We previously demonstrated that
superoxide and H(2)O(2) 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 H(2)O(2)-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% O(2) 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 H(2)O(2) 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% O(2) 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 H(2)O(2) generated by PPHN and
hyperoxia inactivates ecSOD, and intratracheal
catalase enhances
enzyme function. The associated decrease in extracellular
superoxide augments vasodilation, suggesting that H(2)O(2) scavengers may represent an effective
therapy in the clinical management of PPHN.