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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
Flavin adenine dinucleotide increases antioxidant availability and protects neonatal C57Bl6 lungs from high oxygen
Hunter D Montgomery1, Mingyang A Zhang2, Elizabeth Zimmerman2
1Department of Psychiatry, The University of Vermont Medical Center, Burlington, Vermont, United States.
Insights
Flavin adenine dinucleotide (FAD) nasal spray protects neonatal lungs from high oxygen injury by restoring redox balance. This intervention reduces lung damage and inflammation, offering a potential therapy for premature infants.
Area of Science:
- Neonatal physiology
- Pulmonary medicine
- Oxidative stress research
Background:
- Immature lungs in preterm infants are susceptible to oxygen-induced injury.
- Restoring redox homeostasis is crucial for mitigating lung damage.
- Flavin adenine dinucleotide (FAD) supports antioxidant pathways like glutathione reductase (GR) and glutathione (GSH).
Purpose of the Study:
- To investigate if intranasal FAD can protect neonatal lungs from hyperoxic injury.
- To determine if FAD restores redox homeostasis and modulates inflammatory pathways.
- To assess FAD's efficacy in a mouse model of bronchopulmonary dysplasia (BPD).
Main Methods:
- Utilized a C57Bl6/N mouse model exposed to 85% FiO2 to induce hyperoxic lung injury.
- Administered FAD intranasally and measured redox potential (GSH/GSSG Eh) in bronchoalveolar lavage fluid (BALF).
- Assessed lung injury scores, inflammatory cell counts (neutrophils, macrophages) in BALF, and cytokine profiles.
Main Results:
- Intranasal FAD significantly improved the GSH/GSSG Eh (redox potential) in BALF.
- FAD treatment led to reduced lung injury scores and decreased neutrophil infiltration.
- FAD increased macrophage counts in BALF and modulated key inflammatory cytokines (e.g., IL-12p70, IL-27, IL-6).
Conclusions:
- Intranasal FAD effectively protects neonatal lungs against hyperoxic injury in a mouse model.
- FAD treatment restores redox homeostasis and attenuates oxidative stress-induced inflammation.
- FAD shows potential as a therapeutic agent for preventing or treating BPD and related lung injuries in preterm infants.
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 (Eh) 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.
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