Pulmonary Fibrosis and Oxidative Stress

  • Corrine R. Kliment
  • Tim D. Oury
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by progressive fibrosis of the alveolar interstitium. The pathogenesis is thought to involve abnormal re-epithelialization and dysregulated remodeling of the extracellular matrix (ECM) after alveolar injury. There is growing evidence through human and animal studies that oxidative stress plays a role in this dysregulation. Markers of oxidative stress have been identified in the lungs of IPF patients and aberrant antioxidant activity exacerbates pulmonary fibrosis in animal models. In addition, the ECM is a critical component in regulating cellular homeostasis and appropriate wound healing. Recent investigations support that the matrix is a target of oxidative stress in the lung and IPF. ECM degradation products, produced by reactive oxygen species, may promote fibrogenesis by influencing epithelial, mesenchymal, and inflammatory cell activity. The impact of the interactions of oxidative stress and the matrix of the lung remains unclear and may prove to be an important target for new therapies in IPF. Utilizing oxidative species, antioxidants, enzymes, or the tissue matrix as therapeutic targets to control oxidative stress in IPF will continue to be an area of active research and innovative discoveries in the coming years.


Nitric Oxide Hyaluronic Acid Idiopathic Pulmonary Fibrosis Pulmonary Fibrosis Idiopathic Pulmonary Fibrosis Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Bronchoalveolar lavage fluid


Extracellular superoxide dismutase


Idiopathic pulmonary fibrosis


Matrix binding domain






Reactive nitrogen species


Reactive oxygen species



Portions of this writing were reprinted with permission from Elsevier Publishing.


  1. 1.
    American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias (2002) This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 165(2):277–304Google Scholar
  2. 2.
    Gross TJ, Hunninghake GW (2001) Idiopathic pulmonary fibrosis. N Engl J Med 345(7): 517–525PubMedGoogle Scholar
  3. 3.
    Rahman I et al (1999) Systemic and pulmonary oxidative stress in idiopathic pulmonary fibrosis. Free Radic Biol Med 27(1–2):60–68PubMedGoogle Scholar
  4. 4.
    Teramoto S et al (1995) Superoxide anion formation and glutathione metabolism of blood in patients with idiopathic pulmonary fibrosis. Biochem Mol Med 55(1):66–70PubMedGoogle Scholar
  5. 5.
    Daniil ZD et al (2008) Serum levels of oxidative stress as a marker of disease severity in idiopathic pulmonary fibrosis. Pulm Pharmacol Ther 21(1):26–31PubMedGoogle Scholar
  6. 6.
    Raghu G et al (2006) Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 174(7):810–816PubMedGoogle Scholar
  7. 7.
    American Thoracic Society (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161(2 pt 1):646–664Google Scholar
  8. 8.
    Katzenstein AA, Askin FB (1982) Surgical pathology of non-neoplastic lung disease. Major Probl Pathol 13:1–430PubMedGoogle Scholar
  9. 9.
    Korfei M et al (2008) Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 178(8):838–846PubMedPubMedCentralGoogle Scholar
  10. 10.
    Selman M, Pardo A (2002) Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. Respir Res 3:3PubMedPubMedCentralGoogle Scholar
  11. 11.
    Gauldie J et al (1999) Transforming growth factor-beta gene transfer to the lung induces myofibroblast presence and pulmonary fibrosis. Curr Top Pathol 93:35–45PubMedGoogle Scholar
  12. 12.
    Kasai H et al (2005) TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 6:56PubMedPubMedCentralGoogle Scholar
  13. 13.
    Khalil N et al (1996) TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study. Am J Respir Cell Mol Biol 14(2):131–138PubMedGoogle Scholar
  14. 14.
    Sheppard D (2001) Integrin-mediated activation of transforming growth factor-beta(1) in pulmonary fibrosis. Chest 120(1 suppl):49S–53SPubMedGoogle Scholar
  15. 15.
    Beeh KM et al (2002) Glutathione deficiency of the lower respiratory tract in patients with idiopathic pulmonary fibrosis. Eur Respir J 19(6):1119–1123PubMedGoogle Scholar
  16. 16.
    Cantin AM, Hubbard RC, Crystal RG (1989) Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 139(2):370–372PubMedGoogle Scholar
  17. 17.
    Strausz J et al (1990) Oxygen radical production by alveolar inflammatory cells in idiopathic pulmonary fibrosis. Am Rev Respir Dis 141(1):124–128PubMedGoogle Scholar
  18. 18.
    Kinder BW et al (2008) Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest 133(1):226–232PubMedGoogle Scholar
  19. 19.
    Lenz AG et al (2004) Influence of inflammatory mechanisms on the redox balance in interstitial lung diseases. Respir Med 98(8):737–745PubMedGoogle Scholar
  20. 20.
    Obayashi Y et al (1997) The role of neutrophils in the pathogenesis of idiopathic pulmonary fibrosis. Chest 112(5):1338–1343PubMedGoogle Scholar
  21. 21.
    Governa M et al (1999) Role of iron in asbestos-body-induced oxidant radical generation. J Toxicol Environ Health A 58(5):279–287PubMedGoogle Scholar
  22. 22.
    Schapira RM et al (1994) Hydroxyl radicals are formed in the rat lung after asbestos instillation in vivo. Am J Respir Cell Mol Biol 10(5):573–579PubMedGoogle Scholar
  23. 23.
    Haegens A et al (2007) Airway epithelial NF-kappaB activation modulates asbestos-induced inflammation and mucin production in vivo. J Immunol 178(3):1800–1808PubMedGoogle Scholar
  24. 24.
    Rola-Pleszczynski M, Gouin S, Begin R (1984) Asbestos-induced lung inflammation. Role of local macrophage-derived chemotactic factors in accumulation of neutrophils in the lungs. Inflammation 8(1):53–62PubMedGoogle Scholar
  25. 25.
    Dostert C et al (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320(5876):674–677PubMedPubMedCentralGoogle Scholar
  26. 26.
    Pociask DA, Sime PJ, Brody AR (2004) Asbestos-derived reactive oxygen species activate TGF-beta1. Lab Invest 84(8):1013–1023PubMedGoogle Scholar
  27. 27.
    Card JW et al (2003) Attenuation of amiodarone-induced pulmonary fibrosis by vitamin E is associated with suppression of transforming growth factor-beta1 gene expression but not prevention of mitochondrial dysfunction. J Pharmacol Exp Ther 304(1):277–283PubMedGoogle Scholar
  28. 28.
    Caporossi D et al (2003) Cellular responses to H(2)O(2) and bleomycin-induced oxidative stress in L6C5 rat myoblasts. Free Radic Biol Med 35(11):1355–1364PubMedGoogle Scholar
  29. 29.
    Teixeira KC et al (2008) Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine. Pulm Pharmacol Ther 21(2):309–316PubMedGoogle Scholar
  30. 30.
    Tsoutsou PG, Koukourakis MI (2006) Radiation pneumonitis and fibrosis: mechanisms underlying its pathogenesis and implications for future research. Int J Radiat Oncol Biol Phys 66(5):1281–1293PubMedGoogle Scholar
  31. 31.
    Ao X et al (2008) Comparative proteomic analysis of radiation-induced changes in mouse lung: fibrosis-sensitive and -resistant strains. Radiat Res 169(4):417–425PubMedGoogle Scholar
  32. 32.
    Puthawala K et al (2008) Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. Am J Respir Crit Care Med 177(1):82–90PubMedPubMedCentralGoogle Scholar
  33. 33.
    Rube CE et al (2000) 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 47(4):1033–1042PubMedGoogle Scholar
  34. 34.
    Johnston CJ et al (2004) Inflammatory cell recruitment following thoracic irradiation. Exp Lung Res 30(5):369–382PubMedGoogle Scholar
  35. 35.
    Nogee LM et al (2001) A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 344(8):573–579PubMedGoogle Scholar
  36. 36.
    Bitterman PB et al (1986) Familial idiopathic pulmonary fibrosis. Evidence of lung inflammation in unaffected family members. N Engl J Med 314(21):1343–1347PubMedGoogle Scholar
  37. 37.
    Lynch DA (2009) Lung disease related to collagen vascular disease. J Thorac Imaging 24(4):299–309PubMedGoogle Scholar
  38. 38.
    Shi-wen X et al (2000) Autocrine overexpression of CTGF maintains fibrosis: RDA analysis of fibrosis genes in systemic sclerosis. Exp Cell Res 259(1):213–224PubMedGoogle Scholar
  39. 39.
    Baptista AL et al (2006) Structural features of epithelial remodeling in usual interstitial pneumonia histologic pattern. Lung 184(4):239–244PubMedGoogle Scholar
  40. 40.
    Hagimoto N, Kuwano K, Miyazaki H et al (1997) Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen. Am J Respir Cell Mol Biol 17:272–278PubMedGoogle Scholar
  41. 41.
    Kuwano K, Hagimoto N, Kawasaki M et al (1999) Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. J Clin Invest 104:13–19PubMedPubMedCentralGoogle Scholar
  42. 42.
    Sisson TH, Mendez M, Choi K et al (2010) Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med 181:254–263PubMedPubMedCentralGoogle Scholar
  43. 43.
    Li H et al (1996) Expression of TGF-beta 1, PDGF and IGF-1 mRNA in lung of bleomycin-A5-induced pulmonary fibrosis in rats. Chin Med J (Engl) 109(7):533–536Google Scholar
  44. 44.
    Xu YD et al (2003) Release of biologically active TGF-beta1 by alveolar epithelial cells results in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 285(3):L527–L539PubMedGoogle Scholar
  45. 45.
    MacNee W, Rahman I (1995) Oxidants/antioxidants in idiopathic pulmonary fibrosis. Thorax 50(suppl 1):S53–S58PubMedPubMedCentralGoogle Scholar
  46. 46.
    Collard HR et al (2004) Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. Chest 125(6):2169–2174PubMedGoogle Scholar
  47. 47.
    Douglas WW et al (1998) 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 158(1):220–225PubMedGoogle Scholar
  48. 48.
    Flaherty KR et al (2001) Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med 110(4):278–282PubMedGoogle Scholar
  49. 49.
    Rudd RM, Haslam PL, Turner-Warwick M (1981) Cryptogenic fibrosing alveolitis. Relationships of pulmonary physiology and bronchoalveolar lavage to response to treatment and prognosis. Am Rev Respir Dis 124(1):1–8PubMedGoogle Scholar
  50. 50.
    Boomars KA et al (1995) Relationship between cells obtained by bronchoalveolar lavage and survival in idiopathic pulmonary fibrosis. Thorax 50(10):1087–1092PubMedPubMedCentralGoogle Scholar
  51. 51.
    Cassel SL et al (2008) The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A 105(26):9035–9040PubMedPubMedCentralGoogle Scholar
  52. 52.
    Bergeron A et al (2003) Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10. Eur Respir J 22(1):69–76PubMedGoogle Scholar
  53. 53.
    Waghray M et al (2005) Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J 19(7):854–856PubMedGoogle Scholar
  54. 54.
    Ozaki T et al (1992) Neutrophil chemotactic factors in the respiratory tract of patients with chronic airway diseases or idiopathic pulmonary fibrosis. Am Rev Respir Dis 145(1):85–91PubMedGoogle Scholar
  55. 55.
    Ryu YJ et al (2007) Bronchoalveolar lavage in fibrotic idiopathic interstitial pneumonias. Respir Med 101(3):655–660PubMedGoogle Scholar
  56. 56.
    Kinnula VL, Crapo JD (2003) Superoxide dismutases in the lung and human lung diseases. Am J Respir Crit Care Med 167(12):1600–1619PubMedGoogle Scholar
  57. 57.
    Kukin ML, Fuster V (2003) Oxidative stress and cardiac failure, vol xx. Futura Publishing, Armonk, NY, p 291Google Scholar
  58. 58.
    Winyard PG, Blake DR, Evans CH (2000) Free radicals and inflammation, vol ix. Basel, Birkhäuser, p 259Google Scholar
  59. 59.
    Halliwell B (1991) Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med 91(3C):14S–22SPubMedGoogle Scholar
  60. 60.
    Baskin SI, Salem H (eds) (1997) Oxidants, antioxidants, and free radicals. Taylor & Francis, Washington, DC, p 325Google Scholar
  61. 61.
    Ghio AJ et al (2002) Iron regulates xanthine oxidase activity in the lung. Am J Physiol Lung Cell Mol Physiol 283(3):L563–L572PubMedGoogle Scholar
  62. 62.
    Lynch MJ et al (1988) Xanthine oxidase inhibition attenuates ischemic-reperfusion lung injury. J Surg Res 44(5):538–544PubMedGoogle Scholar
  63. 63.
    Terada LS et al (1992) Circulating xanthine oxidase mediates lung neutrophil sequestration after intestinal ischemia-reperfusion. Am J Physiol 263(3 pt 1):L394–L401PubMedGoogle Scholar
  64. 64.
    Dahlgren C, Karlsson A (1999) Respiratory burst in human neutrophils. J Immunol Methods 232(1–2):3–14PubMedGoogle Scholar
  65. 65.
    Derevianko A et al (1997) Endogenous PMN-derived reactive oxygen intermediates provide feedback regulation on respiratory burst signal transduction. J Leukoc Biol 62(2):268–276PubMedGoogle Scholar
  66. 66.
    Hecker L et al (2009) NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 15(9):1077–1081PubMedPubMedCentralGoogle Scholar
  67. 67.
    Manoury B et al (2005) The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respir Res 6:11PubMedPubMedCentralGoogle Scholar
  68. 68.
    Shvedova AA et al (2008) Increased accumulation of neutrophils and decreased fibrosis in the lung of NADPH oxidase-deficient C57BL/6 mice exposed to carbon nanotubes. Toxicol Appl Pharmacol 231(2):235–240PubMedGoogle Scholar
  69. 69.
    Carnesecchi S, Deffert C, Donati Y, Basset O, Hinz B, Preynat-Seauve O, Guichard C, Arbiser JL, Banfi B, Pache JC, Barazzone-Argiroffo C, Krause KH (2011) A key role for nox4 in epithelial cell death during development of lung fibrosis. Antioxid Redox Signal 15:607–619PubMedPubMedCentralGoogle Scholar
  70. 70.
    Hawkins CL, Davies MJ (1998) Degradation of hyaluronic acid, poly- and monosaccharides, and model compounds by hypochlorite: evidence for radical intermediates and fragmentation. Free Radic Biol Med 24(9):1396–1410PubMedGoogle Scholar
  71. 71.
    Rees MD, Hawkins CL, Davies MJ (2004) Hypochlorite and superoxide radicals can act synergistically to induce fragmentation of hyaluronan and chondroitin sulphates. Biochem J 381(pt 1):175–184PubMedPubMedCentralGoogle Scholar
  72. 72.
    Rees MD, Pattison DI, Davies MJ (2005) Oxidation of heparan sulphate by hypochlorite: role of N-chloro derivatives and dichloramine-dependent fragmentation. Biochem J 391(pt 1): 125–134PubMedPubMedCentralGoogle Scholar
  73. 73.
    Eiserich JP et al (2002) Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 296(5577):2391–2394PubMedGoogle Scholar
  74. 74.
    Bruckdorfer R (2005) The basics about nitric oxide. Mol Aspects Med 26(1–2):3–31PubMedGoogle Scholar
  75. 75.
    Hsu YC, Wang LF, Chien YW (2007) Nitric oxide in the pathogenesis of diffuse pulmonary fibrosis. Free Radic Biol Med 42(5):599–607PubMedGoogle Scholar
  76. 76.
    Zeidler P et al (2004) Role of inducible nitric oxide synthase-derived nitric oxide in silica-induced pulmonary inflammation and fibrosis. J Toxicol Environ Health A 67(13): 1001–1026PubMedGoogle Scholar
  77. 77.
    Ricciardolo FL et al (2006) Reactive nitrogen species in the respiratory tract. Eur J Pharmacol 533(1–3):240–252PubMedGoogle Scholar
  78. 78.
    Pfeilschifter J, Eberhardt W, Beck KF (2001) Regulation of gene expression by nitric oxide. Pflugers Arch 442(4):479–486PubMedGoogle Scholar
  79. 79.
    Huie RE, Padmaja S (1993) The reaction of NO with superoxide. Free Radic Res Commun 18(4):195–199PubMedGoogle Scholar
  80. 80.
    Oury TD et al (1995) Nitration of tyrosine by hydrogen peroxide and nitrite. Free Radic Res 23(6):537–547PubMedGoogle Scholar
  81. 81.
    Oury TD, Day BJ, Crapo JD (1996) Extracellular superoxide dismutase: a regulator of nitric oxide bioavailability. Lab Invest 75(5):617–636PubMedGoogle Scholar
  82. 82.
    Eiserich JP et al (1998) Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391(6665):393–397PubMedGoogle Scholar
  83. 83.
    Saleh D, Barnes PJ, Giaid A (1997) Increased production of the potent oxidant peroxynitrite in the lungs of patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 155(5):1763–1769PubMedGoogle Scholar
  84. 84.
    Montuschi P et al (1998) 8-Isoprostane as a biomarker of oxidative stress in interstitial lung diseases. Am J Respir Crit Care Med 158(5 pt 1):1524–1527PubMedGoogle Scholar
  85. 85.
    Psathakis K et al (2006) Exhaled markers of oxidative stress in idiopathic pulmonary fibrosis. Eur J Clin Invest 36(5):362–367PubMedGoogle Scholar
  86. 86.
    Kanoh S, Kobayashi H, Motoyoshi K (2005) Exhaled ethane: an in vivo biomarker of lipid peroxidation in interstitial lung diseases. Chest 128(4):2387–2392PubMedGoogle Scholar
  87. 87.
    Lenz AG, Costabel U, Maier KL (1996) Oxidized BAL fluid proteins in patients with interstitial lung diseases. Eur Respir J 9(2):307–312PubMedGoogle Scholar
  88. 88.
    Bargagli E et al (2007) Analysis of carbonylated proteins in bronchoalveolar lavage of patients with diffuse lung diseases. Lung 185(3):139–144PubMedGoogle Scholar
  89. 89.
    Rottoli P et al (2005) Carbonylated proteins in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics 5(10):2612–2618PubMedGoogle Scholar
  90. 90.
    Bocchino M, Agnese S, Fagone E, Svegliati S, Grieco D, Vancheri C, Gabrielli A, Sanduzzi A, Avvedimento EV (2010) Reactive oxygen species are required for maintenance and differentiation of primary lung fibroblasts in idiopathic pulmonary fibrosis. PLoS One 5(11):e14003PubMedPubMedCentralGoogle Scholar
  91. 91.
    Gorowiec MR, Borthwick LA, Parker SM, Kirby JA, Saretzki GC, Fisher AJ (2012) Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-β1-dependent mechanism. Free Radic Biol Med 52(6):1024–1032PubMedGoogle Scholar
  92. 92.
    Markart P et al (2009) Alveolar oxidative stress is associated with elevated levels of nonenzymatic low-molecular-weight antioxidants in patients with different forms of chronic fibrosing interstitial lung diseases. Antioxid Redox Signal 11(2):227–240PubMedGoogle Scholar
  93. 93.
    Kinnula VL et al (2006) Extracellular superoxide dismutase has a highly specific localization in idiopathic pulmonary fibrosis/usual interstitial pneumonia. Histopathology 49(1):66–74PubMedPubMedCentralGoogle Scholar
  94. 94.
    Lazo JS et al (1990) Bleomycin: a pharmacologic tool in the study of the pathogenesis of interstitial pulmonary fibrosis. Pharmacol Ther 47(3):347–358PubMedGoogle Scholar
  95. 95.
    Sugiura Y (1979) The production of hydroxyl radical from copper(I) complex systems of bleomycin and tallysomycin: comparison with copper(II) and iron(II) systems. Biochem Biophys Res Commun 90(1):375–383PubMedGoogle Scholar
  96. 96.
    Hansen K, Mossman BT (1987) Generation of superoxide (O2−•) from alveolar macrophages exposed to asbestiform and nonfibrous particles. Cancer Res 47(6):1681–1686PubMedGoogle Scholar
  97. 97.
    Anathy V, Aesif SW, Guala AS et al (2009) Redox amplification of apoptosis by caspase dependent cleavage of glutaredoxin-1 and Sglutathionylation of Fas. J Cell Biol 184(2): 241–252PubMedPubMedCentralGoogle Scholar
  98. 98.
    Anathy V, Roberson EC, Cunniff BS et al (2012) Oxidative processing of latent Fas in the endoplasmic reticulum controls the strength of apoptosis. Mol Cell Biol 32(17):3464–3478PubMedPubMedCentralGoogle Scholar
  99. 99.
    Bowler RP et al (2002) Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 282(4):L719–L726PubMedGoogle Scholar
  100. 100.
    Yamazaki C et al (1997) Effect of lecithinized-superoxide dismutase on the interstitial pneumonia model induced by bleomycin in mice. Jpn J Pharmacol 75(1):97–100PubMedGoogle Scholar
  101. 101.
    Fattman CL et al (2003) Enhanced bleomycin-induced pulmonary damage in mice lacking extracellular superoxide dismutase. Free Radic Biol Med 35(7):763–771PubMedGoogle Scholar
  102. 102.
    Bowler RP, Crapo JD (2002) Oxidative stress in airways: is there a role for extracellular superoxide dismutase? Am J Respir Crit Care Med 166(12 pt 2):S38–S43PubMedGoogle Scholar
  103. 103.
    Fattman CL et al (2006) Increased sensitivity to asbestos-induced lung injury in mice lacking extracellular superoxide dismutase. Free Radic Biol Med 40(4):601–607PubMedPubMedCentralGoogle Scholar
  104. 104.
    Adamson IY, Bowden DH (1984) Role of polymorphonuclear leukocytes in silica-induced pulmonary fibrosis. Am J Pathol 117(1):37–43PubMedPubMedCentralGoogle Scholar
  105. 105.
    Adamson IY, Letourneau HL, Bowden DH (1989) Enhanced macrophage-fibroblast interactions in the pulmonary interstitium increases fibrosis after silica injection to monocyte-depleted mice. Am J Pathol 134(2):411–418PubMedPubMedCentralGoogle Scholar
  106. 106.
    Bowden DH, Hedgecock C, Adamson IY (1989) Silica-induced pulmonary fibrosis involves the reaction of particles with interstitial rather than alveolar macrophages. J Pathol 158(1): 73–80PubMedGoogle Scholar
  107. 107.
    Porter DW et al (2001) Time course of pulmonary response of rats to inhalation of crystalline silica: histological results and biochemical indices of damage, lipidosis, and fibrosis. J Environ Pathol Toxicol Oncol 20(suppl 1):1–14PubMedGoogle Scholar
  108. 108.
    Adamson IY, Prieditis H (1998) Silica deposition in the lung during epithelial injury potentiates fibrosis and increases particle translocation to lymph nodes. Exp Lung Res 24(3): 293–306PubMedGoogle Scholar
  109. 109.
    Mariani TJ et al (1996) Localization of type I procollagen gene expression in silica-induced granulomatous lung disease and implication of transforming growth factor-beta as a mediator of fibrosis. Am J Pathol 148(1):151–164PubMedPubMedCentralGoogle Scholar
  110. 110.
    Poole A (1987) Collagen synthesis in rats with silica-induced pulmonary fibrosis. Arch Toxicol Suppl 11:285–287PubMedGoogle Scholar
  111. 111.
    Vuorio EI et al (1989) Characterization of excessive collagen production during development of pulmonary fibrosis induced by chronic silica inhalation in rats. Br J Exp Pathol 70(3): 305–315PubMedPubMedCentralGoogle Scholar
  112. 112.
    Velan GM, Kumar RK, Cohen DD (1993) Pulmonary inflammation and fibrosis following subacute inhalational exposure to silica: determinants of progression. Pathology 25(3): 282–290PubMedGoogle Scholar
  113. 113.
    Carpenter M et al (2005) Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage. Gene Ther 12(8):685–693PubMedGoogle Scholar
  114. 114.
    Epperly MW et al (1999) Intratracheal injection of adenovirus containing the human MnSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis. Int J Radiat Oncol Biol Phys 43(1):169–181PubMedGoogle Scholar
  115. 115.
    Oury TD et al (2002) Depletion of pulmonary EC-SOD after exposure to hyperoxia. Am J Physiol Lung Cell Mol Physiol 283(4):L777–L784PubMedGoogle Scholar
  116. 116.
    Oury TD et al (2001) Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin. Am J Respir Cell Mol Biol 25(2):164–169PubMedGoogle Scholar
  117. 117.
    Tan RJ et al (2004) Redistribution of pulmonary EC-SOD after exposure to asbestos. J Appl Physiol 97(5):2006–2013PubMedGoogle Scholar
  118. 118.
    Behr J (2005) Oxidants and antioxidants in idiopathic pulmonary fibrosis. In: Lynch JP (ed) Idiopathic pulmonary fibrosis: lung biology in health and disease. Marcel Dekker, New York, pp 379–396Google Scholar
  119. 119.
    Shukla A, Ramos-Nino M, Mossman B (2003) Cell signaling and transcription factor activation by asbestos in lung injury and disease. Int J Biochem Cell Biol 35(8):1198–1209PubMedGoogle Scholar
  120. 120.
    Cheng N et al (1999) Role of transcription factor NF-kappaB in asbestos-induced TNFalpha response from macrophages. Exp Mol Pathol 66(3):201–210PubMedGoogle Scholar
  121. 121.
    Murrell GA, Francis MJ, Bromley L (1990) Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 265(3):659–665PubMedPubMedCentralGoogle Scholar
  122. 122.
    Uhal BD et al (1995) Fibroblasts isolated after fibrotic lung injury induce apoptosis of alveolar epithelial cells in vitro. Am J Physiol 269(6 pt 1):L819–L828PubMedGoogle Scholar
  123. 123.
    Selman M, Pardo A (2004) Matrix metalloproteinases and tissue inhibitors. In: Lynch JP (ed) Lung biology in health and disease: idiopathic pulmonary fibrosis. Marcel Dekker, New York, pp 451–480Google Scholar
  124. 124.
    Tan RJ et al (2006) Matrix metalloproteinases promote inflammation and fibrosis in asbestos-induced lung injury in mice. Am J Respir Cell Mol Biol 35(3):289–297PubMedPubMedCentralGoogle Scholar
  125. 125.
    (1995) Pulmonary fibrosis. In: Phan SH, Thrall RS (eds) Lung biology in health and disease. Marcel Dekker, New YorkGoogle Scholar
  126. 126.
    Kumar V, Robbins SL (2007) Robbins basic pathology, vol xiv, 8th edn. Saunders/Elsevier, Philadelphia, PA, p 946Google Scholar
  127. 127.
    Kuhn C III et al (1989) An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis 140(6):1693–1703PubMedGoogle Scholar
  128. 128.
    Kuhn C, McDonald JA (1991) The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. Am J Pathol 138(5):1257–1265PubMedPubMedCentralGoogle Scholar
  129. 129.
    Varki A, Chrispeels MJ (1999) Essentials of glycobiology, vol xvii. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, p 653Google Scholar
  130. 130.
    Bernfield M et al (1999) Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68:729–777PubMedGoogle Scholar
  131. 131.
    Bernfield M et al (1992) Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans. Annu Rev Cell Biol 8:365–393PubMedGoogle Scholar
  132. 132.
    Taylor KR, Gallo RL (2006) Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. FASEB J 20(1):9–22PubMedGoogle Scholar
  133. 133.
    Gotte M, Echtermeyer F (2003) Syndecan-1 as a regulator of chemokine function. ScientificWorldJournal 3:1327–1331PubMedGoogle Scholar
  134. 134.
    Kainulainen V et al (1998) Syndecans, heparan sulfate proteoglycans, maintain the proteolytic balance of acute wound fluids. J Biol Chem 273(19):11563–11569PubMedGoogle Scholar
  135. 135.
    Mollinedo F et al (1997) Major co-localization of the extracellular-matrix degradative enzymes heparanase and gelatinase in tertiary granules of human neutrophils. Biochem J 327(pt 3):917–923PubMedPubMedCentralGoogle Scholar
  136. 136.
    Yang Y et al (2007) Heparanase enhances syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. J Biol Chem 282(18):13326–13333PubMedGoogle Scholar
  137. 137.
    Yu WH, Woessner JF Jr (2000) Heparan sulfate proteoglycans as extracellular docking molecules for matrilysin (matrix metalloproteinase 7). J Biol Chem 275(6):4183–4191PubMedGoogle Scholar
  138. 138.
    Li Q et al (2002) Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111(5):635–646PubMedGoogle Scholar
  139. 139.
    Zuo F et al (2002) Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A 99(9):6292–6297PubMedPubMedCentralGoogle Scholar
  140. 140.
    Rosas IO et al (2008) MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med 5(4):e93PubMedPubMedCentralGoogle Scholar
  141. 141.
    Bartlett AH, Hayashida K, Park PW (2007) Molecular and cellular mechanisms of syndecans in tissue injury and inflammation. Mol Cells 24(2):153–166PubMedGoogle Scholar
  142. 142.
    Fitzgerald ML et al (2000) Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase. J Cell Biol 148(4):811–824PubMedPubMedCentralGoogle Scholar
  143. 143.
    Gao F et al (2008) Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan. J Biol Chem 283(10):6058–6066PubMedPubMedCentralGoogle Scholar
  144. 144.
    Kliment CR et al (2009) Oxidative stress alters syndecan-1 distribution in lungs with pulmonary fibrosis. J Biol Chem 284(6):3537–3545PubMedPubMedCentralGoogle Scholar
  145. 145.
    Kliment CR et al (2008) Extracellular superoxide dismutase protects against matrix degradation of heparan sulfate in the lung. Antioxid Redox Signal 10(2):261–268PubMedPubMedCentralGoogle Scholar
  146. 146.
    Bjermer L, Lundgren R, Hallgren R (1989) Hyaluronan and type III procollagen peptide concentrations in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis. Thorax 44(2):126–131PubMedPubMedCentralGoogle Scholar
  147. 147.
    Petersen SV et al (2004) Extracellular superoxide dismutase (EC-SOD) binds to type i collagen and protects against oxidative fragmentation. J Biol Chem 279(14):13705–13710PubMedGoogle Scholar
  148. 148.
    Jiang D, Liang J, Noble PW (2007) Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol 23:435–461PubMedGoogle Scholar
  149. 149.
    Zaman A et al (2005) Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury. Am J Respir Cell Mol Biol 33(5):447–454PubMedPubMedCentralGoogle Scholar
  150. 150.
    Hawkins CL, Rees MD, Davies MJ (2002) Superoxide radicals can act synergistically with hypochlorite to induce damage to proteins. FEBS Lett 510(1–2):41–44PubMedGoogle Scholar
  151. 151.
    Raats CJ et al (1997) Hydroxyl radicals depolymerize glomerular heparan sulfate in vitro and in experimental nephrotic syndrome. J Biol Chem 272(42):26734–26741PubMedGoogle Scholar
  152. 152.
    Raats CJ, Van Den Born J, Berden JH (2000) Glomerular heparan sulfate alterations: mechanisms and relevance for proteinuria. Kidney Int 57(2):385–400PubMedGoogle Scholar
  153. 153.
    Rees MD et al (2008) Oxidative damage to extracellular matrix and its role in human pathologies. Free Radic Biol Med 44(12):1973–2001PubMedGoogle Scholar
  154. 154.
    Hawkins CL, Davies MJ (2001) Generation and propagation of radical reactions on proteins. Biochim Biophys Acta 1504(2–3):196–219PubMedGoogle Scholar
  155. 155.
    Yaguchi T et al (1998) Immunohistochemical and gelatin zymography studies for matrix metalloproteinases in bleomycin-induced pulmonary fibrosis. Pathol Int 48(12):954–963PubMedGoogle Scholar
  156. 156.
    Kinnula VL et al (2005) Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. Am J Respir Crit Care Med 172(4):417–422PubMedPubMedCentralGoogle Scholar
  157. 157.
    Fu X et al (2003) Hypochlorous acid generated by myeloperoxidase modifies adjacent tryptophan and glycine residues in the catalytic domain of matrix metalloproteinase-7 (matrilysin): an oxidative mechanism for restraining proteolytic activity during inflammation. J Biol Chem 278(31):28403–28409PubMedGoogle Scholar
  158. 158.
    Nelson KK, Melendez JA (2004) Mitochondrial redox control of matrix metalloproteinases. Free Radic Biol Med 37(6):768–784PubMedGoogle Scholar
  159. 159.
    Hayashi T et al (1996) Immunohistochemical study of metalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis. Am J Pathol 149(4):1241–1256PubMedPubMedCentralGoogle Scholar
  160. 160.
    McKeown S et al (2009) MMP expression and abnormal lung permeability are important determinants of outcome in IPF. Eur Respir J 33(1):77–84PubMedGoogle Scholar
  161. 161.
    Cabrera S et al (2007) Overexpression of MMP9 in macrophages attenuates pulmonary fibrosis induced by bleomycin. Int J Biochem Cell Biol 39(12):2324–2338PubMedGoogle Scholar
  162. 162.
    Murthy S et al (2009) Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 297(5): L846–L855PubMedPubMedCentralGoogle Scholar
  163. 163.
    Mossman BT et al (1990) Inhibition of lung injury, inflammation, and interstitial pulmonary fibrosis by polyethylene glycol-conjugated catalase in a rapid inhalation model of asbestosis. Am Rev Respir Dis 141(5 pt 1):1266–1271PubMedGoogle Scholar
  164. 164.
    Meyer A, Buhl R, Magnussen H (1994) The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis. Eur Respir J 7(3):431–436PubMedGoogle Scholar
  165. 165.
    Behr J et al (2002) Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: effects of N-acetylcysteine. Eur Respir J 19(5):906–911PubMedGoogle Scholar
  166. 166.
    Borok Z et al (1991) Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis. Lancet 338(8761):215–216PubMedGoogle Scholar
  167. 167.
    McCord JM, Fridovich I (1968) The reduction of cytochrome c by milk xanthine oxidase. J Biol Chem 243(21):5753–5760PubMedGoogle Scholar
  168. 168.
    McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244(22):6049–6055PubMedGoogle Scholar
  169. 169.
    Marklund SL (1982) Human copper-containing superoxide dismutase of high molecular weight. Proc Natl Acad Sci U S A 79(24):7634–7638PubMedPubMedCentralGoogle Scholar
  170. 170.
    Marklund SL, Holme E, Hellner L (1982) Superoxide dismutase in extracellular fluids. Clin Chim Acta 126(1):41–51PubMedGoogle Scholar
  171. 171.
    Fattman CL et al (2000) Purification and characterization of extracellular superoxide dismutase in mouse lung. Biochem Biophys Res Commun 275(2):542–548PubMedGoogle Scholar
  172. 172.
    Fattman CL, Schaefer LM, Oury TD (2003) Extracellular superoxide dismutase in biology and medicine. Free Radic Biol Med 35(3):236–256PubMedGoogle Scholar
  173. 173.
    Oury TD, Day BJ, Crapo JD (1996) Extracellular superoxide dismutase in vessels and airways of humans and baboons. Free Radic Biol Med 20(7):957–965PubMedGoogle Scholar
  174. 174.
    Demchenko IT et al (2002) Regulation of the brain’s vascular responses to oxygen. Circ Res 91(11):1031–1037PubMedGoogle Scholar
  175. 175.
    Nozik-Grayck E, Suliman HB, Piantadosi CA (2005) Extracellular superoxide dismutase. Int J Biochem Cell Biol 37(12):2466–2471PubMedGoogle Scholar
  176. 176.
    Oury TD et al (1992) Extracellular superoxide dismutase, nitric oxide, and central nervous system O2 toxicity. Proc Natl Acad Sci U S A 89(20):9715–9719PubMedPubMedCentralGoogle Scholar
  177. 177.
    Adachi T et al (1992) The heparin binding site of human extracellular-superoxide dismutase. Arch Biochem Biophys 297(1):155–161PubMedGoogle Scholar
  178. 178.
    Adachi T, Yamnamoto M, Hara H (2001) Heparin-affinity of human extracellular-superoxide dismutase in the brain. Biol Pharm Bull 24(2):191–193PubMedGoogle Scholar
  179. 179.
    Karlsson K, Lindahl U, Marklund SL (1988) Binding of human extracellular superoxide dismutase C to sulphated glycosaminoglycans. Biochem J 256(1):29–33PubMedPubMedCentralGoogle Scholar
  180. 180.
    Karlsson K, Marklund SL (1988) Extracellular-superoxide dismutase association with cell surface-bound sulfated glucosaminoglycans. Basic Life Sci 49:647–650PubMedGoogle Scholar
  181. 181.
    Tan RJ et al (2006) Inflammatory cells as a source of airspace extracellular superoxide dismutase after pulmonary injury. Am J Respir Cell Mol Biol 34(2):226–232PubMedPubMedCentralGoogle Scholar
  182. 182.
    Fattman CL et al (2001) Altered expression of extracellular superoxide dismutase in mouse lung after bleomycin treatment. Free Radic Biol Med 31(10):1198–1207PubMedGoogle Scholar
  183. 183.
    Walter N, Collard HR, King TE Jr (2006) Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc 3(4):330–338PubMedGoogle Scholar
  184. 184.
    Flaherty KR et al (2002) Clinical significance of histological classification of idiopathic interstitial pneumonia. Eur Respir J 19(2):275–283PubMedGoogle Scholar
  185. 185.
    Raghu G et al (1991) Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis 144(2):291–296PubMedGoogle Scholar
  186. 186.
    Zisman DA et al (2000) Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids. Chest 117(6): 1619–1626PubMedGoogle Scholar
  187. 187.
    King TE Jr et al (2009) Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet 374(9685):222–228PubMedGoogle Scholar
  188. 188.
    Modriansky M et al (2002) Anti-/pro-oxidant effects of phenolic compounds in cells: are colchicine metabolites chain-breaking antioxidants? Toxicology 177(1):105–117PubMedGoogle Scholar
  189. 189.
    Mourelle M, Meza MA (1989) Colchicine prevents D-galactosamine-induced hepatitis. J Hepatol 8(2):165–172PubMedGoogle Scholar
  190. 190.
    Rennard SI et al (1988) 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 137(1):181–185PubMedGoogle Scholar
  191. 191.
    Zhang L et al (1992) The protective effect of colchicine on bleomycin-induced pulmonary fibrosis in rats. Chin Med Sci J 7(1):58–60PubMedGoogle Scholar
  192. 192.
    Douglas WW, Ryu JH, Schroeder DR (2000) Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med 161(4 pt 1):1172–1178PubMedGoogle Scholar
  193. 193.
    Giri SN et al (1999) Effects of pirfenidone on the generation of reactive oxygen species in vitro. J Environ Pathol Toxicol Oncol 18(3):169–177PubMedGoogle Scholar
  194. 194.
    Misra HP, Rabideau C (2000) Pirfenidone inhibits NADPH-dependent microsomal lipid peroxidation and scavenges hydroxyl radicals. Mol Cell Biochem 204(1–2):119–126PubMedGoogle Scholar
  195. 195.
    Mitani Y et al (2008) Superoxide scavenging activity of pirfenidone-iron complex. Biochem Biophys Res Commun 372(1):19–23PubMedGoogle Scholar
  196. 196.
    Iyer SN, Gurujeyalakshmi G, Giri SN (1999) 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 291(1):367–373PubMedGoogle Scholar
  197. 197.
    Iyer SN et al (1998) Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model. Exp Lung Res 24(1):119–132PubMedGoogle Scholar
  198. 198.
    Raghu G et al (1999) 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 159(4 pt 1):1061–1069PubMedGoogle Scholar
  199. 199.
    Cuzzocrea S et al (2007) Protective effect of orally administered carnosine on bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol 292(5):L1095–L1104PubMedGoogle Scholar
  200. 200.
    Demedts M et al (2005) High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 353(21):2229–2242PubMedGoogle Scholar
  201. 201.
    Behr J et al (2009) Lung function in idiopathic pulmonary fibrosis—extended analyses of the IFIGENIA trial. Respir Res 10:101PubMedPubMedCentralGoogle Scholar
  202. 202.
    Tomioka H et al (2005) A pilot study of aerosolized N-acetylcysteine for idiopathic pulmonary fibrosis. Respirology 10(4):449–455PubMedGoogle Scholar
  203. 203.
    IPF Clinical Research Network et al (2012) Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 366:1968–1977Google Scholar
  204. 204.
    Day BJ (2008) Antioxidants as potential therapeutics for lung fibrosis. Antioxid Redox Signal 10(2):355–370PubMedPubMedCentralGoogle Scholar
  205. 205.
    Day BJ (2004) Catalytic antioxidants: a radical approach to new therapeutics. Drug Discov Today 9(13):557–566PubMedGoogle Scholar
  206. 206.
    Vujaskovic Z et al (2002) A small molecular weight catalytic metalloporphyrin antioxidant with superoxide dismutase (SOD) mimetic properties protects lungs from radiation-induced injury. Free Radic Biol Med 33(6):857–863PubMedGoogle Scholar
  207. 207.
    Thabut G et al (2003) Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg 126(2):469–475PubMedGoogle Scholar
  208. 208.
    Williams A et al (1999) Compromised antioxidant status and persistent oxidative stress in lung transplant recipients. Free Radic Res 30(5):383–393PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Internal MedicineBrigham and Women’s Hospital, Harvard UniversityBostonUSA
  2. 2.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA

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