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Background: Bronchopulmonary dysplasia (BPD) is a serious lung disease caused by oxidative stress, predominantly affecting premature infants who require prolonged oxygen support. The co-factor flavin adenine dinucleotide (FADH) facilitates glutathione reductase (GR) enzymatic activity, increasing the bioavailability of the antioxidant glutathione (GSH). We hypothesized that intranasal delivery of FADH can reduce lung injury following hyperoxia supplementation (0.85% FiO₂) by altering pro-inflammatory signal transduction pathways in a C57Bl6 newborn mouse model for BPD.

Methods: We used a prolonged hyperoxia-induced lung injury rodent model to recapitulate the clinical and histological changes present in BPD. Newborn mice were housed in FiO₂ 85% (hyperoxic) or 21% O₂ (normoxic) from day of birth until post-natal day (PN) 14. From PN14 to PN21, mice received daily intranasal FADH (7 μM) or saline (control) in a final volume of 1.5 μL/g body weight. BALF and lung tissue samples were collected and evaluated for lung injury, development, and inflammation using standard immunohistological techniques, morphometric analysis, and standard molecular assays. BALF cytokines were measured using a flow cytometric approach (BioLegend). Single data comparisons were performed using paired Student’s t-tests while multiple comparisons used ANOVA followed by post-hoc testing in SigmaPlot.

Results: FADH protected neonatal lungs from high oxygen induced oxidative stress: GSH/GSSG E_h (a measure of oxidative stress) improved from -168.77 mV ± 3.64 mV to -179.10 mV ± 1.85 mV (n=5 BALF measurements). FADH also improved lung injury scores from 0.047±0.007 to 0.007±0.004 (p<0.001), decreased neutrophil migration (p<0.001), and increased macrophages (p<0.001) when compared to age-matched untreated pups similarly housed at 85% FiO₂. The level of IL-12p70, IL-27, IL-6, and IL-1a measured from BALF obtained from FADH treated mice housed at 85% FiO₂ (n=4) were significantly higher compared to saline treated pups (n=7) similarly housed under chronic hyperoxia.

Conclusions: FADH protects neonatal lungs from hyperoxic injury by enhancing antioxidant capacity and modulating inflammatory interleukin signaling.

Significances: The mechanisms identified through this study could be targeted as a potential adjunct therapy for BPD patients to reduce high oxygen induced lung injury.