title: Superoxide dismutase 3 dysregulation in a murine model of neonatal lung injury.
abstract: Bronchopulmonary dysplasia (BPD), a common chronic respiratory disease that occurs after premature birth, is believed to be secondary to oxidative damage from hyperoxia and inflammation, which leads to impaired alveolar formation and chronic lung dysfunction. We hypothesized that extracellular superoxide dismutase (SOD)3, an antioxidant uniquely targeted to the extracellular matrix (ECM) and alveolar fluid, might have a different response (down-regulation) to hyperoxic injury and recovery in room air (RA), thereby contributing to the persistent airspace injury and inflammation. We used a murine BPD model using postnatal hyperoxia (O2) (4 or 5 d) followed by short-term recovery (14 d) in RA, which mimics the durable effects after injury during alveolar development. This was associated with significantly increased mRNA expression for antioxidant genes mediated by nuclear factor erythroid 2-related factor (Nrf2) in the O2 (n = 4) versus RA group (n = 5). SOD3, an Nrf2-independent antioxidant, was significantly reduced in the O2-exposed mice compared with RA. Immunohistochemistry revealed decreased and disrupted SOD3 deposition in the alveolar ECM of O2-exposed mice. Furthermore, this distinct hyperoxic antioxidant and injury profile was reproducible in murine lung epithelial 12 cells exposed to O2. Overexpression of SOD3 rescued the injury measures in the O2-exposed cells. We establish that reduced SOD3 expression correlates with alveolar injury measures in the recovered neonatal hyperoxic lung, and SOD3 overexpression attenuates hyperoxic injury in an alveolar epithelial cell line. Such findings suggest a candidate mechanism for the pathogenesis of BPD that may lead to targeted interventions.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Hataya K
authors.initials: HK
authors.lastname: Poonyagariyagorn
authors.forename: Shana
authors.initials: S
authors.lastname: Metzger
authors.forename: Dustin
authors.initials: D
authors.lastname: Dikeman
authors.forename: Armando Lopez
authors.initials: AL
authors.lastname: Mercado
authors.forename: Alla
authors.initials: A
authors.lastname: Malinina
authors.forename: Carla
authors.initials: C
authors.lastname: Calvi
authors.forename: Sharon
authors.initials: S
authors.lastname: McGrath-Morrow
authors.forename: Enid R
authors.initials: ER
authors.lastname: Neptune
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000737:chemistry; D001997:Bronchopulmonary Dysplasia / Q000201:enzymology / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D018496:Hyperoxia; D007249:Inflammation; D008168:Lung / Q000473:pathology*; D055370:Lung Injury / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D020545:Respiratory Mucosa / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D010100:Oxygen
keywords: Nrf-2; bronchopulmonary dysplasia; extracellular superoxide dismutase; hyperoxia, murine lung epithelial 12