Introduction Nitric Oxide Source of NO in exhaled air Measurement Asthma COPD Cystic fibrosis Bronchiectasis Primary ciliary dyskinesia Rhinitis Interstitial lung diseases Pulmonary hypertension Occupational diseases Infections Chronic cough Lung cancer Lung transplant rejection Adult respiratory distress syndrome Diffuse Panbronchiolitis Carbon Monoxide Source of exhaled CO Measurement Asthma COPD Bronchiectasis Cystic fibrosis Interstitial lung disease Allergic rhinitis Infections Other conditions Exhaled Hydrocarbons Origin Measurement Asthma COPD Cystic Fibrosis Other lung diseases Exhaled Breath Condensate Origin Hydrogen peroxide Eicosanoids Products of lipid peroxidation Vasoactive amines NO-related products Ammonia Electrolytes Hydrogen ions Proteins and cytokines Other Methods Exhaled temperature Combined gas chromatography/spectroscopy The selected ion flow tube (SIFT) technique Polymer-coated surface-acoustic-wave resonators Future Directions Standardization of measurements Clinical application Profiles of mediators Measuring devices New markers

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.163.7.2009041

Exhaled markers of pulmonary disease.

During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from iNOS seems to be a proinflammatory mediator with immunomodulatory effects. The concentration of this molecule in exhaled air is abnormal in activated states of different inflammatory airway diseases, and its monitoring is potentially a major advance in the management of, e.g., asthma. Finally, the production of NO under oxidative stress conditions secondarily generates strong oxidizing agents (reactive nitrogen species) that may modulate the development of chronic inflammatory airway diseases and/or amplify the inflammatory response. The fundamental mechanisms driving the altered NO bioactivity under pathological conditions still need to be fully clarified, because their regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways.

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Nitric Oxide in Health and Disease of the Respiratory System

Airway concentrations of many reactive nitrogen and oxygen species are high in asthma. The stability and bioactivities of these species are pH-dependent; however, the pH of the airway during acute asthma has not previously been studied. As with gastric and urinary acidification, asthmatic airway acidification could be expected dramatically to alter the concentrations and bioactivities/cytotoxicities of endogenous nitrogen oxides. Here, we demonstrate that the pH of deaerated exhaled airway vapor condensate is over two log orders lower in patients with acute asthma (5.23 ± 0.21, n = 22) than in control subjects (7.65 ± 0.20, n = 19, p < 0.001) and normalizes with corticosteroid therapy. Values are highly reproducible, unaffected by salivary or therapeutic artifact, and identical to samples taken directly from the lower airway. Further, at these low pH values, the endogenous airway compound, nitrite, is converted to nitric oxide (NO) in quantities sufficient largely to account for the concentrations of NO i...

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.161.3.9911005

Endogenous airway acidification. Implications for asthma pathophysiology.

Background Responses to inhaled corticosteroids (ICSs) and leukotriene receptor antagonists (LTRAs) vary among asthmatic patients. Objective We sought to determine whether responses to ICSs and LTRAs are concordant for individuals or whether asthmatic patients who do not respond to one medication respond to the other. Methods Children 6 to 17 years of age with mild-to-moderate persistent asthma were randomized to one of 2 crossover sequences, including 8 weeks of an ICS, fluticasone propionate (100 μg twice daily), and 8 weeks of an LTRA, montelukast (5-10 mg nightly depending on age), in a multicenter, double-masked, 18-week trial. Response was assessed on the basis of improvement in FEV 1 and assessed for relationships to baseline asthma phenotype-associated biomarkers. Results Defining response as improvement in FEV 1 of 7.5% or greater, 17% of 126 participants responded to both medications, 23% responded to fluticasone alone, 5% responded to montelukast alone, and 55% responded to neither medication. Compared with those who responded to neither medication, favorable response to fluticasone alone was associated with higher levels of exhaled nitric oxide, total eosinophil counts, levels of serum IgE, and levels of serum eosinophil cationic protein and lower levels of methacholine PC 20 and pulmonary function; favorable response to montelukast alone was associated with younger age and shorter disease duration. Greater differential response to fluticasone over montelukast was associated with higher bronchodilator use, bronchodilator response, exhaled nitric oxide levels, and eosinophil cationic protein levels and lower methacholine PC 20 and pulmonary function values. Conclusions Response to fluticasone and montelukast vary considerably. Children with low pulmonary function or high levels of markers associated with allergic inflammation should receive ICS therapy. Other children could receive either ICSs or LTRAs.

https://www.jacionline.org/article/S0091-6749(04)03055-6/pdf

Characterization of within-subject responses to fluticasone and montelukast in childhood asthma

The relatively recent detection of nitric oxide (NO) in the exhaled breath has prompted a great deal of experimentation in an effort to understand the pulmonary exchange dynamics. There has been very little progress in theoretical studies to assist in the interpretation of the experimental results. We have developed a two-compartment model of the lungs in an effort to explain several fundamental experimental observations. The model consists of a nonexpansile compartment representing the conducting airways and an expansile compartment representing the alveolar region of the lungs. Each compartment is surrounded by a layer of tissue that is capable of producing and consuming NO. Beyond the tissue barrier in each compartment is a layer of blood representing the bronchial circulation or the pulmonary circulation, which are both considered an infinite sink for NO. All parameters were estimated from data in the literature, including the production rates of NO in the tissue layers, which were estimated from expe...

A two-compartment model of pulmonary nitric oxide exchange dynamics

Exhaled nitric oxide (NO) may aid in monitoring pulmonary disease. The single-breath NO profile (subjects with nose clip) was described as a NO peak followed by a plateau (NO(PLAT)). Published exhaled NO values vary greatly, possibly due to contamination with nasal NO and differing respiratory maneuvers. We developed a technique to measure pulmonary NO, without nasal NO, by having the subject maintain a positive expiratory pressure (ensuring vellum closure), and we examined the variation in NO(PLAT) over a range of expiratory flows (4.2 to 1,550 ml/s). NO(PLAT) values rose almost 35-fold (3.2 +/- 1.4 ppb to 110.5 +/- 54.8 ppb) with decreasing flow, described by NO(PLAT) = 208.6795 x (flow rate)(-0.5995). However, NO excretion showed an almost 11-fold rise as flow increased. In summary, we present a simple technique for measuring exhaled NO without contamination by nasal NO. There is a marked flow dependence of exhaled NO concentration and excretion. Exhaled pulmonary NO is best measured at very low flow r...

Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide.

Exhaled nitric oxide (ENO) is used increasingly as a surrogate marker of airway inflammation in research protocols that may incorporate standard efficacy measures, such as spirometry before and after bronchodilator, which could affect ENO measurements. In seven healthy volunteers and 11 mild asthmatic subjects, we measured ENO before and serially for 1 h after spirometry. On two additional days in the subjects with asthma, we reexamined the effect of spirometry as before, followed by the serial measurement of ENO for 1 h after two puffs of salbutamol (100 m g/puff) by metered-dose inhaler or matching placebo. As early as 1 min after spirometry, ENO fell by 13% and 10% in the normal and asthmatic subjects, respectively. In both groups, ENO returned to baseline over 1 h. In the asthmatic subjects, salbutamol caused a significant mean increase of the order of 10 parts per billion in ENO (p , 0.001) for 1 h as compared with placebo inhaler. We conclude that spirometry and b 2 -agonist may perturb ENO values and recommend that studies control for these factors. Silkoff PE, Wakita S, Chatkin J, Ansarin K, Gutierrez C, Caramori M, McClean P, Slutsky AS, Zamel N, Chapman KR. Exhaled nitric oxide after b 2 - agonist inhalation and spirometry in asthma. AM J RESPIR CRIT CARE MED 1999;159:940‐944.

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.159.3.9805044

Suguru Wakita

Papers

Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide.

Exhaled Nitric Oxide after β2-agonist Inhalation and Spirometry in Asthma