Targeting Histone Deacetylases in Idiopathic Pulmonary Fibrosis: A Future Therapeutic Option

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options, and there is a huge unmet need for new therapies. A growing body of evidence suggests that the histone deacetylase (HDAC) family of transcriptional corepressors has emerged as crucial mediators of IPF pathogenesis. HDACs deacetylate histones and result in chromatin condensation and epigenetic repression of gene transcription. HDACs also catalyse the deacetylation of many non-histone proteins, including transcription factors, thus also leading to changes in the transcriptome and cellular signalling. Increased HDAC expression is associated with cell proliferation, cell growth and anti-apoptosis and is, thus, a salient feature of many cancers. In IPF, induction and abnormal upregulation of Class I and Class II HDAC enzymes in myofibroblast foci, as well as aberrant bronchiolar epithelium, is an eminent observation, whereas type-II alveolar epithelial cells (AECII) of IPF lungs indicate a significant depletion of many HDACs. We thus suggest that the significant imbalance of HDAC activity in IPF lungs, with a "cancer-like" increase in fibroblastic and bronchial cells versus a lack in AECII, promotes and perpetuates fibrosis. This review focuses on the mechanisms by which Class I and Class II HDACs mediate fibrogenesis and on the mechanisms by which various HDAC inhibitors reverse the deregulated epigenetic responses in IPF, supporting HDAC inhibition as promising IPF therapy.

Keywords: (pan-)HDAC-inhibitor; Class I-HDAC-inhibitor; bronchiolar basal cells; bronchiolization; fibroblast-to-myofibroblast differentiation (FMD); histone acetylation; histone deacetylase (HDAC); idiopathic pulmonary fibrosis (IPF); non-histone protein acetylation; type-II alveolar epithelial cell (AECII).

Figure 1

Imbalanced histone deacetylase activities in IPF. IPF is characterised by a significant imbalance of histone deacetylase (HDAC) activities, with an abnormal increase of HDAC expression in fibroblasts/myofibroblasts and bronchiolar basal cells, but a lack of HDAC expression in AECII due to ER stress, senescence and apoptosis. This imbalance contributes and perpetuates the fibrotic process. Abbreviations: ECM: extracellular matrix; FMD: fibroblast-to-myofibroblast differentiation; AECII: type-I/-II alveolar epithelial cell; ROS: reactive oxygen species; SASP: senescence-associated secretory phenotype; HAT: histone acetyltransferase; P = phosphorylation, Me = methylation, Ac = acetylation.

Figure 2

Expression and localisation of HDAC6 in IPF lungs and normal control lungs. (A) Representative immunohistochemistry (IHC) for proSP-C (AECII marker), HDAC6 and cytokeratin-7 (KRT7, marker for simple epithelia) in IPF lungs. Robust expression of HDAC6 was observed in AECII (proSP-C⁺ KRT7⁺, indicated by arrows) as well as hyperplastic AEC-like cells lining the alveoli (proSP-C^- KRT7⁺, indicated by blue arrowheads) and in bronchial epithelium (BE). (B) Robust expression of HDAC6 in fibroblast foci (FF) as well as KRT5⁺ bronchiolar basal cells and ciliated bronchial cells. (C) Representative IHC for proSP-C and HDAC6 in normal control lungs. HDAC6 was expressed in ciliated bronchial epithelium but not in AECII or normal lungs. Faint HDAC6 immunostaining was observed in the interstitium of normal lungs. Taken with permission from the study by Korfei et al. (2015) [165] (supplement), with modifications.

Figure 3

Summary of putative therapeutic effects of HDAC-inhibitor treatment on IPF. For details, see discussion. Abbreviations: IPF: idiopathic pulmonary fibrosis; ECM: extracellular matrix; FMD: fibroblast-to-myofibroblast differentiation; AECI/II: type-I/-II alveolar epithelial cell; Ac = acetylation; ↑: upregulation; ↓: downregulation.