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AMPK/MTOR/TP53 Signaling Pathway Regulation by Calcitonin Gene-Related Peptide Reduces Oxygen-Induced Lung Damage in Neonatal Rats through Autophagy Promotion

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Abstract

Our previous studies indicated that calcitonin gene-related peptide (CGRP) alleviates hyperoxia-induced lung injury and suggested the possible involvement of autophagy in this process. Herein, we aimed to further explore the potential involvement of tumor protein p53 (TP53) and autophagy in the mode of action of CGRP against hyperoxia-induced lung injury in vitro and in vivo. The study conducted tests on type II alveolar epithelial cells (AECII) and rats that were subjected to hyperoxia treatment or combined treatment of hyperoxia with CGRP, CGRP inhibitor, rapamycin (an autophagy agonist), 3-methyladenine (3-MA, an autophagy inhibitor), TP53 silencing/inhibitor (pifithrin-α), or expression vector/activator (PRIMA-1 (2,2-bis(hydroxymethyl)-3-quinuclidinone)) and their corresponding controls. We found that oxidative stress, apoptosis, and autophagy were all increased by hyperoxia treatment in vitro. However, treating AECII cells with CGRP reversed hyperoxia-induced oxidative stress and apoptosis but further promoted autophagy. In addition, the combined treatment with rapamycin or TP53 silencing with CGRP promoted the effect of CGRP, while contrary results were obtained with combined therapy with 3-MA or TP53 overexpression. In vivo, the number of hyperoxia-induced autophagosomes was promoted in the lung tissue of neonatal rats. Furthermore, hyperoxia increased the expression levels of AMP-activated protein kinase (AMPK) alpha 1 (also known as protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1)) but inhibited TP53 and mechanistic target of rapamycin (MTOR); these expression trends were regulated by CGRP treatment. In conclusion, we showed that CGRP can attenuate hyperoxia-induced lung injury in neonatal rats by enhancing autophagy and regulating the TP53/AMPK/MTOR crosstalk axis.

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Availability of Data and Materials

The datasets generated during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by (1) the Natural Science Foundation of Shenzhen Science and Technology Innovation Commission in 2020 [grant number JCYJ20190813141207091], (2) the Natural Science Foundation of Shenzhen Science and Technology Innovation Commission in 2021 [grant number JCYJ20210324111806016], (3) the Natural Science Foundation of Shenzhen Science and Technology Innovation Commission in 2022 [grant number JCYJ20220530142015035], (4) Futian Healthcare Research Project, Shenzhen, 2023 [grant number FTWS2023063]. .

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  1. Neonatal Intensive Care Unit, Women and Children Health Institute of Futian, Jintian South Road No. 2002, Futian District, Shenzhen, 518045, China

    Shaohua Wang, Zhengzhuang Zou, Zanmei Tang & Jian Deng

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  1. Shaohua Wang
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S. W.: investigation; data curation; writing—original draft; supervision; funding acquisition. Z. Z.: validation, investigation, formal analysis. Z. T.: resources, validation. J. D.: resources.

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Correspondence to Shaohua Wang.

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This experiment obtained approval from the Medical Ethics Committee of Women and Children Health Institute of Futian (Approval date: 2019/7/30). The committee carefully reviewed the research protocol, ensuring compliance with ethical guidelines and regulations. The study was performed in conformity with the principles outlined in the Basel Declaration on Animal Research Ethics.

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Wang, S., Zou, Z., Tang, Z. et al. AMPK/MTOR/TP53 Signaling Pathway Regulation by Calcitonin Gene-Related Peptide Reduces Oxygen-Induced Lung Damage in Neonatal Rats through Autophagy Promotion. Inflammation (2024). https://doi.org/10.1007/s10753-023-01963-7

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