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Original article
Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis
  1. Martina Korfei1,2,
  2. Sylwia Skwarna1,2,
  3. Ingrid Henneke1,2,
  4. BreAnne MacKenzie1,2,
  5. Oleksiy Klymenko1,2,
  6. Shigeki Saito3,
  7. Clemens Ruppert1,2,4,
  8. Daniel von der Beck1,2,
  9. Poornima Mahavadi1,2,
  10. Walter Klepetko5,11,
  11. Saverio Bellusci1,2,4,
  12. Bruno Crestani6,11,
  13. Soni Savai Pullamsetti1,2,7,
  14. Ludger Fink2,4,8,
  15. Werner Seeger1,2,4,
  16. Oliver Holger Krämer9,
  17. Andreas Guenther1,2,4,10,11
  1. 1Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
  2. 2Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL)
  3. 3Department of Medicine, Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Tulane University Health Science Center, New Orleans, Louisiana, USA
  4. 4Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany
  5. 5Department of Thoracic Surgery, Vienna General Hospital, Vienna, Austria
  6. 6CHU Paris Nord-Val de Seine, Hôpital Xavier Bichat-Claude Bernard, Paris, France
  7. 7Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
  8. 8Institute of Pathology and Cytology, Wetzlar, Germany
  9. 9Department of Toxicology, University Medical Center, Mainz, Germany
  10. 10Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany
  11. 11European IPF Network and European IPF Registry
  1. Correspondence to Professor Andreas Guenther, Department of Internal Medicine II, Justus-Liebig-University Giessen, Klinikstrasse 36, Giessen D-35392, Germany; Andreas.Guenther{at}


Background Activation and differentiation of fibroblasts into contractile protein-expressing myofibroblasts and their acquired apoptosis-resistant phenotype are critical factors towards the development of idiopathic pulmonary fibrosis (IPF), a fatal disease characterised by distorted pulmonary structure and excessive extracellular matrix (ECM) deposition. The molecular mechanisms underlying these processes in IPF remain incompletely understood. We investigated the possible implication of aberrant overexpression and activity of histone deacetylases (HDACs) in IPF.

Methods We analysed lung tissues from patients with sporadic IPF (n=26) and non-diseased control lungs (n=16) for expression of class I and II HDACs. Primary IPF fibroblasts were treated with HDAC inhibitors (HDACi) LBH589 or valproic acid (VPA).

Results Compared to control lungs, protein levels of class I (HDAC1, HDAC2, HDAC3, HDAC8) and class II HDACs (HDAC4, HDAC 5, HDAC 7, HDAC 9) were significantly elevated in IPF lungs. Using immunohistochemistry, strong induction of nearly all HDAC enzymes was observed in myofibroblasts of fibroblast foci and in abnormal bronchiolar basal cells at sites of aberrant re-epithelialisation in IPF lungs, but not in controls. Treatment of primary IPF fibroblasts with the pan-HDACi LBH589 resulted in significantly reduced expression of genes associated with ECM synthesis, proliferation and cell survival, as well as in suppression of HDAC7, and was paralleled by induction of endoplasmic reticulum stress and apoptosis. The profibrotic and apoptosis-resistant phenotype of IPF fibroblasts was also partly attenuated by the class I HDACi VPA.

Conclusions Aberrant overexpression of HDACs in basal cells of IPF lungs may contribute to the bronchiolisation process in this disease. Similarly, generation and apoptosis resistance of IPF fibroblasts are mediated by enhanced activity of HDAC enzymes. Therefore, pan-HDAC inhibition by LBH589 may present a novel therapeutic option for patients with IPF.

  • Idiopathic pulmonary fibrosis

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