Abstract
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, Nrf2-deficient (Nrf2−/−) and wild-type (Nrf2+/+) mice neonatally exposed to hyperoxia were infected with RSV. To investigate the prenatal antioxidant effect on neonatal oxidative lung injury, time-pregnant Nrf2−/− and Nrf2+/+ 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 Nrf2−/− mice than in Nrf2+/+ 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 Nrf2−/− 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 Nrf2−/− 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.
Highlights
Lungs of preterm infants born at 24–36 weeks of gestational age are in the saccular phase of lung development
Greater respiratory syncytial virus (RSV)-induced neutrophilic inflammation (1 d post-IN) was found in Nrf2−/− mice neonatally exposed to O2 than in those neonatally exposed to air, and the heightened neutrophilic infiltration was remained elevated in neonatal O2 -exposed
The current study demonstrated that oxidative lung injury caused by hyperoxia during postnatal lung development increased pulmonary susceptibility to RSV-induced injury and inflammation in young adulthood, indicating long term respiratory consequences of Bronchopulmonary dysplasia (BPD)-like phenotypes
Summary
Lungs of preterm infants born at 24–36 weeks of gestational age are in the saccular phase of lung development. Extensive developmental changes are represented by widening of distal airways for subsequent formation of alveoli, differentiation of type 1 and 2 alveolar cells, and thinning of the air–blood barrier [1]. Alveolarization in fetal and new-born lungs is critical as the type 2 cells produce surfactants but are involved in innate immunity [2]. Bronchopulmonary dysplasia (BPD) is a common outcome of the very low birth weight premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress. It is one of the most frequent causes of chronic respiratory morbidity in survivors of premature birth [4,5]
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