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Superoxide Dismutase Improves Oxygenation and Reduces Oxidation in Neonatal Pulmonary Hypertension

Departments of Pediatrics and Physiology and Biophysics, State University of New York at Buffalo, Buffalo; Departments of Pediatrics and Medicine, and the CardioPulmonary Research Institute, Winthrop-University Hospital, State University of New York at Stony Brook, Mineola, New York; and Department of Pediatrics, Northwestern University, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Satyan Lakshminrusimha, M.D., Division of Neonatology, Women and Children's Hospital of Buffalo, 219 Bryant Street, Buffalo, NY 14222. E-mail: slakshmi{at}buffalo.edu

Rationale: Hyperoxic ventilation in the management of persistent pulmonary hypertension of the newborn (PPHN) can result in the formation of reactive oxygen species, such as superoxide anions, which can inactivate nitric oxide (NO) and cause vasoconstriction and oxidation.

Objective: To compare the effect of intratracheal recombinant human superoxide dismutase (rhSOD) and/or inhaled NO (iNO) on systemic oxygenation, contractility of pulmonary arteries (PAs), and lung reactive oxygen species (isoprostane, 3-nitrotyrosine) levels in neonatal lambs with PPHN.

Methods: Six newborn lambs with PPHN (induced by antenatal ductal ligation) were killed at birth. Twenty-six PPHN lambs were ventilated for 24 h with 100% O₂ alone (n = 6) or O₂ combined with rhSOD (5 mg/kg intratracheally) at birth (n = 4), rhSOD at 4 h of age (n = 5), iNO (20 ppm, n = 5), or rhSOD + iNO (n = 6). Contraction responses of fifth-generation PAs to norepinephrine and KCl, lung isoprostane levels, and 3-nitrotyrosine fluorescent intensity were measured.

Results: Systemic oxygenation was impaired in PPHN lambs and significantly improved (up to threefold) in both rhSOD groups with or without iNO. Oxygenation improved more rapidly with the combination of rhSOD + iNO compared with either intervention alone. Norepinephrine- and KCl-induced contractions and lung isoprostane levels were significantly increased by 100% O₂ compared with nonventilated newborn lambs with PPHN. Both rhSOD and iNO mitigated the increased PA contraction response and lung isoprostane levels. Intratracheal rhSOD decreased the enhanced lung 3-nitrotyrosine fluorescence observed with iNO therapy.

Conclusion: Intratracheal rhSOD and/or iNO rapidly increase oxygenation and reduce both vasoconstriction and oxidation in newborn lambs with PPHN. This has important implications for clinical trials of rhSOD and iNO in newborn infants with PPHN.

Key Words: isoprostanes • nitric oxide • oxygen • pulmonary hypertension • superoxide dismutase

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Hyperoxic ventilation causes oxidant injury and can contribute to worsening of pulmonary hypertension in newborns. What This Study Adds to the Field Intratracheal recombinant human superoxide dismutase improves oxygenation and reduces pulmonary arterial contractility and oxidation (isoprostane levels) in an ovine model of neonatal pulmonary hypertension

 

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