Journal article

Publication year: 2015

Pages: 1022-1032

Journal: Thorax

Volume number: 70

Issue number: 11

ISSN: 0040-6376

eISSN: 1468-3296

Open access status: Bronze

DOI Link: https://doi.org/10.1136/thoraxjnl-2014-206411

Publisher: BMJ Publishing Group

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.

Harvard Citation style: Korfei, M., Skwarna, S., Henneke, I., MacKenzie, B., Klymenko, O., Saito, S., et al. (2015) Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis, Thorax, 70(11), pp. 1022-1032. https://doi.org/10.1136/thoraxjnl-2014-206411

APA Citation style: 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., Fink, L., Seeger, W., Kraemer, O., & Guenther, A. (2015). Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis. Thorax. 70(11), 1022-1032. https://doi.org/10.1136/thoraxjnl-2014-206411