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Postnatal budesonide improved lung function in preterm lambs exposed to antenatal steroids and chorioamnionitis

Pediatric Research (2024)Cite this article

Abstract

Background

A combination of budesonide and surfactant decreases the rates of BPD in infants and lung injury in preterm sheep. Whether this combination will show benefit in the setting of chorioamnionitis and antenatal steroids is not known.

Methods

Ewes at 123 ± 1 day gestational age received intra-amniotic (IA) injections of 10 mg LPS before being randomized to receive either 0.25 mg/kg maternal betamethasone phosphate and acetate or saline by intramuscular (IM) injection at 48 and 24 h prior to delivery at 125 ± 1 day. Lambs (N = 6–9/group) underwent intentionally injurious ventilation for 15 min, then lambs received surfactant mixed with either: (1) saline; or (2) Budesonide 0.25 mg/kg and were ventilated for 4 h.

Results

Compared with LPS-exposed animals that received no IM steroid treatment, betamethasone exposed fetuses had improved hemodynamic stability, lung compliance, and ventilation efficiency. The addition of budesonide to surfactant further improved markers of injury and pro-inflammatory cytokine mRNA in both betamethasone IM or no IM lambs exposed to LPS IA. Antenatal betamethasone and IA LPS exposures decreased budesonide levels in the fetal lung and plasma.

Conclusion

Antenatal betamethasone stabilizes physiologic parameters in LPS treated lambs. Budesonide mixed with surfactant further decreases injury and improves respiratory physiology in betamethasone treated animals.

Impact

  • Antenatal betamethasone improved lung and systemic physiology in the setting of intra-amniotic LPS. The addition of budesonide to the surfactant further improved lung function.

  • Budesonide levels in the plasma and lung were lower in lambs exposed to either LPS or LPS and Betamethasone animals, and these findings were not explained by increased esterification in the lungs.

  • The combination of antenatal steroids and budesonide with surfactant had the lowest markers of pro-inflammatory cytokines in the lung of LPS exposed animals.

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Fig. 1: Experimental design for mechanically ventilated animals.
Fig. 2: Plasma and lung budesonide levels.
Fig. 3: mRNA responses in the lung and liver.

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Data availability

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

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Author information

Authors and Affiliations

  1. Division of Neonatology, Cardinal Glennon Children’s Hospital, Saint Louis University, Saint Louis, MO, 63104, USA

    Noah H. Hillman, Emily Royse & Hayley Grzych

  2. School of Women’s and Infants’ Health, University of Western Australia, Perth, WA, 6009, Australia

    Matthew W. Kemp, Haruo Usada, Hideyuki Ikeda, Yuki Takahashi, Tsukasa Takahashi, Alan H. Jobe & Erin Fee

  3. Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore

    Matthew W. Kemp

  4. Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, 45229, USA

    Alan H. Jobe

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Contributions

Conception and design: NH, AJ, MK, EF; Animal procedures: NH, MK, EF; Experimental Analysis: NH, MK, ER; Manuscript preparation: NH, AJ, MK, EF; All authors approved the final manuscript as submitted.

Corresponding author

Correspondence to Noah H. Hillman.

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Competing interests

NHH, AJH, and MWK are listed as authors on patent for the combination of budesonide and surfactant.

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Hillman, N.H., Kemp, M.W., Royse, E. et al. Postnatal budesonide improved lung function in preterm lambs exposed to antenatal steroids and chorioamnionitis. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03092-9

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