Medical ProgressAirway nitrogen oxide measurements in asthma and other pediatric respiratory diseases☆,☆☆
Section snippets
Airway nitrogen oxides
Noninvasive lung function tests have recently been developed for airway inflammation. Most of these tests involve measurement of nitrogen oxides. In 1991, Gustafsson et al16 reported the presence of nitric oxide in human breath, and several investigators subsequently observed high levels of NO in the breath of adults with asthma. Exhaled NO levels are now known also to be elevated in pediatric asthma and to decrease with anti-inflammatory therapy17, 18, 19, 20 (Fig 1).
Clinical measurement of nitric oxide
Gas-phase NO is most accurately measured in the clinical setting with the use of a chemiluminescent reaction between NO and ozone to form nitrogen dioxide, oxygen, and a photon.27 The machinery required is sensitive to <1 part per billion but is relatively expensive (over $10,000). This type of equipment has been used for decades to monitor environmental air pollution.
To measure airway NO levels, children begin by breathing NO-free air from a reservoir or filtering system. They may then perform
Exhaled NO and asthmatic airway inflammation
No matter which technique is used, differences in exhaled NO concentration between patients with asthma and healthy control subjects are robust. Mixed expired vital capacity NO concentrations are ~6 ppb in health but 2 to 3 times higher in asthma.18, 31, 36 Similar differences are observed in mixed tidal breathing measurements of NO19 and with on-line measurements.33 For perspective, these parts-per-billion levels of NO produced endogenously in the airway are 3 orders of magnitude less than
Expired NO in disease states other than asthma
Expired NO values are normal or lower than normal in all non-asthmatic pediatric obstructive pulmonary diseases. In particular, values are low in cystic fibrosis,47 possibly because of quenching by neutrophil-derived superoxide and/or prokaryotic denitrification, and in ciliary dyskinesia,48 perhaps reflecting decreased activity of NOS 3.49 Further, expired NO measurements have been used successfully to distinguish preschool children with isolated virus-induced wheezing (low values) from those
Additional factors to consider when interpreting an expired nitric oxide value
Expired NO concentrations do not always exclusively and directly reflect NOS expression or activity. Complete pharmacologic inhibition of NOS does not eliminate NO from expired air,45, 56 and hypernitrosopnea in the asthmatic guinea pig is not associated with NOS upregulation.56 Several additional determinants of exhaled NO values should be borne in mind when interpreting the results of clinical tests.
Other noninvasive markers for airway inflammation
Gas-phase NO is not the only compound that can be measured noninvasively in expired air and used to differentiate normal from inflamed lungs. For example, concentrations of nitrite are elevated in exhaled breath condensate from asthmatic subjects.68 Of note, levels fall somewhat during exacerbations in parallel with falling pH and increasing expired NO, suggesting that NO evolution from nitrite protonation contributes to hypernitrosopnea.57 Further, elevations of expired carbon monoxide
Conclusions and applications
Nitrogen oxides are endogenously produced compounds with a variety of roles in pediatric lung physiology and pathology. They are produced by three isoforms of NOS, all of which have been identified in the lung. The nitrogen oxide products of these enzymes can be measured by noninvasive techniques, which have already proven useful in the management of pediatric lung inflammation. Equipment for measuring expired NO is now available at many centers around the world. Both the European Respiratory
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Cited by (24)
Nitric Oxide in Airway Inflammation
2010, Nitric OxideNitric Oxide in Airway Inflammation
2009, Nitric Oxide: Biology and PathobiologySNOR and wheeze: The asthma enzyme?
2005, Trends in Molecular MedicineRelationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children
2003, Journal of Allergy and Clinical ImmunologyNitric oxide in respiratory diseases
2002, Pharmacology and TherapeuticsCitation Excerpt :The role of exhaled NO in pulmonary disease has also been reviewed by others (Bernareggi & Cremona, 1999; Ashutosh, 2000; Berlyne & Barnes, 2000; Hunt & Gaston, 2000; Marshall & Stamler, 2000; Kharitonov & Barnes, 2001; Yates, 2001).
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Supported by National Institutes of Health grant RO1 BL59337 (B.G.), Virginia Thoracic Society (J.H.), National Institutes of Health Asthma Center Grant 1U19-A134607 (B.G. and J.H.), Cystic Fibrosis Foundation Grant No. GASTON95GO (B.G.), American Lung Association Grant No. RG-110-N (B.G.), and the University of Virginia Children’s Medical Center (B.G.).
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Reprint requests: Benjamin Gaston, MD, Department of Pediatrics, Box 386, The University of Virginia Health System, Charlottesville VA, 22951.