Lower Airway Nitric Oxide Research Articles

Measurements of upper and lower airway nitric oxide in healthy adults

Introduction. Nasal nitric oxide (NO) measurement can be a useful tool for monitoring upper airway diseases. However, there is a considerable lack of validation data. Aims. To evaluate the repeatability and intra-subject variations of nasal NO output (nV NO) in healthy adults and to study its correlation with lower airway NO parameters. Methods. nV NO was measured in healthy non-smokers at baseline (N = 31, age: 28 ± 6 years), after 1 h (N = 15), 1 d (N = 15), 1 week (N = 17), and compared using the Bland–Altman method. At baseline, lower airway NO parameters (F ENO, flux of NO in the conducting airways and alveolar NO concentration) were also measured and correlated to nV NO (Spearman correlation). Multivariate regression analysis was used to assess the factors influencing nV NO. Results. Baseline median nV NO was 465 (interquartile range (IQR) = 404–536) nL min−1. The mean differences between the baseline and repeated measurements were not significant (p > 0.05). The coefficient of repeatability (mean: 118, IQR = 88–181 nL min−1) and coefficient of variation (mean: 9.1%) were low. We found no correlation between nV NO and lower airway NO parameters (p > 0.05). Sex (β = −0.52, p = 0.02) and body weight (β = −0.65, p = 0.03) influenced nV NO (model: p = 0.04, R 2 = 0.31). Conclusion. nasal NO output has good repeatability in healthy adults. The NO productions of lower and upper airways are not related in health, but nasal NO output seems to be affected by sex and body weight.

Reduced Nasal Nitric Oxide Production in Cystic Fibrosis Patients with Elevated Systemic Inflammation Markers

BackgroundNitric oxide (NO) is produced within the respiratory tract and can be detected in exhaled bronchial and nasal air. The concentration varies in specific diseases, being elevated in patients with asthma and bronchiectasis, but decreased in primary ciliary dyskinesia. In cystic fibrosis (CF), conflicting data exist on NO levels, which are reported unexplained as either decreased or normal. Functionally, NO production in the paranasal sinuses is considered as a location-specific first-line defence mechanism. The aim of this study was to investigate the correlation between upper and lower airway NO levels and blood inflammatory parameters, CF-pathogen colonisation, and clinical data.Methods and FindingsNasal and bronchial NO concentrations from 57 CF patients were determined using an electrochemical analyser and correlated to pathogen colonisation of the upper and lower airways which were microbiologically assessed from nasal lavage and sputum samples. Statistical analyses were performed with respect to clinical parameters (lung function, BMI), laboratory findings (CRP, leucocytes, total-IgG, fibrinogen), and anti-inflammatory and antibiotic therapy. There were significant correlations between nasal and bronchial NO levels (rho = 0.48, p<0.001), but no correlation between NO levels and specific pathogen colonisation. In patients receiving azithromycin, significantly reduced bronchial NO and a tendency to reduced nasal NO could be found. Interestingly, a significant inverse correlation of nasal NO to CRP (rho = −0.28, p = 0.04) and to leucocytes (rho = −0.41, p = 0.003) was observed. In contrast, bronchial NO levels showed no correlation to clinical or inflammatory parameters.ConclusionGiven that NO in the paranasal sinuses is part of the first-line defence mechanism against pathogens, our finding of reduced nasal NO in CF patients with elevated systemic inflammatory markers indicates impaired upper airway defence. This may facilitate further pathogen acquisition in the sinonasal area, with consequences for lung colonisation and the overall outcome in CF.

Lower Airway Nitric Oxide is Increased in Children with Sickle Cell Disease

To determine alveolar and airways nitric oxide (NO) levels in children with sickle cell disease (SCD). Multiple flows fractional exhaled NO (FE(NO)), bronchial NO flux (J'aw(NO)), and alveolar NO concentration (Ca(NO)) were determined prospectively in 16 non-atopic children with SCD in a tertiary ambulatory clinic and compared with those in 10 children with primary ciliary dyskinesia and 22 healthy control subjects. Differences in FE(NO), J'aw(NO), and Ca(NO) were compared with mixed model analysis and Mann-Whitney tests. Children with SCD had reference range FE(NO) at 50 mL/sec, but FE(NO) was elevated across all flows compared with healthy control subjects (mean difference=2.10±0.91 parts per billion, P=.03). Subjects with SCD had increased J'aw(NO) (1177±533 picoliters per second versus 833±343 picolitres per second, P=.03), and Ca(NO) was no different from control subjects. In contrast, children with primary ciliary dyskinesia had decreased FE(NO) (mean difference=3.36±1.24 parts per billion, P<.01) and J'aw(NO) (507±259 picoliters per second versus 833±343 picoliters per second, P<.01). Lower airways NO is increased in children with SCD. Elevation of J'aw(NO) may represent dysregulation of NO metabolism or subclinical airways inflammation.

Influence of ventilatory settings on exhaled nitric oxide during high frequency oscillatory ventilation

Nitric oxide (NO), which is produced in the lower airways, diffuses from cells into the air space and can be measured in exhaled air. The influence of high frequency oscillatory ventilation on the production of exhaled NO (eNO) has not been thoroughly studied. The objectives of this study are to establish an animal model for evaluation of lower airway NO and to evaluate settings in terms of frequency, mean airway pressure (MAP), amplitude pressure (amplitude), and inspiratory time ratio (t(I)/t(E)) during high frequency oscillatory ventilation on the production of eNO. An observational animal study was performed on 12 female New Zealand White rabbits, which were anesthetized, tracheotomized and ventilated using a SensorMedics 3100A HFOV ventilator (SM3100A). The concentration of NO in exhaled gas was measured by chemiluminescence continuously from the nose and the side hole of the adaptor of endotracheal tube. The individual effects of the respiratory settings were evaluated. The results were analyzed by paired t-test or by the generalized estimating equation method. We found that the lower airway was the main source of the eNO, that amplitude, MAP, and t(I)/t(E) were positively correlated with the level of eNO and that frequency was negatively correlated with the level of eNO. These findings fit the stretch theory for the production of endogenous NO. Monitoring of eNO during HFOV may provide insights into lung mechanics and ventilation efficiency and be used in the future as a guide during clinical practice.

Documentation of the nasal nitric oxide response to humming: methods evaluation

Nitric oxide (NO) is present at higher concentrations in the nasal cavity than in the lower airway, and at even higher concentrations within the paranasal sinuses proper. When the paranasal sinus ostia are patent, acoustic activity produced by vocalization with closed lips (humming) promotes mixing of sinus with nasal gases, producing a further increase in nasal NO. We wished to evaluate procedures for the documentation of the nasal NO response to humming. We compared two ATS-recommended sampling methods: 1) active exhalation of lower airway gas (parallel technique) and 2) passive aspiration of nasal gas with closed velopharynx (series technique). Variables controlled for included sampling rate, external resistance (parallel method), humming frequency, humming duration, and intertrial interval. Prior to upper airway sampling, exhaled lower airway NO was determined utilizing ATS-standardized technique. Ten volunteers (seven males and three females, aged 21-58) with no history of respiratory allergies or sino-nasal disease were studied in a single session each. The parallel technique documented an increase in nasal NO during the humming manoeuvre in all subjects (mean ratio of humming-to-quiet NO, 4.2), whereas the series technique did so in eight of 10 subjects (mean ratio 2.1). Correcting for admixture from the lower airway, the ratio of humming-to-quiet NO was greater with the parallel than series sampling technique (P < 0.05). Documentation of the response of nasal NO to humming in subjects without sino-nasal disease was consistently achievable by parallel sampling using commercially available equipment. Specific operational procedures are proposed.

Airway Nitric Oxide in Patients With Cystic Fibrosis Is Associated With Pancreatic Function, Pseudomonas Infection, and Polyunsaturated Fatty Acids

Airway nitric oxide (NO) is low or normal in cystic fibrosis (CF) patients. This may affect bacterial status since NO has antimicrobial properties. Arachidonic acid (AA), which is increased in the serum and airways of CF patients, has been shown to reduce NO levels. The aim of this study was to investigate whether airway NO level correlates with genotype and pancreatic function, and whether low airway NO level is associated with bacterial infection and increased serum AA level in CF patients. Nasal NO (nNO) and exhaled NO (eNO) were measured according to the European Respiratory Society/American Thoracic Society standard in 59 CF patients aged 7 to 55 years, 80% of whom were pancreatic insufficient (PI) and 51% were chronically infected with Pseudomonas aeruginosa. PI CF patients had significantly lower nNO levels than pancreatic-sufficient (PS) patients. Airway NO level did not correlate with lung function or inflammatory parameters. PI patients chronically infected with P aeruginosa had significantly lower nNO levels than noninfected PI patients. nNO level correlated inversely with the AA/docosahexaenoic acid ratio, and eNO with the essential fatty acid (FA) deficiency index, which is the ratio between mead acid and AA. CF patients with PI, which is associated with more severe genotypes, had lower airway NO levels than patients with PS. Low NO level was correlated to chronic P aeruginosa infection, and an association was found between airway NO level and the abnormal serum phospholipid FA pattern.

NO pathway in CF and non-CF children.

Controversy exists concerning abnormalities of the nitric oxide (NO) pathway in cystic fibrosis (CF) lung disease. Although some studies suggested that NO activity is impaired in CF, changes in NO production in young children have not been studied. We hypothesized that nitric oxide synthase (NOS II) expression is decreased in young children with CF, leading to decreased production of lower airway NO, and that decreased NOS II expression is related to airway inflammation. Accordingly, we measured lower airway exhaled NO, nitrate, and NOS II expression in airway epithelium and macrophages by bronchoscopy, bronchoalveolar lavage (BAL), and bronchial brushing in 13 children with CF, 4 adolescent patients with CF, and 14 disease control children. Lower airway NO and nitrate were not different between CF and disease controls. Immunostaining studies of NOS II expression in airway epithelial cells and macrophages were similar in CF and control patients. Within the CF group, however, expression of NOS II was inversely related to BAL neutrophil counts and IL-8, two markers of airway inflammation. We conclude that lower airway NO, nitrate levels, and NOS II expression are not different in young children with CF and disease control patients, but that NOS II expression decreases in CF as airway inflammation increases.

Nasal and lower airway levels of nitric oxide in prematurely born infants.

Nitric oxide (NO) is produced by various cells in the respiratory tract, but the majority is released from the paranasal sinuses in adults. The paranasal sinuses in infants are only partially pneumatised. Thus, nasal NO would be predicted to be low in infants measured soon after birth and/or born very prematurely; this has implications for the measurement of exhaled NO and interpretation of the results obtained. To determine whether nasal NO could be detected in very immature infants, particularly soon after birth, and whether nasal or lower airway NO levels were influenced by gestational age or postnatal age. Fifteen infants, with median gestational age of 27 weeks (range 25-32 weeks). Nasal and lower airway NO measurements were attempted on days 1, 3, 5, 7, 14, 21, and 28 after birth. Measurements were only made while the infants remained ventilated. Nasal NO was sampled directly from the nasal space and lower airway. NO was sampled from a catheter positioned so that its tip lay at the lower end of the endotracheal tube. Nasal NO was detected in all infants on all study occasions and the levels were greater than those from the lower airway. Nasal and lower airway NO levels did not correlate significantly with gestational age, but lower airway NO levels correlated with postnatal age (r=0.86, p=0.014). Even in very immature infants examined in the first day after birth, care must be taken to avoid contamination with nasal NO, if lower airway levels are to be accurately assessed.

Single Breath Analysis of Endogenous Nitric Oxide in the Newborn

Nitric oxide (NO) is found in the exhaled gas of humans immediately after birth. However, variations of endogenous NO concentration during the breathing cycle have not been studied in newborns. We examined 24 newborns without acute respiratory compromise during spontaneous nasal breathing. Gas was sampled from the tip of a thin nasal catheter placed in the hypopharynx. Endogenous NO concentrations measured by chemiluminescence were assigned to the breathing cycle using synchronized CO₂ recording. Exhaled NO could reproducibly be measured at 1.9 ± 0.2 parts per billion (ppb, mean ± SEM). Autoinhaled nasal NO peaks during regular breathing were 12.0 ± 1.7 ppb and reached intermittent maxima of 52.2 ± 5.8 ppb. During regular breathing 6 infants exhibited sudden decreases of nasal NO peaks to periods with <50% amplitude suggesting transient shortage of autoinhaled nasal NO. We conclude that tidal NO analysis can be used to assess upper and lower airway NO production noninvasively during spontaneous breathing in the newborn.

Airway nitric oxide in infants with acute wheezy bronchitis.

Concentrations of nitric oxide (NO) in exhaled air are increased in children and adults with asthma, and NO measurements are used as a non-invasive marker to monitor airway inflammation in these patients. To define the role of NO in infants with acute wheezy bronchitis, we measured nasal and end-tidal NO concentrations in 17 infants with acute virus-associated wheezy bronchitis, in 22 term infants without respiratory disease, and in nine premature infants. Nasal NO measurements were performed with an olive placed in the infant's nose; end-tidal NO concentrations were assessed during tidal breathing through a snuggly fitting face mask. Both end-tidal NO concentrations and nasal NO concentrations were reduced in infants with acute wheezy bronchitis. There were no differences in NO concentrations between term infants and premature infants. Measurements by both techniques were highly reproducible, as assessed by repeated measurements three times daily on three consecutive days in eight premature infants. Reduced airway NO concentrations in infants with virus-associated acute wheezy bronchitis are in contrast to findings in adults where both upper and lower airway NO levels are increased in patients with asthma. Whether this reflects a different inflammatory reaction to upper airway infections in acutely wheezy infants or pathophysiologic differences in airway response remains to be determined.