title: Developmental differences in hyperoxia-induced oxidative stress and cellular responses in the murine lung.
abstract: Exposure of newborn mice to high inspired oxygen elicits a distinct phenotype of compromised alveolar and vascular development, although lethality during long-term exposure is lower in newborns compared to adults. As the effects of hyperoxia are mediated by excessive reactive oxygen species (ROS) generation, we hypothesized that newborn mice may exhibit enhanced expression of antioxidant defenses or attenuated ROS generation compared with adults. We measured subcellular oxidant responses to acute hyperoxia in lung slices and alveolar epithelial cells at varying time points during postnatal murine lung development. Oxidant stress was assessed using RoGFP, a ratiometric protein thiol redox sensor, targeted to the cytosol or the mitochondrial matrix. In contrast to newborn resistance to oxygen-induced mortality, cells of lung slices from younger mice demonstrated exaggerated mitochondrial matrix oxidant stress compared to adults, whereas oxidant stress responses in the cytosol were absent. Cell death in lung slices from newborn mice exposed to 48h of hyperoxia was also greater than for adults. Consistent with these findings, expression of antioxidant enzymes in newborn lungs was lower than in adults, and induction of antioxidant levels and activity during 24h of in vivo exposure was absent. However, expression of the reactive oxygen species-generating enzyme NADPH oxidase 1 was increased with hyperoxic exposure in the young but not the adult lung. Collectively, these results suggest that the greater lethality in adult animals may be more likely attributed to processes such as inflammation than to differences in antioxidant defenses. Therapies for neonatal and adult oxidative lung injury should therefore consider and address developmental differences in oxidative stress responses.
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, IL 60611, USA. Electronic address: s-berkelhamer@northwestern.edu.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Berkelhamer
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Gina A
authors.initials: GA
authors.lastname: Kim
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Josiah E
authors.initials: JE
authors.lastname: Radder
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wedgwood
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Lyubov
authors.initials: L
authors.lastname: Czech
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Robin H
authors.initials: RH
authors.lastname: Steinhorn
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
mesh_terms: D000367:Age Factors; D000818:Animals; D005260:Female; D018496:Hyperoxia / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1
keywords: Developmental differences; Free radicals; Lung development; Mitochondrial oxidative stress; NADPH oxidase 1; Oxidative lung injury; Subcellular response