Lightning Talk + Poster ESA-SRB-ANZOS 2025 in conjunction with ENSA

Antenatal exposure to intraamniotic ciclesonide matures the preterm sheep lung (128586)

Kathryn L Gatford 1 2 , Ashley S Meakin 3 , Mitchell C Lock 3 , Stacey L Holman 3 , Saba Albetawi 3 , Yoshi Tan 1 2 3 , Jack R T Darby 3 , Megan J Wallace 4 5 , Timothy J Cole 6 , Andrew Tai 2 7 8 , Vicki L Clifton 9 , Michael D Wiese 10 , Michael J Stark 2 7 8 , Janna L Morrison 3
  1. School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
  2. Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
  3. Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia
  4. Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
  5. The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  6. Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  7. Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
  8. Women's & Children's Hospital, Adelaide, South Australia, Australia
  9. Mater Medical Research Institute - University of Queensland, Woolloongabba, QLD, Australia
  10. Centre for Pharmaceutical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia

Background: Antenatal corticosteroids (ACS) stimulate lung maturation, reducing risks of respiratory diseases and death for preterm babies, but also impact brain development and later function. We are therefore investigating whether ciclesonide, a glucocorticoid prodrug with tissue-specific activation, can stimulate lung maturation without impacting the preterm sheep brain. As the placenta also expresses activating enzymes, we have evaluated functional and molecular outcomes after intraamniotic administration of ciclesonide to bypass placental activation.

Methods: Twin-bearing pregnant ewes were randomised to antenatal treatment with ciclesonide (0.5, 1 or 2 mg/kg estimated fetal weight) 48 h before delivery. Maternal and fetal plasma samples were collected at pre, 1, 2, 4, 24 and 48 h after intraamniotic ciclesonide administration and concentrations of the active form, des-ciclesonide, were measured using established LC-MS/MS assays. Lambs (4-5/group) were delivered preterm by C-section at ~130 gestational days (term ~150d), ventilated for 60 minutes with volume guarantee (target volume 7 ml/kg, ETCO2 45-50 mmHg), then humanely killed for tissue collection. Expression of glucocorticoid responsive genes was measured in the lung (lower right lobe) and brain (prefrontal cortex and hippocampus); molecular and structural indices of lung maturation were also determined. Data was analysed by two-way repeated measures ANOVA with P<0.05 considered statistically significant.

Results: Following intraamniotic ciclesonide administration, des-ciclesonide was rapidly detected in plasma of treated lambs, with limited transfer to maternal circulation, and no transfer to the untreated twin except at 2mg/kg. Dynamic lung compliance was higher in treated than untreated twins (P=0.033), which coincided with lower PER1 and SCNN1G expression (P=0.019 and P=0.018, respectively), and higher AQP5 expression (P=0.031). Expression of glucocorticoid responsive genes in the prefrontal cortex and hippocampus was similar in treated and untreated twins.

Conclusions: Intrauterine des-ciclesonide exposure matures the preterm lung without activating glucocorticoid-mediated signalling in the brain in this clinically-relevant sheep model of preterm birth.