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Postnatal hypoxic preconditioning attenuates lung damage from hyperoxia in newborn mice

Pediatric Research volume 97, pages 1684–1695 (2025)Cite this article

Abstract

Background

Preterm infants frequently require oxygen supplementation at birth. However, preterm lung is especially sensible to structural and functional damage caused by oxygen free radicals.

Methods

The adaptive mechanisms implied in the fetal-neonatal transition from a lower to a higher oxygen environment were evaluated in a murine model using a custom-designed oxy-chamber. Pregnant mice were randomly assigned to deliver in 14% (hypoxic preconditioning group) or 21% (normoxic group) oxygen environment. Eight hours after birth FiO2 was increased to 100% for 60 min and then switched to 21% in both groups. A control group remained in 21% oxygen throughout the study.

Results

Mice in the normoxic group exhibited thinning of the alveolar septa, increased cell death, increased vascular damage, and decreased synthesis of pulmonary surfactant. However, lung histology, lamellar bodies microstructure, and surfactant integrity were preserved in the hypoxic preconditioning group after the hyperoxic insult.

Conclusion

Postnatal hyperoxia has detrimental effects on lung structure and function when preceded by normoxia compared to controls. However, postnatal hypoxic preconditioning mitigates lung damage caused by a hyperoxic insult.

Impact

  • Hypoxic preconditioning, implemented shortly after birth mitigates lung damage caused by postnatal supplemental oxygenation.

  • The study introduces an experimental mice model to investigate the effects of hypoxic preconditioning and its effects on lung development. This model enables researchers to delve into the intricate processes involved in postnatal lung maturation.

  • Our findings suggest that hypoxic preconditioning may reduce lung parenchymal damage and increase pulmonary surfactant synthesis in reoxygenation strategies during postnatal care.

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Fig. 1: Experimental Design: model of postnatal hypoxic preconditioning.
Fig. 2: Assessment of oxygen saturation, respiratory rate and heart rate in mice offspring.
Fig. 3: Study of the effect of hypoxic preconditioning on the lung parenchyma and development of the pulmonary vasculature of the lungs of mice in P1.
Fig. 4: Hypoxic preconditioning increases pulmonary surfactant levels in P1 mice offspring.
Fig. 5: Study of the effect of hypoxic preconditioning on the lung parenchyma and development of the pulmonary vasculature of the lungs of mice in P7.
Fig. 6: HP increases pulmonary surfactant levels at P7.

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Data availability

All data are available in the main text or the supplementary materials.

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Acknowledgements

We would like to acknowledge Professor Francisco Blanes, School of Informatic, Dept. of Computer Engineering of the Universitat Politècnica de València (UPV) for support and helpful design oxy-chamber to develop of animal model; P. García-Tárraga for the experimental support at the Laboratory of Comparative Neurobiology of the University of Valencia (UV).

Funding

Consellería of Innovation, Universities, Science and Society digital of the Community of Valencia (Spain) grant GV/2018/021. (IT-C). Consellería of Innovation, Universities, Science and Society digital of the Community of Valencia (Spain) grant GV/2021/188. (IT-C). RETICS funded by the PN 2018-2021 (Spain), ISCIII- Sub-Directorate General for Research Assessment and Promotion and the European Regional Development Fund(FEDER), reference RD16/0022/0001 and FIS PI20/0964 grant from the Instituto de Salud Carlos III (Ministry of Science, Spain) (IM, MV).

Author information

Authors and Affiliations

  1. Neonatal Research Group, Health Research Institute La Fe (IISLAFE), Valencia, Spain

    Iván Millan, Máximo Vento & Isabel Torres-Cuevas

  2. Laboratory of Comparative Neurobiology, Instituto Cavanilles de Biodiversidad y Biologia Evolutiva, University of Valencia, Paterna, Valencia, Spain

    Iván Millan & José Manuel García-Verdugo

  3. Department of Physiology, University of Valencia, Burjassot, Spain

    Salvador Pérez, Miguel Ángel Asensi & Isabel Torres-Cuevas

  4. Department of Cell Biology, Functional Biology and Physical Anthropology, University of Valencia, Burjassot, Spain

    Sergio Rius-Pérez

  5. Division of Neonatology, University and Polytechnic Hospital La Fe (HULAFE), Valencia, Spain

    Máximo Vento

Authors
  1. Iván Millan
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  2. Salvador Pérez
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  3. Sergio Rius-Pérez
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  4. Miguel Ángel Asensi
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  5. Máximo Vento
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  6. José Manuel García-Verdugo
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  7. Isabel Torres-Cuevas
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Contributions

Conceived and designed the experiments: I.T.-C. and M.V. Performed the experiments: I.T.-C., I.M., S.P., S.R., M.A., J.M.G.-V. Animal procedure: I.T.-C., I.M., and S.P.; Writing—original draft: I.T.-C., S.P., and M.V.; Writing—review & editing: I.T.-C., S.P., and M.V.

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Correspondence to Máximo Vento or Isabel Torres-Cuevas.

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Millan, I., Pérez, S., Rius-Pérez, S. et al. Postnatal hypoxic preconditioning attenuates lung damage from hyperoxia in newborn mice. Pediatr Res 97, 1684–1695 (2025). https://doi.org/10.1038/s41390-024-03457-0

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