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PMID: 15894605 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Review

Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy.

American journal of respiratory and critical care medicine ·Vol. 172 ·No. 4 ·2005-08-15 ·Pages 417-22

Kinnula VL, Fattman CL, Tan RJ, Oury TD

Abstract

Idiopathic ulmonary fibrosis (histopathology of usual interstitial pneumonia) is a progressive lung disease of unknown etiology. No treatment has been shown to improve the prognosis of the patients with this disease. Recent evidence, including the observations that the patients with idiopathic pulmonary fibrosis have higher levels of oxidant stress than control patients, and a recent multicenter European study examining the effect of the antioxidant N-acetylcysteine on the progression of idiopathic pulmonary fibrosis suggest that the cellular redox state may play a significant role in the progression of this disease. These complex mechanisms include activation of growth factors as well as regulation of matrix metalloproteinases and protease inhibitors. Potential future approaches for the therapy of interstitial pulmonary fibrosis may involve synthetic agents able to modulate cellular redox state. Investigation into therapeutic approaches to inhibit oxidant-mediated reactions in the initiation and progression of pulmonary fibrosis may provide hope for the future treatment of this disease.

MeSH Terms
Animals Antioxidants/metabolism Disease Models, Animal Free Radicals Humans Lung/metabolism Oxidation-Reduction Oxidative Stress Pulmonary Fibrosis/metabolism,therapy Reactive Oxygen Species/metabolism Transforming Growth Factor beta/metabolism
Chemicals
Antioxidants Free Radicals Reactive Oxygen Species Transforming Growth Factor beta
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kinnula Vuokko L
Department of Medicine, Division of Pulmonary Medicine, University of Helsinki, P.O. Box 22 (Haartmaninkatu 4), FI-00014 Helsinki, Finland. [email protected]
Fattman Cheryl L
Tan Roderick J
Oury Tim D
References (66)
66 references, click to expand
  1. Increased oxidation of extracellular glutathione by bronchoalveolar inflammatory cells in diffuse fibrosing alveolitis.
    Eur Respir J. 1995 Aug;8(8):1286-92 PMID: 7489792
  2. Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1.
    J Biol Chem. 1995 Dec 22;270(51):30334-8 PMID: 8530457
  3. Administration of truncated secretory leukoprotease inhibitor ameliorates bleomycin-induced pulmonary fibrosis in hamsters.
    Am J Respir Crit Care Med. 1996 Jan;153(1):369-74 PMID: 8542145
  4. Inactivation of tissue inhibitor of metalloproteinase-1 by peroxynitrite.
    FEBS Lett. 1996 Feb 26;381(1-2):21-4 PMID: 8641430
  5. Exhaled markers of pulmonary disease.
    Am J Respir Crit Care Med. 2001 Jun;163(7):1693-722 PMID: 11401895
  6. Idiopathic pulmonary fibrosis.
    N Engl J Med. 2001 Aug 16;345(7):517-25 PMID: 11519507
  7. Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin.
    Am J Respir Cell Mol Biol. 2001 Aug;25(2):164-9 PMID: 11509325
  8. Altered expression of extracellular superoxide dismutase in mouse lung after bleomycin treatment.
    Free Radic Biol Med. 2001 Nov 15;31(10):1198-207 PMID: 11705698
  9. Expression and regulation of hemeoxygenase 1 in healthy human lung and interstitial lung disorders.
    Hum Pathol. 2001 Nov;32(11):1257-63 PMID: 11727267
  10. Inducible nitric oxide synthase, but not xanthine oxidase, is highly expressed in interstitial pneumonias and granulomatous diseases of human lung.
    Am J Clin Pathol. 2002 Jan;117(1):132-42 PMID: 11789718
  11. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.
    Am J Respir Crit Care Med. 2002 Jan 15;165(2):277-304 PMID: 11790668
  12. Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice.
    Am J Physiol Lung Cell Mol Physiol. 2002 Mar;282(3):L585-93 PMID: 11839555
  13. Clinical significance of histological classification of idiopathic interstitial pneumonia.
    Eur Respir J. 2002 Feb;19(2):275-83 PMID: 11866008
  14. Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis.
    Am J Physiol Lung Cell Mol Physiol. 2002 Apr;282(4):L719-26 PMID: 11880297
  15. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans.
    Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6292-7 PMID: 11983918
  16. Myofibroblasts and mechano-regulation of connective tissue remodelling.
    Nat Rev Mol Cell Biol. 2002 May;3(5):349-63 PMID: 11988769
  17. Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: effects of N-acetylcysteine.
    Eur Respir J. 2002 May;19(5):906-11 PMID: 12030732
  18. SOD mimetics are coming of age.
    Nat Rev Drug Discov. 2002 May;1(5):367-74 PMID: 12120412
  19. A small molecular weight catalytic metalloporphyrin antioxidant with superoxide dismutase (SOD) mimetic properties protects lungs from radiation-induced injury.
    Free Radic Biol Med. 2002 Sep 15;33(6):857-63 PMID: 12208373
  20. Cellular glutathione and thiols metabolism.
    Biochem Pharmacol. 2002 Sep;64(5-6):1019-26 PMID: 12213601
  21. Mitochondria-mediated apoptosis of lung epithelial cells in idiopathic interstitial pneumonias.
    Lab Invest. 2002 Dec;82(12):1695-706 PMID: 12480919
  22. Oxidative stress in lung epithelial cells from patients with idiopathic interstitial pneumonias.
    Eur Respir J. 2003 Feb;21(2):232-40 PMID: 12608435
  23. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase.
    J Biol Chem. 2003 Apr 4;278(14):12384-9 PMID: 12531888
  24. In vivo antioxidant treatment protects against bleomycin-induced lung damage in rats.
    Br J Pharmacol. 2003 Mar;138(6):1037-48 PMID: 12684259
  25. Superoxide dismutases in the lung and human lung diseases.
    Am J Respir Crit Care Med. 2003 Jun 15;167(12):1600-19 PMID: 12796054
  26. 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. 2003 Aug 1;278(31):28403-9 PMID: 12759346
  27. Extracellular superoxide dismutase in biology and medicine.
    Free Radic Biol Med. 2003 Aug 1;35(3):236-56 PMID: 12885586
  28. Enhanced bleomycin-induced pulmonary damage in mice lacking extracellular superoxide dismutase.
    Free Radic Biol Med. 2003 Oct 1;35(7):763-71 PMID: 14583340
  29. Expression of the thioredoxin system in interstitial lung disease.
    J Pathol. 2003 Nov;201(3):363-70 PMID: 14595747
  30. Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats.
    Eur Respir J. 2003 Dec;22(6):900-5 PMID: 14680076
  31. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.
    N Engl J Med. 2004 Jan 8;350(2):125-33 PMID: 14711911
  32. Mechanisms of pulmonary fibrosis.
    Annu Rev Med. 2004;55:395-417 PMID: 14746528
  33. Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches.
    Drugs. 2004;64(4):405-30 PMID: 14969575
  34. Extracellular superoxide dismutase (EC-SOD) binds to type i collagen and protects against oxidative fragmentation.
    J Biol Chem. 2004 Apr 2;279(14):13705-10 PMID: 14736885
  35. Catalytic antioxidants: a radical approach to new therapeutics.
    Drug Discov Today. 2004 Jul 1;9(13):557-66 PMID: 15203091
  36. The transcription factor NRF2 protects against pulmonary fibrosis.
    FASEB J. 2004 Aug;18(11):1258-60 PMID: 15208274
  37. Matrix metalloproteinases as modulators of inflammation and innate immunity.
    Nat Rev Immunol. 2004 Aug;4(8):617-29 PMID: 15286728
  38. Expression of glutaredoxin is highly cell specific in human lung and is decreased by transforming growth factor-beta in vitro and in interstitial lung diseases in vivo.
    Hum Pathol. 2004 Aug;35(8):1000-7 PMID: 15297967
  39. Mitochondrial redox control of matrix metalloproteinases.
    Free Radic Biol Med. 2004 Sep 15;37(6):768-84 PMID: 15304253
  40. Redistribution of pulmonary EC-SOD after exposure to asbestos.
    J Appl Physiol (1985). 2004 Nov;97(5):2006-13 PMID: 15298984
  41. Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis.
    J Clin Invest. 1987 Jun;79(6):1665-73 PMID: 3034979
  42. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production.
    Proc Natl Acad Sci U S A. 1987 Aug;84(16):5788-92 PMID: 2886992
  43. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis.
    Am Rev Respir Dis. 1989 Feb;139(2):370-2 PMID: 2913886
  44. The eosinophil component of the alveolitis in idiopathic pulmonary fibrosis. Signs of eosinophil activation in the lung are related to impaired lung function.
    Am Rev Respir Dis. 1989 Feb;139(2):373-7 PMID: 2536526
  45. Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis.
    Lancet. 1991 Jul 27;338(8761):215-6 PMID: 1676780
  46. Administration of alpha 1-proteinase inhibitor ameliorates bleomycin-induced pulmonary fibrosis in hamsters.
    Am Rev Respir Dis. 1992 Mar;145(3):651-6 PMID: 1372163
  47. Inactivation of alpha 1-proteinase inhibitor by peroxynitrite.
    Chem Res Toxicol. 1992 May-Jun;5(3):425-31 PMID: 1504267
  48. Cell and tissue responses to oxidative damage.
    Lab Invest. 1993 Sep;69(3):261-74 PMID: 8377469
  49. The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis.
    Eur Respir J. 1994 Mar;7(3):431-6 PMID: 8013597
  50. Generation and disposal of reactive oxygen metabolites in the lung.
    Lab Invest. 1995 Jul;73(1):3-19 PMID: 7603038
  51. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals.
    Am J Respir Crit Care Med. 1995 Sep;152(3):1055-60 PMID: 7663783
  52. Extracellular glutathione peroxidase in human lung epithelial lining fluid and in lung cells.
    Am J Physiol. 1996 Feb;270(2 Pt 1):L173-82 PMID: 8779985
  53. Redox-mediated activation of latent transforming growth factor-beta 1.
    Mol Endocrinol. 1996 Sep;10(9):1077-83 PMID: 8885242
  54. Increased production of the potent oxidant peroxynitrite in the lungs of patients with idiopathic pulmonary fibrosis.
    Am J Respir Crit Care Med. 1997 May;155(5):1763-9 PMID: 9154889
  55. Transforming growth factor-beta1 is a potent inhibitor of glutathione synthesis in the lung epithelial cell line A549: transcriptional effect on the GSH rate-limiting enzyme gamma-glutamylcysteine synthetase.
    Am J Respir Cell Mol Biol. 1997 Nov;17(5):599-607 PMID: 9374111
  56. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression.
    Am J Respir Crit Care Med. 1997 Dec;156(6):1897-901 PMID: 9412572
  57. Disruption of redox homeostasis in the transforming growth factor-alpha/c-myc transgenic mouse model of accelerated hepatocarcinogenesis.
    J Biol Chem. 1998 Jun 19;273(25):15846-53 PMID: 9624185
  58. 8-Isoprostane as a biomarker of oxidative stress in interstitial lung diseases.
    Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 1):1524-7 PMID: 9817703
  59. Reactive oxygen and nitrogen intermediates increase transforming growth factor-beta1 release from human epithelial alveolar cells through two different mechanisms.
    Am J Respir Cell Mol Biol. 1999 Jul;21(1):128-36 PMID: 10385601
  60. Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia.
    Am J Respir Crit Care Med. 1999 Oct;160(4):1354-60 PMID: 10508828
  61. Mechanism of hypochlorite-mediated inactivation of proteinase inhibition by alpha 2-macroglobulin.
    Biochemistry. 1999 Oct 19;38(42):13983-90 PMID: 10529245
  62. Manganese superoxide dismutase and catalase are coordinately expressed in the alveolar region in chronic interstitial pneumonias and granulomatous diseases of the lung.
    Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):615-21 PMID: 10673208
  63. Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice.
    Am J Respir Crit Care Med. 2000 Jul;162(1):225-31 PMID: 10903246
  64. Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches.
    Free Radic Biol Med. 2000 May 1;28(9):1405-20 PMID: 10924859
  65. The role of the redox protein thioredoxin in cell growth and cancer.
    Free Radic Biol Med. 2000 Aug;29(3-4):312-22 PMID: 11035260
  66. Characteristic elevation of matrix metalloproteinase activity in idiopathic interstitial pneumonias.
    Am J Respir Crit Care Med. 2000 Nov;162(5):1949-56 PMID: 11069839
Article Info
Journal
American journal of respiratory and critical care medicine
Abbr.
Am J Respir Crit Care Med
ISSN
1073-449X
DOI
10.1164/rccm.200501-017PP
Email
[email protected]
Published
2005-08-15
Epub
2005-00-13
Pages
417-22
Language
English
Region
United States
NLM ID
9421642
PMCID
PMC2718525
Subset
IM
Grants
NHLBI NIH HHS · R01 HL063700 · United States
NIEHS NIH HHS · 1F30ES013621 · United States
NHLBI NIH HHS · R01 HL63700 · United States
NHLBI NIH HHS · R01 HL73745 · United States
External Links
PubMed source DOI: 10.1164/rccm.200501-017PP PMC Full Text View journal details
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