Recombinant human superoxide dismutase reduces lung injury caused by inhaled nitric oxide and hyperoxia

Robbins, Carolyn; Horowitz, Stuart; Merritt, T. Allen; Kheiter, A; Tierney, John; Narula, Pramod; Davis, Jonathan M.

doi:10.1152/ajplung.1997.272.5.l903

Cited by 31 publications

(25 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies suggest that both mechanisms likely contribute to the improvement in oxygenation in this animal model with pulmonary hypertension and severe parenchymal lung disease (1,10,16). Intratracheal administration of rhSOD has been shown to reduce the severity of lung injury caused by mechanical ventilation with hyperoxia in newborn piglets, potentially improving intrapulmonary shunt (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 endogenously produced and exogenously delivered NO (14).…”

Section: Discussionmentioning

confidence: 86%

“…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).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Superoxide Dismutase Improves Gas Exchange and Pulmonary Hemodynamics in Premature Lambs

Kinsella

Parker²,

Davis³

2005

Am J Respir Crit Care Med

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

Superoxide Dismutase Improves Gas Exchange and Pulmonary Hemodynamics in Premature Lambs

Kinsella

Parker²,

Davis³

2005

Am J Respir Crit Care Med

View full text Add to dashboard Cite

show abstract

“…In fact, the superoxide scavenger SOD significantly increased the in vitro relaxant activity of NO (40). Moreover, the combination of high doses of inhaled NO (100 ppm) and 90% O 2 caused oxidative damage in mechanically ventilated newborn piglets, which was mitigated by the use of recombinant human SOD (41). Therefore, the use of SOD might be suggested as a way of reducing the toxicity and augmenting the response to inhaled NO, which may lead to novel clinical strategies to improve the treatment of neonatal pulmonary hypertension.…”

Section: Vascular Response To Carbon Monoxidementioning

confidence: 99%

Relaxant Effects of Carbon Monoxide Compared with Nitric Oxide in Pulmonary and Systemic Vessels of Newborn Piglets

et al. 2000

View full text Add to dashboard Cite

Nitric oxide (NO) has been implicated in a number of diverse physiologic processes, including regulation of vascular tone. Carbon monoxide (CO) is another endogenously generated diatomic gas that may play an important physiologic role in vascular smooth muscle homeostasis. The purpose of this study was to compare the responses to exogenous NO and CO in isolated vessels (pulmonary arteries, pulmonary veins, and mesenteric arteries) from 12-to 24-h-old and 2-wk-old piglets. Vessels precontracted with the thromboxane A 2 mimetic U46619 (10 Ϫ7 M) relaxed in response to CO (2 ϫ 10 Ϫ6 to 2 ϫ 10 Ϫ4 M) and NO (2 ϫ 10 Ϫ9 to 2 ϫ 10 Ϫ7 M); these effects were not affected by endothelium removal but were completely abolished by the soluble guanylate cyclase inhibitor ODQ (10 Ϫ5 M). In pulmonary arteries, the maximal relaxation to NO increased with postnatal age from 33 Ϯ 4% of the precontraction value to 56 Ϯ 5%, in 12-to 24-h-old and 2-week-old piglets, respectively (p Ͻ 0.01), but the response to CO decreased from 25 Ϯ 3% to 12 Ϯ 1%, respectively (p Ͻ 0.01). The maximal response to CO was greater in pulmonary veins than in pulmonary or mesenteric arteries for both age groups (p Ͻ 0.01). Vasorelaxation induced by endogenous NO (stimulated by acetylcholine) was also greater in pulmonary veins when compared with pulmonary arteries and increased with postnatal age in both vessels. In contrast, no age-related differences were observed in the vasorelaxation induced by the cGMP analog 8-bromo cGMP in pulmonary arteries. When the response to NO was analyzed under three different extracellular O 2 concentrations (PO 2 4.51 Ϯ 0.03, 19.32 Ϯ 0.17, and 86 Ϯ 0.62, kPa), no significant differences were found. However, in the presence of superoxide dismutase (100 U/mL). the response to CO remained unchanged, and the response to NO improved in pulmonary arteries from 2-week-old but not from newborn piglets. In conclusion, both NO and CO relaxed neonatal vessels through soluble guanylate cyclase activation. However, when compared with NO, CO exhibited a poor vasorelaxant activity. Pulmonary vasorelaxation induced by NO increased with postnatal age, whereas that induced by CO decreased. Changes in extracellular oxygen concentration did not alter the pulmonary vascular response to NO. However, the presence of superoxide dismutase improved the response to NO, indicating that oxidant activity limits the vasorelaxant response to NO but not to CO. (Pediatr Res 48: 546-553, 2000) Abbreviations NO, nitric oxide CO, carbon monoxide sGC, soluble guanylate cyclase HO, heme oxygenase SOD, superoxide dismutase U46619, 9,11-dideoxy-11␣,9␣-epoxymethano-prostaglandinNO is known to be involved in the regulation of multiple physiologic processes, including the regulation of pulmonary vascular tone (1). On the other hand, another diatomic gas, CO, traditionally considered as a toxic pollutant, poisons by binding to the iron-containing heme group found in Hb and other enzymes (2). Recently, evidence is accumulating that CO can be also a physiologic endogenous ...

show abstract

“…Although it has been shown that the preterm rats were not more susceptible to O 2 -induced lung damage and lethality than full-term newborns (46,47), it is also possible that inhaled NO would not have had similar effects on preterm rats as observed in this study of term neonatal rats. We exposed our neonatal rats to 95% oxygen for 6 d, which can cause higher mortality and more severe signs of lung inflammation and fibroproliferative changes on lung histology (48,49). At Denver's altitude, this level of hyperoxia would be more similar to exposure of 75-80% FiO 2 at sea level.…”

Section: No Improves Alveolarization In Bpdmentioning

confidence: 99%

“…This likely accounts for less severe acute lung injury in our study, but still provides a model of impaired lung development, which more closely mimics the "new BPD" in the postsurfactant era (3,4). Past studies have examined the combined effects of inhaled NO treatment during acute exposure to hyperoxia (21)(22)(23)(24)48,49). In contrast, we have examined the effects of late NO treatment after hyperoxia exposure to more directly examine its effects during recovery from acute lung injury.…”

Section: No Improves Alveolarization In Bpdmentioning

confidence: 99%

Inhaled Nitric Oxide Enhances Distal Lung Growth after Exposure to Hyperoxia in Neonatal Rats

et al. 2005

View full text Add to dashboard Cite

Exposure of newborn rats to hyperoxia impairs alveolarization and vessel growth, causing abnormal lung structure that persists during infancy. Recent studies have shown that impaired angiogenesis due to inhibition of vascular endothelial growth factor (VEGF) signaling decreases alveolar and vessel growth in the developing lung, and that nitric oxide (NO) mediates VEGFdependent angiogenesis. The purpose of this study was to determine whether hyperoxia causes sustained reduction of lung VEGF, VEGF receptor, or endothelial NO synthase (eNOS) expression during recovery, and whether inhaled NO improves lung structure in infant rats after neonatal exposure to hyperoxia. Newborn rat pups were randomized to hyperoxia [fraction of inspired oxygen (FiO 2 ), 1.00] or room air exposure for 6 d, and then placed in room air with or without inhaled NO (10 ppm) for 2 wk. Rats were then killed for studies, which included measurements of body weight, lung weight, right ventricular hypertrophy (RVH), morphometric analysis of alveolarization (by mean linear intercept (MLI), radial alveolar counts (RAC), and vascular volume (Vv), and immunostaining and Western blot analysis. In comparison with controls, neonatal hyperoxia reduced body weight, increased MLI, and reduced RAC in infant rats. Lung VEGF, VEGFR-2, and eNOS protein expression were reduced after hyperoxia. Inhaled NO treatment after hyperoxia increased body weight and improved distal lung growth, as demonstrated by increased RAC and Vv and decreased MLI. We conclude that neonatal hyperoxia reduced lung VEGF expression, which persisted during recovery in room air, and that inhaled NO restored distal lung growth in infant rats after neonatal hyperoxia. BPD is the chronic lung disease of infancy that follows ventilator and oxygen therapy for acute respiratory failure after premature birth (1). Traditionally, BPD has been defined by the presence of persistent respiratory signs and symptoms, the need for supplemental oxygen to treat hypoxemia, and an abnormal chest radiograph at 36 wk corrected age. Over the years, the clinical course of premature infants with BPD has changed, reflecting the effects of improved survival of babies who are less mature and have lower birth weights, as well as changes in therapeutic strategies, such as surfactant therapy and modes of mechanical ventilation (2,3). Infants with BPD now have less severe initial acute respiratory disease, and at autopsy, lung histology is predominantly characterized by arrested lung development, including impaired alveolar and vascular growth (4).Although mechanisms that impair lung growth in BPD are poorly understood, recent studies suggest that disruption of VEGF function plays a pivotal role in the pathogenesis of BPD. Bhatt et al. (5) have shown decreased lung VEGF mRNA and protein expression, as well as a reduction of the VEGF receptor, flt-1 (VEGFR-1), in the lungs of infants with fatal BPD. In addition, VEGF protein levels are reduced in the tracheal aspirates obtained from premature newborns with BPD, as well a...

show abstract

Recombinant human superoxide dismutase reduces lung injury caused by inhaled nitric oxide and hyperoxia

Cited by 31 publications

References 0 publications

Superoxide Dismutase Improves Gas Exchange and Pulmonary Hemodynamics in Premature Lambs

Superoxide Dismutase Improves Gas Exchange and Pulmonary Hemodynamics in Premature Lambs

Relaxant Effects of Carbon Monoxide Compared with Nitric Oxide in Pulmonary and Systemic Vessels of Newborn Piglets

Inhaled Nitric Oxide Enhances Distal Lung Growth after Exposure to Hyperoxia in Neonatal Rats

Contact Info

Product

Resources

About