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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents



ID: 723976.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis
Authors:Korfei, M.; Skwarna, S.; Henneke, I.; MacKenzie, B.; Klymenko, O.; Saito, S.; Ruppert, C.; von der Beck, D.; Mahavadi, P.; Klepetko, W.; Bellusci, S.; Crestani, B.; Pullamsetti, S. S.; Fink, L.; Seeger, W.; Kramer, O. H.; Guenther, A.
Date of Publication (YYYY-MM-DD):2015-11
Title of Journal:Thorax
Volume:70
Issue / Number:11
Start Page:1022
End Page:1032
Audience:Not Specified
Abstract / Description: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.
Free Keywords:Cells, Cultured; Female; Fibroblasts/metabolism/pathology; *Gene Expression Regulation; Histone Deacetylase 2/biosynthesis/genetics; Histone Deacetylases/biosynthesis/*genetics; Humans; Idiopathic Pulmonary Fibrosis/*genetics/metabolism/pathology; Male; Middle Aged; RNA/*genetics; Real-Time Polymerase Chain Reaction; Idiopathic pulmonary fibrosis
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Department of Medicine, Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Tulane University Health Science Center, New Orleans, Louisiana, USA. 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. Department of Thoracic Surgery, Vienna General Hospital, Vienna, Austria European IPF Network and European IPF Registry. CHU Paris Nord-Val de Seine, Hopital Xavier Bichat-Claude Bernard, Paris, France European IPF Network and European IPF Registry. 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. 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. Department of Toxicology, University Medical Center, Mainz, Germany. 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.
Identifiers:ISSN:1468-3296 (Electronic) 0040-6376 (Linking) %R 10.1136/thoraxjnl-2014-206411
URL:http://www.ncbi.nlm.nih.gov/pubmed/26359372
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