Abstract
Therapeutic interventions effective in reestablishing redox homeostasis in preterm infants require further investigation because immature lungs are extremely vulnerable to high-oxygen-induced lung injury. Flavin adenine dinucleotide (FAD) facilitates glutathione reductase (GR) activity and increases the bioavailability of the antioxidant glutathione (GSH). As such, we hypothesize that intranasal delivery of FAD can attenuate hyperoxic lung injury by restoring redox homeostasis, thereby altering pro-inflammatory signal transduction pathways. The term C57Bl6/N mouse model exposed to 0.85 fraction of inspired oxygen (85% [Formula: see text]) was used to model high oxygen-induced oxidative stress and bronchopulmonary dysplasia (BPD). Our studies show that FAD protects neonatal lungs (males and females) from high oxygen-induced oxidative stress by improving GSH/oxidized glutathione (GSSG) redox potential (E(h)) from -168.77 mV ± 3.64 mV to -179.10 mV ± 1.85 mV; measured in bronchoalveolar lavage fluid (BALF). FAD 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 in BALF (P < 0.001) when compared with age-matched vehicle-treated pups similarly housed at 85% [Formula: see text]. Cytokine profiling revealed that FAD treatment significantly enhanced the secretion of multiple interleukin family cytokines under hyperoxic conditions relative to both room air and untreated 85% [Formula: see text] control groups. In particular, IL-12p70, IL-27, IL-6, and IL-1α were markedly elevated, suggesting that FAD modulates inflammatory signaling pathways activated during oxidative stress. Collectively, these findings indicate that FAD treatment modulates inflammatory signaling pathways activated during hyperoxia, potentially contributing to cellular adaptation or protection.NEW & NOTEWORTHY Our findings support a conceptual shift in neonatal antioxidant therapy. Using a mouse model of preterm lungs and high oxygen-induced oxidative stress, we found that intranasal delivery of flavin adenine dinucleotide (FAD) improved newborn lung health. FAD restored redox balance, reduced neutrophilia, and modulated cytokines associated with lung development and repair.