Transcriptomic analysis of the developing rabbit's lung: implication of premature birth and post-natal oxygen exposure

Preterm birth alters normal lung development, leading to bronchopulmonary dysplasia (BPD). Preterm rabbit is being recognized as a relevant BPD model, but a deeper molecular characterization is needed. The aim was to characterize premature birth and postnatal oxygen impact on lung molecular pathways. Preterm pups delivered at 28 days of gestation were randomly assigned to hyperoxia (HOX 70% O2, n=12) or room-air (RA, 21% O2, n=27) for 14 days. Lungs were harvested at postnatal days 1, 3, 5, 7, 9, 11, and 14. Age-matched term pups were used as controls (n=27). Radial alveolar count (RAC), acute lung injury (ALI) and transcriptomic analyses were performed. Term pups showed significantly better RAC and ALI scores compared to preterm groups (P< 0.05 Term vs RA; and P<0.001 Term vs HOX), while the HOX group showed significantly worse RAC and ALI scores than preterm RA and term animals (P<0.001). The amount of differentially expressed genes between term and preterm pups increases with increasing distance from birth. On day 14, 1056 genes appear dysregulated due to premature birth. Pathway enrichment analysis showed that premature birth alone triggers the upregulation of pro-inflammatory and immune activation pathways and downregulates lung and vasculature development pathways. These pathways are exacerbated by postnatal oxygen exposure. Premature birth by itself leads to a lung and vasculature developmental gap compared to age-matched term controls, which can be enhanced by postnatal HOX exposure, highlighting the translational value of preterm rabbits for studying the dysregulation of lung development-related pathways common to human BPD.