1. Academic Validation
  2. Indeno[1,2,3-cd]pyrene enhances the sensitivity of airway epithelial cells to ferroptosis and aggravates asthma

Indeno[1,2,3-cd]pyrene enhances the sensitivity of airway epithelial cells to ferroptosis and aggravates asthma

  • Chemosphere. 2024 Jul 16:363:142885. doi: 10.1016/j.chemosphere.2024.142885.
Hongmiao Yu 1 Caiyan Zhang 2 Hongguang Pan 3 Xia Gao 4 Xiang Wang 1 Wenfeng Xiao 1 Shang Yan 3 Yajing Gao 1 Jinrong Fu 5 Yufeng Zhou 6
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China.
  • 2 Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
  • 3 Department of Otorhinolaryngology, Shenzhen Children's Hospital, Shenzhen, Guangdong, China.
  • 4 Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 5 Department of General Medicine, Children's Hospital of Fudan University, Shanghai, China. Electronic address: fujinrong@fudan.edu.cn.
  • 6 Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China. Electronic address: yfzhou1@fudan.edu.cn.
Abstract

Particulate matter of aerodynamic diameter ≤2.5 μm (PM2.5) exposure induces oxidative stress in lung tissues. Ferroptosis is a form of regulated cell death based on oxidative damage and lipid peroxidation. Whether PM2.5 exposure-induced oxidative stress can promote Ferroptosis to aggravate asthma is not known. To investigate if PM2.5 exposure induces oxidative stress to promote Ferroptosis and influence asthma development, a cockroach extract-induced asthma model in mice was used for in vivo studies. Airway epithelial cell (AEC) Ferroptosis was detected by assays (CCK8, malonaldehyde, and 4-hydroxynonenal). Molecular mechanisms were investigated by real-time reverse transcription-quantitative polymerase chain reaction, western blotting, flow cytometry, liquid chromatography-tandem mass spectrometry, and chromatin immunoprecipitation. We found that exposure to PM2.5 and Indeno[1,2,3-cd] pyrene (IP; one of the prominent absorbed polycyclic aromatic hydrocarbons in PM2.5) enhanced the sensitivity of AECs to Ferroptosis to aggravate asthma, whereas Ferroptosis inhibitors and cytosolic Phospholipase A2 (cPLA2) inhibitors reversed this augmented inflammatory response in mice suffering from asthma. IP treatment enhanced cPLA2 expression/activation through Aryl Hydrocarbon Receptor (AhR) genomic and non-genomic pathways, resulting in arachidonic-acid release to promote the sensitivity of AECs to Ferroptosis. IP exposure enhanced the release of leukotriene-B4 from lung macrophages, resulting in enhanced expression of acyl-coA synthetase long chain family member4 (ACSL4) and the sensitivity of AECs to Ferroptosis. This finding suggests that exposure to PM2.5 and IP promote Ferroptosis sensitivity in AECs to aggravate asthma, which may provide new targets for the prevention and treatment of asthma.

Keywords

Aryl Hydrocarbon Receptor; Asthma; Ferroptosis; PM(2.5); Polycyclic aromatic hydrocarbons.

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