The translational potential of the preterm rabbit as a BPD animal model

Background: Bronchopulmonary dysplasia (BPD) is the most common complication of premature babies born with underdeveloped lungs. Animal models are pivotal to study its pathophysiology. Given the low maintenance cost and the short gestation period, BPD mouse models are commonly used in pre-clinical practice. However, unlike babies who are born at term in the alveolar phase, mice are naturally delivered with structurally immature (although functional) lungs in the saccular phase (gestational age, GA 21th). Rabbits share some of the mice practical advantages, but they are born at term (GA 31th) in the alveolar phase of lung development, as it occurs in humans and can be delivered prematurely (GA 28th). To date, a comparative transcriptomic analysis is lacking. The aim of the study was to compare the relevant gene expression (GE) profiles of both species to evaluate the rabbit translational potential as a BPD model. Methods: GE analysis was performed on lung samples from term (GA 31th) and preterm (GA 28th) rabbits and compared with the mouse lung GE dataset (GA 18.5th and GA 21th) generated by Beauchemin K.J. et al (GSE74243). Pathways enrichment analysis was performed based on differentially expressed genes identified in each species (GA 18.5th vs GA 21th and GA 28th vs GA 31th). Common pathways involved in lung development of preterm rabbits and term mice were evaluated. Results: Lung development-related pathways such as cell cycle and mitosis-related processes were significantly enriched in both GA 18.5th mice and preterm-delivered (GA 28th) rabbits lungs, compared to their term counterparts. Common pathways, including angiogenesis, vasculature development, humoral immune system, and leukocyte migration, were found to be enriched in both species delivered at term, despite their different lung developmental phases. In contrast, no enriched common pathways emerged from the comparison between preterm rabbits and term mice. Conclusion: Our analysis revealed that common enriched pathways are present in mice and rabbits born both preterm and term, despite their different lung development phases. Since preterm delivery is not feasible in mice, this study suggests a potential higher translational of the preterm rabbit model for studying the dysregulation of lung development-related pathways, leading to BPD in humans.