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Postnatal steroids as lung protective and anti-inflammatory in preterm lambs exposed to antenatal inflammation

Pediatric Research volume 95, pages 931–940 (2024)Cite this article

Abstract

Background

Lung inflammation and impaired alveolarization precede bronchopulmonary dysplasia (BPD). Glucocorticoids are anti-inflammatory and reduce ventilator requirements in preterm infants. However, high-dose glucocorticoids inhibit alveolarization. The effect of glucocorticoids on lung function and structure in preterm newborns exposed to antenatal inflammation is unknown. We hypothesise that postnatal low-dose dexamethasone reduces ventilator requirements, prevents inflammation and BPD-like lung pathology, following antenatal inflammation.

Methods

Pregnant ewes received intra-amniotic LPS (E.coli, 4 mg/mL) or saline at 126 days gestation; preterm lambs were delivered 48 h later. Lambs were randomised to receive either tapered intravenous dexamethasone (LPS/Dex, n = 9) or saline (LPS/Sal, n = 10; Sal/Sal, n = 9) commencing <3 h after birth. Respiratory support was gradually de-escalated, using a standardised protocol aimed at weaning from ventilation towards unassisted respiration. Tissues were collected at day 7.

Results

Lung morphology and mRNA levels for inflammatory mediators were measured. Respiratory support requirements were not different between groups. Histological analyses revealed higher tissue content and unchanged alveolarization in LPS/Sal compared to other groups. LPS/Dex lambs exhibited decreased markers of pulmonary inflammation compared to LPS/Sal.

Conclusion

Tapered low-dose dexamethasone reduces the impact of antenatal LPS on ventilation requirements throughout the first week of life and reduces inflammation and pathological thickening of the preterm lung

Impact

  • We are the first to investigate the combination of antenatal inflammation and postnatal dexamethasone therapy in a pragmatic study design, akin to contemporary neonatal care. We show that antenatal inflammation with postnatal dexamethasone therapy does not reduce ventilator requirements, but has beneficial maturational impacts on the lungs of preterm lambs at 7 days of life. Appropriate tapered postnatal dexamethasone dosing should be explored for extuabtion of oxygen-dependant neonates.

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Fig. 1: Study protocol and animal allocations.
Fig. 2: pH, PaCO2, HCO3-, PaO2, pF ratio and oxygenation index of Sal/Sal lambs, LPS/Sal lambs or LPS/Dex lambs.
Fig. 3: Heat maps depicting intensity of ventilator support in preterm lambs.
Fig. 4: Representative images depicting variability in the lung parenchyma of preterm lambs within the same treatment group.
Fig. 5: Proliferating cells (top panel) or inflammatory cells (bottom panel) within the lungs of preterm lambs on day 7 of life.
Fig. 6: IL-1α, IL-1β, IL-6 and IL-8 messenger RNA expression in the lungs of Sal/Sal lambs, LPS/Sal lambs and LPS/Dex lambs.

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Data availability

All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.

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Funding

Funding

This research was supported by: NHMRC Project Grant (1057759); NHMRC Centre for Research Excellence (1057514); NHMRC Career Development Fellowship (Peter Noble, 1045824); 2 NHMRC Senior Research Fellowships (Moss 1043294; Pillow,1077691); Victorian Government’s Operational Infrastructure Support Program; West Australian Government’s Medical and Health Research Infrastructure Fund. Unrestricted equipment and consumable support was provided by Chiesi Farmaceutici S.p.A. (poractant alfa); Fisher & Paykel Healthcare (ventilator circuits); and ICU Medical (arterial monitoring lines).

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Nursing and Health Sciences, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia

    Paris C. Papagianis

  2. School of Human Sciences, The University of Western Australia, Crawley, WA, Australia

    Peter B. Noble, Siavash Ahmadi-Noorbakhsh, Donna Savigni & J. Jane Pillow

  3. Department of Obstetrics and Gynaecology, School of Clinical Health Sciences, Monash University, Clayton, VIC, Australia

    Timothy J. M. Moss

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Contributions

P.C.P. designed and performed tissue analyses, collected data, analysed data and drafted manuscript. S.A. and P.B.N. performed experiments. T.J.M. helped design and perform tissue analyses, contributed to the interpretation and presentation of data and drafted manuscript. J.J.P. conceived the study, was responsible for the study design, had overall responsibility for and supervised all aspects of lamb studies and drafted manuscript. J.J.P. and P.B.N. obtained funding for the study. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Paris C. Papagianis.

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Competing interests

Jane Pillow has acted as a consultant on behalf of The University of Western Australia for Chiesi Farmaceutici S.p.A. on projects unrelated to the focus of the current manuscript.

Ethics

Study protocols were reviewed and approved by The University of Western Australia Animal Ethics Committee (RA-3/100/1301).

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Papagianis, P.C., Noble, P.B., Ahmadi-Noorbakhsh, S. et al. Postnatal steroids as lung protective and anti-inflammatory in preterm lambs exposed to antenatal inflammation. Pediatr Res 95, 931–940 (2024). https://doi.org/10.1038/s41390-023-02911-9

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