Allergy Asthma Immunol Res.  2016 Jan;8(1):12-21. 10.4168/aair.2016.8.1.12.

Exhaled NO: Determinants and Clinical Application in Children With Allergic Airway Disease

• Kim HB
• Eckel SP
• Kim JH
• Gilliland

• KMID: 2166645
• DOI: http://doi.org/10.4168/aair.2016.8.1.12

Abstract

Nitric oxide (NO) is endogenously released in the airways, and the fractional concentration of NO in exhaled breath (FeNO) is now recognized as a surrogate marker of eosinophilic airway inflammation that can be measured using a noninvasive technique suitable for young children. Although FeNO levels are affected by several factors, the most important clinical determinants of increased FeNO levels are atopy, asthma, and allergic rhinitis. In addition, air pollution is an environmental determinant of FeNO that may contribute to the high prevalence of allergic disease. In this review, we discuss the mechanism for airway NO production, methods for measuring FeNO, and determinants of FeNO in children, including host and environmental factors such as air pollution. We also discuss the clinical utility of FeNO in children with asthma and allergic rhinitis and further useful directions using FeNO measurement.

Keyword

Nitric oxide; children; asthma; allergic rhinitis; air pollution

MeSH Terms

Air Pollution
Asthma
Biomarkers
Child*
Eosinophils
Humans
Inflammation
Nitric Oxide
Prevalence
Rhinitis
Nitric Oxide

Figure

• 

  Fig. 1 Schematic overview on metabolism of ʟ-arginine and regulation in the airways. ʟ-Arginine is transported into the cell via the cationic amino acid transport (CAT) system and can be metabolized by two groups of enzymes: nitric oxide synthases [constitutive NOS (cNOS) and inducible NOS (iNOS)] and arginases (I and II). NOS converts ʟ-arginine in two steps to NO and ʟ-citrulline with NG-hydroxy-ʟ-arginine as an intermediate. cNOS is activated by an increase in the intracellular concentration of Ca2+, which catalyzes NO synthesis that can bind either thiol groups leading to S-nitrosothiols (R-SNO) or the iron of soluble guanylyl cyclase (sGC) that stimulate the conversion of GTP to cGMP, then both have a variety of physiological effects in the airway. Pro-inflammatory cytokines [interleukin-4 (IL-4), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α)] activate transcription factors and induce iNOS expression, which leads to the prolonged release of high amounts of NO. iNOS-derived NO react with a broad spectrum of molecules such as superoxide (O2-) radicals and transition metals, which can lead to nitration of most classes of biomolecules (nitrative stress). ʟ-citrulline can be converted to ʟ-arginine by argininosuccinate. Lipopolysaccharide (LPS) and Th2 cytokines might lead to over-expression of arginase, then leads to the increased generation of proline and polyamines from ʟ-ornithine.

• 

  Fig. 2 Schematic diagram of two compartments of alveolar NO and airway NO. During exhalation, gas with an NO in the alveolar region, CANO (ppb) passes through the airways. During its passage, NO diffuses from the airway walls to the bronchial lumen. Thus, the concentration of exhaled NO, FeNO is a function of J'awNO and CANO. The maximal flux of NO from the airway wall into the lumen, J'awNO (pl·s-1) is the product of the airway wall concentration of NO, CawNO (ppb) and airway tissue diffusing capacity, DawNO (pl·s-1·ppb-1).

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