Inhibition of HDAC8 Ameliorates Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disease with high mortality, and fibroblast‐myofibroblast differentiation (FMD) is thought to be a key event in the pathogenesis of IPF. Histone deacetylase 8 (HDAC8) has been shown to associate with α‐smooth muscle actin (α‐SMA; a marker of FMD) and regulates cell contractility in vascular smooth muscle cells. However, the role of HDAC8 in FMD or pulmonary fibrosis has never been investigated. This study investigated the role of HDAC8 in pulmonary fibrosis, with a focus on FMD. We observed that HDAC8 expression was increased in IPF lung tissue as well as TGF‐β1‐treated normal human lung fibroblasts (NHLFs). Our immunoprecipitation experiments revealed that HDAC8 associated with α‐SMA in TGF‐β1‐treated NHLFs. HDAC8 inhibition with NCC170 (HDAC8‐ selective inhibitor) repressed TGF‐β1‐induced fibroblast contraction and α‐SMA protein expression in NHLFs cultured in collagen gels. HDAC8 inhibition with HDAC8 siRNA also repressed TGF‐β1‐induced expression of CTGF and PAI‐1, and increased PPAR‐γ expression in NHLFs. Chromatin immunoprecipitation quantitative PCR (ChIP‐qPCR) using an antibody against H3K27ac (histone H3 acetylated at lysine 27; a known HDAC8 substrate and a marker for active enhancers) suggested that HDAC8 inhibition with NCC170 ameliorated TGF‐β1‐ induced loss of H3K27ac at the PPAR‐γ gene enhancer. Furthermore, NCC170 treatment significantly decreased fibrosis measured by Ashcroft score as well as type‐1 collagen expression in bleomycin‐treated mouse lungs. In conclusion, these data suggest that HDAC8 contributes to pulmonary fibrosis and that there is a therapeutic potential for HDAC8 inhibitors to treat IPF as well as other fibrotic lung diseases.Support or Funding InformationWetmore Foundation: Shigeki Saito M1: 555007G1; Louisiana Clinical and Translational Science (LA CaTS) Center: Shigeki Saito 1 U54 GM104940This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.