Pneumologie 2014; 68 - A28
DOI: 10.1055/s-0034-1376797

Aberrant expression and activity of histone deacetylases (HDAC) in lungs of patients with sporadic idiopathic pulmonary fibrosis (IPF)

M Korfei 1, 7, S Skwarna 1, I Henneke 1, O Klymenko 1, G Dahlem 1, S Ziegler 1, D von der Beck 1, W Klepetko 2, L Fink 3, 7, W Seeger 4, 7, O Krämer 5, A Guenther 6, 7
  • 1Justus-Liebig-University Gießen, Biomedical Research Center Seltersberg (BFS), Gießen
  • 2Vienna General Hospital, Department of Thoracic Surgery, Vienna
  • 3Justus-Liebig-University Gießen, Institute for Pathology, Gießen
  • 4Justus-Liebig-University Gießen, Department of Internal Medicine, Gießen
  • 5Medical Center of the University Mainz, Institute of Toxicology, Mainz
  • 6Justus-Liebig-University Gießen, Department of Internal Medicine, Gießen and Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein
  • 7University of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL)

Introduction: Histone deacetylases (HDACs) are enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on histones, resulting in epigenetic repression of gene transcription. HDACs can also catalyze deacetylation of many non-histone proteins, such as the tumor suppressor p53, resulting in inhibition of its pro-apoptotic activity. HDACs thus pivotally control gene expression and cellular signaling. Due to their anti-apoptotic activity, HDACs are upregulated in many cancers. Here, we describe for the first time a biochemical characterization of Class-I/-II/-III-HDACs in lungs from patients with sporadic IPF (n = 16) and organ donors (n = 26). Methods: Lung tissue was analyzed by RT-PCR, immunoblotting and immunohistochemistry (IHC). Results: Compared to donors, protein-levels of Class-I- (HDAC1, 2, 3 and 8) and Class-II-HDACs (HDAC4, 5, 7, 9, 10), and of the Class-III-HDAC Sirtuin-1 were significantly elevated in IPF lungs. By means of IHC, strong nuclear induction of HDACs 1 – 3 and Sirtuin-1 was observed in myofibroblasts of fibroblast foci (FF) and in abnormal bronchiolar basal cells at sites of aberrant re-epithelialization in IPF lungs, but not in donors. Similarly, induced cytoplasmic expression of Class-II-HDACs: 4, 5, 7, 9, 10 and of the Class-III-HDAC Sirtuin-2 could be encountered in FF and basal cells in IPF. Importantly, type-II alveolar epithelial cells (AECII) of IPF-lungs did not reveal notable expression of Class-I/-II/-III-HDACs, possibly due to severe ER stress in this cell type. But IPF-AECII indicated induced cytoplasmic expression of HDAC6 – a Class-IIb-HDAC involved in aggresome formation. Conclusions: We suggest that fibroblast proliferation, fibroblast-to-myofibroblast differentiation and the apoptosis-resistant phenotype of fibroblasts and myofibroblasts in IPF may be mediated due to enhanced expression and action of Class-I/-II/-III-HDACs. Similarly, aberrant overexpression of HDACs in basal cells of IPF lungs may cause the exaggerated, proliferative character of this cell type in IPF and thus govern the process of bronchiolization in this disease. We conclude that HDACs may be novel molecular targets for IPF therapy.