CeO2 nanoparticles induce pulmonary fibrosis via activating S1P pathway as revealed by metabolomics.
CeO2 nanoparticles induce pulmonary fibrosis via activating S1P pathway as revealed by metabolomics.
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DOI：
10.1016/j.nantod.2022.101559
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发表时间：
2022-08
期刊：
影响因子：
17.4
通讯作者：
L. Cui;Xiang Wang;Xinyuan Zhao;Bingbing Sun;T. Xia;Shen Hu
中科院分区：
文献类型：
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作者：
L. Cui;Xiang Wang;Xinyuan Zhao;Bingbing Sun;T. Xia;Shen Hu
CeO 2纳米颗粒（NPs）可引起肺纤维化，但其分子机制尚不清楚。在这项研究中，我们进行了基于质谱的全球代谢组学分析的人支气管上皮BEAS-2B细胞处理的CeO 2纳米粒子与不同的纵横比，并评估其对支气管上皮细胞的毒性通过各种基于细胞的功能测定。虽然CeO 2 NP在12.5 μg/mL至25 μg/mL的剂量范围内对支气管上皮细胞显示出低细胞毒性，但代谢组学分析显示，CeO 2 NP显著改变了1-磷酸鞘氨醇、脂肪酸氧化、炎症等细胞代谢途径中的许多代谢物，尤其是具有高纵横比的那些。在急性和慢性暴露于CeO 2NP的小鼠模型中进一步验证了代谢组学结果的稳健性。CeO 2纳米颗粒通过增强早期生长反应蛋白1（EGR-1）的表达，以纵横比依赖的方式上调BEAS-2B细胞中转化生长因子β 1（TGF-β1）的水平。此外，体外和体内实验均显示CeO 2纳米颗粒可显著诱导鞘氨醇激酶1（SHPK 1）、磷酸化Smad 2/3和肺纤维化标志物的表达。此外，SPHK 1、TGFβ受体或Smad 3磷酸化均能显著减弱CeO 2 NPs的促纤维化作用，且SPHK 1-S1 P通路对TGF-β1介导的肺纤维化的影响大于Smad 2/3通路。总的来说，我们的研究已经确定了BEAS-2B细胞暴露于具有不同纵横比的CeO 2NPs的代谢组学变化，并揭示了传统功能测定可能错过的代谢活动的微妙变化。更重要的是，我们发现了一个以前未知的分子机制，潜在的CeO 2NP诱导的肺纤维化与不同的纵横比，脱落的CeO 2NPs的环境危害潜力的新见解。
CeO2nanoparticles (NPs) have been shown to cause lung fibrosis, however, the underlying molecular mechanisms are not well understood. In this study, we have conducted a mass spectrometry-based global metabolomic analysis of human bronchial epithelial BEAS-2B cells treated by CeO2NPs with different aspect ratios and assessed their toxicity on the bronchial epithelial cells by various cell-based functional assays. Although CeO2NPs at doses ranging from 12.5 μg/mL to 25 μg/mL displayed low cytotoxicity on the bronchial epithelial cells, the metabolomic analysis revealed a number of metabolites in the cellular metabolic pathways of sphingosine-1-phosphate, fatty acid oxidation, inflammation,etc.were significantly altered by CeO2NPs, especially those with high aspect ratios. The robustness of metabolomics findings was further validated in mouse models upon acute and chronic exposures to CeO2NPs. Mechanistically, CeO2NPs upregulated transforming growth factor beta-1 (TGF-β1) levels in BEAS-2B cells in an aspect ratio-dependent manner through enhancing the expression of early growth response protein 1 (EGR-1). In addition, bothin vitroandin vivostudies demonstrated that CeO2NPs significantly induced the expression of sphingosine kinase 1 (SHPK1), phosphorylated Smad2/3 and lung fibrosis markers. Moreover, targeting SPHK1, TGFβ receptor or Smad3 phosphorylation significantly attenuated the fibrosis-promoting effects of CeO2NPs, and SPHK1-S1P pathway exerted a greater effect on the TGF-β1-mediated lung fibrosis compared to the conventional Smad2/3 pathway. Collectively, our studies have identified the metabolomic changes in BEAS-2B cells exposed to CeO2NPs with different aspect ratios and revealed the subtle changes in metabolic activities that traditional functional assays might have missed. More importantly, we have discovered a previously unknown molecular mechanism underlying CeO2NP-induced lung fibrosis with different aspect ratios, shedding new insights on the environmental hazard potential of CeO2NPs.