Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia.

Susan Fisher,Ashley Trumpie,Cassidy Delaney,Laurie Sherlock,Clyde Wright,Sarah Mckenna,Russell Bowler,Laura Hernandez-Lagunas,Eva Nozik-Grayck

doi:10.3390/antiox7030042

Abstract

Background: A naturally occurring single nucleotide polymorphism (SNP), (R213G), in extracellular superoxide dismutase (SOD3), decreases SOD3 matrix binding affinity. Humans and mature mice expressing the R213G SNP exhibit increased cardiovascular disease but decreased lung disease. The impact of this SNP on the neonatal lung at baseline or with injury is unknown. Methods: Wild type and homozygous R213G mice were injected with intraperitoneal bleomycin or phosphate buffered saline (PBS) three times weekly for three weeks and tissue harvested at 22 days of life. Vascular and alveolar development were evaluated by morphometric analysis and immunostaining of lung sections. Pulmonary hypertension (PH) was assessed by right ventricular hypertrophy (RVH). Lung protein expression for superoxide dismutase (SOD) isoforms, catalase, vascular endothelial growth factor receptor 2 (VEGFR2), endothelial nitric oxide synthase (eNOS) and guanosine triphosphate cyclohydrolase-1 (GTPCH-1) was evaluated by western blot. SOD activity and SOD3 expression were measured in serum. Results: In R213G mice, SOD3 lung protein expression decreased, serum SOD3 protein expression and SOD serum activity increased compared to wild type (WT) mice. Under control conditions, R213G mice developed pulmonary vascular remodeling (decreased vessel density and increased medial wall thickness) and PH; alveolar development was similar between strains. After bleomycin injury, in contrast to WT, R213G mice were protected from impaired alveolar development and their vascular abnormalities and PH did not worsen. Bleomycin decreased VEGFR2 and GTPCH-1 only in WT mice. Conclusion: R213G neonatal mice demonstrate impaired vascular development and PH at baseline without alveolar simplification, yet are protected from bleomycin induced lung injury and worsening of pulmonary vascular remodeling and PH. These results show that vessel bound SOD3 is essential in normal pulmonary vascular development, and increased serum SOD3 expression and SOD activity prevent lung injury in experimental bronchopulmonary dysplasia (BPD) and PH.

Highlights

Bronchopulmonary dysplasia (BPD) is a disorder of lung development affecting preterm infants resulting in respiratory morbidities that can persist through adulthood [1]
SOD3 compared to wild type (WT) mice (Figure 1b), recapitulating what we reported previously in adult mice [7]
We evaluated if the R213 G mice compensate for low lung SOD3 content by upregulating other key antioxidant enzymes in the neonatal lung

Summary

Introduction

Bronchopulmonary dysplasia (BPD) is a disorder of lung development affecting preterm infants resulting in respiratory morbidities that can persist through adulthood [1]. Interventions to prevent and treat BPD complicated by PH are limited, there is an urgent need to improve understanding of the mechanisms contributing to the development of these frequent and burdensome diseases of prematurity. Premature neonates have decreased antioxidant defenses, and increased oxidative stress due to oxygen therapy, infection, and mechanical ventilation [6]. Despite compelling evidence that an imbalance of oxidative stress contributes to BPD and PH, generalized antioxidant therapies have not proven efficacious to preventing or treating these diseases [6]. Humans and mature mice expressing the R213 G SNP exhibit increased cardiovascular disease but decreased lung disease. The impact of this SNP on the neonatal lung at baseline or with injury is unknown

Methods

Results

Conclusion