Generic placeholder image

Current Respiratory Medicine Reviews


ISSN (Print): 1573-398X
ISSN (Online): 1875-6387

Review Article

Exhaled Nitric Oxide in COPD

Author(s): Andras Bikov*, Martina Meszaros and Zsofia Lazar

Volume 15 , Issue 2 , 2019

Page: [71 - 78] Pages: 8

DOI: 10.2174/1573398X14666181025150537


Chronic obstructive pulmonary disease (COPD) is a common and progressive disorder which is characterised by pathological abnormalities driven by chronic airway inflammation. The assessment of airway inflammation in routine clinical practice in COPD is limited to surrogate blood markers. Fractional exhaled nitric oxide (FENO) is a marker of eosinophilic airway inflammation in asthma, and it can predict steroid responsiveness and help tailor corticosteroid treatment. The clinical value of FENO in COPD is less evident, but some studies suggest that it may be a marker of the eosinophilic endotype. More importantly, mathematical methods allow investigation of the alveolar/small airway production of NO which potentially better reflects inflammatory changes in anatomical sites, most affected by COPD. This review summarises the pathophysiological role of nitric oxide in COPD, explains the methodology of its measurement in exhaled air and discusses clinical findings of FENO in COPD.

Keywords: Airway inflammation, biomarkers, COPD, lung, nitric oxide, respiratory system.

Graphical Abstract
Global Initiative for Chronic Obstructive Lung Disease 2017. Available from:
Vestbo J, Hogg JC. Convergence of the epidemiology and pathology of COPD. Thorax 2006; 61(1): 86-8.
Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010; 11: 122.
Celli BR, Locantore N, Yates J, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185(10): 1065-72.
Brightling CE. Chronic obstructive pulmonary disease phenotypes, biomarkers, and prognostic indicators. Allergy Asthma Proc 2016; 37(6): 432-8.
Horvath I, Barnes PJ, Loukides S, et al. A European Respiratory Society technical standard: Exhaled biomarkers in lung disease. Eur Respir J 2017; 49(4) pii: 1600965
Bikov A, Lazar Z, Horvath I. Established methodological issues in electronic nose research: how far are we from using these instruments in clinical settings of breath analysis? J Breath Res 2015; 9(3) 034001
Lázár Z, Horváth I, Vestbo J, Bikov A. Exhaled breath condensate in chronic obstructive pulmonary disease: Methodological challenges and clinical application. Minerva Pneumological 2018; 57(2): 42-56.
Lazar Z, Bikov A, Martinovszky F, Galffy G, Losonczy G, Horvath I. Exhaled breath temperature in patients with stable and exacerbated COPD. J Breath Res 2014; 8(4)046002
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention 2017. Available from:
Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011; 184(5): 602-15.
Lazar Z, Kelemen A, Galffy G, Losonczy G, Horvath I, Bikov A. Central and peripheral airway nitric oxide in patients with stable and exacerbated chronic obstructive pulmonary disease. J Breath Res 2018; 12(3) 036017
Zietkowski Z, Kucharewicz I, Bodzenta-Lukaszyk A. The influence of inhaled corticosteroids on exhaled nitric oxide in stable chronic obstructive pulmonary disease. Respir Med 2005; 99(7): 816-24.
Clini E, Bianchi L, Pagani M, Ambrosino N. Endogenous nitric oxide in patients with stable COPD: Correlates with severity of disease. Thorax 1998; 53(10): 881-3.
Hogman M, Lehtimaki L, Dinh-Xuan AT. Utilising exhaled nitric oxide information to enhance diagnosis and therapy of respiratory disease - current evidence for clinical practice and proposals to improve the methodology. Expert Rev Respir Med 2017; 11(2): 101-9.
Zeidler PC, Castranova V. Role of nitric oxide in pathological responses of the lung to exposure to environmental/occupational agents. Redox Rep 2004; 9(1): 7-18.
Brindicci C, Kharitonov SA, Ito M, et al. Nitric oxide synthase isoenzyme expression and activity in peripheral lung tissue of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010; 181(1): 21-30.
Guo FH, Deraeve HR, Rice TW, Stuehr DJ, Thunnissen F, Erzurum SC. Continuous nitric-oxide synthesis by inducible nitric-oxide synthase in normal human airway epithelium in-vivo. Proc Natl Acad Sci USA 1995; 92: 7809-13.
Ward JK, Belvisi MG, Fox AJ. Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro. J Clin Invest 1993; 92: 736-42.
Jiang W-T, Liu X-S, Xu Y-J, Ni W, Chen S-X. Expression of nitric oxide synthase isoenzyme in lung tissue of smokers with and without chronic obstructive pulmonary disease. Chin Med J (Engl) 2015; 128(12): 1584-9.
Dinh-Xuan AT, Higenbottan TW, Chelland CA. Impairment of endothelium-dependent pulmonary artery relaxation in chronic obstructive lung disease. N Engl J Med 1991; 324: 1539-47.
Miles PR, Bowman L, Rengasamy A, Huffman L. Alveolar type II cells cNOS activity and ATP levels are increased by lung surfactant or DPPC vesicles. Am J Physiol 1997; 273: 339-46.
Miles PR, Bowman L, Rengasamy A, Huffman L. Constitutive nitric oxide production by rat alveolar macrophages. Am J Physiol 1998; 274(3): 360-8.
Peinado VI, Barbera JA, Ramirez J, et al. Endothelial dysfunction in pulmonary arteries of patients with mild COPD. Am J Physiol 1998; 274: 908-13.
Barberà JA, Peinado VI, Santos S, Ramirez J, Roca J, Rodriguez-roisin R. Reduced expression of endothelial nitric oxide synthase in pulmonary arteries of smokers. Am J Respir Crit Care Med 2001; 164: 709-13.
Yang Q, Shigemura N, Underwood MJ, et al. NO and EDHF pathways in pulmonary arteries and veins are impaired in COPD patients. Vascul Pharmacol 2012; 57(2-4): 113-8.
Edirisinghe I, Yang SR, Yao H, Rajendrasozhan S. VEGFR-2 inhibition augments cigarette smoke-induced oxidative stress and inflammatory responses leading to endothelial dysfunction. FASEB J 2008; 22: 2297-310.
Arif E, Ahsan A, Vibhuti A, et al. Endothelial nitric oxide synthase gene variants contribute to oxidative stress in COPD. Biochem Biophys Res Commun 2007; 361(1): 182-8.
Ricciardolo FLM, Caramori G, Ito K, et al. Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease. J Allergy Clin Immunol Pract 2005; 116(5): 1028-35.
Heitzer T, Brockhoff C, Mayer B, et al. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: evidence for a dysfunctional nitric oxide synthase. Circ Res 2000; 86(2): E36-41.
Maestrelli P, Páska C, Saetta M, et al. Decreased haem oxygenase-1 and increased inducible nitric oxide synthase in the lung of severe COPD patients. Eur Respir J 2003; 21(6): 971-6.
Nakayama DK, Geller DA, Lowenstein CJ, et al. Cytokines and lipopolysaccharide induce nitric oxide synthase in cultured rat pulmonary artery smooth muscle. Am J Respir Cell Mol Biol 1992; 7: 471-6.
Kleinert H, Pautz A, Linker K, Schwarz PM. Regulation of the expression of inducible nitric oxide synthase Eur J Pharmacol 2004; 500(1-3 SPEC. ISS.): 255-66.
Geller DA, Billiar TR. Molecular biology of nitric oxide synthases. Cancer Metastasis Rev 1998; 17(1): 7-23.
Dupont LL, Glynos C, Bracke KR, Brouckaert P, Brusselle GG. Role of the nitric oxide-soluble guanylyl cyclase pathway in obstructive airway diseases. Pulm Pharmacol Ther 2014; 29(1): 1-6.
Kruzliakm P, Maruyama J, Maruyama K. Role of nitric oxide in pathophysiology and treatment of pulmonary hypertension. Vitam Horm 2014; 96: 407-24.
Ichinose M, Sugiura H, Yamagata S, Koarai A, Shirato K. Increase in Reactive Nitrogen Species Production in Chronic Obstructive Pulmonary Disease Airways. Am J Respir Crit Care Med 2000; 162: 701-6.
Mikkelsen RB, Wardman P. Biological chemistry of reactive oxygen and nitrogen. Mechanisms, and radiation-induced signal transduction. Oncogene 2003; 22: 5734-54.
Burney S, Niles JC, Dedon PC, Tannenbaum SR. DNA damage in deoxynucleosides and oligonucleotides treated with peroxynitrite. Chem Res Toxicol 1999; 12(6): 513-20.
Wink DA, Kasprzak KS, Maragos CM, et al. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 1991; 254(5034): 1001-3.
Stern AM, Zhu J. Advances in applied microbiology. Elsevier 2014; Vol. 87: pp. 187-220.
Barnes PJ. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discov 2013; 12(7): 543-59.
Østergaard L, Stankevicius E, Andersen MR, et al. Diminished NO release in chronic hypoxic human endothelial cells. Am J Physiol Heart Circ Physiol 2007; 293(5): H2894-903.
Ziesche R, Petkov V, Williams J, et al. Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue. Proc Natl Acad Sci U S A 1996; 93(22): 12478-83.
Robinson MA, Baumgardner JE, Otto CM. Oxygen-dependent regulation of nitric oxide production by inducible nitric oxide synthase. Free Radic Biol Med 2011; 51(11): 1952-65.
Nagao K, Takenaka S, Yamaji R, Inui H, Nakano Y. Nitric oxide synthase induction, cGMP elevation, and biopterin synthesis in vascular smooth muscle cells stimulated with interleukin-1β in hypoxia. J Biochem 2003; 133(4): 501-5.
Melillo G, Taylor LS, Brooks A, Cox GW, Varesio L. Regulation of inducible nitric oxide synthase expression in IFN-gamma-treated murine macrophages cultured under hypoxic conditions. The Journal of Immunology 1996; 157(6): 2638-44.
Palmer LA, Semenza GL, Stoler MH, Johns RA. Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am J Physiol Lung Cell Mol Physiol 1998; 274(2): L212-19.
Mi Z, Rapisarda A, Taylor L, et al. Synergystic induction of HIF-1α transcriptional activity by hypoxia and lipopolysaccharide in macrophages. Cell Cycle 2008; 7(2): 232-41.
Ward ME, Toporsian M, Scott JA, et al. Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant. J Clin Invest 2005; 115(11): 3128-39.
Silkoff P. History, technical and regulatory aspects of exhaled nitric oxide. J Breath Res 2008; 2(3) 037001
Tamasi L, Bohacs A, Bikov A, et al. Exhaled nitric oxide in pregnant healthy and asthmatic women. J Asthma 2009; 46(8): 786-91.
Antus B, Horvath I, Barta I. Assessment of exhaled nitric oxide by a new hand-held device. Respir Med 2010; 104(9): 1377-80.
ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005; 171(8): 912-30.
Kapande KM, McConaghy LA, Douglas I, et al. Comparative repeatability of two handheld fractional exhaled nitric oxide monitors. Pediatr Pulmonol 2012; 47(6): 546-50.
Silkoff PE, McClean PA, Slutsky AS, et al. Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide. Am J Respir Crit Care Med 1997; 155(1): 260-7.
Hogman M. Innovative exhaled breath analysis with old breathing manoeuvres-is there a problem or an advantage? J Breath Res 2017; 11(3) 031001
Hogman M, Thornadtsson A, Liv P, et al. Effects of growth and aging on the reference values of pulmonary nitric oxide dynamics in healthy subjects. J Breath Res 2017; 11(4) 047103
Travers J, Marsh S, Aldington S, et al. Reference ranges for exhaled nitric oxide derived from a random community survey of adults. Am J Respir Crit Care Med 2007; 176(3): 238-42.
Olin AC, Rosengren A, Thelle DS, Lissner L, Bake B, Toren K. Height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample. Chest 2006; 130(5): 1319-25.
Mandhane PJ, Hanna SE, Inman MD, et al. Changes in exhaled nitric oxide related to estrogen and progesterone during the menstrual cycle. Chest 2009; 136(5): 1301-7.
Iwamoto J, Pendergast DR, Suzuki H, Krasney JA. Effect of graded exercise on nitric oxide in expired air in humans. Respir Physiol 1994; 97(3): 333-45.
Zetterquist W, Pedroletti C, Lundberg JO, Alving K. Salivary contribution to exhaled nitric oxide. Eur Respir J 1999; 13(2): 327-33.
Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343(8890): 133-5.
Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 1991; 181(2): 852-7.
Grasemann H, Michler E, Wallot M, Ratjen F. Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis. Pediatr Pulmonol 1997; 24(3): 173-7.
Kharitonov SA, Wells AU, O’Connor BJ, et al. Elevated levels of exhaled nitric oxide in bronchiectasis. Am J Respir Crit Care Med 1995; 151(6): 1889-93.
de Gouw HW, Grunberg K, Schot R, Kroes AC, Dick EC, Sterk PJ. Relationship between exhaled nitric oxide and airway hyperresponsiveness following experimental rhinovirus infection in asthmatic subjects. Eur Respir J 1998; 11(1): 126-32.
Bikov A, Hull JH, Kunos L. Exhaled breath analysis, a simple tool to study the pathophysiology of obstructive sleep apnoea. Sleep Med Rev 2016; 27: 1-8.
Corradi M, Majori M, Cacciani GC, Consigli GF, de’Munari E, Pesci A. Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease. Thorax 1999; 54(7): 572-5.
Ansarin K, Chatkin JM, Ferreira IM, Gutierrez CA, Zamel N, Chapman KR. Exhaled nitric oxide in chronic obstructive pulmonary disease: relationship to pulmonary function. Eur Respir J 2001; 17(5): 934-8.
Rutgers SR, Meijer RJ, Kerstjens HA, van der Mark TW, Koeter GH, Postma DS. Nitric oxide measured with single-breath and tidal-breathing methods in asthma and COPD. Eur Respir J 1998; 12(4): 816-9.
Rutgers SR, van der Mark TW, Coers W, et al. Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease. Thorax 1999; 54(7): 576-80.
Lehouck A, Carremans C, De Bent K, Decramer M, Janssens W. Alveolar and bronchial exhaled nitric oxide in chronic obstructive pulmonary disease. Respir Med 2010; 104(7): 1020-6.
Dummer JF, Epton MJ, Cowan JO, et al. Predicting corticosteroid response in chronic obstructive pulmonary disease using exhaled nitric oxide. Am J Respir Crit Care Med 2009; 180(9): 846-52.
Malinovschi A, Janson C, Holmkvist T, Norback D, Merilainen P, Hogman M. Effect of smoking on exhaled nitric oxide and flow-independent nitric oxide exchange parameters. Eur Respir J 2006; 28(2): 339-45.
Sugiura H, Ichinose M. Nitrative stress in inflammatory lung diseases. Nitric Oxide 2011; 25(2): 138-44.
Clini E, Cremona G, Campana M, et al. Production of endogenous nitric oxide in chronic obstructive pulmonary disease and patients with cor pulmonale. Correlates with echo-Doppler assessment. Am J Respir Crit Care Med 2000; 162(2 Pt 1): 446-50.
Fabbri LM, Romagnoli M, Corbetta L, et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167(3): 418-24.
Alcazar-Navarrete B, Romero-Palacios PJ, Ruiz-Sancho A, Ruiz-Rodriguez O. Diagnostic performance of the measurement of nitric oxide in exhaled air in the diagnosis of COPD phenotypes. Nitric Oxide 2016; 54: 67-72.
Guo Y, Hong C, Liu Y, Chen H, Huang X, Hong M. Diagnostic value of fractional exhaled nitric oxide for asthma-chronic obstructive pulmonary disease overlap syndrome. Medicine (Baltimore) 2018; 97(23) e10857
Colak Y, Afzal S, Nordestgaard BG, Marott JL, Lange P. Combined value of exhaled nitric oxide and blood eosinophils in chronic airway disease: The Copenhagen General Population Study. Eur Respir J 2018
Papi A, Romagnoli M, Baraldo S, et al. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162(5): 1773-7.
Bafadhel M. Eosinophils in COPD: Are we nearly there yet? Lancet Respir Med 2017; 5(12): 913-4.
Ferreira IM, Hazari MS, Gutierrez C, Zamel N, Chapman KR. Exhaled nitric oxide and hydrogen peroxide in patients with chronic obstructive pulmonary disease: effects of inhaled beclomethasone. Am J Respir Crit Care Med 2001; 164(6): 1012-5.
Kunisaki KM, Rice KL, Janoff EN, Rector TS, Niewoehner DE. Exhaled nitric oxide, systemic inflammation, and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease: A prospective study. Ther Adv Respir Dis 2008; 2(2): 55-64.
Lehtimaki L, Kankaanranta H, Saarelainen S, et al. Bronchial nitric oxide is related to symptom relief during fluticasone treatment in COPD. Eur Respir J 2010; 35(1): 72-8.
Southworth T, Beech G, Foden P, Kolsum U, Singh D. The reproducibility of COPD blood eosinophil counts. Eur Respir J 2018.
Alcazar-Navarrete B, Ruiz Rodriguez O, Conde Baena P, Romero Palacios PJ, Agusti A. Persistently elevated exhaled nitric oxide fraction is associated with increased risk of exacerbation in COPD. Eur Respir J 2018; 51(1) pii: 1701457
Lim CS, Rani FA, Tan LE. Response of exhaled nitric oxide to inhaled corticosteroids in patients with stable COPD: A systematic review and meta-analysis. Clin Respir J 2018; 12(1): 218-26.
Santus P, Radovanovic D, Mascetti S, et al. Effects of bronchodilation on biomarkers of peripheral airway inflammation in COPD. Pharmacol Res 2018; 133: 160-9.
Zhao H, Li R, Lv Y, et al. Albuterol inhalation increases FeNO level in steroid-naive asthmatics but not COPD patients with reversibility. Clin Respir J 2017; 11(3): 328-36.
Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med 2006; 173(10): 1114-21.
Agusti AG, Villaverde JM, Togores B, Bosch M. Serial measurements of exhaled nitric oxide during exacerbations of chronic obstructive pulmonary disease. Eur Respir J 1999; 14(3): 523-8.
Antus B, Barta I, Horvath I, Csiszer E. Relationship between exhaled nitric oxide and treatment response in COPD patients with exacerbations. Respirology 2010; 15(3): 472-7.
Bhowmik A, Seemungal TA, Donaldson GC, Wedzicha JA. Effects of exacerbations and seasonality on exhaled nitric oxide in COPD. Eur Respir J 2005; 26(6): 1009-15.
Soter S, Barta I, Antus B. Predicting sputum eosinophilia in exacerbations of COPD using exhaled nitric oxide. Inflammation 2013; 36(5): 1178-85.
Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350(26): 2645-53.
Gelb AF, Barnes PJ, George SC, Ricciardolo FL, DiMaria G, Zamel N. Review of exhaled nitric oxide in chronic obstructive pulmonary disease. J Breath Res 2012; 6(4) 047101
Cristescu SM, Mandon J, Harren FJ, Merilainen P, Hogman M. Methods of NO detection in exhaled breath. J Breath Res 2013; 7(1)017104
George SC, Hogman M, Permutt S, Silkoff PE. Modeling pulmonary nitric oxide exchange. J Appl Physiol (1985) 2004; 96(3): 831-9.
Lazar Z, Horvath P, Puskas R, et al. A suitable protocol for measuring alveolar nitric oxide in asthma with differing severity to assess peripheral airways inflammation. J Asthma 2018; 56(6): 1-26.
Karvonen T, Kankaanranta H, Saarelainen S, Moilanen E, Lehtimaki L. Comparison of feasibility and estimates of central and peripheral nitric oxide parameters by different mathematical models. J Breath Res 2017; 11(4) 047102
Roy K, Borrill ZL, Starkey C, et al. Use of different exhaled nitric oxide multiple flow rate models in COPD. Eur Respir J 2007; 29(4): 651-9.
Brindicci C, Ito K, Torre O, Barnes PJ, Kharitonov SA. Effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on nitric oxide production and its metabolites in healthy control subjects, healthy smokers, and COPD patients. Chest 2009; 135(2): 353-67.
Brindicci C, Ito K, Resta O, Pride NB, Barnes PJ, Kharitonov SA. Exhaled nitric oxide from lung periphery is increased in COPD. Eur Respir J 2005; 26(1): 52-9.
Gelb AF, Flynn Taylor C, Krishnan A, et al. Central and peripheral airway sites of nitric oxide gas exchange in COPD. Chest 2010; 137(3): 575-84.
McCurdy MR, Sharafkhaneh A, Abdel-Monem H, Rojo J, Tittel FK. Exhaled nitric oxide parameters and functional capacity in chronic obstructive pulmonary disease. J Breath Res 2011; 5(1) 016003
Hogman M, Holmkvist T, Wegener T, et al. Extended NO analysis applied to patients with COPD, allergic asthma and allergic rhinitis. Respir Med 2002; 96(1): 24-30.
Bazeghi N, Gerds TA, Budtz-Jorgensen E, Hove J, Vestbo J. Exhaled nitric oxide measure using multiple flows in clinically relevant subgroups of COPD. Respir Med 2011; 105(9): 1338-44.
Short PM, Williamson PA, Lipworth BJ. Effects of extra-fine inhaled and oral corticosteroids on alveolar nitric oxide in COPD. Lung 2012; 190(4): 395-401.

© 2022 Bentham Science Publishers | Privacy Policy