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Thorax 63:916-924 doi:10.1136/thx.2007.091181
  • Chronic obstructive pulmonary disease

Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema

  1. D Goven1,
  2. A Boutten1,2,
  3. V Leçon-Malas2,
  4. J Marchal-Sommé1,
  5. N Amara1,
  6. B Crestani1,3,
  7. M Fournier4,
  8. G Lesèche5,
  9. P Soler1,
  10. J Boczkowski1,6,
  11. M Bonay1,7
  1. 1
    Inserm, U700, Université Paris 7, Faculté de Médecine Denis Diderot-site Bichat, Paris, France
  2. 2
    Services de Biochimie A, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris (AP-HP) et Université Paris 7 Denis Diderot, Paris, France
  3. 3
    Pneumologie A, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris (AP-HP) et Université Paris 7 Denis Diderot, Paris, France
  4. 4
    Pneumologie B, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris (AP-HP) et Université Paris 7 Denis Diderot, Paris, France
  5. 5
    Chirurgie Thoracique, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris (AP-HP) et Université Paris 7 Denis Diderot, Paris, France
  6. 6
    Centre d’Investigation Clinique 007 et Hôpital Bichat, Assistance Publique-Hôpitaux de Paris (AP-HP) et Université Paris 7 Denis Diderot, Paris, France
  7. 7
    Physiologie-Explorations Fonctionnelles, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris (AP-HP) et Université Paris 7 Denis Diderot, Paris, France
  1. Dr M Bonay, Inserm U700, Faculté de Médecine Paris 7, Site X Bichat, BP416, 75870 Paris Cedex 18, France; marcel.bonay{at}bch.aphp.fr
  • Received 25 September 2007
  • Accepted 30 April 2008
  • Published Online First 17 June 2008

Abstract

Background: Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, plays a role in the pathophysiology of smoking-related pulmonary emphysema. Expression of several antioxidant proteins, such as heme oxygenase-1 (HO-1), glutathione peroxidase 2 (GPX2) and NAD(P)H:quinone oxidoreductase 1 (NQO1), results from an equilibrium created by positive or negative regulation by the transcription factors Nrf2, Keap1 and Bach1, respectively. However, whether the expression of these transcription factors is altered in emphysema and could account for decreased expression of antioxidant proteins is not known. A study was undertaken to investigate the expression and subcellular localisation of Nrf2, Keap1 and Bach1 as potential regulators of HO-1, GPX2 and NQO1 in alveolar macrophages, a key cell in oxidative stress, in lung surgical specimens from non-smokers without emphysema and smokers with and without emphysema.

Methods and results: Western blot, immunohistochemical and laser scanning confocal analysis revealed that the Nrf2 protein level decreased significantly in whole lung tissue and alveolar macrophages (cytosol and nucleus) in patients with emphysema compared with those without emphysema. Conversely, Bach1 and Keap1 levels were increased in patients with emphysema. These modifications were associated with a parallel decrease in the expression of HO-1, GPX2 and NQO1 at the cellular level, which was inversely correlated with airway obstruction and distension indexes, and increased macrophage expression of the lipid peroxidation product 4-hydroxy-2-nonenal. Silencing RNA experiments in vitro in THP-1 cells were performed to confirm the cause-effect relation between the loss of Nrf2 and the decrease in HO-1, NQO1 and GPX2 expression. Nrf2/Keap1-Bach1 equilibrium was altered in alveolar macrophages in pulmonary emphysema, which points to a decreased stress response phenotype.

Conclusions: This finding opens a new view of the pathophysiology of emphysema and could provide the basis for new therapeutic approaches based on preservation and/or restoration of such equilibrium.

Footnotes

  • Funding: Part of this work was supported by grants from Centre d’Assistance Respiratoire à Domicile d’Ile de France (CARDIF) and Boehringer-Ingelheim. NA and MB were supported by Chancellerie des Universités de Paris (Legs Poix) and JB by INSERM and Assistance Publique-Hôpitaux de Paris (Contrat d’Interface).

  • Competing interests: None.

  • Ethics approval: This study was approved by the local ethics committee of Saint Germain en Laye hospital (20 rue Amargis, 78100 Saint Germain en Laye, France) and stored biopsies were reported to our institutional board (Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Carré Historique de l’Hôpital Saint-Louis, 1 avenue Claude Vellefaux 75010 Paris, France).