Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease

McCurnin, Donald; Pierce, Richard A.; Chang, Leslie; Gibson, Linda L.; Osborne-Lawrence, Sherri; Yoder, Bradley A.; Kerecman, Jay D.; Albertine, Kurt H.; Winter, Vicki T.; Coalson, Jacqueline J.; Crapo, James D.; Grubb, Peter H.; Shaul, Philip W.

doi:10.1152/ajplung.00347.2004

Cited by 195 publications

(162 citation statements)

References 47 publications

(70 reference statements)

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“…(21)(22)(23)(24)(25) INO may decrease baseline airway resistance by inhibiting abnormal elastin deposition or smooth muscle proliferation. (22,24,26) Increased alveolarization could improve pulmonary compliance and oxygenation (21)(22)(23)(24). Stimulation of angiogenesis and/or inhibition of vascular smooth muscle proliferation could also improve oxygenation.…”

Section: Discussionmentioning

confidence: 99%

One-Year Respiratory Outcomes of Preterm Infants Enrolled in the Nitric Oxide (to Prevent) Chronic Lung Disease Trial

Hibbs

Walsh

Martin

et al. 2008

The Journal of Pediatrics

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Objective-To identify whether inhaled nitric oxide treatment decreased indicators of long-term pulmonary morbidities after discharge from the NICU.Study design-The NO CLD trial enrolled preterm infants (<1250g) between 7-21 days of age who were ventilated and at high risk for BPD. Follow-up occurred at 12 ± 3 months of age adjusted for prematurity; long-term pulmonary morbidities and other outcomes were reported by parents during structured blinded interviews.

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Section: Discussionmentioning

confidence: 99%

One-Year Respiratory Outcomes of Preterm Infants Enrolled in the Nitric Oxide (to Prevent) Chronic Lung Disease Trial

Hibbs

Walsh

Martin

et al. 2008

The Journal of Pediatrics

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“…In addition, the administration of inhaled NO gas (iNO) in the same model improved early pulmonary function. However, with iNO these improvements were transient and there was negligible impact on ventilatory support requirements (13). Studies of NOS and iNO in the primate and other animal models of BPD led to trials of iNO therapy in preterm human infants.…”

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

Postnatal Estradiol Up-regulates Lung Nitric Oxide Synthases and Improves Lung Function in Bronchopulmonary Dysplasia

McCurnin

Pierce

Willis³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Nitric oxide (NO) plays an important role in lung development and perinatal lung function, and pulmonary NO synthases (NOS) are decreased in bronchopulmonary dysplasia (BPD) following preterm birth. Fetal estradiol levels increase during late gestation and estradiol up-regulates NOS, suggesting that after preterm birth estradiol deprivation causes attenuated lung NOS resulting in impaired pulmonary function. Objective: To test the effects of postnatal estradiol administration in a primate model of BPD over 14 days after delivery at 125 days of gestation (term 5 185 d). Methods: Cardiopulmonary function was assessed by echocardiography and whole body plethysmography. Lung morphometric and histopathologic analyses were performed, and NOS enzymatic activity and abundance were measured. Measurements and Main Results: Estradiol caused an increase in blood pressure and ductus arteriosus closure. Expiratory resistance and lung compliance were also improved, and this occurred before spontaneous ductal closure. Furthermore, both oxygenation and ventilation indices were improved with estradiol, and the changes in lung function and ventilatory support requirements persisted throughout the study period. Whereas estradiol had negligible effect on indicators of lung inflammation and on lung structure assessed after the initial 14 days of ventilatory support, it caused an increase in lung neuronal and endothelial NOS enzymatic activity. Conclusions: In a primate model of BPD, postnatal estradiol treatment had favorable cardiovascular impact, enhanced pulmonary function, and lowered requirements for ventilatory support in association with an up-regulation of lung NOS. Estradiol may be an efficacious postnatal therapy to improve lung function and outcome in preterm infants.The signaling molecule nitric oxide (NO), generated by nitric oxide synthase (NOS), plays a key role in multiple processes in the mature lung (1, 2). In the developing lung, NO participates in pulmonary vascularization, alveolarization, and airway branching, and also counteracts apoptosis in multiple lung cell types (3-6). In the perinatal period, epithelium-derived NO is critically involved in the regulation of lung liquid production and of peripheral contractile elements (7, 8), and it also mediates pulmonary vasomotor tone (9). In studies of lungs from fetal baboons, we showed that all three NOS isoforms, neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), are principally expressed in proximal respiratory epithelium, and that there are maturational increases in their abundance and in NO production during the early third trimester (10). Thus, pulmonary NOS expression is up-regulated during fetal development in the primate, and this process may be critical to lung structural development and airway, parenchymal, and pulmonary vascular function in the early postnatal period.Bronchopulmonary dysplasia (BPD) is a devastating primary complication of premature birth that develops in the preterm human lung following ventilatory and oxyg...

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“…4 Until recently, the effects of iNO on vascular tone and ventilation perfusion matching were assumed to be responsible for its benefit, 5 but recent animal model investigation has shown that deficient endogenous NO disrupts pulmonary parenchymal and vascular development and that exogenous NO may benefit the developing lung by its effects on vascular remodeling, inflammation and pulmonary edema, lung mechanics, lung growth, angiogenesis and airway smooth muscle. [6][7][8][9][10][11][12][13][14][15][16][17] Despite these intriguing animal model findings, the benefit of iNO in premature infants has not been consistently demonstrated in randomized clinical trials. Several small trials demonstrated an increase in oxygenation with iNO therapy, but no significant impact on the primary endpoints of death and/or BPD was demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure

et al. 2007

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Objective: Inhaled nitric oxide (iNO) use in infants >1500 g, but <34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD).Study Design: Infants born at <34 weeks gestation with a birth weight >1500 g with respiratory failure were randomly assigned to receive placebo or iNO.Results: Twenty-nine infants were randomized. There were no differences in baseline characteristics, but the status at randomization showed a statistically significant difference in the use of high-frequency ventilation (P ¼ 0.03). After adjustment for oxygenation index entry strata, there was no difference in death and/or BPD (adjusted relative risk (RR) 0.80, 95% confidence interval (CI) 0.43 to 1.48; P ¼ 0.50), death (adjusted RR 1.26, 95% CI 0.47 to 3.41; P ¼ 0.65) or BPD (adjusted RR 0.40, 95% CI 0.47 to 3.41; P ¼ 0.21).Conclusions: Although sample size limits our ability to make definitive conclusions, this small pilot trial of iNO use in premature infants >1500 g and <34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death.

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Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease

Cited by 195 publications

References 47 publications

One-Year Respiratory Outcomes of Preterm Infants Enrolled in the Nitric Oxide (to Prevent) Chronic Lung Disease Trial

One-Year Respiratory Outcomes of Preterm Infants Enrolled in the Nitric Oxide (to Prevent) Chronic Lung Disease Trial

Postnatal Estradiol Up-regulates Lung Nitric Oxide Synthases and Improves Lung Function in Bronchopulmonary Dysplasia

Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure

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