title: Mouse lung development and NOX1 induction during hyperoxia are developmentally regulated and mitochondrial ROS dependent.
abstract: Animal models demonstrate that exposure to supraphysiological oxygen during the neonatal period compromises both lung and pulmonary vascular development, resulting in a phenotype comparable to bronchopulmonary dysplasia (BPD). Our prior work in murine models identified postnatal maturation of antioxidant enzyme capacities as well as developmental regulation of mitochondrial oxidative stress in hyperoxia. We hypothesize that consequences of hyperoxia may also be developmentally regulated and mitochondrial reactive oxygen species (ROS) dependent. To determine whether age of exposure impacts the effect of hyperoxia, neonatal mice were placed in 75% oxygen for 72 h at either postnatal day 0 (early postnatal) or day 4 (late postnatal). Mice exposed to early, but not late, postnatal hyperoxia demonstrated decreased alveolarization and septation, increased muscularization of resistance pulmonary arteries, and right ventricular hypertrophy (RVH) compared with normoxic controls. Treatment with a mitochondria-specific antioxidant, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), during early postnatal hyperoxia protected against compromised alveolarization and RVH. In addition, early, but not late, postnatal hyperoxia resulted in induction of NOX1 expression that was mitochondrial ROS dependent. Because early, but not late, exposure resulted in compromised lung and cardiovascular development, we conclude that the consequences of hyperoxia are developmentally regulated and decrease with age. Attenuated disease in mitoTEMPO-treated mice implicates mitochondrial ROS in the pathophysiology of neonatal hyperoxic lung injury, with potential for amplification of ROS signaling through NOX1 induction. Furthermore, it suggests a potential role for targeted antioxidant therapy in the prevention or treatment of BPD.
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois.
authors.forename: Ankur
authors.initials: A
authors.lastname: Datta
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois.
authors.forename: Gina A
authors.initials: GA
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois.
authors.forename: Joann M
authors.initials: JM
authors.lastname: Taylor
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois.
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Gugino
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois.
authors.forename: Kathryn N
authors.identifier: http://orcid.org/0000-0002-8604-7023
authors.initials: KN
authors.lastname: Farrow
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois saraberk@buffalo.edu.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Berkelhamer
mesh_terms: D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000201:enzymology*; D004790:Enzyme Induction; D018496:Hyperoxia / Q000201:enzymology*; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000209:etiology; D008168:Lung / Q000201:enzymology / Q000254:growth & development / Q000473:pathology; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D010084:Oxidation-Reduction; 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; C000614711:NOX1 protein, mouse
keywords: NADPH oxidase; bronchopulmonary dysplasia; lung development; oxidative lung injury