N6-Methyladenosine Modification of CDH1 mRNA Promotes PM2.5-Induced Pulmonary Fibrosis via Mediating Epithelial Mesenchymal Transition

Abstract The association between ambient airborne fine particulate matter (PM2.5) exposure and respiratory diseases has been investigated in epidemiological studies. To explore the potential mechanism of PM2.5-induced pulmonary fibrosis, 60 mice were divided into 3 groups to expose to different leve...

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Published in:Toxicological sciences 2022-01, Vol.185 (2), p.143-157
Main Authors: Ning, Jie, Du, Hairong, Zhang, Yaling, Liu, Qingping, Jiang, Tao, Pang, Yaxian, Tian, Xiaochen, Yan, Liqun, Niu, Yujie, Zhang, Rong
Format: Article
Language:English
Subjects:
Adenosine - analogs & derivatives
Animals
Cadherins - genetics
Epithelial-Mesenchymal Transition
Mice
Particulate Matter - toxicity
Pulmonary Fibrosis - chemically induced
Pulmonary Fibrosis - genetics
RNA, Messenger - genetics
RNA, Messenger - metabolism
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Summary:Abstract The association between ambient airborne fine particulate matter (PM2.5) exposure and respiratory diseases has been investigated in epidemiological studies. To explore the potential mechanism of PM2.5-induced pulmonary fibrosis, 60 mice were divided into 3 groups to expose to different levels of PM2.5 for 8 and 16 weeks: filtered air, unfiltered air, and concentrated PM2.5 air, respectively. BEAS-2B cells were treated with 0, 25, 50, and 100 μg/ml PM2.5 for 24 h. The biomarkers of pulmonary fibrosis, epithelial-mesenchymal transition, N6-methyladenosine (m6A) modification, and metabolism of mRNAs were detected to characterize the effect of PM2.5 exposure. The results illustrated that PM2.5 exposure induced pathological alteration and pulmonary fibrosis in mice. The expression of E-cadherin was decreased whereas vimentin and N-cadherin expression were increased in a dose- and time-dependent manner after PM2.5 exposure. Mechanistically, PM2.5 exposure increased the levels of METTL3-mediated m6A modification of CDH1 mRNA. As a target gene of miR-494-3p, YTHDF2 was upregulated by miR-494-3p down-regulation and then recognized m6A-modified CDH1 mRNA to inhibit the E-cad expression, consequently induced the EMT progression after PM2.5 exposure. Our study indicated that PM2.5 exposure triggered EMT progression to promote the pulmonary fibrosis via miR-494-3p/YTHDF2 recognized and METTL3 mediated m6A modification.
ISSN:1096-6080
1096-0929
DOI:10.1093/toxsci/kfab133