Abstract:
Radiation-induced pulmonary fibrosis (RIPF) represents a serious complication observed in individuals undergoing thoracic radiation therapy. Currently, effective interventions for RIPF are unavailable. Prior research has demonstrated that nintedanib, a Food and Drug Administration (FDA)-approved anti-fibrotic agent for idiopathic pulmonary fibrosis, exerts therapeutic effects on chronic fibrosing interstitial lung disease. This research aimed to investigate the anti-fibrotic influences of nintedanib on RIPF and reveal the fundamental mechanisms. To assess its therapeutic impact, a mouse model of RIPF was established. The process involved nintedanib administration at various time points, both prior to and following thoracic radiation. In the RIPF mouse model, an assessment was conducted on survival rates, body weight, computed tomography features, histological parameters, and changes in gene expression. In vitro experiments were performed to discover the mechanism underlying the therapeutic impact of nintedanib on RIPF. Treatment with nintedanib, administered either two days prior or four weeks after thoracic radiation, significantly alleviated lung pathological changes, suppressed collagen deposition, and improved the overall health status of the mice. Additionally, nintedanib demonstrated significant mitigation of radiation-induced inflammatory responses in epithelial cells by inhibiting the PI3K/AKT and MAPK signaling pathways. Furthermore, nintedanib substantially inhibited fibroblast-to-myofibroblast transition by suppressing the TGF-β/Smad and PI3K/AKT/mTOR signaling pathways. These findings suggest that nintedanib exerts preventive and therapeutic effects on RIPF by modulating multiple targets instead of a single anti-fibrotic pathway and encourage the further clinical trials to determine the efficacy of nintedanib in patients with RIPF.
摘要:
辐射诱导的肺纤维化(RIPF)是在接受胸部放射治疗的个体中观察到的严重并发症。目前,目前尚无有效的RIPF干预措施.之前的研究表明尼达尼布,美国食品和药物管理局(FDA)批准的特发性肺纤维化抗纤维化药物,对慢性纤维化间质性肺病有治疗作用。本研究旨在研究尼达尼布对RIPF的抗纤维化作用,并揭示其基本机制。为了评估其治疗效果,建立RIPF小鼠模型。该过程涉及尼达尼布在不同时间点的管理,胸部放射之前和之后。在RIPF小鼠模型中,对生存率进行了评估,体重,计算机断层扫描特征,组织学参数,和基因表达的变化。进行体外实验以发现尼达尼布对RIPF的治疗影响的潜在机制。用尼达尼布治疗,在胸部放疗前两天或四周后给药,显著缓解肺部病理变化,抑制胶原蛋白沉积,改善了小鼠的整体健康状况。此外,尼达尼布通过抑制PI3K/AKT和MAPK信号通路显著缓解上皮细胞中辐射诱导的炎症反应。此外,尼达尼布通过抑制TGF-β/Smad和PI3K/AKT/mTOR信号通路显著抑制成纤维细胞向肌成纤维细胞的转化。这些发现表明,尼达尼布通过调节多个靶标而不是单个抗纤维化途径对RIPF发挥预防和治疗作用,并鼓励进一步的临床试验来确定尼达尼布在RIPF患者中的疗效。