Abstract
Background
Continuous positive airway pressure (CPAP) is a primary mode of respiratory support for preterm infants. Animal studies have shown long-term detrimental effects on lung/airway development, particularly airway (AW) hyper-reactivity, as an unfortunate consequence of neonatal CPAP. Since the hyaluronan (HA) synthesizing enzyme hyaluronan synthase-3 (HAS3) is involved in various adult pulmonary disorders, the present study used a neonatal mouse model to investigate the role of HAS3 in CPAP-induced AW hyper-reactivity.
Methods
Male and female neonatal mice were fitted with a custom-made mask for delivery of daily CPAP 3 h/day for 7 days. At postnatal day 21 (2 weeks after CPAP ended), airway (AW) hyper-reactivity and HAS3 expression were assessed with and without in vitro HAS3 siRNA treatment.
Results
MRIs of 3-day-old mice confirmed that CPAP increased lung volume with incrementing inflation pressures. CPAP increased AW reactivity in both male and female mice, which was associated with increased airway smooth muscle and epithelial HAS3 immunoreactivity. CPAP did not affect HA accumulation, but HAS3 siRNA reversed CPAP-induced AW hyper-reactivity and reduced HAS3 expression.
Conclusions
These data in mice implicate a role for HAS3 in long-term effects of CPAP in the developing airway in the context of preterm birth and CPAP therapy.
Impact
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Neonatal CPAP increases airway smooth muscle and epithelial HAS3 expression in mice.
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CPAP-induced airway hyper-reactivity is modulated by HAS3.
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These data enhance our understanding of the role mechanical forces play on lung development.
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These data are a significance step toward understanding CPAP effects on developing airway.
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These data may impact clinical recognition of the ways that CPAP may contribute to wheezing disorders of former preterm infants.
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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.
Funding
This work was funded by the National Heart, Lung and Blood Institute (Bethesda, MD) Grants R01HL138402 (P.M.M. and C.M.P.), R01HL056470 (Y.S.P. and R.J.Martin.), NIH grant S10-OD024996, NHLBI PO1HL107147 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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C.A.M., A.G., A.M., V.C. and P.M.M. made substantial contributions to data acquisition and analysis; C.A.F. and B.O.E. performed MRIs; V.C.H. and R.J.Midura. provided technical and data interpretation expertise; P.M.M., C.M.P., Y.S.P. and R.J.Martin. contributed to conception and experimental design. P.M.M. drafted the manuscript and all authors revised it critically for intellectual content and approval of the submitted and final version.
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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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Mayer, C.A., Ganguly, A., Mayer, A. et al. CPAP-induced airway hyper-reactivity in mice is modulated by hyaluronan synthase-3. Pediatr Res 92, 685–693 (2022). https://doi.org/10.1038/s41390-021-01695-0
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DOI: https://doi.org/10.1038/s41390-021-01695-0
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