Systems-level insights into bronchopulmonary dysplasia from meta-analysis of genome-scale studies

Despite marked improvements in survival following preterm birth, the incidence of bronchopulmonary dysplasia (BPD) remains the most prevalent complication of prematurity and carries the risk of long-term morbidity. Characterising the cellular and molecular mechanisms driving disease progression is critical for informing clinical management and improving outcomes. To this end, we conducted a meta-analysis of genome-scale studies to identify molecular pathways implicated in BPD progression in both human cohorts and animal models.

Gene lists associated with BPD in humans, and in rodent models, were extracted from systematically identified genome-scale studies. These gene lists were subsequently analysed using the meta-analysis by information content (MAIC) algorithm, which integrates multiple datasets to generate a single aggregated, ranked gene list based on the cumulative strength of evidence for each gene. Comparative analyses were then performed between the human and rodent BPD datasets, as well as between the human BPD dataset and our previously generated Acute Respiratory Distress Syndrome MAIC dataset.

Across all analyses, a consistent enrichment of genes involved in leukocyte-mediated antigen presentation and lymphocyte development and activation was observed, suggesting a shift from acute innate immune injury toward a more sustained lymphoid-driven inflammatory process during BPD progression. Comparative analyses revealed limited overlap between BPD and ARDS gene sets, suggesting divergent disease mechanisms, while still highlighting shared immune activation pathways. Human-rodent comparisons showed divergence in tissue remodelling signatures, likely reflecting differences in sample sources, yet converged on key conserved signals such as CD3E and IL1R2, implicating common inflammatory regulatory mechanisms.

MAIC effectively identifies conserved molecular signatures in BPD highlighting lymphoid lineage signatures that are not readily apparent in the primary data. These signatures offer insights relevant to immune-modulatory therapeutic strategies, highlighting key processes involved in antigen presentation and modulation of T-cell activation and development during the progression of Bronchopulmonary Dysplasia.