METHODS: We investigated the prophylactic and therapeutic effects of selenite, a selenium derivative, in ILD using a murine model of bleomycin-induced idiopathic pulmonary fibrosis (IPF). We further elucidated the underlying mechanism using in vitro cell models and examined their relevance in human tissue specimens. The therapeutic effect of selenite in bleomycin-administered mice was assessed by respiratory function and histochemical changes. Selenite-induced apoptosis and reactive oxygen species (ROS) production in murine lung fibroblasts were measured.
RESULTS: Selenite, administered 1 day (inflammation phase) or 8 days (fibrotic phase) after bleomycin, prevented and treated deterioration of lung function and pulmonary fibrosis in mice. Mechanistically, selenite inhibited the proliferation and induced apoptosis of murine lung fibroblasts after bleomycin treatment both in vitro and in vivo. In addition, selenite upregulated glutathione reductase (GR) and thioredoxin reductase (TrxR) in murine lung fibroblasts, but not in lung epithelial cells, upon bleomycin treatment. GR and TrxR inhibition eliminates the therapeutic effects of selenite. Furthermore, we found that GR and TrxR were upregulated in the human lung fibroblasts of IPF patient samples.
CONCLUSIONS: Selenite induces ROS production and apoptosis in murine lung fibroblasts through GR and TrxR upregulation, thereby providing a therapeutic effect in bleomycin-induced IPF.
方法:我们研究了亚硒酸盐的预防和治疗效果,硒衍生物,使用博来霉素诱导的特发性肺纤维化(IPF)的小鼠模型在ILD中。我们使用体外细胞模型进一步阐明了潜在的机制,并检查了它们在人体组织标本中的相关性。通过呼吸功能和组织化学变化评估亚硒酸盐在博来霉素给药小鼠中的治疗效果。测量了亚硒酸盐诱导的鼠肺成纤维细胞中的细胞凋亡和活性氧(ROS)的产生。
结果:亚硒酸盐,博来霉素后1天(炎症期)或8天(纤维化期),预防和治疗小鼠肺功能恶化和肺纤维化。机械上,亚硒酸盐在体外和体内均抑制博莱霉素处理后小鼠肺成纤维细胞的增殖并诱导其凋亡。此外,亚硒酸盐上调小鼠肺成纤维细胞中的谷胱甘肽还原酶(GR)和硫氧还蛋白还原酶(TrxR),但不是在肺上皮细胞中,博来霉素治疗。GR和TrxR抑制消除了亚硒酸盐的治疗效果。此外,我们发现GR和TrxR在IPF患者的人肺成纤维细胞中上调。
结论:亚硒酸盐通过GR和TrxR上调诱导小鼠肺成纤维细胞产生ROS和凋亡,从而在博来霉素诱导的IPF中提供治疗效果。