Murine Neonatal Oxidant Lung Injury: NRF2-Dependent Predisposition to Adulthood Respiratory Viral Infection and Protection by Maternal Antioxidant

• Main Authors: Hye-Youn Cho (Author), Laura Miller-DeGraff (Author), Ligon A. Perrow (Author), Wesley Gladwell (Author), Vijayalakshmi Panduri (Author), Fred B. Lih (Author), Steven R. Kleeberger (Author)
• Format: Book
• Published: MDPI AG, 2021-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

10.3390/antiox10121874
2076-3921