CPAP protects against hyperoxia-induced increase in airway reactivity in neonatal mice

Abstract

Background

Oxygen and continuous positive airway pressure (CPAP) are primary modes of respiratory support for preterm infants. Animal models, however, have demonstrated adverse unintended effects of hyperoxia and CPAP on lung development. We investigate the effects of combined neonatal hyperoxia and CPAP exposure on airway function and morphology in mice.

Methods

Newborn mice were exposed to hyperoxia (40% O2) 24 h/day for 7 consecutive days with or without daily (3 h/day) concomitant CPAP. Two weeks after CPAP and/or hyperoxia treatment ended, lungs were assessed for airway (AW) hyperreactivity and morphology.

Results

CPAP and hyperoxia exposure alone increased airway reactivity compared to untreated control mice. CPAP-induced airway hyperreactivity was associated with epithelial and smooth muscle proliferation. In contrast, combined CPAP and hyperoxia treatment no longer resulted in increased airway reactivity, which was associated with normalization of smooth muscle and epithelial proliferation to values similar to untreated mice.

Conclusions

Our data suggest that the combination of CPAP and hyperoxia decreases the adverse consequences on airway remodeling of either intervention alone. The complex interaction between mechanical stretch (via CPAP) and hyperoxia exposure on development of immature airways has implications for the pathophysiology of airway disease in former preterm infants receiving non-invasive respiratory support.

Impact

  • CPAP and mild hyperoxia exposure alone increase airway reactivity in the neonatal mouse model.

  • In contrast, combined CPAP and hyperoxia no longer induce airway hyperreactivity.

  • Combined CPAP and hyperoxia normalize smooth muscle and epithelial proliferation to control values.

  • Interaction between CPAP-induced stretch and mild hyperoxia exposure on immature airways has important implications for airway pathophysiology in former preterm infants.

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Fig. 1: Airway (AW) responses to methacholine challenge in the in vitro living lung slice preparation from 21-day-old male mice pretreated wtih 7 days of neonatal (P1-7) CPAP and/or hyperoxia.
Fig. 2: Immunohistochemical analysis (H&E staining) of airway thickness in P21-day-old mice following neonatal (P1–7) CPAP with or without prior concomitant hyperoxia exposure.
Fig. 3: Immunohistochemical analysis of airway α-smooth muscle actin staining in P21-day-old mice following neonatal (P1–7) CPAP with or without prior concomitant hyperoxia exposure.
Fig. 4: Airway PCNA immunoreactivity for smooth muscle and epithelial cells in P21-day-old mice following neonatal (P1-7 days) CPAP and/or hyperoxia exposure.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to acknowledge the commitment from Morgan Hazard for assistance with CPAP exposure. This study was funded by the National Heart, Lung and Blood Institute (Bethesda, MD) Grants R01HL138402 and R01HL056470 and the Department of Pediatrics, Rainbow Babies and Children’s Hospital, Cleveland, Ohio. This study was also funded in part by generous financial contributions from William and Lois Briggs.

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P.M.M., C.A.M., A.J., C.M.P., and Y.S.P. made substantial contributions to data acquisition and analysis; all authors provided technical and data interpretation expertise; P.M.M. and R.J.M. contributed to conception and experimental design and drafted the manuscript; and all authors revised it critically for intellectual content and approval of the submitted and final version.

Corresponding author

Correspondence to Richard J. Martin.

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The authors declare no competing interests.

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All procedures were carried out in accordance with the National Institute of Health (NIH) guidelines for care and use of laboratory animals and were approved by the Animal Care and Use Committee at Case Western Reserve University.

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MacFarlane, P.M., Mayer, C.A., Jafri, A. et al. CPAP protects against hyperoxia-induced increase in airway reactivity in neonatal mice. Pediatr Res (2020). https://doi.org/10.1038/s41390-020-01212-9

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