Chest
Volume 138, Issue 3, September 2010, Pages 682-692
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Recent Advances in Chest Medicine
Exhaled Nitric Oxide in Pulmonary Diseases: A Comprehensive Review

https://doi.org/10.1378/chest.09-2090Get rights and content

The upregulation of nitric oxide (NO) by inflammatory cytokines and mediators in central and peripheral airway sites can be monitored easily in exhaled air. It is now possible to estimate the predominant site of increased fraction of exhaled NO (FeNO) and its potential pathologic and physiologic role in various pulmonary diseases. In asthma, increased FeNO reflects eosinophilic-mediated inflammatory pathways moderately well in central and/or peripheral airway sites and implies increased inhaled and systemic corticosteroid responsiveness. Recently, five randomized controlled algorithm asthma trials reported only equivocal benefits of adding measurements of FeNO to usual clinical guideline management including spirometry; however, significant design issues may exist. Overall, FeNO measurement at a single expiratory flow rate of 50 mL/s may be an important adjunct for diagnosis and management in selected cases of asthma. This may supplement standard clinical asthma care guidelines, including spirometry, providing a noninvasive window into predominantly large-airway-presumed eosinophilic inflammation. In COPD, large/central airway maximal NO flux and peripheral/small airway/alveolar NO concentration may be normal and the role of FeNO monitoring is less clear and therefore less established than in asthma. Furthermore, concurrent smoking reduces FeNO. Monitoring FeNO in pulmonary hypertension and cystic fibrosis has opened up a window to the role NO may play in their pathogenesis and possible clinical benefits in the management of these diseases.

Section snippets

NO as a Mediator of Inflammatory Airway Disease

Endogenous NO plays a critical role in regulating airway function and has both beneficial and detrimental effects on airway function. NO is a gaseous signaling molecule that is generated by three isoenzymes of NO synthase (NOS) that are differentially regulated and expressed in the airways and appear to play different pathophysiologic roles.2

NO Synthases

All NOS isoenzymes convert l-arginine to l-citrulline with the generation of NO. Constitutive NOS (cNOS) isoenzymes include neuronal NOS (NOS1) and endothelial NOS (NOS3), both of which are activated by calcium ions to produce small amounts of NO, which is presumed to play a local regulatory role, such as neurotransmission (NOS1) and regulation of local blood flow (NOS3). Inducible NOS (NOS2) is not constitutively expressed but is induced by inflammatory and infectious stimuli and produces

Endothelial NOS

NOS3 is expressed in endothelial cells of the bronchial and pulmonary circulation and plays a role in regulating vascular flow.4 It is also expressed in alveolar endothelial cells and airway epithelial cells throughout the respiratory tract. NOS3 may play a role in reducing plasma exudation in the airways,5 whereas epithelial NOS3 may regulate ciliary beating and, therefore, mucociliary clearance.2 Defective NOS3 function may contribute to airway hyperresponsiveness in animal models of asthma.2

Neuronal NOS

NOS1 is localized to cholinergic nerves in the airways and mediates inhibitory nonadrenergic noncholinergic neural bronchodilatation, acting as a functional antagonist of its cotransmitter, acetylcholine.8 Arginase, which shows increased activity in asthma, reduces NO synthesis by NOS1, resulting in increased neuronal bronchoconstriction.9 NOS1 is also expressed in airway epithelial cells and type 1 pneumocytes, and there is evidence that its expression and activity are increased in the

Inducible NOS

Increased NOS2 expression is found in the airway epithelial cells of patients with asthma and is reduced by inhaled corticosteroids (ICS).13 Increased NOS2 expression is also found in the peripheral lung and small airways in patients with COPD.7, 14 Oxidative stress generates superoxide anions and, in combination with NO, may result in the formation of the highly reactive species peroxynitrite, which is increased in the exhaled breath condensate of COPD patients15 and may account for the

Modeling of NO Excretion in the Lungs

Exhaled NO was first detected in the exhaled breath of mammals in 1991,19 and by 1997, with the first report of a strong inverse dependence on the exhalation flow,20 it was clear that the exchange dynamics were unique. Hence, previous quantitative frameworks to understand the exchange principles of gases such as oxygen, carbon dioxide, nitrogen, and water would need to be advanced significantly.21 Since 1998, numerous research groups have made significant contributions toward our fundamental

Exhaled NO in Asthma

Historically, the assessment of patients with obstructive lung diseases such as asthma and COPD has focused on lung function measurements. However, particularly in mild disease, most patients do not demonstrate spirometric abnormalities. An alternative perspective, provided by a biomarker reflecting underlying inflammatory activity, is potentially helpful.43 In this regard, measuring FeNO may have practical clinical applications in selected patients because it is precise and reproducible and

Randomized Algorithm Studies in Asthma

Recent studies49, 65, 66, 67, 68 that have compared add-on FeNO to clinical guideline management, asthma randomized treatment algorithm studies (ASTRAL), have been equivocal for the use of FeNO to reduce asthma exacerbations or improve asthma control. However, there may have been significant design issues for many of these studies that may have led to incorrect conclusions.69 ASTRAL studies, such as the FeNO studies, require different methodologic design features from a traditional RCT that are

Exhaled NO in Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a hemodynamic state characterized by elevation of the pulmonary arterial pressure and is associated with increased pulmonary vascular resistance, leading to deterioration in cardiopulmonary function and premature death.75 PAH is commonly caused by, or associated with, an underlying pulmonary or systemic disease. When PAH is present in the absence of an identifiable cause or associated underlying disease, it is referred to as idiopathic PAH (IPAH) or

Exhaled NO in CF

CF is characterized by abnormal ion transport across the respiratory epithelium, resulting in increased airway mucus viscosity, chronic infection, and inflammation. Unlike in other inflammatory airway diseases such as asthma, FeNO is typically decreased in CF patients.87 Flow-independent NO exchange parameters such as J'awNO are also altered in CF patients. One study suggested that airway NO diffusion capacity was elevated in CF and airway wall and CANO were reduced,88 whereas others have

Exhaled NO in COPD

COPD is an inflammatory disease of both large and small airways and alveoli that is predominantly mediated by cytokines and interleukins via neutrophilic cellular pathways.99 In stable COPD, FeNO measurements need to be obtained in concurrent nonsmokers to avoid misleading reduction in FeNO. When measured at a single expiratory flow rate, FeNO has been elevated52, 100, 101 or normal2 and increased with exacerbations.102, 103 Papi et al102 and Kunisaki et al103 reported that an elevated FeNO in

Summary

The upregulation of NO by inflammatory cytokines and mediators in central and peripheral airway sites can be monitored easily in exhaled air. It is now possible to estimate the predominant site of increased FeNO and its potential pathologic and physiologic role in various pulmonary diseases. In asthma, increased FeNO reflects eosinophilic-mediated inflammatory pathways moderately well in central and or peripheral airway sites and implies increased inhaled and systemic corticosteroid

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