Reduced iron bioavailability drives acute high‑altitude lung injury through HIF1&alpha; activation and mitophagy

Geng,Yumei; Hu,Yu; Wang,Huijie; Zhang,Fang; Ge,Ri-Li

doi:10.3892/mmr.2025.13580

August-2025 Volume 32 Issue 2

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August-2025 Volume 32 Issue 2

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Article Open Access

Reduced iron bioavailability drives acute high‑altitude lung injury through HIF1α activation and mitophagy

Authors:
- Yumei Geng
- Yu Hu
- Huijie Wang
- Fang Zhang
- Ri-Li Ge
View Affiliations / Copyright

Affiliations: Research Center for High Altitude Medicine, Qinghai University, Xining, Qinghai 810001, P.R. China, Department of Pharmacy, Qinghai Provincial Traffic Hospital, Xining, Qinghai 810008, P.R. China, Department of Respiratory and Critical Care Medicine, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China

Copyright: © Geng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 215
|
Published online on: May 27, 2025

https://doi.org/10.3892/mmr.2025.13580
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Abstract

High‑altitude pulmonary injury, characterized by pulmonary edema and pulmonary hypertension, is mechanistically driven by dysregulated mitophagy, as evidenced by impaired mitochondrial quality control in endothelial cells under hypobaric hypoxia. Iron supplementation for individuals who have ascended rapidly to high altitudes can effectively mitigate the phenomenon of hypoxic pulmonary vasoconstriction; however, the precise role and detailed mechanisms remain to be determined. The present study aimed to explore the role and mechanism of iron in acute hypoxia‑induced lung injury. Sprague‑Dawley rats were initially placed in a hypobaric hypoxia chamber for various durations to determine the optimal time for acute hypoxia‑induced lung injury. The rats were exposed to a hypobaric hypoxia chamber for 3 days, during which they were treated with an iron chelator or iron sucrose. Mean pulmonary artery pressure (mPAP) was measured to assess hypoxic pulmonary vascular response. Furthermore, the degree of lung injury was assessed by calculating the pulmonary wet/dry weight ratio, and via morphological evaluation of lung tissues and the pulmonary vasculature. Immunofluorescence and western blot analysis were performed to assess hypoxia‑inducible factor 1α (HIF1α) expression and mitophagy levels. Edu and Cell Counting Kit 8 assays were conducted to evaluate cell proliferation under acute hypoxia. In addition, immunofluorescence and western blot analysis were performed to evaluate the expression levels of proteins associated with cell apoptosis and mitophagy. The results indicated that mitophagy (LC3B‑II/LC3B‑I expression), pulmonary edema (lung wet/dry weight ratio) and lung injury score were most significant after 3 days of hypoxia. However, mitophagy (LC3B‑II/LC3B‑I ratio) and lung injury scores peaked after 4 weeks of hypoxic conditions. Furthermore, an iron chelator was observed to promote pulmonary edema, elevate mPAP and cause lung injury. Conversely, iron sucrose was shown to attenuate lung injury in acute hypoxia. The mechanistic findings indicated that acute hypoxia induced HIF1α activation and increased mitophagy, which promoted a reduction in proliferation and an increase in the apoptosis of pulmonary artery endothelial cells. Furthermore, the iron chelator promoted, whereas iron sucrose ameliorated, the abnormal alterations in pulmonary artery endothelial cells under acute hypoxia. In conclusion, the present study demonstrated that a reduction in iron bioavailability in acute hypoxia may promote HIF1α activation and increased mitophagy, which in turn has been linked to the development of pulmonary edema, elevated mPAP and lung injury. The administration of iron supplementation may be considered an effective method for the alleviation of the aforementioned abnormalities resulting from acute hypoxia.

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Medicine International

Reduced iron bioavailability drives acute high‑altitude lung injury through HIF1α activation and mitophagy

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