Published ahead of print on September 28, 2006, doi:10.1164/rccm.200605-676OC Am. J. Respir. Crit. Care Med., Volume 174, Number 12, December 2006, 1370-1377 A more recent version of this article appeared on December 15, 2006
Submitted on May 18, 2006 Superoxide Dismutase Improves Oxygenation and Reduces Oxidation in Neonatal Pulmonary HypertensionSatyan Lakshminrusimha1*,1 Department of Pediatrics, State Univeristy of New York at Buffalo, Buffalo, NY, USA, 2 Department of Pediatrics, State Univeristy of New York at Buffalo, Buffalo, NY, USA; Departments of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY, USA, 3 Department of Pediatrics, Northwestern University, Chicago, IL, USA, 4 Departments of Pediatrics and Medicine and the CardioPulmonary Research Institute, Winthrop-University Hospital, State University of New York at Stony Brook, Mineola, NY, USA * To whom correspondence should be addressed. 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 (ROS) such as superoxide anions, which can inactivate nitric oxide (NO) and cause vasoconstriction and oxidation. Objective: To compare the effect of intratracheal(IT) recombinant human superoxide dismutase (rhSOD) and/or inhaled NO (iNO) on systemic oxygenation, contractility of pulmonary arteries (PA) and lung ROS (isoprostane, 3-nitrotyrosine) levels in neonatal lambs with PPHN. Methods: Six newborn lambs with PPHN (induced by antenatal ductal ligation) were sacrificed at birth. Twenty-six PPHN lambs were ventilated for 24h with 100%O2 alone (n=6), or combined with rhSOD (5mg/kg IT) at birth (n=4), rhSOD at 4h of age (n=5), iNO (20ppm, n=5) or rhSOD+iNO (n=6). Contraction responses of fifth generation PA 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 3-fold) in both rhSOD groups with/without iNO. Oxygenation improved more rapidly with the combination of rhSOD+iNO compared to either intervention alone. NE and KCl induced contractions and lung isoprostane levels were significantly increased by 100%O2 compared to newborn lambs. Both rhSOD and iNO mitigated the increased PA contraction response and lung isoprostane levels. IT-rhSOD decreased the enhanced lung 3-nitrotyrosine fluorescence observed with iNO therapy. Conclusion: IT-rhSOD and/or iNO rapidly increase oxygenation and reduce both vasoconstriction and oxidation in newborns with PPHN. This has important implications for clinical trials of rhSOD and iNO in newborn infants with PPHN. Key words: Pulmonary hypertension, Superoxide dismutase, Nitric oxide, Oxygen, Isoprostanes
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