Allergy and Critical Care Medicine, Dept of Medicine, University of Alabama at Birmingham, Birmingham, AL.
Eur Respir J. 2014 May;43(5):1448-58. doi: 10.1183/09031936.00095113. Epub 2014 Mar 6.
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.
特发性肺纤维化（IPF）是一种致命的疾病，治疗药物的疗效仅略有改善。表观遗传改变有助于 IPF 的发病机制。组蛋白去乙酰化酶抑制剂，丁酸钠（SAHA）已被批准用于癌症的临床应用；然而，其在调节成纤维细胞存活和肺纤维化方面的潜在疗效尚未得到广泛研究。我们研究了 SAHA 对原代 IPF 肌成纤维细胞凋亡的影响以及在小鼠模型中对损伤诱导的肺纤维化的影响。SAHA 诱导 IPF 肌成纤维细胞凋亡，这种作用至少部分是通过上调促凋亡基因 Bak 和下调抗凋亡基因 Bcl-xL 介导的。这些与细胞凋亡相关的基因表达的改变与组蛋白修饰和 DNA 甲基化的改变有关。除了治疗细胞中预期的更高水平的组蛋白乙酰化外，我们还检测到其他组蛋白修饰的改变，如组蛋白甲基化。在博来霉素诱导的肺纤维化的小鼠模型中，与仅用博来霉素组相比，接受 SAHA 治疗的小鼠显示出肺纤维化减少和肺功能改善。这些结果表明，组蛋白去乙酰化酶抑制剂通过调节肌成纤维细胞对细胞凋亡的敏感性，可能为 IPF 提供一种新的治疗策略。
