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Unravelling Bronchopulmonary Dysplasia Through Multi-Omics Meta-Analysis

You can see our previous MAIC analyses at the following links:

• Influenza A
• COVID-19
• ARDS (password protected until publication)!

Understanding the molecular mechanisms that contribute to BPD could aid in risk prediction, targeted therapies, and understanding disease mechanisms. The heterogeneity of the disease has hampered efforts to identify reliable, consistent biomarkers. So far, though some candidates have been identified (e.g. SPOCK2, CRP), no gene has been significantly associated with the development of BPD via Genome-Wide Association Studies (GWAS) or exome sequencing. This is despite indications from twin studies of the heritability of BPD. Transcriptomic data have been used to identify four endotypes of BPD, distinguished by T helper cell and T cell signalling. Together, these and other studies reflect an effort to incorporate insights from genome-scale research, complementing the longstanding emphasis on clinical studies in the field.

Rodent models, particularly murine models, have been widely employed to study the pathophysiology of BPD. Anatomical and physiological differences have prevented in-depth research of ventilator-induced lung injury in this model, and research has concentrated primarily on hyperoxia-induced lung injury, mimicking the impaired alveolar development and inflammation observed in preterm infants. Comparative transcriptomic analyses across species can provide valuable insights into common mechanisms while also highlighting potential species-specific responses.

Integrating results from heterogeneous sources can allow for novel insights. We conducted a systematic review of the BPD literature, focusing on genome-scale studies in humans and rodents. Results were extracted from identified studies, where possible, and analysed using MAIC. MAIC is a previously described algorithm that uses data-driven gene list weightings to produce a comprehensive ranked list of genes associated with the trait of interest.

Our findings demonstrate that BPD is a complex disease which involves dysregulation in adaptive immune signalling, vascular development and extracellular matrix organisation. Of note, several of our analyses highlighted the involvement of T cell-associated genes, suggesting that adaptive immunity may play a larger role in BPD pathogenesis than previously appreciated.