Superoxide dismutase 3 dysregulation in a murine model of neonatal lung injury

Hataya K. Poonyagariyagorn, Shana Metzger, Dustin Dikeman, Armando Lopez Mercado, Alla Malinina, Carla Calvi, Sharon McGrath-Morrow, Enid R. Neptune

Research output: Contribution to journalArticlepeer-review

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 in flammation. 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 signi ficantly increased mRNA expression for antioxidant genesmediated by nuclear factor erythroid 2-related factor (Nrf2) in the O2 (n = 4) versus RA group (n = 5). SOD3, an Nrf2-independent antioxidant, was signi ficantly 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 profi le was reproducible in murine lung epithelial 12 cells exposed to O2. Overexpression of SOD3 rescued the injurymeasures 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.

Original languageEnglish (US)
Pages (from-to)380-390
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume51
Issue number3
DOIs
StatePublished - Sep 2014

Keywords

  • Bronchopulmonary dysplasia
  • Extracellular superoxide dismutase
  • Hyperoxia
  • Murine lung epithelial 12
  • Nrf-2

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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