Abstract Background Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature infants caused by disrupted lung development and the injurious effects of mechanical ventilation. Advances in neonatal care have improved survival at lower gestational ages, but have also resulted in a growing population of children living with BPD. These children experience heightened susceptibility to respiratory infections and impaired lung growth, which contribute to long-term respiratory morbidity. Despite its clinical importance, the cellular and transcriptomic landscape of the BPD lung remains poorly defined. Methods We obtained de-identified formalin-fixed paraffin-embedded (FFPE) lungs sections of premature infants with BPD (n = 9), premature infants who died of extrapulmonary causes (n = 6) and aged-matched full-term infants (n = 9). We performed genome-wide spatial transcriptomics using the GeoMX platform and completed gene ontology enrichment analysis and cell deconvolution on differentially expressed genes. Confirmatory immunofluorescence (IF) was completed on FFPE sections of lungs from subjects of identified molecular targets. Results In the airways of BPD lungs, we observed a significant downregulation of CC16 (a club cell-derived protein), FOXJ1, and several other cilia-associated proteins. Immunofluorescence confirmed reduced CC16 expression along with markedly shorter cilia (∼2 µm) in BPD subjects. Cellular composition of the airway epithelium was also altered, with fewer club and mucociliary cells and an increased proportion of fibroblasts and goblet cells compared with controls.In the parenchyma, BPD lungs demonstrated significantly reduced expression of surfactant proteins A and D, validated by immunofluorescence staining. Additionally, the parenchyma displayed elevated levels of antimicrobial peptides, consistent with chronic neutrophilic inflammation. Conclusions BPD lungs had significant transcriptome alterations compared to controls related to genes involved in the protective barrier function to prevent airway infection either through anti-inflammatory mechanisms and/or mucociliary clearance. CC16 is secretory protein produced by club cells that has anti-inflammatory functions and decreased levels of CC16 are associated with asthma and early-onset COPD. Decreased cilia height, along with decreased expression of cilia-related genes, may increase susceptibility to infection by impairing mucociliary function. Lower expression of surfactant proteins that have anti-microbial properties may impact the protection of infection in BPD patients. Further understanding the role of these genes in the protection of respiratory infections and complications in BPD may reveal potential therapeutic targets for this vulnerable and growing patient population. This abstract is funded by: R01 HL171622-01A1/04 (FP, TX - USA).
King et al. (Fri,) studied this question.