Oral Presentation ESA-SRB-APEG-NZSE 2022

Glucocorticoid signalling and inflammatory changes in response to maternal asthma and betamethasone treatment in near-term lambs (#52)

Joshua L Robinson 1 2 , Andrea J Roff 1 , Sarah J Hammond 1 2 , Jack RT Darby 2 , Andrew Tai 1 3 , Tim JM Moss 4 , Ashley Meakin 2 , Stacey Holman 2 , Andrew Davies 5 , Beverly S Muhlhausler 6 , Robert J Bischof 7 , Vicki L Clifton 8 , Megan J Wallace 4 9 , Janna L Morrison 2 , Michael J Stark 1 10 , Kathryn L Gatford 1
  1. Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
  2. Early Origins of Adult Health Research Group, University of South Australia, Adelaide, SA, Australia
  3. Respiratory and Sleep Medicine, Women's and Children's Hospital, Adelaide, SA, Australia
  4. The Ritchie Centre, Hudson Institute for Medical Research, Melbourne, VIC, Australia
  5. Biomedicine Discovery Institute, Monash University, Melbourne, SA, Australia
  6. Food and Nutrition Research Centre, University of Adelaide, Adelaide, SA, Australia
  7. School of Science, Psychology and Sport, Federation University, Melbourne, VIC, Australia
  8. Mater Research Institute, University of Queensland, Brisbane, QLD, Australia
  9. Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
  10. Neonatal Medicine, Women's and Children's Hospital, Adelaide, SA, Australia

Maternal asthma is associated with neonatal respiratory morbidity, indicating lung immaturity at birth. Lung maturation can be stimulated by glucocorticoids and inflammation. Maternal asthma reduces glucocorticoid signalling and modulates the inflammatory response in the fetal lung, potential mechanisms contributing to respiratory morbidity in babies of asthmatic mothers. Antenatal betamethasone is routinely used to induce lung development in preterm babies. We therefore hypothesised that betamethasone would mature the lungs of lambs of asthmatic ewes.

Ewes were sensitised to house dust mite (HDM) and an asthmatic phenotype induced by fortnightly HDM lung challenges; controls (n=11) received saline. Pregnant asthmatic ewes were randomised to antenatal saline (n=9) or betamethasone (n=8, 12 mg i.m.) at 138 and 139 days of gestation (dG). At 140 dG (term, 150 dG), lambs (control: n=16, asthma: n=14, asthma+betamethasone: n=12) were delivered by Caesarean section and ventilated (45 minutes) prior to lung tissue collection for RT-qPCR. Data were analysed using mixed models.

Compared to controls, asthma lambs had lower glucocorticoid receptor (p=0.017) and IL-6 (p=0.042) gene expression. Expression of surfactant protein (SP)-A, SP-B, and SP-C was higher but expression of IL-6 (p=0.014), 11βHSD1 (p=0.010), and KDR (p=0.008) was lower in the asthma+betamethasone lambs compared to controls. TNFα (p=0.001), mineralocorticoid receptor (p=0.002), and 11βHSD1 (p=0.010) gene expression was reduced with betamethasone compared to asthma lambs, while SP-B and SP-C expression was increased. Gene expression of SP-D, 11βHSD2, hypoxia-related genes (HIF1α, HIF2α, HIF3α, FLT1) and inflammatory cytokines (IL-1β, IL-5, IL-8) did not differ between groups.

Impaired fetal lung development in response to maternal asthma in pregnancy may be the result of lower glucocorticoid receptor expression and IL-6 driven lung maturation. Betamethasone improved lung maturity by increasing SP gene expression, despite downregulation of upstream genes. Further exploration of these pathways may highlight targets to improve lung outcomes in babies of asthmatic women.