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.
Abstract
HDACi SAHA induces IPF fibroblast apoptosis, modulates Bcl-2 family genes and ameliorates mice lung fibrosis http://ow.ly/sPLMI
Footnotes
This article has supplementary material available from www.erj.ersjournals.com
Support statement: This study was supported by grants from the American Heart Association (09SDG2260095 to Y.Y. Sanders), the American Thoracic Society Foundation/Coalition for Pulmonary Fibrosis and the Pulmonary Fibrosis Foundation Research Program 2011 (to Y.Y. Sanders), and the National Institute of Health (HL082818 to J.S. Hagood, HL092906 to N. Ambalavanan and HL14470 to V.J. Thannickal).
Conflict of interest: Disclosures can be found alongside the online version of this article at www.erj.ersjournals.com
- Received June 4, 2013.
- Accepted December 16, 2013.
- ©ERS 2014