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

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

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
Published online on: May 27, 2025 https://doi.org/10.3892/mmr.2025.13580
Article Number: 215
Copyright: © Geng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Penaloza D and Arias-Stella J: The heart and pulmonary circulation at high altitudes: Healthy highlanders and chronic mountain sickness. Circulation. 115:1132–1146. 2007. View Article : Google Scholar : PubMed/NCBI
2	Mirrakhimov AE and Strohl KP: High-altitude pulmonary hypertension: An update on disease pathogenesis and management. Open Cardiovasc Med J. 10:19–27. 2016. View Article : Google Scholar : PubMed/NCBI
3	Sydykov A, Mamazhakypov A, Maripov A, Kosanovic D, Weissmann N, Ghofrani HA, Sarybaev AS and Schermuly RT: Pulmonary hypertension in acute and chronic high altitude maladaptation disorders. Int J Environ Res Public Health. 18:16922021. View Article : Google Scholar : PubMed/NCBI
4	Luks AM, Swenson ER and Bärtsch P: Acute high-altitude sickness. Eur Respir Rev. 26:1600962017. View Article : Google Scholar : PubMed/NCBI
5	Sharma A, Ahmad S, Ahmad T, Ali S and Syed MA: Mitochondrial dynamics and mitophagy in lung disorders. Life Sci. 284:1198762021. View Article : Google Scholar : PubMed/NCBI
6	Liu R, Xu C, Zhang W, Cao Y, Ye J, Li B, Jia S, Weng L, Liu Y, Liu L and Zheng M: FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia. Cell Death Dis. 13:6342022. View Article : Google Scholar : PubMed/NCBI
7	Bao C, Liang S, Han Y, Yang Z, Liu S, Sun Y, Zheng S, Li Y, Wang T, Gu Y, et al: The novel lysosomal autophagy inhibitor (ROC-325) ameliorates experimental pulmonary hypertension. Hypertension. 80:70–83. 2023. View Article : Google Scholar : PubMed/NCBI
8	Zhang J, Li Y, Chen Y, Yu X, Wang S, Sun H, Zheng X, Zhang L, Wang Y and Zhu D: Circ-calm4 regulates hypoxia-induced pulmonary artery smooth muscle autophagy by binding Purb. J Mol Cell Cardiol. 176:41–54. 2023. View Article : Google Scholar : PubMed/NCBI
9	Smith TG, Talbot NP, Privat C, Rivera-Ch M, Nickol AH, Ratcliffe PJ, Dorrington KL, León-Velarde F and Robbins PA: Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: Two randomized controlled trials. JAMA. 302:1444–1450. 2009. View Article : Google Scholar : PubMed/NCBI
10	Altamura S, Bärtsch P, Dehnert C, Maggiorini M, Weiss G, Theurl I, Muckenthaler MU and Mairbäurl H: Increased hepcidin levels in high-altitude pulmonary edema. J Appl Physiol (1985). 118:292–298. 2015. View Article : Google Scholar : PubMed/NCBI
11	Lan M, Wu S and Fernandes TM: Iron deficiency and pulmonary arterial hypertension. Nutr Clin Pract. 37:1059–1073. 2022. View Article : Google Scholar : PubMed/NCBI
12	Schiavi A, Strappazzon F and Ventura N: Mitophagy and iron: Two actors sharing the stage in age-associated neuronal pathologies. Mech Ageing Dev. 188:1112522020. View Article : Google Scholar : PubMed/NCBI
13	Brogyanyi T, Kejík Z, Veselá K, Dytrych P, Hoskovec D, Masařik M, Babula P, Kaplánek R, Přibyl T, Zelenka J, et al: Iron chelators as mitophagy agents: Potential and limitations. Biomed Pharmacother. 179:1174072024. View Article : Google Scholar : PubMed/NCBI
14	Shimoda LA and Laurie SS: HIF and pulmonary vascular responses to hypoxia. J Appl Physiol (1985). 116:867–874. 2014. View Article : Google Scholar : PubMed/NCBI
15	Feng J, Zhan J and Ma S: LRG1 promotes hypoxia-induced cardiomyocyte apoptosis and autophagy by regulating hypoxia-inducible factor-1α. Bioengineered. 12:8897–8907. 2021. View Article : Google Scholar : PubMed/NCBI
16	Fu ZJ, Wang ZY, Xu L, Chen XH, Li XX, Liao WT, Ma HK, Jiang MD, Xu TT, Xu J, et al: HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury. Redox Biol. 36:1016712020. View Article : Google Scholar : PubMed/NCBI
17	Imray C, Wright A, Subudhi A and Roach R: Acute mountain sickness: Pathophysiology, prevention, and treatment. Prog Cardiovasc Dis. 52:467–484. 2010. View Article : Google Scholar : PubMed/NCBI
18	Beidleman BA, Fulco CS, Glickman EL, Cymerman A, Kenefick RW, Cadarette BS, Andrew SP, Staab JE, Sils IV and Muza SR: Acute mountain sickness is reduced following 2 days of staging during subsequent ascent to 4300 m. High Alt Med Biol. 19:329–338. 2018. View Article : Google Scholar : PubMed/NCBI
19	Yang SL, Ibrahim NA, Jenarun G and Liew HB: Incidence and determinants of acute mountain sickness in Mount Kinabalu, Malaysia. High Alt Med Biol. 21:265–272. 2020. View Article : Google Scholar : PubMed/NCBI
20	Hsu TY, Weng YM, Chiu YH, Li WC, Chen PY, Wang SH, Huang KF, Kao WF, Chiu TF and Chen JC: Rate of ascent and acute mountain sickness at high altitude. Clin J Sport Med. 25:95–104. 2015. View Article : Google Scholar : PubMed/NCBI
21	Pu X, Lin X, Qi Y, Li Y, Li T, Liu Y and Wei D: Effects of Fdft 1 gene silencing and VD3 intervention on lung injury in hypoxia-stressed rats. Genes Genomics. 44:1201–1213. 2022. View Article : Google Scholar : PubMed/NCBI
22	Zeng Y, Cao W, Huang Y, Zhang H, Li C, He J, Liu Y, Gong H and Su Y: Huangqi Baihe Granules alleviate hypobaric hypoxia-induced acute lung injury in rats by suppressing oxidative stress and the TLR4/NF-κB/NLRP3 inflammatory pathway. J Ethnopharmacol. 324:1177652024. View Article : Google Scholar : PubMed/NCBI
23	Dai C, Lin X, Qi Y, Wang Y, Lv Z, Zhao F, Deng Z, Feng X, Zhang T and Pu X: Vitamin D3 improved hypoxia-induced lung injury by inhibiting the complement and coagulation cascade and autophagy pathway. BMC Pulm Med. 24:92024. View Article : Google Scholar : PubMed/NCBI
24	Dongiovanni P, Valenti L, Ludovica Fracanzani A, Gatti S, Cairo G and Fargion S: Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. Am J Pathol. 172:738–747. 2008. View Article : Google Scholar : PubMed/NCBI
25	Matute-Bello G, Downey G, Moore BB, Groshong SD, Matthay MA, Slutsky AS and Kuebler WM; Acute Lung Injury in Animals Study Group, : An official American Thoracic Society workshop report: Features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol. 44:725–738. 2011. View Article : Google Scholar : PubMed/NCBI
26	Jiang Y, Guo Y, Feng X, Yang P, Liu Y, Dai X, Zhao F, Lei D, Li X, Liu Y and Li Y: Iron metabolism disorder regulated by BMP signaling in hypoxic pulmonary hypertension. Biochim Biophys Acta Mol Basis Dis. 1869:1665892023. View Article : Google Scholar : PubMed/NCBI
27	Zhai K, Deng L, Wu Y, Li H, Zhou J, Shi Y, Jia J, Wang W, Nian S, Jilany Khan G, et al: Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4. J Adv Res. S2090-1232(24)00355-2. 2024.(Epub ahead of print). View Article : Google Scholar
28	Zhai K, Wang W, Zheng M, Khan GJ, Wang Q, Chang J, Dong Z, Zhang X, Duan H, Gong Z and Cao H: Protective effects of Isodon suzhouensis extract and glaucocalyxin A on chronic obstructive pulmonary disease through SOCS3-JAKs/STATs pathway. Food Front. 4:511–523. 2023. View Article : Google Scholar
29	Duan H, Wang W, Li S, Khan GJ, Ma Y, Liu F, Zhai K, Hu H and Wei Z: The potential mechanism of Isodon suzhouensis against COVID-19 via EGFR/TLR4 pathways. Food Sci Hum Well. 13:3245–3255. 2024. View Article : Google Scholar
30	Naeije R: Physiological adaptation of the cardiovascular system to high altitude. Prog Cardiovasc Dis. 52:456–466. 2010. View Article : Google Scholar : PubMed/NCBI
31	Zhang Y, Lu Y and Jin L: Iron metabolism and ferroptosis in physiological and pathological pregnancy. Int J Mol Sci. 23:93952022. View Article : Google Scholar : PubMed/NCBI
32	Muckenthaler MU, Mairbäurl H and Gassmann M: Iron metabolism in high-altitude residents. J Appl Physiol (1985). 129:920–925. 2020. View Article : Google Scholar : PubMed/NCBI
33	Patrician A, Dawkins T, Coombs GB, Stacey B, Gasho C, Gibbons T, Howe CA, Tremblay JC, Stone R, Tymko K, et al: Global research expedition on altitude-related chronic health 2018 iron infusion at high altitude reduces hypoxic pulmonary vasoconstriction equally in both lowlanders and healthy andean highlanders. Chest. 161:1022–1035. 2022. View Article : Google Scholar : PubMed/NCBI
34	Willie CK, Patrician A, Hoiland RL, Williams AM, Gasho C, Subedi P, Anholm J, Drane A, Tymko MM, Nowak-Flück D, et al: Influence of iron manipulation on hypoxic pulmonary vasoconstriction and pulmonary reactivity during ascent and acclimatization to 5050 m. J Physiol. 599:1685–1708. 2021. View Article : Google Scholar : PubMed/NCBI
35	Engebretsen BJ, Irwin D, Valdez ME, O'Donovan MK, Tucker A and van Patot MT: Acute hypobaric hypoxia (5486 m) induces greater pulmonary HIF-1 activation in hilltop compared to madison rats. High Alt Med Biol. 8:312–321. 2007. View Article : Google Scholar : PubMed/NCBI
36	He G, Nie JJ, Liu X, Ding Z, Luo P, Liu Y, Zhang BW, Wang R, Liu X, Hai Y and Chen DF: Zinc oxide nanoparticles inhibit osteosarcoma metastasis by downregulating β-catenin via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway. Bioact Mater. 19:690–702. 2022.PubMed/NCBI
37	Chen Y, Li X, Wang Z, Yuan S, Shen X, Xie X, Xing K and Zhu Q: Iron deficiency affects oxygen transport and activates HIF1 signaling pathway to regulate phenotypic transformation of VSMC in aortic dissection. Mol Med. 30:902024. View Article : Google Scholar : PubMed/NCBI
38	Liu Y, Xiang D, Zhang H, Yao H and Wang Y: Hypoxia-inducible factor-1: A potential target to treat acute lung injury. Oxid Med Cell Longev. 2020:88714762020. View Article : Google Scholar : PubMed/NCBI
39	Lin H and Jin F: Advancement of pathological role of hypoxia-inducible factor 1 in acute lung injury. Int J Respir. 39:1885–1889. 2019.
40	Mahroum N, Alghory A, Kiyak Z, Alwani A, Seida R, Alrais M and Shoenfeld Y: Ferritin-from iron, through inflammation and autoimmunity, to COVID-19. J Autoimmun. 126:1027782022. View Article : Google Scholar : PubMed/NCBI
41	Kell DB and Pretorius E: Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 6:748–773. 2014. View Article : Google Scholar : PubMed/NCBI
42	Liu T and Zhao D: Research progress of role of reactive oxygen species in acute lung injury acute respiratory distress syndrome. Int J Respir. 39:1890–1894. 2019.
43	An HS, Yoo JW, Jeong JH, Heo M, Hwang SH, Jang HM, Jeong EA, Lee J, Shin HJ, Kim KE, et al: Lipocalin-2 promotes acute lung inflammation and oxidative stress by enhancing macrophage iron accumulation. Int J Biol Sci. 19:1163–1177. 2023. View Article : Google Scholar : PubMed/NCBI