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Melatonin Protects Against Hyperoxia-Induced Apoptosis in Alveolar Epithelial type II Cells by Activating the MT2/PI3K/AKT/ETS1 Signaling Pathway

  • HYPEROXIA-INDUCED APOPTOSIS
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Abstract

Purpose

Hyperoxia-induced apoptosis in alveolar epithelial type II cells (AECIIs) plays a critical role in the development of bronchopulmonary dysplasia (BPD). Melatonin has been shown to improve BPD. However, the protective effect of melatonin on hyperoxia-induced apoptosis in AECIIs and the precise mechanisms involved remain unclear.

Methods

Human alveolar epithelial type II A549 cells were treated with hyperoxia as an in vitro model to investigate the antiapoptotic mechanism of melatonin. CCK-8 assays were performed to investigate the viability of A549 cells. Hoechst 33,258 staining was carried out to quantify apoptosis in A549 cells. The protein expression levels of E26 oncogene homolog 1 (ETS1), Bcl-2, Bax, Bim, Wnt, β-catenin, AKT and phosphorylated AKT were measured by western blotting. LY294002, SC79 and the downregulation of ETS1, melatonin receptor 1 (MT1) and MT2 with specific siRNAs were used to investigate the role of the PI3K/AKT pathway, ETS1, MT1 and MT2 in hyperoxia-induced apoptosis in A549 cells.

Results

Melatonin prevented hyperoxia-induced apoptosis in A549 cells, and the upregulation of E26 oncogene homolog 1 (ETS1) contributed to the antiapoptotic effect of melatonin. Melatonin activated the PI3K/AKT axis, which led to ETS1 upregulation and inhibited apoptosis in hyperoxia-exposed A549 cells. Furthermore, melatonin-induced activation of the PI3K/AKT axis, upregulation of ETS1 and inhibition of apoptosis were reversed by melatonin receptor 2 (MT2) siRNA in hyperoxia-exposed A549 cells.

Conclusion

Melatonin prevents hyperoxia-induced apoptosis by activating the MT2/PI3K/AKT/ETS1 axis in alveolar epithelial cells.

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Abbreviations

AECIIs:

Alveolar epithelial type II cells

BPD:

Bronchopulmonary dysplasia

ETS1:

E26 oncogene homolog 1

MTs:

Melatonin receptors

MT1:

Melatonin receptor 1

MT2:

Melatonin receptor 2

TGM2:

Transglutaminase 2

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Neonatology, Jiangxi Provincial Children’s Hospital, No. 1666, DieziHu Road, Honggutan District, Nanchang, 330038, Jiangxi, China

    Fan He, Qiao-Fang Wang, Lin Li, Cong Yu, Chun-Zi Liu, Wen-Chao Wei & Li-Ping Chen

  2. Second Department of Respiratory Disease, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, No. 152, Aiguo Road, DongHu District, Nanchang, 330006, Jiangxi, China

    Huan-Yu Li

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Contributions

LPC and HYL contributed to the study conception and design. Material preparation, data collection and analysis were performed by FH, QFW LL, CY, CZL, and WCW. The first draft of the manuscript was written by FH, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Li-Ping Chen or Huan-Yu Li.

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He, F., Wang, QF., Li, L. et al. Melatonin Protects Against Hyperoxia-Induced Apoptosis in Alveolar Epithelial type II Cells by Activating the MT2/PI3K/AKT/ETS1 Signaling Pathway. Lung 201, 225–234 (2023). https://doi.org/10.1007/s00408-023-00610-0

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