Superoxide dismutase improves oxygenation and reduces oxidation in neonatal pulmonary hypertension

Satyanarayana Lakshminrusimha, James A. Russell, Stephen Wedgwood, Sylvia F. Gugino, Jeffrey A. Kazzaz, Jonathan M. Davis, Robin H Steinhorn

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1370-1377
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume174
Issue number12
DOIs
StatePublished - Dec 15 2006
Externally publishedYes

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Persistent Fetal Circulation Syndrome
Pulmonary Hypertension
Superoxide Dismutase
Isoprostanes
Lung
Newborn Infant
Pulmonary Artery
Vasoconstriction
Reactive Oxygen Species
Norepinephrine
Nitric Oxide
Parturition
Superoxides
Ligation
Ventilation
Fluorescence
Clinical Trials

Keywords

  • Isoprostanes
  • Nitric oxide
  • Oxygen
  • Pulmonary hypertension
  • Superoxide dismutase

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Superoxide dismutase improves oxygenation and reduces oxidation in neonatal pulmonary hypertension. / Lakshminrusimha, Satyanarayana; Russell, James A.; Wedgwood, Stephen; Gugino, Sylvia F.; Kazzaz, Jeffrey A.; Davis, Jonathan M.; Steinhorn, Robin H.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 174, No. 12, 15.12.2006, p. 1370-1377.

Research output: Contribution to journalArticle

Lakshminrusimha, Satyanarayana ; Russell, James A. ; Wedgwood, Stephen ; Gugino, Sylvia F. ; Kazzaz, Jeffrey A. ; Davis, Jonathan M. ; Steinhorn, Robin H. / Superoxide dismutase improves oxygenation and reduces oxidation in neonatal pulmonary hypertension. In: American Journal of Respiratory and Critical Care Medicine. 2006 ; Vol. 174, No. 12. pp. 1370-1377.
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abstract = "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.",
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AU - Wedgwood, Stephen

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AU - Kazzaz, Jeffrey A.

AU - Davis, Jonathan M.

AU - Steinhorn, Robin H

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N2 - 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.

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