Superoxide Dismutase Improves Gas Exchange and Pulmonary Hemodynamics in Premature Lambs

Abstract

Rationale: Oxidant stress may increase the severity of respiratory distress syndrome (RDS) after premature birth by altering vasoreactivity and increasing lung edema, but the acute effects of superoxide dismutase (SOD) treatment on gas exchange, lung compliance (CL), and pulmonary vascular resistance in premature animals with RDS are unknown. Objective: We studied the effects of intratracheal recombinant human SOD treatment (rhSOD) on gas exchange, CL, and pulmonary hemodynamics in 46 premature lambs with RDS. Methods: After C-section delivery, lambs were randomly assigned to treatment with SOD (2.5-10 mg/kg) with or without inhaled nitric oxide (iNO, 5 ppm), and mechanically ventilated for 4 hours. At the end of the study, pressure-volume curves and wet-dry lung weights were measured to assess CL and edema, respectively. Keywords: bronchopulmonary dysplasia; chronic lung disease; mechanical ventilation; pulmonary hypertension; surfactant Acute lung injury in premature lambs contributes to the severity of respiratory distress syndrome (RDS), which is characterized by progressive deterioration in oxygenation, worsening lung compliance, and pulmonary edema (1). Multiple factors contribute to acute lung injury in RDS, but oxidant stress plays a critical role (1, 2). In experimental RDS in premature lambs, treatment with exogenous surfactant improves oxygenation and decreases lung injury (3-5). However, extremely premature lambs do not have sustained improvement in oxygenation despite repeated doses of surfactant (6), suggesting that factors other than surfactant deficiency contribute to lung injury in this setting. Because the immature lung lacks sufficient antioxidant host defenses to (Received in original form January 29, 2005; accepted in final form June 6, 2005) Supported by grants from the National Institutes of Health (SCOR: P50 HL 57144, RO1 HL01942, and RO1 HL64158).Correspondence and requests for reprints should be addressed to John P. Kinsella combat the oxidant stress induced by exposure to high inspired oxygen concentrations after premature delivery (7-9), therapies designed to augment endogenous antioxidant activity have engendered considerable interest (10).Inhaled nitric oxide (iNO) holds promise as an adjunctive treatment for RDS because of its effects on pulmonary vasodilation, V /Q matching, lung inflammation, and oxidant stress (1, 11). Intratracheal administration of recombinant human superoxide dismutase (rhSOD) has also been shown to reduce the severity of lung injury caused by mechanical ventilation with hyperoxia in newborn piglets (12, 13). Moreover, via its effects on reducing the activity of toxic free radicals, intratracheal treatment with rhSOD may enhance the bioavailability of endogenously produced NO and augment the pulmonary vasodilator response to iNO (14). However, the mechanisms responsible for the beneficial effects of intratracheal treatment with rhSOD and the interactive effects of rhSOD and iNO have not been studied in a premature animal model of RDS.The role of oxidant st...

Sustained lung activity of a novel chimeric protein, SOD2/3, after intratracheal administration

“…[23]. In contrast, a number of studies performed in disease models of chronic pulmonary hypertension, such as the ductal closure in preterm lambs, group B streptococcal- induced pulmonary hypertension in newborn lambs, or monocrotaline-induced pulmonary hypertension have found that SOD treatment did not alter, or even blunted vasoconstriction [1, 31, 32]. Other published studies are consistent with our observation that in the systemic circulation, SOD activity can enhance vasodilation.…”

Circulatory Effects of Inhaled Iloprost in the Newborn Preterm Lamb

“…Hypoxemia in the premature lamb model is a result of several factors, the most important being decreased oxygen uptake due to surfactant deficiency, PH, and intrapulmonary and extrapulmonary shunts (4,13,19,22). Surfactant was administered before initiation of ventilation resembling prophylactic surfactant administration in human infants.…”

Neonatal hyperoxia alters the host response to influenza A virus infection in adult mice through multiple pathways

“…Interestingly, infants born prematurely and treated with recombinant human copper-zinc superoxide dismutase (CuZn-SOD) had improved pulmonary function and reduced hospitalization rates at one year of corrected age (8). Furthermore, recombinant human CuZn-SOD and overexpression of extracellular (EC)-superoxide dismutase (SOD) in alveolar type II epithelial cells have been shown to preserve lung development in preterm lambs and newborn mice, respectively, that had been exposed to high levels of oxygen at birth (1,2,24,27). Lung-specific overexpression of EC-SOD has also been shown to prevent influenza-induced lung injury in adult mice (40).…”