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Fine Particulate Matter Injury Airway Barrier Through Oxidative Stress Promotes the Demethylase FTO Regulating IKKβ m6A Modification and NF-κB Activation in Asthma
41 Pages Posted: 9 May 2022
More...Abstract
Abstract: PM2.5 poses a significant risk to acute asthma attack, by promoting oxidative stress and inflammation. However, the components responsible for these effects have not been fully evaluated. In present study, we found the level of oxidative stress in cells was increased as well as the expression level of the demethylase FTO after PM2.5 exposure. Meanwhile, the level of m6A modification in 3'-UTR of IKKβ was decreased based on MeRIP-seq result. Thus, we hypotheses that PM2.5 destroyed airway barrier by reduction of IKKβ m6A modification, which was regulated by FTO though oxidative stress. We report for the first time a significant increase of both FTO mRNA and protein levels in AECs, compared either to PBS control subjects or to NAC individuals. We demonstrate that PM2.5 is associated with increased FTO expression, intracellular ROS levels and exacerbated inflammation in human lung AECs, by apply RNA immunoprecipitation, PCR, Western blot. In addition, knockdown of FTO in AECs induces basal IKKβ demethylation in 3'-UTR. Our finding uncovered that PM2.5 injury airway barrier through oxidative stress promoting the demethylase FTO, consequently activated NF-κB through IKKβ. These findings may potential molecular therapeutic targets and establish the theoretical evidence for the application of targets in clinical transformation.
Funding: This work was supported by the National Natural Science Foundation of China (81970026, 82000029), Health Commission of Sichuan Province (19ZD002, 20PJ209), Chengdu High-level Key Clinical Specialty Construction Project (ZX20201202020), Chengdu Science and Technology Bureau (2021-YF09-00102-SN, 2020-YF05-00003-SN), the program for combination of Medical and Engineering of Southwest Jiaotong University (2682021ZTPY007, 2682020ZT8).
Declaration of Interest: None to declare.
Ethical Approval: The experimental protocol was reviewed and approved by the Institutional Animal Care and Use Committee of the Southwest Medical University.
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