Surfactant dysfunction after inhalation of nitric oxide

Hallman, Mikko; Waffarn, Feizal; Bry, Kristina; Turbow, Robert; Kleinman, Michael T.; Mautz, William J.; Rasmussen, Ronald E.; Bhalla, Deepak K.; Phalen, Robert F.

doi:10.1152/jappl.1996.80.6.2026

Cited by 49 publications

(25 citation statements)

References 17 publications

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“…Interestingly, in a model of acute lung injury from sepsis and hyperoxia, there was no difference in total surfactant levels or large aggregates in lavages between wild and inducible NOS (Ϫ/Ϫ) knockout mice (4). The conflicting results between in vivo and in vitro studies may be explained by the presence of various antioxidants within epithelial lining fluid in vivo not present in vitro, which inactivates the toxic intermediates of NO, such as peroxynitrite (26,27,29,43,60), methemoglobin (30,31,33), and nitrogen dioxide (45), which affect SP synthesis, secretion, or function.…”

Section: Discussionmentioning

confidence: 99%

Increased pulmonary blood flow does not alter surfactant protein gene expression in lambs within the first week of life

Lee¹,

Ovadia²,

Azakie³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Neonates and infants with congenital heart disease with increased pulmonary blood flow suffer morbidity from poor oxygenation and decreased lung compliance. In a previous experiment involving 4-wk-old lambs with pulmonary hypertension secondary to increased pulmonary blood flow following an in utero placement of an aortopulmonary vascular graft, we found a decrease in surfactant protein (SP)-A gene expression as well as a decrease in SP-A and SP-B protein contents. To determine the timing of these changes, the objective of the present study was to characterize the effect of increased pulmonary blood flow and pulmonary hypertension on SP-A, -B, and -C gene expressions and protein contents within the first week of life. Of eight fetal lambs that underwent the in utero placement of the shunt, there was no difference in the expression of SP-A, -B, and -C mRNA levels or SP-A and -B protein contents compared with age-matched controls. The results showed that, in this model of congenital heart disease with pulmonary hypertension and increased pulmonary blood flow, the effect of the shunt on SP gene expression and protein content was not apparent within the first week of life.congenital heart disease AMONG NEONATES AND INFANTS with congenital heart disease with increased pulmonary blood flow, the presence of the systemicto-pulmonary communication often leads to progressive structural and functional changes in the pulmonary vascular bed, leading to pulmonary hypertension. The structural changes include increased muscularity of small pulmonary arteries with early distal extension, intimal hyperplasia, scarring and thrombosis, and a reduction in the number of intra-acinar arteries, as well as the arterial-to-alveolar ratio. These vascular changes result in eventual obliteration of the pulmonary vascular bed with elevation in pulmonary vascular resistance and extreme sensitivity to vasoconstricting stimuli. If uncorrected, these children will suffer from morbidity from cyanosis and myocardial failure (12,34,49).Multiple studies have shown that increased pulmonary blood flow and/or pressure affect endothelial cell functions within the alveolar space. Grigg et al. (22) found elevated levels of endothelin-1 (ET-1) in bronchoalveolar lavage in children with congenital heart disease with increased pulmonary blood flow. Ishikawa et al. (36) found elevated plasma ET-1 levels in children with ventricular septal defects who had both volume and pressure overload to the pulmonary circulation but not in children with atrial septal defects who had only volume overload. In cultured human vascular endothelial cells, shear stress stimulated the synthesis of mRNA for platelet-derived growth factors-A and -B (48), tissue plasminogen activator (20), and intercellular adhesion molecule-1 (46).Recently, increased pulmonary blood flow and/or pressure has also been shown to affect pulmonary epithelial cell functions. Wang et al. (59) showed that, in an isolated, constantly inflated, blood-perfused rat lung, increased left atrial pressure increa...

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Section: Discussionmentioning

confidence: 99%

Increased pulmonary blood flow does not alter surfactant protein gene expression in lambs within the first week of life

Lee¹,

Ovadia²,

Azakie³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Reports regarding the effect of NO in oxidative stress, however, are conflicting (43). In experimental studies, several authors found a worse clinical outcome or surfactant dysfunction as a result of lipid peroxidation or damage to surfactant protein, but they often used very high doses of NO (40 -100 ppm) combined with high and stable FIO 2 levels (80 -100%) (19,43,49). Because of these data, wide use of iNO therapy in preterm infants is unwarranted by most neonatologists (13)(14)(15)50).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, iNO may interact with oxygen to form nitrogen dioxide and peroxynitrites, which would enhance pulmonary toxicity. This is a main concern when dealing with premature infants, who already are unable to face oxidant stress (18,19). However, at low dosage and in experimental models, NO is described as antioxidant at the lung level, able to counteract oxidative stress and enhance surfactant function (20,21).…”

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confidence: 99%

Early Inhaled Nitric Oxide Improves Oxidative Balance in Very Preterm Infants

Hamon

Fresson²,

Nicolas

et al. 2005

Pediatr Res

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Inhaled nitric oxide (iNO) improves oxygenation in premature infants, but concern has been raised about its potential oxidative toxicity. We designed this study to assess the oxidative balance in premature infants who were exposed to low dose iNO and the relationship with their clinical outcome on day 28 of life. A total of 274 infants who were Ͻ32 wk gestation were randomized at birth to receive 5 ppm of iNO if they presented with hypoxemic respiratory failure. Nonhypoxemic infants were studied as the reference group. Blood samples were withdrawn 24 h apart, within the first 4 d of life, to assess malondialdehyde (MDA) concentration as oxidative stress marker and total plasmatic glutathione (GSH), intraerythrocyte GSH peroxidase, and GSH reductase activities as antioxidant defenses. After 24 h, the rise in MDA was blunted in the iNO group compared with controls and was close to the reference infants. Conversely, GSH was more stable in the iNO group, when there was no difference for the GSH peroxidase and GSH reductase activities. On day 28, Oxygen dependence was linked with a higher increase in MDA as was the risk for death, whereas intraventricular hemorrhage was associated with a higher initial drop in GSH. Early low-dose iNO in hypoxemic preterm infants improves oxidative balance and seems to be clinically beneficial up to day 28 of life. Since 1992, several randomized trials have shown that inhaled nitric oxide (iNO) significantly improved oxygenation in term or near-term infants, with a significant reduction in the use of extracorporeal membrane oxygenation (1-6). In 1997, Skimming et al. (7) were the first to report a positive response of 23 premature infants with respiratory distress syndrome to low-dose iNO (5 ppm). Since then, a few clinical trials involving a small number of premature infants have shown that the initial improvement in oxygenation seemed to be transient (8 -10) because no improvement in mortality or in morbidity had been demonstrated (11). However, most of these studies were considering iNO therapy in premature infants who had severe hypoxemic respiratory failure or refractory hypoxemia (8,10,11) or were at an advanced stage of respiratory insufficiency (12). Most of them used a high dosage of iNO (10 -20 ppm).Finally, concerns have been raised about specific side effects of this new molecule that could worsen long-term outcome after an initial improvement in this high-risk population (13)(14)(15). Besides the risk for increased brain hemorrhage as a result of a prolonged bleeding time (16), neonatologists remain cautious in the use of this treatment because NO behaves as a "chameleon" molecule for the oxidative balance. Endogenous NO is incriminated in the cascade leading to cerebral lesions in perinatal experimental models of hypoxo-ischemic injuries (17). In addition, iNO may interact with oxygen to form nitrogen dioxide and peroxynitrites, which would enhance pulmonary toxicity. This is a main concern when dealing with Received May 20, 2004; accepted September 27, 2004

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“…Some investigations have shown inhibition of surfactant function by NO [13,14], but the clinical significance of these results is limited by the fact that they were shown in vitro, or in experimental studies with high NO doses. NO affects platelet aggregation, and bleeding complications may be more frequent side effects in premature newborn infants [15].…”

Section: Discussionmentioning

confidence: 99%

Plasma Cyclic Guanosine Monophosphate Reflecting the Severity of Persistent Pulmonary Hypertension of the Newborn

et al. 2001

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The aim of the study was to examine the relationship between the plasma concentration of cyclic guanosine monophosphate (cGMP) and pulmonary pressure and hypoxia defined by oxygenation index (OI) in newborn infants with severe persistent pulmonary hypertension (PPHN) on inhaled nitric oxide (NO). In this prospective study, 18 newborn infants having Doppler ultrasound-diagnosed PPHN and treated with NO were investigated. The ratio of pulmonary artery to systemic artery pressure (PAP/SAP) and OI was assessed before treatment and at 0.5, 1, 12, and 24 h from the beginning of NO. At these time points, plasma concentrations of cGMP could be determined in 11 patients. The association of birth asphyxia as assessed by Apgar 1 min and 5 min and plasma cGMP before the NO treatment was examined. The initial median plasma concentration of cGMP was 37.3 pmol/ml (IQR 13.3–79.6). After the start of NO, cGMP increased significantly within 60 min (p = 0.003) and peaked at 12 h. Initial plasma cGMP was associated with Apgar score (1 and 5 min). OI decreased within 30 min of NO and PAP/SAP within 60 min. Persistent high PAP/SAP after 1 h of NO was associated with low cGMP concentration (r = 0.70, p = 0.02). We conclude that a significant increase in plasma cGMP is already evident after 60 min of NO therapy. This effect is accompanied by changes in oxygenation index and in pulmonary artery pressure. Initial plasma concentrations of cGMP were associated with hypoxia assessed as Apgar score.

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Surfactant dysfunction after inhalation of nitric oxide

Cited by 49 publications

References 17 publications

Increased pulmonary blood flow does not alter surfactant protein gene expression in lambs within the first week of life

Increased pulmonary blood flow does not alter surfactant protein gene expression in lambs within the first week of life

Early Inhaled Nitric Oxide Improves Oxidative Balance in Very Preterm Infants

Plasma Cyclic Guanosine Monophosphate Reflecting the Severity of Persistent Pulmonary Hypertension of the Newborn

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