosis. Exp Lung Res 1992;18:29–43.

    Article  CAS  PubMed  Google Scholar 

  72. Johnston CJ, Wright, TW, Rubin P, Finkelstein JN. Alterations in the expression of chemokine mRNA levels in fibrosis-resistant and-sensitive mice after thoracic irradiation. Exp Lung Res 1998;24:321–337.

    Article  CAS  PubMed  Google Scholar 

  73. Finkelstein JN, Johnston CJ, Baggs R, Rubin P. Early alterations in extracellular matrix and transforming growth factor beta gene expression in mouse lung indicative of late radiation fibrosis. Int J Radiat Oncol Biol Phys 1994;28:621–631.

    CAS  PubMed  Google Scholar 

  74. Breen E, Shull S, Burne S, et al. Bleomycin regulation of transforming growth factor-beta mRNA in rat lung fibroblasts. Am J Respir Cell Mol Biol 1992;6:146–152.

    CAS  PubMed  Google Scholar 

  75. Williams AO, Flanders KC, Saffiotti U. Immunohistochemical localization of transforming growth factor-beta 1 in rats with experimental silicosis, alveolar type II hyperplasia, and lung cancer. Am J Pathol 1993;142:1831–1840.

    CAS  PubMed  Google Scholar 

  76. Raghow B, Irish P, Kang AH. Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis. J Clin Invest 1989;84:1836–1842.

    Article  CAS  PubMed  Google Scholar 

  77. Ehrhart EJ, Segarini P, Tsang ML, Carroll AG, Barcellos-Hoff MH. Latent transforming growth factor beta1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation. FASEB J 1997;11:991–1002.

    CAS  PubMed  Google Scholar 

  78. Munger JS, Huang X, Kawakatsu H, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999;96:319–328.

    Article  CAS  PubMed  Google Scholar 

  79. Pittet JF, Griffiths MJ, Geiser T, et al. TGF-beta is a critical mediator of acute lung injury. J Clin Invest 2001;107:1537–1544.

    Article  CAS  PubMed  Google Scholar 

  80. Dhainaut JF, Charpentier J, Chiche JD. Transforming growth factor-beta: a mediator of cell regulation in acute respiratory distress syndrome. Crit Care Med 2003;31:S258–S264.

    Article  CAS  PubMed  Google Scholar 

  81. Zhao Y, Shah DU. Expression of transforming growth factor-beta type I and type II receptors is altered in rat lungs undergoing bleomycin-induced pulmonary fibrosis. Exp Mol Pathol 2000;69:67–78.

    Article  CAS  PubMed  Google Scholar 

  82. Franko AJ, Sharplin J, Ghahary A, Barcellos-Hoff MH. Immunohistochemical localization of transforming growth factor beta and tumor necrosis factor alpha in the lungs of fibrosis-prone and “non-fibrosing” mice during the latent period and early phase after irradiation. Radiat Res 1997;147:245–256.

    Article  CAS  PubMed  Google Scholar 

  83. Zhang K, Flanders KC, Phan SH. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis. Am J Pathol 1995;147:352–361.

    CAS  PubMed  Google Scholar 

  84. Bartram U, Speer CP. The role of transforming growth factor beta in lung development and disease. Chest 2004;125:574–765.

    Article  Google Scholar 

  85. Breitkopf K, Haas S, Wiercinska E, Singer MV, Dooley S. Anti-TGF-beta strategies for the treatment of chronic liver disease. Alcohol Clin Exp Res 2005;29:121S–131S.

    Article  CAS  PubMed  Google Scholar 

  86. Goumenos DS, Tsamandas AC, Oldroyd S, et al. Transforming growth factor-beta(1) and myofibroblasts: a potential pathway towards renal scarring in human glomerular disease. Nephron, 2001;87:240–248.

    Article  CAS  PubMed  Google Scholar 

  87. Fireman E, Shahar I, Shoval S, Messer G, Dvash S, Grief J. Morphological and biochemical properties of alveolar fibroblasts in interstitial lung diseases. Lung 2001;179:105–117.

    Article  CAS  PubMed  Google Scholar 

  88. Pache JC, Christakos PG, Gannon DE, Mitchell JJ, Low RB, Leslie KO. Myofibroblasts in diffuse alveolar damage of the lung. Mod Pathol 1998;11:1064–1070.

    CAS  PubMed  Google Scholar 

  89. Warshamana GS, Pociask DA, Fisher KJ, Liu JY, Sime PJ, Brody AR. Titration of non-replicating adenovirus as a vector for transducing active TGF-beta1 gene expression causing inflammation and fibrogenesis in the lungs of C57BL/6 mice. Int J Exp Pathol 2002;83:183–201.

    Article  CAS  PubMed  Google Scholar 

  90. Warshamana GS, Pociask DA, Sime P, Schwartz DA, Brody AR. Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice. Am J Respir Cell Mol Biol 2002;27:705–713.

    CAS  PubMed  Google Scholar 

  91. Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997;100:768–776.

    Article  CAS  PubMed  Google Scholar 

  92. Kolb M, Bonniaud P, Galt T, et al. Differences in the fibrogenic response after transfer of active transforming growth factor-beta1 gene to lungs of “fibrosis-prone” and “fibrosis-resistant” mouse strains. Am J Respir Cell Mol Biol 2002;27:141–150.

    CAS  PubMed  Google Scholar 

  93. Giri SN. Novel pharmacological approaches to manage interstitial lung fibrosis in the twenty-first century. Annu Rev Pharmacol Toxicol 2003;43:73–95.

    Article  CAS  PubMed  Google Scholar 

  94. Kelly M, Kolb M, Bonniaud P, Gauldie J. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Des 2003;9:39–49.

    Article  CAS  PubMed  Google Scholar 

  95. Cui X, Shimizu I, Lu G, et al. Inhibitory effect of a soluble transforming growth factor beta type II receptor on the activation of rat hepatic stellate cells in primary culture. J Hepatol 2003;39:731–737.

    Article  CAS  PubMed  Google Scholar 

  96. Yamamoto H, Ueno H, Ooshima A, Takeshita A. Adenovirus-mediated transfer of a truncated transforming growth factor-beta (TGF-beta) type II receptor completely and specifically abolishes diverse signaling by TGF-beta in vascular wall cells in primary culture. J Biol Chem 1996;271:16,253–16,259.

    Article  CAS  PubMed  Google Scholar 

  97. Rowland-Goldsmith MA, Maruyama H, Kusama T, Ralli S, Korc M. Soluble type II transforming growth factor-beta (TGF-beta) receptor inhibits TGF-beta signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor formation. Clin Cancer Res 2001;7:2931–2940.

    CAS  PubMed  Google Scholar 

  98. Yata Y, Gotwals P, Koteliansky V, Rockey DC. Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-beta soluble receptor: implications for antifibrotic therapy. Hepatology 2002;35:1022–1030.

    Article  CAS  PubMed  Google Scholar 

  99. Wang Q, Wang Y, Hyde DM, et al. Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters. Thorax 1999;54:805–812.

    Article  CAS  PubMed  Google Scholar 

  100. Wang Q, Hyde DM, Gotwals PJ, Giri SN. Effects of delayed treatment with transforming growth factor-beta soluble receptor in a three-dose bleomycin model of lung fibrosis in hamsters. Exp Lung Res 2002;28:405–417.

    Article  CAS  PubMed  Google Scholar 

  101. Schmidt-Weber CB, Blaser K. Regulation and role of transforming growth factor-beta in immune tolerance induction and inflammation. Curr Opin Immunol 2004;16:709–716.

    Article  CAS  PubMed  Google Scholar 

  102. Qi Z, Atsuchi N, Ooshima A, Takeshita A, Ueno H. Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. Proc Natl Acad Sci USA 1999;96:2345–2349.

    Article  CAS  PubMed  Google Scholar 

  103. Sakamoto T, Ueno H, Sonoda K, et al. Blockade of TGF-beta by in vivo gene transfer of a soluble TGF-beta type II receptor in the muscle inhibits corneal opacification, edema and angiogenesis. Gene Ther 2000;7:1915–1924.

    Article  CAS  PubMed  Google Scholar 

  104. Ueno H, Sakamoto T, Nakamura T, et al. A soluble transforming growth factor beta receptor expressed in muscle prevents liver fibrogenesis and dysfunction in rats. Hum Gene Ther 2000;11:33–42.

    Article  CAS  PubMed  Google Scholar 

  105. Christ M, McCartney-Francis NL, Kulkarni AB, et al. Immune dysregulation in TGF-beta 1-deficient mice. J Immunol 1994;153:1936–1946.

    CAS  PubMed  Google Scholar 

  106. Border WA, Noble NA, Yamamoto T, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 1992;360:361–364.

    Article  CAS  PubMed  Google Scholar 

  107. Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 1990;346:371–374.

    Article  CAS  PubMed  Google Scholar 

  108. Hill C, Flyvbjerg A, Rasch R, Bak M, Logan A. Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney. J Endocrinol 2001;170:647–651.

    Article  CAS  PubMed  Google Scholar 

  109. McCormick LL, Zhang Y, Tootell E, Gilliam AC. Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol 1999;163:5693–5699.

    CAS  PubMed  Google Scholar 

  110. Denis M. Neutralization of transforming growth factor-beta 1 in a mouse model of immune-induced lung fibrosis. Immunology 1994;82:584–590.

    CAS  PubMed  Google Scholar 

  111. Ruzek MC, Hawes M, Pratt B, et al. Minimal effects on immune parameters following chronic anti-TGF-beta monoclonal antibody administration to normal mice. Immunopharmacol Immunotoxicol 2003;25:235–257.

    Article  CAS  PubMed  Google Scholar 

  112. Kolb M, Margetts PJ, Sime PJ, Gauldie J. Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J Physiol Lung Cell Mol Physiol 2001;280:L1327–L1334.

    CAS  PubMed  Google Scholar 

  113. Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 1990;346:281–284.

    Article  CAS  PubMed  Google Scholar 

  114. Hildebrand A, Romaris M, Rasmussen LM, et al. Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem J 1994;302(Pt 2): 527–534.

    CAS  PubMed  Google Scholar 

  115. Huijun W, Long C, Zhigang Z, Feng J, Muyi G. Ex vivo transfer of the decorin gene into rat glomerulus via a mesangial cell vector suppressed extracellular matrix accumulation in experimental glomerulonephritis. Exp Mol Pathol 2005;78:17–24.

    Article  PubMed  CAS  Google Scholar 

  116. Giri SN, Hyde DM, Braun RK, Gaarde W, Harper JR, Pierschbacher MD. Antifibrotic effect of decorin in a bleomycin hamster model of lung fibrosis. Biochem Pharmacol 1997;54:1205–1216.

    Article  CAS  PubMed  Google Scholar 

  117. Sime PJ, Xing Z, Foley R, Graham FL, Gauldie, J. Transient gene transfer and expression in the lung. Chest 1997;111:89S–94S.

    Article  CAS  PubMed  Google Scholar 

  118. Gauldie J, Graham F, Xing Z, Braciak T, Foley R, Sime PJ. Adenovirus-vector-mediated cytokine gene transfer to lung tissue. Ann NY Acad Sci 1996;796:235–244.

    Article  CAS  PubMed  Google Scholar 

  119. Kolb M, Margetts PJ, Galt T, et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med 2001;163:770–777.

    CAS  PubMed  Google Scholar 

  120. Thatcher TH, Burgess HA, Van Kirk JR, Redonnet M, Sime PJ, Gauldie J. Decorin gene therapy inhibits silica-induced pulmonary fibrosis in a pre-clinical animal model [Abstract]. Am J Respir Crit Care Med 2003;167:A583.

    Google Scholar 

  121. Shimizukawa M, Ebina M, Narumi K, Kikuchi T, Munakata H, Nukiwa T. Intratracheal gene transfer of decorin reduces subpleural fibroproliferation induced by bleomycin. Am J Physiol Lung Cell Mol Physiol 2003;284:L526–L532.

    CAS  PubMed  Google Scholar 

  122. Barcellos-Hoff MH, Dix TA. Redox-mediated activation of latent transforming growth factor-beta 1. Mol Endocrinol 1996;10:1077–1083.

    Article  CAS  PubMed  Google Scholar 

  123. Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts. J Immunol 2005;175:7708–7718.

    CAS  PubMed  Google Scholar 

  124. Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine transforming growth factor beta signaling in systemic sclerosis fibroblasts. Arthritis Rheum 2005;52:2897–2905.

    Article  CAS  PubMed  Google Scholar 

  125. Fjellbirkeland L, Cambier S, Broaddus VC, et al. Integrin alphavbeta8-mediated activation of transforming growth factor-beta inhibits human airway epithelial proliferation in intact bronchial tissue. Am J Pathol 2003;163:533–542.

    CAS  PubMed  Google Scholar 

  126. Sheppard D. Integrin-mediated activation of transforming growth factor-beta(1) in pulmonary fibrosis. Chest 2001;120:49S–53S.

    Article  CAS  PubMed  Google Scholar 

  127. Khalil N, Corne S, Whitman C, Yacyshyn H. Plasmin regulates the activation of cell-associated latent TGF-beta 1 secreted by rat alveolar macrophages after in vivo bleomycin injury. Am J Respir Cell Mol Biol 1996;15:252–259.

    CAS  PubMed  Google Scholar 

  128. Isono M, Soda M, Inoue A, Akiyoshi H, Sato K. Reverse transformation of hepatic myofibroblast-like cells by TGFbeta1/LAP. Biochem Biophys Res Commun 2003;311:959–965.

    Article  CAS  PubMed  Google Scholar 

  129. Luttenberger T, Schmid-Kotsas A, Menke A, et al. Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis. Lab Invest 2000;80:47–55.

    Article  CAS  PubMed  Google Scholar 

  130. Zhang Y, McCormick LL, Gilliam AC. Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J Invest Dermatol 2003;121:713–719.

    Article  CAS  PubMed  Google Scholar 

  131. Isaka Y, Tsujie M, Ando Y, et al. Transforming growth factor-beta 1 antisense oligodeoxynucleotides block interstitial fibrosis in unilateral ureteral obstruction. Kidney Int 2000;58:1885–1892.

    Article  CAS  PubMed  Google Scholar 

  132. Tanaka M, Nyce JW. Respirable antisense oligonucleotides: a new drug class for respiratory disease. Respir Res 2001;2:5–9.

    Article  CAS  PubMed  Google Scholar 

  133. Popescu FD. Antisense-and RNA interference-based therapeutic strategies in allergy. J Cell Mol Med 2005;9:840–853.

    Article  CAS  PubMed  Google Scholar 

  134. Nyce J. Respirable antisense oligonucleotides: a new, third drug class targeting respiratory disease. Curr Opin Allergy Clin Immunol 2002;2:533–536.

    Article  PubMed  Google Scholar 

  135. Ball HA, Sandrasagra A, Tang L, Van Scott M, Wild J, Nyce JW. Clinical potential of respirable antisense oligonucleotides (RASONs) in asthma. Am J Pharmacogenomics 2003;3:97–106.

    Article  CAS  PubMed  Google Scholar 

  136. Ali S, Leonard SA, Kukoly CA, et al. Absorption, distribution, metabolism, and excretion of a respirable antisense oligonucleotide for asthma. Am J Respir Crit Care Med 2001;163:989–993.

    CAS  PubMed  Google Scholar 

  137. Dreyfus DH, Matczuk A, Fuleihan R. An RNA external guide sequence ribozyme targeting human interleukin-4 receptor alpha mRNA. Int Immunopharmacol 2004;4:1015–1027.

    Article  CAS  PubMed  Google Scholar 

  138. Duan W, Chan JH, McKay K, et al. Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med 2005;171:571–578.

    Article  PubMed  Google Scholar 

  139. Chen ES, Greenlee BM, Wills-Karp M, Moller DR. Attenuation of lung inflammation and fibrosis in interferon-gamma-deficient mice after intratracheal bleomycin. Am J Respir Cell Mol Biol 2001;24: 545–555.

    CAS  PubMed  Google Scholar 

  140. Sempowski GD, Derdak S, Phipps RP. Interleukin-4 and interferon-gamma discordantly regulate collagen biosynthesis by functionally distinct lung fibroblast subsets. J Cell Physiol 1996;167:290–296.

    Article  CAS  PubMed  Google Scholar 

  141. Kaufman J, Sime PJ, Phipps RP. Expression of CD154 (CD40 ligand) by human lung fibroblasts: differential regulation by IFN-gamma and IL-13, and implications for fibrosis. J Immunol 2004; 172:1862–1871.

    CAS  PubMed  Google Scholar 

  142. Tredget EE, Wang R, Shen Q, Scott PG, Ghahary A. Transforming growth factor-beta mRNA and protein in hypertrophic scar tissues and fibroblasts: antagonism by IFN-alpha and IFN-gamma in vitro and in vivo. J Interferon Cytokine Res 2000;20:143–151.

    Article  CAS  PubMed  Google Scholar 

  143. Ghosh AK, Yuan W, Mori Y, Chen S, Varga J. Antagonistic regulation of type I collagen gene expression by interferon-gamma and transforming growth factor-beta. Integration at the level of p300/CBP transcriptional coactivators. J Biol Chem 2001;276:11,041–11,048.

    Article  CAS  PubMed  Google Scholar 

  144. Higashi K, Inagaki Y, Fujimori K, Nakao A, Kaneko H, Nakatsuka I. Interferon-gamma interferes with transforming growth factor-beta signaling through direct interaction of YB-1 with Smad3. J Biol Chem 2003;278:43,470–43,479.

    Article  CAS  PubMed  Google Scholar 

  145. Chen Y, Chen J, Dong J, Liu W. Antifibrotic effect of interferon gamma in silicosis model of rat. Toxicol Lett 2005;155:353–360.

    Article  CAS  PubMed  Google Scholar 

  146. Gurujeyalakshmi G, Giri SN. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression. Exp Lung Res 1995;21:791–808.

    Article  CAS  PubMed  Google Scholar 

  147. Kalra S, Utz JP, Ryu JH. Interferon gamma-1b therapy for advanced idiopathic pulmonary fibrosis. Mayo Clin Proc 2003;78:1082–1087.

    Article  CAS  PubMed  Google Scholar 

  148. 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;341:1264–1269.

    Article  CAS  PubMed  Google Scholar 

  149. 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 2004;350:125–133.

    Article  CAS  PubMed  Google Scholar 

  150. King TE, Jr, Safrin S, Starko KM, et al. Analyses of efficacy end points in a controlled trial of interferon-gamma1b for idiopathic pulmonary fibrosis. Chest 2005:127:171–177.

    Article  CAS  PubMed  Google Scholar 

  151. Bajwa EK, Ayas NT, Schulzer M, Mak E, Ryu JH, Malhotra A. Interferon-gamma1b therapy in idiopathic pulmonary fibrosis: a metaanalysis. Chest 2005;128:203–206.

    Article  CAS  PubMed  Google Scholar 

  152. 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;291:367–373.

    CAS  PubMed  Google Scholar 

  153. Cain WC, Stuart RW, Lefkowitz DL, Starnes JD, Margolin S, Lefkowitz SS. Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone. Int J Immunopharmacol 1998;20: 685–695.

    Article  CAS  PubMed  Google Scholar 

  154. Gurujeyalakshmi G, Hollinger MA, Giri SN. Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level. Am J Physiol 1999;276:L311–L318.

    CAS  PubMed  Google Scholar 

  155. Shihab FS, Bennett WM, Yi H, Andoh TF. Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. Am J Transplant 2002;2:111–119.

    Article  CAS  PubMed  Google Scholar 

  156. Di Sario A, Bendia E, Macarri G, et al. The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen alpha1(I), TIMP-1 and MMP-2. Dig Liver Dis 2004; 36:744–751.

    Article  PubMed  CAS  Google Scholar 

  157. Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999; 289:211–218.

    CAS  PubMed  Google Scholar 

  158. Brook NR, Waller JR, Bicknell GR, Nicholson ML. The experimental agent pirfenidone reduces profibrotic gene expression in a model of tacrolimus-induced nephrotoxicity. J Surg Res 2005;125:137–143.

    Article  CAS  PubMed  Google Scholar 

  159. Garcia L, Hernandez I, Sandoval A, et al. Pirfenidone effectively reverses experimental liver fibrosis. J Hepatol 2002;37:797–805.

    Article  CAS  PubMed  Google Scholar 

  160. Al-Bayati MA, Xie Y, Mohr FC, Margolin SB, Giri SN. Effect of pirfenidone against vanadate-induced kidney fibrosis in rats. Biochem Pharmacol 2002;64:517–525.

    Article  CAS  PubMed  Google Scholar 

  161. Iyer SN, Wild JS, Schiedt MJ, et al. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med 1995;125:779–785.

    CAS  PubMed  Google Scholar 

  162. Kehrer JP, Margolin SB. Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice. Toxicol Lett 1997;90:125–132.

    Article  CAS  PubMed  Google Scholar 

  163. Iyer SN, Margolin SB, Hyde DM, Giri SN. Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model. Exp Lung Res 1998;24:119–132.

    Article  CAS  PubMed  Google Scholar 

  164. 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 1999;159:1061–1069.

    CAS  PubMed  Google Scholar 

  165. Nagai S, Hamada K, Shigematsu M, Taniyama M, Yamauchi S, Izumi T. Open-label compassionate use one year-treatment with pirfenidone to patients with chronic pulmonary fibrosis. Intern Med 2002;41:1118–1123.

    Article  CAS  PubMed  Google Scholar 

  166. 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 2005;171:1040–1047.

    Article  PubMed  Google Scholar 

  167. Savage DG, Antman KH. Imatinib mesylate—a new oral targeted therapy. N Engl J Med 2002;346: 683–693.

    Article  CAS  PubMed  Google Scholar 

  168. Heldin C-H, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 1999;79:1283–1316.

    CAS  PubMed  Google Scholar 

  169. Maeda A, Hiyama K, Yamakido H, Ishioka S, Yamakido M. Increased expression of platelet-derived growth factor A and insulin-like growth factor-I in BAL cells during the development of bleomycin-induced pulmonary fibrosis in mice. Chest 1996;109:780–786.

    Article  CAS  PubMed  Google Scholar 

  170. Yoshida M, Sakuma J, Hayashi S, et al. A histologically distinctive interstitial pneumonia induced by overexpression of the interleukin 6, transforming growth factor beta 1, or platelet-derived growth factor B gene. Proc Natl Acad Sci USA 1995;92:9570–9574.

    Article  CAS  PubMed  Google Scholar 

  171. Homma S, Nagaoka I, Abe H, et al. Localization of platelet-derived growth factor and insulin-like growth factor I in the fibrotic lung. Am J Respir Crit Care Med 1995;152:2084–2089.

    CAS  PubMed  Google Scholar 

  172. Rice AB, Moomaw CR, Morgan DL, Bonner JC. Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am J Pathol 1999;155:213–221.

    CAS  PubMed  Google Scholar 

  173. 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 2004;114:1308–1316.

    CAS  PubMed  Google Scholar 

  174. Aono Y, Nishioka Y, Inayama M, et al. Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 2005;171:1279–1285.

    Article  PubMed  Google Scholar 

  175. Blumberg B, Evans RM. Orphan nuclear receptors—new ligands and new possibilities. Genes Dev 1998;12:3149–3155.

    Article  CAS  PubMed  Google Scholar 

  176. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000;43:527–550.

    Article  CAS  PubMed  Google Scholar 

  177. Kota BP, Huang TH, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res 2005;51:85–94.

    Article  CAS  PubMed  Google Scholar 

  178. Tontonoz P, Graves RA, Budavari AI, et al. Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha. Nucleic Acids Res 1994;22:5628–5634.

    Article  CAS  PubMed  Google Scholar 

  179. Rosen ED, Sarraf P, Troy AE, et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611–617.

    Article  CAS  PubMed  Google Scholar 

  180. Barak Y, Nelson MC, Ong ES, et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 1999;4:585–595.

    Article  CAS  PubMed  Google Scholar 

  181. Lehrke M, Lazar MA. The many faces of PPAR gamma. Cell 2005;123:993–999.

    Article  CAS  PubMed  Google Scholar 

  182. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995;270:12,953–12,956.

    Article  CAS  PubMed  Google Scholar 

  183. He W, Barak Y, Hevener A, et al. Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci USA 2003;100:15,712–15,717.

    Article  CAS  PubMed  Google Scholar 

  184. Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J, Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994;331:1188–1193.

    Article  CAS  PubMed  Google Scholar 

  185. Rangwala SM, Lazar MA. Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. Trends Pharmacol Sci 2004;25:331–336.

    Article  CAS  PubMed  Google Scholar 

  186. Standiford TJ, Keshamouni VG, Reddy RC. Peroxisome proliferator-activated receptor-γ as a regulator of lung inflammation and repair. Proc Am Thorac Soc 2005;2:226–231.

    Article  CAS  PubMed  Google Scholar 

  187. Alleva DG, Johnson EB, Lio FM, Boehme SA, Conlon PJ, Crowe PD. Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-gamma: counter-regulatory activity by IFN-gamma. J Leukoc Biol 2002; 71:677–685.

    CAS  PubMed  Google Scholar 

  188. Kon K, Ikejima K, Hirose M, et al. Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride. Biochem Biophys Res Commun 2002;291:55–61.

    Article  CAS  PubMed  Google Scholar 

  189. Ando M, Murakami Y, Kojima F, et al. Retrovirally introduced prostaglandin D2 synthase suppresses lung injury induced by bleomycin. Am J Respir Cell Mol Biol 2003;28:582–591.

    Article  CAS  PubMed  Google Scholar 

  190. Cuzzocrea S, Wayman NS, Mazzon E, et al. The cyclopentenone prostaglandin 15-deoxy-Delta (12,14)-prostaglandin J(2) attenuates the development of acute and chronic inflammation. Mol Pharmacol 2002;61:997–1007.

    Article  CAS  PubMed  Google Scholar 

  191. Cuzzocrea S, Pisano B, Dugo L, et al. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. Eur J Pharmacol 2004;483:79–93.

    Article  CAS  PubMed  Google Scholar 

  192. Cuzzocrea, S, Mazzon, E, Dugo, L, et al. Reduction in the evolution of murine type II collagen-induced arthritis by treatment with rosiglitazone, a ligand of the peroxisome proliferator-activated receptor gamma. Arthritis Rheum 2003;48:3544–3556.

    Article  CAS  PubMed  Google Scholar 

  193. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JA. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995;83:813–819.

    Article  CAS  PubMed  Google Scholar 

  194. Shimizu K, Shiratori K, Kobayashi M, Kawamata H. Troglitazone inhibits the progression of chronic pancreatitis and the profibrogenic activity of pancreatic stellate cells via a PPARgamma-independent mechanism. Pancreas 2004;29:67–74.

    Article  CAS  PubMed  Google Scholar 

  195. Yuan GJ, Zhang ML, Gong ZJ. Effects of PPARg agonist pioglitazone on rat hepatic fibrosis. World J Gastroenterol 2004;10:1047–1051.

    CAS  PubMed  Google Scholar 

  196. Jaster R, Lichte P, Fitzner B, et al. Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells. J Cell Mol Med 2005;9:670–682.

    Article  CAS  PubMed  Google Scholar 

  197. van Westerloo DJ, Florquin S, de Boer AM, et al. Therapeutic effects of troglitazone in experimental chronic pancreatitis in mice. Am J Pathol 2005;166:721–728.

    PubMed  Google Scholar 

  198. Burgess HA, Daugherty LE, Thatcher TH, et al. PPAR gamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2005;288:L1146–L1153.

    Article  CAS  PubMed  Google Scholar 

  199. Thatcher TH, Burgess HA, Daugherty LE, Redonnet M, Phipps RP, Sime PJ. PPAR-gamma agonists inhibit TGF-beta-induced myofibroblast differentiation in vitro and silica-induced pulmonary fibrosis in vivo. [Abstract]. Am J Respir Crit Care Med 2004;169:A301.

    Google Scholar 

  200. Genovese T, Cuzzocrea S, Di Paola R, et al. Effect of rosiglitazone and 15-deoxy-Delta 12,14-prostaglandin J2 on bleomycin-induced lung injury. Eur Respir J 2005;25:225–234.

    Article  CAS  PubMed  Google Scholar 

  201. Harris SG, Phipps RP. Prostaglandin D(2), its metabolite 15-d-PGJ(2), and peroxisome proliferator activated receptor-gamma agonists induce apoptosis in transformed, but not normal, human T lineage cells. Immunology 2002;105:23–34.

    Article  CAS  PubMed  Google Scholar 

  202. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001;7: 48–52.

    Article  CAS  PubMed  Google Scholar 

  203. Li L, Lao J, Davaille J, et al. 15-deoxy-Delta 12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors. J Biol Chem 2001;276:38,152–38,158.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, The University of Rochester School of Medicine, Rochester, NY, USA

    Patricia J. Sime MD, FRCP, R. Matthew Kottmann MD, Heather F. Lakatos MSc & Thomas H. Thatcher PhD

Authors
  1. Patricia J. Sime MD, FRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Matthew Kottmann MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heather F. Lakatos MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas H. Thatcher PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press

About this chapter

Cite this chapter

Sime, P.J., Kottmann, R.M., Lakatos, H.F., Thatcher, T.H. (2008). The Role of TGF-β in Radiation and Chemotherapy Induced Pulmonary Fibrosis: Inhibition of TGF-β as a Novel Therapeutic Strategy. In: Transforming Growth Factor-β in Cancer Therapy, Volume I. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-292-2_40

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-292-2_40

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-714-3

  • Online ISBN: 978-1-59745-292-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation