title: Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice.
abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal disease, and therapeutic agents have shown only modest efficacy. Epigenetic alterations contribute to the pathogenesis of IPF. The histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), has been approved for clinical use in cancer; however, its potential efficacy in modulating fibroblast survival and lung fibrosis has not been extensively investigated. We investigated the effects of SAHA on apoptosis of primary IPF myofibroblasts and on injury-induced lung fibrosis in a murine model. SAHA-induced apoptosis of IPF myofibroblasts, an effect that was mediated, at least in part, by upregulation of the pro-apoptotic gene Bak and downregulation of the anti-apoptotic gene Bcl-xL. Alterations in the expression of these apoptosis-related genes were associated with histone modifications and changes in DNA methylation. In addition to the expected higher levels of histone acetylation in treated cells, we also detected changes in other histone modifications, such as histone methylation. In a murine model of bleomycin-induced pulmonary fibrosis, SAHA-treated mice displayed decreased lung fibrosis and improved lung function compared to the bleomycin only group. These results suggest that histone deacetylase inhibitors may offer a new therapeutic strategy in IPF by modulating myofibroblast susceptibility to apoptosis.
authors.affiliation: Allergy and Critical Care Medicine, Dept of Medicine, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Yan Y
authors.initials: YY
authors.lastname: Sanders
authors.forename: James S
authors.initials: JS
authors.lastname: Hagood
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
mesh_terms: D000818:Animals; D017209:Apoptosis; D001761:Bleomycin; D049109:Cell Proliferation; D002470:Cell Survival; D019175:DNA Methylation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy*; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000166:cytology; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D001761:Bleomycin; D000077337:Vorinostat; D006655:Histone Deacetylases