Conforti Franco, Davies Elizabeth R, Calderwood Claire J, Thatcher Thomas H, Jones Mark G, Smart David E, Mahajan Sumeet, Alzetani Aiman, Havelock Tom, Maher Toby M, Molyneaux Philip L, Thorley Andrew J, Tetley Teresa D, Warner Jane A, Packham Graham, Ganesan A, Skipp Paul J, Marshall Benjamin J, Richeldi Luca, Sime Patricia J, O'Reilly Katherine M A, Davies Donna E
The Brooke Laboratory, Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, University Hospital Southampton, Southampton, UK.
NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK.
Oncotarget. 2017 Jul 25;8(30):48737-48754. doi: 10.18632/oncotarget.17114.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects.
特发性肺纤维化（IPF）是一种通常影响老年人的进行性疾病。其预后较差且治疗方法有限。由于表观遗传改变与IPF相关，组蛋白去乙酰化酶（HDAC）抑制剂提供了一种新的治疗策略来满足未满足的医疗需求。本研究调查了美国食品药品监督管理局（FDA）批准的HDAC抑制剂罗米地辛作为抗纤维化治疗的潜力，并评估了可能在未来临床试验中有用的靶点参与生物标志物。罗米地辛的抗纤维化作用在体外和体内均进行了评估，同时评估了其对II型肺泡细胞（ATII）的任何有害影响。分析了IPF或对照供体的支气管肺泡灌洗液（BALF）中赖氨酰氧化酶（LOX）的存在情况。与组蛋白乙酰化增加同时，罗米地辛有效抑制成纤维细胞增殖、肌成纤维细胞分化和LOX表达。ATII细胞数量及其板层小体未受影响。在体内，罗米地辛抑制博来霉素诱导的肺纤维化，同时抑制LOX表达。与对照组相比，IPF患者BALF中的LOX显著升高。这些数据显示了罗米地辛的抗纤维化作用，支持其作为IPF新治疗方法的潜在用途，其中LOX作为评估早期靶点效应的伴随生物标志物。
