We previously demonstrated that superoxide and H2O2 promote pulmonary arterial vasoconstriction in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). Because extracellular superoxide dismutase (ecSOD) augments vasodilation, we hypothesized that H2O2-mediated ecSOD inactivation contributes to pulmonary arterial vasoconstriction in PPHN lambs. ecSOD activity was decreased in pulmonary arterial smooth muscle cells (PASMCs) isolated from PPHN lambs relative to controls. Exposure to 95% O2 to mimic hyperoxic ventilation reduced ecSOD activity in control PASMCs. In both cases, these events were associated with increased protein thiol oxidation, as detected by the redox sensor roGFP. Accordingly, exogenous H2O2 decreased ecSOD activity in control PASMCs, and PEG-catalase restored ecSOD activity in PPHN PASMCs. In intact animal studies, ecSOD activity was decreased in fetal PPHN lambs, and in PPHN lambs ventilated with 100% O2 relative to controls. In ventilated PPHN lambs, administration of a single dose of intratracheal PEG-catalase enhanced ecSOD activity, reduced superoxide levels, and improved oxygenation. We propose that H2O2 generated by PPHN and hyperoxia inactivates ecSOD, and intratracheal catalase enhances enzyme function. The associated decrease in extracellular superoxide augments vasodilation, suggesting that H2O2 scavengers may represent an effective therapy in the clinical management of PPHN. Antioxid. Redox Signal. 15, 1497–1506.
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