Sugizaki Toshifumi, Tanaka Ken-Ichiro, Asano Teita, Kobayashi Daisuke, Hino Yuuki, Takafuji Ayaka, Shimoda Mikako, Mogushi Kaoru, Kawahara Masahiro, Mizushima Tohru
1Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
2Laboratory of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishi-Tokyo, 202-8585 Japan.
Cell Death Discov. 2019 Nov 18;5:146. doi: 10.1038/s41420-019-0226-y. eCollection 2019.
Alveolar epithelial injury induced by reactive oxygen species (ROS) and abnormal collagen production by activated fibroblasts (myofibroblasts) is involved in the onset and exacerbation of idiopathic pulmonary fibrosis (IPF). Compared with alveolar epithelial cells, lung fibroblasts, especially myofibroblasts, exhibit an apoptosis-resistance phenotype (apoptosis paradox) that appears to be involved in IPF pathogenesis. Thus, we screened for chemicals eliciting preferential cytotoxicity of LL29 cells (lung fibroblasts from an IPF patient) compared with A549 cells (human lung alveolar epithelial cell line) from medicines already in clinical use. We identified idebenone, a synthetic analogue of coenzyme Q10 (CoQ, an antioxidant) that has been used clinically as a brain metabolic stimulant. Idebenone induced cell growth inhibition and cell death in LL29 cells at a lower concentration than in A549 cells, a feature that was not observed for other antioxidant molecules (such as CoQ) and two IPF drugs (pirfenidone and nintedanib). Administration of idebenone prevented bleomycin-induced pulmonary fibrosis and increased pulmonary ROS levels. Importantly, idebenone also improved pulmonary fibrosis and lung function when administered after the development of fibrosis, whereas administration of CoQ similarly prevented bleomycin-induced pulmonary fibrosis, but had no effect after its development. Administration of idebenone, but not CoQ, suppressed bleomycin-induced increases in lung myofibroblasts. In vitro, treatment of LL29 cells with idebenone, but not CoQ, suppressed TGF-β-induced collagen production. These results suggest that in addition to antioxidant activity, idebenone exerts inhibitory activity on the function of lung fibroblasts, with the former activity being preventative and the latter therapeutic for bleomycin-induced fibrosis. Thus, we propose that idebenone may be more therapeutically beneficial for IPF patients than current treatments.
活性氧（ROS）诱导的肺泡上皮损伤以及活化的成纤维细胞（肌成纤维细胞）产生的异常胶原蛋白与特发性肺纤维化（IPF）的发生和加重有关。与肺泡上皮细胞相比，肺成纤维细胞，尤其是肌成纤维细胞，表现出抗凋亡表型（凋亡悖论），这似乎与IPF的发病机制有关。因此，我们从已用于临床的药物中筛选出对LL29细胞（一名IPF患者的肺成纤维细胞）相较于A549细胞（人肺泡上皮细胞系）具有优先细胞毒性的化学物质。我们鉴定出艾地苯醌，它是辅酶Q10（CoQ，一种抗氧化剂）的合成类似物，已在临床上用作脑代谢刺激剂。艾地苯醌在LL29细胞中诱导细胞生长抑制和细胞死亡的浓度低于A549细胞，其他抗氧化分子（如CoQ）和两种IPF药物（吡非尼酮和尼达尼布）未观察到这一特性。给予艾地苯醌可预防博来霉素诱导的肺纤维化并增加肺部ROS水平。重要的是，在纤维化形成后给予艾地苯醌也可改善肺纤维化和肺功能，而给予CoQ同样可预防博来霉素诱导的肺纤维化，但在纤维化形成后无效。给予艾地苯醌而非CoQ可抑制博来霉素诱导的肺肌成纤维细胞增加。在体外，用艾地苯醌而非CoQ处理LL29细胞可抑制TGF-β诱导的胶原蛋白产生。这些结果表明，除了抗氧化活性外，艾地苯醌对肺成纤维细胞的功能具有抑制活性，前者的活性对博来霉素诱导的纤维化具有预防作用，后者具有治疗作用。因此，我们提出艾地苯醌对IPF患者可能比目前的治疗方法更具治疗益处。
