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 (downregulation) 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.

Bronchopulmonary dysplasia: Pathogenesis and treatment (Review)

“…Certain studies performed on premature babies concluded that severe lung injury and inflammatory changes may be mitigated and the requirement for mechanical ventilation may be reduced with no associated adverse effects by prophylactic intratracheal administration of recombinant human CuZn superoxide dismutase (rhSOD). Prophylactic administration of intratracheal rhSOD to premature babies at birth with a birth weight ranging from 600 to 1,200 g and a high risk of developing BPD was associated with reduced respiratory episodes, including wheezing, asthma and respiratory infections, as concluded in a randomized placebo-controlled trial (98). Trials have suggested that rhSOD is able to prevent long-term lung injury due to oxygen exposure in high-risk pre-mature neonates (99,100).…”

“…An upcoming therapy for the prevention of BPD development is the supplementation of human recombinant anti-oxidant enzymes (92,98). Certain studies performed on premature babies concluded that severe lung injury and inflammatory changes may be mitigated and the requirement for mechanical ventilation may be reduced with no associated adverse effects by prophylactic intratracheal administration of recombinant human CuZn superoxide dismutase (rhSOD).…”

Hyperoxia induces paracellular leak and alters claudin expression by neonatal alveolar epithelial cells

“…Neonatal animals have been shown to have a greater increase in antioxidant availability, particularly by AECs, in response to a hyperoxia challenge relative to adult animals . However, over time, when the neonatal protection against oxygen diminishes, antioxidant responses, such as Nrf‐2 activity and the availability of enzymes such as superoxide dismutase, glutathione reductase and catalase, may be impaired …”

“…37,38 However, over time, when the neonatal protection against oxygen diminishes, antioxidant responses, such as Nrf-2 activity and the availability of enzymes such as superoxide dismutase, glutathione reductase and catalase, may be impaired. 35,[39][40][41] Limited information is available about the effects of hyperoxia on claudin localization and expression. Recently, Xu et al 21 In AECs isolated from neonatal lungs, we showed a significant down-regulation of claudin-3 and claudin-18 expression with hyperoxia exposure, but no alteration in claudin-5 protein abundance.…”

Unbalanced Oxidant‐Antioxidant Status: A Potential Therapeutic Target for Coronary Chronic Total Occlusion in Very Old Patients

“…MDA affected the stability and the transcriptional functions of Nrf2. Notably, it was suggested that PECGGp activated SOD3 expression via Nrf2 pathway, protecting rat hearts against oxidative damage by decreasing MDA levels [49]. …”