title: Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL).
authors.forename: Martina
authors.initials: M
authors.lastname: Korfei
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL).
authors.forename: Sylwia
authors.initials: S
authors.lastname: Skwarna
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL).
authors.forename: Ingrid
authors.initials: I
authors.lastname: Henneke
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL).
authors.forename: BreAnne
authors.initials: B
authors.lastname: MacKenzie
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL).
authors.forename: Oleksiy
authors.initials: O
authors.lastname: Klymenko
authors.affiliation: Department of Medicine, Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Tulane University Health Science Center, New Orleans, Louisiana, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL) Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Ruppert
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL).
authors.forename: Daniel
authors.initials: D
authors.lastname: von der Beck
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL).
authors.forename: Poornima
authors.initials: P
authors.lastname: Mahavadi
authors.affiliation: Department of Thoracic Surgery, Vienna General Hospital, Vienna, Austria European IPF Network and European IPF Registry.
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL) Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
authors.affiliation: CHU Paris Nord-Val de Seine, Hôpital Xavier Bichat-Claude Bernard, Paris, France European IPF Network and European IPF Registry.
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL) Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL) Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany Institute of Pathology and Cytology, Wetzlar, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Fink
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL) Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Department of Toxicology, University Medical Center, Mainz, Germany.
authors.forename: Oliver Holger
authors.initials: OH
authors.lastname: Krämer
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL) Excellence Cluster Cardio-Pulmonary System (ECCPS), Giessen, Germany Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany European IPF Network and European IPF Registry.
authors.forename: Andreas
authors.initials: A
authors.lastname: Guenther
mesh_terms: D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D056464:Histone Deacetylase 2 / Q000096:biosynthesis / Q000235:genetics; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D000099186:Histone Deacetylase 3
chemical_list: D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D012313:RNA; D000099186:Histone Deacetylase 3
keywords: Idiopathic pulmonary fibrosis