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 antiapoptotic 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. @ERSpublications HDACi SAHA induces IPF fibroblast apoptosis, modulates Bcl-2 family genes and ameliorates mice lung fibrosis

Mechanisms of Lung Fibrosis Resolution

“…71 Furthermore, suberoylanilide hydroxamic acid reduced postinflammatory fibrosis in bleomycin-treated mice mediated, at least in part, by modulating Bak and Bcl-xl levels in the lungs. 71 Targeting myofibroblast stress fiber formation through, either the Rho-associated kinase pathway or myocardin-related transcription factor/serum response factor signaling, induced preexisting lung myofibroblasts of IPF patients to undergo apoptosis. 41,55 Specific pharmacological agents targeting these pathways also reduced postinflammatory lung fibrosis in bleomycin-treated mice.…”

“…69 Apoptosis has also been identified as a primary mechanism of myofibroblast removal in the bleomycin lung fibrosis model. 55,70,71 An accumulating body of literature demonstrates that lung fibroblasts and myofibroblasts in both mouse fibrosis models and IPF acquire an apoptosis-resistant phenotype. 41,48,55,59,70,71 Several mechanisms by which myofibroblasts evade apoptosis have been identified, 72 and several common mechanistic themes have emerged.…”

“…62,76 Several recent murine studies demonstrate that pharmacological strategies to induce myofibroblast apoptosis after fibrosis were already established and can accelerate resolution. 41,55,70,71 The histone deacetylase inhibitor…”

“…Recent preclinical investigations support the concept that targeting intrinsic lung myofibroblast dedifferentiation, apoptosis, or senescence pathways effectively promotes resolution and may prove to be practical approaches for treatment of lung fibrosis. 41,50,55,70,71 There are clearly significant gaps in understanding lung fibrosis resolution likely reflecting the biological complexity and limitations in the animal models and basic scientific methods previously available to investigators. However, accelerated improvements in biotechnology and bioinformatics are revolutionizing biomedical research, and it is likely these new techniques and discoveries will continue to improve the understanding of the mechanisms of lung fibrosis resolution.…”

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…histone deacetylation in their promoter regions (41). Recently, Sanders et al (42) reported that pharmacological regulation of histone acetylation ameliorated bleomycin-induced pulmonary fibrosis in mice, suggesting a new therapeutic avenue for IPF. Noncoding RNAs in small or long forms establish a complex network of transcriptional regulators that can control and modulate different cell programs.…”