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High Dose of Estrogen Protects the Lungs from Ischemia–Reperfusion Injury by Downregulating the Angiotensin II Signaling Pathway

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Abstract

We explored the sex difference in lung ischemia–reperfusion injury (LIRI) and the role and mechanism of estrogen (E2) and angiotensin II (Ang II) in LIRI. We established a model of LIRI in mice. E2, Ang II, E2 inhibitor (fulvestrant), and angiotensin II receptor blocker (losartan) were grouped for treatment. The lung wet/dry weight ratio, natural killer (NK) cells (by flow cytometry), neutrophils (by flow cytometry), expression of key proteins (by Western blot, immunohistochemistry, ELISA, and immunofluorescence), and expression of related protein mRNA (by qPCR) were detected. The ultrastructure of the alveolar epithelial cells was observed by transmission electron microscopy. We found that E2 and Ang II played an important role in the progression of LIRI. The two signaling pathways showed obvious antagonism, and E2 regulates LIRI in the different sexes by downregulating Ang II, leading to a better prognosis. E2 and losartan reduced the inflammatory cell infiltration in lung tissue and key inflammatory factors in serum while fulvestrant and Ang II had the opposite effect. The protective effect of E2 was related with AKT, p38, COX2, and HIF-1α.

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Acknowledgements

We thank all our colleagues who helped us during the current study. We greatly appreciate the kind assistance of Doctors in the Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, for the assistance in discussing the key issues of this study.

Funding

This project was supported by the Natural Science Foundation of Hubei Province [2020CFB703].

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Authors and Affiliations

  1. Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

    Peng Dai, Jutong He, Ming Xu, Jinping Zhao, Xuefeng Zhou & Hexiao Tang

  2. Department of Rheumatology and Immunology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

    Yanhong Wei

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Contributions

Peng Dai, Jutong He, Yanhong Wei, and Hexiao Tang conceived and designed the study. Peng Dai and Jutong He contributed to the literature search, animal experiment, and data collection. Peng Dai and Xuefeng Zhou contributed to the data analysis. Xuefeng Zhou, Ming Xu, Jinping Zhao, and Hexiao Tang contributed to data interpretation. Peng Dai, Xuefeng Zhou, Jinping Zhao, and Hexiao Tang contributed to write and revise the report. Jinping Zhao and Hexiao Tang contributed to the figures of the report. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jinping Zhao, Xuefeng Zhou or Hexiao Tang.

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Ethics Approval

This experiment was approved by the Animal Ethics Committee of Zhongnan Hospital of Wuhan University (Approval No ZN2022115). We confirm that all experiments were performed in accordance with the Laboratory Animal-Guideline for ethical review of animal welfare. We confirm that the authors complied with the ARRIVE guidelines.

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The authors declare no competing interests.

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Peng Dai, Jutong He, and Yanhong Wei are co-first authors.

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Dai, P., He, J., Wei, Y. et al. High Dose of Estrogen Protects the Lungs from Ischemia–Reperfusion Injury by Downregulating the Angiotensin II Signaling Pathway. Inflammation (2024). https://doi.org/10.1007/s10753-024-01973-z

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  • DOI: https://doi.org/10.1007/s10753-024-01973-z

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