Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice
YY Sanders, JS Hagood, H Liu… - European …, 2014 - Eur Respiratory Soc
European Respiratory Journal, 2014•Eur Respiratory Soc
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 …
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 …
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.
European Respiratory Society