Abstract
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.
Highlights
After birth, with initiation of ventilation of the lungs, pulmonary vascular resistance normally decreases, and pulmonary blood flow increases by 10-fold [7, 37]
We recently reported that administration of intratracheal recombinant human superoxide dismutase (SOD) improved oxygenation and reduced oxidative stress in pulmonary hypertension of the newborn (PPHN) lambs ventilated with 100% O2 for 24 h [26]
We previously showed that superoxide levels were increased in fetal PPHN pulmonary arteries relative to fetal controls, and that superoxide scavenging enhanced the relaxation of isolated fetal PPHN pulmonary arteries to the NO donor SNAP [3]
Summary
With initiation of ventilation of the lungs, pulmonary vascular resistance normally decreases, and pulmonary blood flow increases by 10-fold [7, 37]. This process is regulated by a complex and incompletely understood interaction between a series of mechanical and biochemical factors [11]. Persistent pulmonary hypertension of the newborn (PPHN) is a serious disorder of newborn infants occurring in two to six per 1,000 live births, with a significant risk of morbidity and death [22]. Significant improvements in systemic arterial oxygenation can be achieved by vasodilation of the pulmonary circulation, which limits blood flow through extrapulmonary shunt pathways. Clinical management of PPHN includes mechanical ventilation with high levels of inspired oxygen and inhaled
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
