Find in Library

NRF2 protects against oxidant-associated airway disorders via cytoprotective gene induction. To examine if NRF2 is an important determinant of respiratory syncytial virus (RSV) susceptibility after neonate lung injury, <i>Nrf2</i>-deficient (<i>Nrf2</i>^−/−) and wild-type (<i>Nrf2</i>^+/+) mice neonatally exposed to hyperoxia were infected with RSV. To investigate the prenatal antioxidant effect on neonatal oxidative lung injury, time-pregnant <i>Nrf2</i>^−/− and <i>Nrf2</i>^+/+ mice were given an oral NRF2 agonist (sulforaphane) on embryonic days 11.5–17.5, and offspring were exposed to hyperoxia. Bronchoalveolar lavage and histopathologic analyses determined lung injury. cDNA microarray analyses were performed on placenta and neonatal lungs. RSV-induced pulmonary inflammation, injury, oxidation, and virus load were heightened in hyperoxia-exposed mice, and injury was more severe in hyperoxia-susceptible <i>Nrf2</i>^−/− mice than in <i>Nrf2</i>^+/+ mice. Maternal sulforaphane significantly alleviated hyperoxic lung injury in both neonate genotypes with more marked attenuation of severe neutrophilia, edema, oxidation, and alveolarization arrest in <i>Nrf2</i>^−/− mice. Prenatal sulforaphane altered different genes with similar defensive functions (e.g., inhibition of cell/perinatal death and inflammation, potentiation of angiogenesis/organ development) in both strains, indicating compensatory transcriptome changes in <i>Nrf2</i>^−/− mice. Conclusively, oxidative injury in underdeveloped lungs NRF2-dependently predisposed RSV susceptibility. In utero sulforaphane intervention suggested NRF2-dependent and -independent pulmonary protection mechanisms against early-life oxidant injury.