Superoxide dismutase improves oxygenation and reduces oxidation in neonatal pulmonary hypertension.
BACKGROUND
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% O(2) alone (n = 6) or O(2) 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% O(2) 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.


CONCLUSIONS
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.
Lakshminrusimha
Satyan
S
Department of Pediatrics, State University of New York at Buffalo, NY, USA. slakshmi@buffalo.edu
Russell
James A
JA
Wedgwood
Stephen
S
Gugino
Sylvia F
SF
Kazzaz
Jeffrey A
JA
Davis
Jonathan M
JM
Steinhorn
Robin H
RH
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D028421:Isoprostanes / Q000032:analysis; D008168:Lung / Q000737:chemistry; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D010547:Persistent Fetal Circulation Syndrome / Q000503:physiopathology*; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins / Q000494:pharmacology; D012756:Sheep; D013482:Superoxide Dismutase / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D014661:Vasoconstriction / Q000187:drug effects
D028421:Isoprostanes; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D011189:Potassium Chloride; D013482:Superoxide Dismutase; D010100:Oxygen; D009638:Norepinephrine