Abstract：
The toxicity of silica nanoparticles (SiNPs) to lung is known. We previously demonstrated that exposure to SiNPs promoted pulmonary impairments, but the precise pathogenesis remains elucidated. Ferroptosis has now been identified as a unique form of oxidative cell death, but whether it participated in SiNPs-induced lung injury remains unclear. In this work, we established a rat model with sub-chronic inhalation exposure of SiNPs via intratracheal instillation, and conducted histopathological examination, iron detection, and ferroptosis-related lipid peroxidation and protein assays. Moreover, we evaluated the effect of SiNPs on epithelial ferroptosis, possible mechanisms using in vitro-cultured human bronchial epithelial cells (16HBE) cells, and also assessed the ensuing impact on fibroblast activation for fibrogenesis. Consequently, fibrotic lesions occurred in the rat lungs, concomitantly by enhanced lipid peroxidation, iron overload, and ferroptosis. Consistently, the in vitro data showed SiNPs triggered oxidative stress and caused the accumulation of lipid peroxides, resulting in ferroptosis. Importantly, the mechanistic investigation revealed miR-21-5p as a key player in the epithelial ferroptotic process induced by SiNPs via targeting GCLM for GSH depletion. Of note, ferrostatin-1 could greatly suppress ferroptosis and alleviate epithelial injury and ensuing fibroblast activation by SiNPs. In conclusion, our findings first revealed SiNPs triggered epithelial ferroptosis through miR-21-5p/GCLM signaling and thereby promoted fibroblast activation for fibrotic lesions, and highlighted the therapeutic potential of inhibiting ferroptosis against lung impairments upon SiNPs exposure.
摘要：
二氧化硅纳米颗粒(SiNP)对肺的毒性是已知的。我们之前证明了暴露于SiNPs会促进肺损伤，但确切的发病机制仍未阐明。Ferroptosis现在被认为是一种独特的氧化细胞死亡形式，但其是否参与SiNPs诱导的肺损伤尚不清楚.在这项工作中,我们通过气管内滴注建立了SiNPs亚慢性吸入暴露的大鼠模型，并进行了组织病理学检查，铁检测,以及与铁凋亡相关的脂质过氧化和蛋白质测定。此外，我们评估了SiNPs对上皮铁蛋白的影响，使用体外培养的人支气管上皮细胞（16HBE）细胞的可能机制，并评估了对成纤维细胞活化的影响。因此,大鼠肺发生纤维化病变,伴随着增强的脂质过氧化，铁过载，和铁中毒。始终如一，体外数据显示SiNPs引发氧化应激并导致脂质过氧化物的积累，导致铁中毒。重要的是,机制研究显示,miR-21-5p在SiNPs通过靶向GCLM清除GSH诱导的上皮铁生成过程中起关键作用.值得注意的是，通过SiNPs可以极大地抑制铁凋亡并减轻上皮损伤和随后的成纤维细胞活化。总之,我们的研究结果首次揭示了SiNPs通过miR-21-5p/GCLM信号传导触发上皮铁凋亡，从而促进纤维化病变的成纤维细胞活化，并强调了在SiNP暴露后抑制铁凋亡对抗肺损伤的治疗潜力。
