Stickstoffmonoxid in verschiedenen Kompartimenten des Atemtrakts – Vergleich der Daten von Nichtrauchern und Rauchern

Zusammenfassung

Wir untersuchten mittels verschiedener Atemflüsse, ob sich Unterschiede zwischen Rauchern und Nichtrauchern hinsichtlich der differenziellen NO-Parameter Bronchialwand-Konzentration (C_aw), alveolare Konzentration (C_alv) und Diffusionskoeffizient (D_awNO) ergeben. Die 34 untersuchten beschwerdefreien, nicht therapierten Raucher weisen im Vergleich zu 43 gesunden Nichtrauchern signifikant niedrigere FeNO-Werte auf. Die Analyse der differenziellen NO-Parameter mittels des 2-Kompartimenten-Modells der NO-Produktion belegt unter Rauchern eine signifikant verminderte bronchiale NO-Konzentration, jedoch keine signifikante Änderung der dem Alveolarbereich zugerechneten NO-Fraktion. Die Zusammenhänge zwischen den einzelnen NO-Parametern der Nichtraucher passen zum 2-Kompartimenten-Modell. Im Gegensatz dazu weisen Raucher eine monotone positive Korrelation zwischen den verminderten C_aw und FeNO unter allen fünf Flussraten auf. Das könnte darauf zurückzuführen sein, dass das alveolare NO der Raucher teilweise aus dem bronchialen Bereich stammt. Das passt zu deren signifikant erniedrigten FEV₁-, FEF₅₀- und FEF₇₅-Werten, welche mit Turbulenzen und unterschiedlichen Verzögerungen des exspiratorischen Gasabflusses im Bronchiolo-Alveolarbereich einhergehen. Wir stellen die Hypothese auf, dass der verminderten NO-Konzentration in der Bronchialwand des Rauchers eine pathophysiologische Rolle bei der Manifestation eines Small airways disease zukommt.

Abstract

Our aim was to determine by means of five exhaled flow rates differential parameters of FeNO and the relations between them in smokers and non-smokers. 34 smokers (without respiratory symptoms and medication) were examined. Compared to 43 healthy non-smokers, FeNO was significantly lower. The analysis of the differential NO parameters by means of the two-compartment model of NO production revealed a significant decrease in the bronchial NO concentration, but no significant changes of NO in alveolar fraction by smokers. The relations between differential parameters in non-smokers confirm the theoretical expectations of the two-compartment model. Conversely, smokers exhibit an abnormal remarkable correlation, namely, a high correlation between the reduced C_aw und FeNO at all five flow rates. It may be assumed that the alveolar NO fraction in smokers is to some extent of bronchial origin. Such a preposition is in line with significantly decreases of FEV₁, FEF₅₀ and FEF₇₅ in smokers, which are associated with turbulences, flow inhomogeneity and a varied delay of expiration time from the peripheral airways. We hypothesize that the decreased NO concentration in the bronchial wall of smokers plays a pathophysiological role in the genesis of small airways disease.

Literatur

• 1 Kharitonov S A, Yates D, Robbins R A et al. Increased nitric oxide in exhaled air of asthmatic patients.  Lancet. 1994;  343 133-135
• 2 Silvestri M, Spallarossa D, Frangova Yourukova V et al. Orally exhaled nitric oxide levels are related to the degree of blood eosinophilia in atopic children with mild-intermittent asthma.  Eur Respir J. 1999;  13 321-326
• 3 Ihre E, Gyllfors P, Gustafsson L E et al. Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge.  Eur Respir J. 2006;  27 1152-1159
• 4 Spanier A J, Kahn R S, Hornung R W et al. Environmental exposures, nitric oxide synthase genes, and exhaled nitric oxide in asthmatic children.  Pediatr Pulmonol. 2009;  44 812-819
• 5 Smith A D, Cowan J O, Filsell S et al. Diagnosing asthma. Comparisons between exhaled nitric oxide measurements and conventional tests.  Am J Respir Crit Care Med. 2004;  169 473-478
• 6 Zacharasiewicz A, Wilson N, Lex C et al. Clinical use of non-invasive measurements of airway inflammation in steroid reduction in children.  Am J Respir Crit Care Med. 2005;  171 1077-1082
• 7 Zeiger R S, Szefler S J, Phillips B R et al. Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma.  J Allergy Clin Immunol. 2006;  117 45-52
• 8 Tsujino I, Nishimura M, Kamachi A et al. Exhaled nitric oxide – is it really a good marker of airway inflammation in bronchial asthma?.  Respiration. 2000;  67 645-651
• 9 Tsoukias N M, George S C. A two-compartment model of pulmonary nitric oxide exchange dynamics.  J Appl Physiol. 1998;  85 653-666
• 10 Silkoff P E, Sylvester J T, Zamel N et al. Airway nitric oxide diffusion in asthma: role in pulmonaly function and bronchial responsiveness.  Am J Respir Crit Care Med. 2000;  161 1218-1228
• 11 Silkoff P E, McClean P A, Slutzky A S 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;  155 260-267
• 12 Lehtimaki L, Kankaanranta H, Saarelainen S et al. Inhaled fluticasone decreases bronchial but not alveolar nitric oxide output in asthma.  Eur Respir J. 2001;  18 635-639
• 13 American Thoracic Society . 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;  171 912-930
• 14 Baur X, Barbinova L. Latex allergen exposure increases exhaled nitric oxide in symptomatic health care workers.  Eur Respir J. 2005;  25 309-316
• 15 Jörres R A. Modelling the production of nitric oxide within the human airways.  Eur Respir j. 2000;  16 555-560
• 16 Gold D R, Wang X, Wypij D et al. Effects of cigarette smoking on lung function in adolescent boys and girls.  N Engl J Med. 1996;  335 931-937
• 17 Buist A S, Vollmer W M, Wu Y et al. Effects of cigarette smoking on lung function in four population samples in the People’s Republic China. The PRS-US Cardiovascular and Cardiopulmonary Research Group.  Am J Respir Crit Care Med. 1995;  151 1393-1400
• 18 Milaat W A, el-Ganai F M. Effects of cigarette smoking on lung function of Saudi students.  Asia Pac J Public Health. 1998;  10 39-42
• 19 Mahut B, Trinquart L, Le Bourgeois M et al. Multicentre trial evaluating alveolar NO fraction as a marker of asthma control and severity.  Allergy. 2009;  [Epub ahead of print]
• 20 Hogman M, Holmkvist , Wegener T et al. Extended NO analysis applied to patients with COPD, allergic asthma and allergic rhinitis.  Respir Med. 2002;  96 24-30
• 21 Suresh V, Shelley D A, Shin H W et al. Effect of heterogeneous ventilation and nitric oxide production on exhaled nitric oxide profiles.  J Appl Physiol. 2008;  104 1743-1752
• 22 Shin H W, Condorelli P, Rose-Gottron C M et al. Probing the impact of axial diffusion on nitric oxide exchange dynamics with heliox.  Appl Physiol. 2007;  97 874-882
• 23 Brindicci C, Ito K, Resta O et al. Exhaled nitric oxide from lung periphery is increased in COPD.  Eur Respir J. 2005;  26 52-59
• 24 Yang X L, Liu Y, Luo H Y. Respiratory flow in obstructed airways.  J Biomech. 2006;  39 2743-2751
• 25 Roy K, Borrill Z L, Starkey C et al. Use of different exhaled nitric oxide multiple flow rate models in COPD.  Eur Respir J. 2007;  29 651-659
• 26 Brindicci C, Ito K, Torre O et al. 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;  135 353-367
• 27 Shin H W, Condorelli P, Rose-Gottron C M et al. Probing of impact of axial diffusion on nitric oxide exchange dynamics with heliox.  J Appl Physiol. 2004;  97 874-882
• 28 Condorelli P, Shin H W, Aledia A S et al. A simple technique to characterize proximal and peripheral nitric oxide exchange using constant flow exhalations and an axial diffusion model.  J Appl Physiol. 2007;  102 417-25
• 29 Gelb A F, Flynn Taylor C F, Krishnan A et al. Central and peripheral airways sites of nitric oxide gas exchange in COPD.  Chest. 2010;  137 575-84
• 30 Lehtimaki L, Kankaanranta H, Saarelainen S et al. Inhaled fluticasone decreases bronchial nitric oxide is related to symptom relief during fluticasone treatment in COPD.  Eur Respir J. 2010;  35 72-78
• 31 van Veen I H, Sterk P J, Schot R et al. Alveolar nitric oxide versus measures of peripheral airway dysfunction in severe asthma.  Eur Respir J. 2006;  27 951-956
• 32 Barbinova L, Baur X. Weibel’s Modell der Morphometrie der Lungen (WML) und die Voraussetzungen des 2-Kompartimenten Modell (2-KM) der NO-Produktion.  Pneumologie. 2010;  64 S176
• 33 Weibel E R. Morphometry of the human lung.. Berlin: Springer-Verlag; 1963
• 34 Van Muylem A, Noel C, Paiva M. Modelling of impact of gas molecular diffusion on nitric oxide expired profile.  J Appl Physiol. 2003;  94 119-127
• 35 Barbinova L, Baur X. Effects of flow rates on the estimation of differential NO Parameters.  Am J Respir Crit Care Med. 2010;  181 A4270
• 36 Gelb A F, Taylor C F, Nussbaum E et al. Alveolar and airway sites of nitric oxide inflammation in treated asthma.  Am J Respir Crit Care Med. 2004;  170 737-741
• 37 Kharitonov S A, Robbins R A, Yates D et al. Acute and chronic effects of cigarette smoking on exhaled nitric oxide.  Am J Respir Crit Care Med. 1995;  152 609-612
• 38 Hoyt J C, Robbins R A, Habib M et al. Cigarette smoke decreases inducible nitric oxide synthase in lung epithelial cells.  Exp Lung Res. 2003;  29 17-28
• 39 Rytila P, Rehn T, Ilumets H et al. Increased oxidative stress in asymptomatic current chronic smokers and GOLD stage 0 COPD.  Respir Res. 2006;  7 69
• 40 Ferrer E, Peinado V I, Diez M et al. Effects of cigarette smoke on endothelial function of pulmonary arteries in the guinea pig.  Respir Res. 2009;  10 76
• 41 Brindicci C, Kharitonov S A, 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 21-30
• 42 Malinovschi A, Janson C, Holmkvist T et al. Effect of smoking on exhaled nitric oxide and flow-independent nitric oxide exchange parameters.  Eur Respir J. 2006;  28 339-345
• 43 Pietropaoli A P, Perillo I B, Perkins P T et al. Smokers have reduced nitric oxide production by conducting airways but normal levels in the alveoli.  Inhal Toxicol. 2007;  19 533-541
• 44 Olin A C, Rosengren A, Thelle D S et al. Height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample.  Chest. 2006;  130 1319-1325
• 45 Borrill Z L, Roy K, Vesey R S et al. Non-invasive biomarkers and pulmonary function in smokers.  Inter J Chron Obstruct Pulmon Dis. 2008;  3 171-183
• 46 Dupuy P M, Shore S A, Drazen J M et al. Bronchodilator action of inhaled nitric oxide in guinea pigs.  Clin Invest. 1992;  90 421-428
• 47 Sanna A, Kurtansky A, Veriter C et al. Bronchodilator effect of inhaled nitric oxide in healthy men.  Am J Respir Crit Care Med. 1994;  150 1702-1704