Idebenone has preventative and therapeutic effects on pulmonary fibrosis via preferential suppression of fibroblast activity
Idebenone has preventative and therapeutic effects on pulmonary fibrosis via preferential suppression of fibroblast activity
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DOI：
10.1038/s41420-019-0226-y
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发表时间：
2019-11-18
影响因子：
7
通讯作者：
Mizushima, Tohru
中科院分区：
文献类型：
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作者：
Sugizaki, Toshifumi;Tanaka, Ken-ichiro;Mizushima, Tohru
由活性氧（ROS）和活化的成纤维细胞（肌成纤维细胞）的异常胶原产生诱导的肺泡上皮损伤参与特发性肺纤维化（IPF）的发作和恶化。与肺泡上皮细胞相比，肺成纤维细胞，特别是肌成纤维细胞，表现出凋亡抵抗表型（凋亡悖论），似乎参与了IPF的发病机制。因此，我们筛选了与来自已在临床使用的药物的A549细胞（人肺泡上皮细胞系）相比，引发LL 29细胞（来自IPF患者的肺成纤维细胞）的优先细胞毒性的化学物质。我们确定了艾地苯醌，辅酶Q（10）（辅酶Q（10），一种抗氧化剂）的合成类似物，已在临床上用作大脑代谢兴奋剂。艾地苯醌在LL 29细胞中诱导细胞生长抑制和细胞死亡的浓度低于A549细胞，这一特征在其他抗氧化分子（如CoQ（10））和两种IPF药物（吡非尼酮和尼达尼布）中未观察到。艾地苯醌的给药预防了博莱霉素诱导的肺纤维化并增加了肺ROS水平。重要的是，艾地苯醌在纤维化发生后给药也能改善肺纤维化和肺功能，而辅酶Q（10）的给药同样能预防博来霉素诱导的肺纤维化，但在纤维化发生后没有效果。艾地苯醌的给药，而不是辅酶Q（10），抑制博莱霉素诱导的肺肌成纤维细胞的增加。在体外，用艾地苯醌处理LL 29细胞，而不是辅酶Q（10），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，艾地苯醌对肺成纤维细胞的功能发挥抑制活性，前者的活性是预防性的，后者治疗博来霉素诱导的纤维化。因此，我们认为艾地苯醌可能比目前的治疗方法对IPF患者更有益。
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 Q(10) (CoQ(10), 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(10)) 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(10) similarly prevented bleomycin-induced pulmonary fibrosis, but had no effect after its development. Administration of idebenone, but not CoQ(10), suppressed bleomycin-induced increases in lung myofibroblasts. In vitro, treatment of LL29 cells with idebenone, but not CoQ(10), suppressed TGF-beta-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.