Attenuation of Experimental Bronchopulmonary Dysplasia by Dimethyl Fumarate

Abstract Background Innovative therapies for bronchopulmonary dysplasia (BPD) in neonates are needed. Dimethyl fumarate (DMF) is a methyl ester of fumaric acid that is an approved drug. The goal was to explore the role of DMF in BPD utilizing a hyperoxia-induced murine model of experimental BPD. Methods In our mouse model of experimental moderate-BPD, DMF was administered on postnatal (PN) days 2 and 4. On PN14, we evaluated lung histology, lung morphometry, and used Western blotting. Results DMF improved lung histology in male and female mice, with recovery of chord length, septal thickness, and radial alveolar counts. There was a significant reduction in cell death, increase in cell proliferation, and lung vascularization after DMF treatment. Nuclear factor erythroid -2-related factor (Nrf-2) expression decreased, while nuclear factor-kappa-light-chain enhancer of activated B cells (NF-κB) expression levels increased in the BPD lungs. These effects were reversed after treatment with DMF. We found a decrease in heme oxygenase (HO)-1 expression after DMF treatment, with no change in selective mitochondrial markers of oxidative stress. Conclusion This is the first study to demonstrate the efficacy of systemically administered DMF to promote the resolution of experimental moderate-BPD. DMF putatively acted via Nrf-2 -dependent and -independent cell signaling pathways. Impact Dimethyl fumarate (DMF) is an approved drug for lung fibrosis treatment. We used our experimental moderate-BPD mouse model to evaluate the impact of DMF treatment. DMF improved lung histology and morphometry, with a significant reduction in cell death, and an increase in cell proliferation and lung vascularization after DMF treatment. Nrf-2 expression decreased in response to hyperoxia in male and female lungs, while NF-κB expression levels increased. These were reversed with DMF treatment. This is the first study to demonstrate the efficacy of DMF to promote the resolution of experimental moderate-BPD in the mouse model.