Early-life serum protein profiles associated with bronchopulmonary dysplasia in extremely preterm infants

BACKGROUND: Bronchopulmonary dysplasia (BPD) affects the most immature preterm infants and can result in long term pulmonary morbidity. Yet, how prenatal and neonatal exposures perturb early proteome maturation and contribute to BPD pathogenesis remains unclear. METHODS: In a cohort of 176 extremely preterm infants (born < 28 weeks gestational age) previously enrolled in a multicenter randomized trial, 825 longitudinal serum samples were collected the first five postnatal weeks. 98 of 176 infants were defined as having BPD based on need for any respiratory support at 36 weeks postnatal age. Proteomic analysis was conducted using proximity extension assay from Olink. Mixed models, adjusted for gestational age, study center, and randomization group, also including an interaction term between BPD and time, were used to analyse differences in longitudinal protein trajectories by BPD status. False discovery rate correction was applied. RESULTS: Out of 538 analysed proteins, 108 exhibited distinct longitudinal trajectories in infants with BPD. Among the top significant proteins, several have previously been associated with BPD (e.g. lower Secretoglobin family 3A member 1 [SCGB3A1] and higher intercellular adhesion molecule 1 [ICAM-1]), while others represent novel findings (e.g. lower Leukocyte differentiation antigen CD84). Network and functional enrichment analysis revealed involvement in multiple biological processes, with many of the top significant proteins related to immune function. Some proteins showed associations specific to more mature infants (e.g. Stem cell factor). CONCLUSION: Differences in early serum protein trajectories are evident in infants who develop BPD. Our findings suggest associations consistent with proposed pathophysiological mechanisms. Clinical factors likely interact with immune-related proteins in the development of BPD. Mitigating inflammation by stabilising potential protective factors could be important for BPD prevention. TRIAL REGISTRATION: ClinicalTrial.gov identifier NCT03201588.