Flow-independent nitric oxide exchange parameters in healthy adults

Shin, Hye‐Won; Rose-Gottron, Christine M.; Perez, Federico; Cooper, Dan M.; Wilson, Archie F.; George, Steven C.

doi:10.1152/jappl.2001.91.5.2173

Cited by 27 publications

(37 citation statements)

References 32 publications

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“…Low Jaw,NO and high Calv,NO may have different pathophysiological effects and roles, and, therefore, may be pharmacologically corrected using different drugs, including iNOS inhibitors or NOS donors [7]. The present study has shown a significant correlation between Calv,NO and both FEV1 and FEV1/FVC ratio, which was not seen in either healthy subjects [27] or in mild asthmatics [15,26], suggesting that Calv,NO in COPD patients may reflect peripheral inflammation and remodelling resulting in increased peripheral resistance. Calv,NO might be an early and simple marker to diagnose early stages of peripheral inflammation in COPD.…”

Section: Copd Severitymentioning

confidence: 44%

Exhaled nitric oxide from lung periphery is increased in COPD

Brindicci¹

2005

European Respiratory Journal

181

161

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Single constant flow exhaled nitric oxide (eNO) cannot distinguish between the sources of NO. The present study measured eNO at multiple expired flows (MEFeNO) to partition NO into alveolar (Calv,NO) and bronchial (Jaw,NO) fractions to investigate peripheral lung contribution to eNO in chronic obstructive lung disease (COPD).MEFeNO were made in 81 subjects including 18 nonsmokers, 16 smokers and 47 COPD patients of different severity by the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD): 0 (n514), 1 (n57), 2 (n511), 3 (n58) and 4 (n57).COPD severity was correlated with an increased Calv,NO regardless of the patient's smoking habit or current treatment. The levels of Calv,NO (in ppb) were 1.4¡0.09 in nonsmokers, 2.1¡0.1 in smokers categorised as GOLD stage 0 (smokers-GOLD0), 3.3¡0.18 in GOLD1-2 and 3.4¡0.1 in GOLD3-4. Jaw,NO levels (pL?s -1 ) were higher in nonsmokers than smokers-GOLD0 (716.2¡33.3versus 464.7¡41.8), GOLD3-4 (609.4¡71). Diffusion of NO in the airways (Daw,NO pL?ppb -1 s -1 ) was higher (p,0.05) in GOLD3-4 than in nonsmokers (15¡1.2 versus 11¡0.5) and smokers-GOLD0 (11.6¡0.5). MEFeNO measurements were reproducible, free from day-to-day and diurnal variation and were not affected by bronchodilators.In conclusion, chronic obstructive pulmonary disease is associated with elevated alveolar nitric oxide. Measurements of nitric oxide at multiple expired flows may be useful in monitoring inflammation and progression of chronic obstructive pulmonary disease, and the response to anti-inflammatory treatment.KEYWORDS: Chronic obstructive pulmonary disease, exhaled nitric oxide, multiple expiratory flow, small airway inflammation S ingle expiratory flow exhaled nitric oxide (eNO) measurements are simple, highly reproducible [1], have been used to monitor larger airway inflammation in asthma research [2], and are now moving into clinical practice [3]. However, small airways and lung parenchyma are the predominant sites of inflammation in patients with chronic obstructive pulmonary disease (COPD) [4]. Progression of COPD is associated with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the small airway wall by inflammatory cells [4]. There is a high level of expression of inducible NO synthase (iNOS) presence in sputum macrophages [5], alveolar walls, small airway epithelium and vascular smooth muscle of COPD patients [5,6]. In patients with COPD this may result in an increased production of NO and NO-related species in the lung periphery, which through the function of peroxynitrite may amplify the inflammation and lead to inhaled corticosteroid (ICS) resistance, particularly as the disease becomes more severe [7].The current single expiratory technique measures predominantly larger airway-derived NO and may only partially reflect peripheral inflammation [8,9]. eNO is often in the normal range or even reduced in moderate COPD [10], probably due to down-regulation of endothelial NO synthase (eNOS) [11] and iNOS [12] by cigarette ...

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Section: Copd Severitymentioning

confidence: 44%

Exhaled nitric oxide from lung periphery is increased in COPD

Brindicci¹

2005

European Respiratory Journal

181

161

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“…The prediction of a zero or near-zero alveolar concentration in the presence of a zero alveolar source suggests the possibility that previous reports of CA NO values that range from 1 to 5 ppb (7,10,18,19,20) may represent NO in or near the alveolar and respiratory bronchiole region, but the source may be the airways because of backdiffusion. The most commonly used technique to estimate CA NO is a plot of V NO vs. V E (30).…”

Section: Impact Of Axial Diffusion On Flow-independent No Parametersmentioning

confidence: 80%

“…Mean (SD) values for C NOpeak , W 50 , and V I,II in the absence or presence of the 2-min heliox tidal breathing were 52 (20) and 53 (30) ppb, 139 (28) and 124 (27) ml, and 544 (88) and 485 (55) ml, respectively. In addition, mean (SD) values for C*E NO,50 in the absence or presence of the 2-min heliox tidal breathing were 10.8 (5.94) and 11.4 (6.53) ppb, respectively, and were not statistically different.…”

Section: Resultsmentioning

confidence: 99%

“…The characteristics of NO gas exchange are unique compared with other endogenous gases because exhaled NO is thought to have a significant alveolar and airway source (6,8,15,22). A two-compartment model is commonly used to characterize NO exchange dynamics for healthy and diseased lungs (9,11,13,20,21,23,24,27,29), by partitioning exhaled NO into airway and alveolar contributions using three flow-independent NO exchange parameters: maximum flux of NO from the airways (JЈaw NO ), the diffusing capacity of NO in the airways (Daw NO ), and the steady-state alveolar concentration (CA NO ). However, the two-compartment model considers only convection of NO in the airways as a transport mechanism and has neglected axial diffusion of NO in the gas phase to preserve mathematical simplicity.…”

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confidence: 99%

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Probing the impact of axial diffusion on nitric oxide exchange dynamics with heliox

Shin

Condorelli

Rose-Gottron

et al. 2004

Journal of Applied Physiology

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Shin, Hye-Won, Peter Condorelli, Christine M. Rose-Gottron, Dan M. Cooper, and Steven C. George. Probing the impact of axial diffusion on nitric oxide exchange dynamics with heliox. J Appl Physiol 97: 874 -882, 2004. First published April 30, 2004 10.1152/ japplphysiol.01297.2003.-Exhaled nitric oxide (NO) is a potential noninvasive index of lung inflammation and is thought to arise from the alveolar and airway regions of the lungs. A two-compartment model has been used to describe NO exchange; however, the model neglects axial diffusion of NO in the gas phase, and recent theoretical studies suggest that this may introduce significant error. We used heliox (80% helium, 20% oxygen) as the insufflating gas to probe the impact of axial diffusion (molecular diffusivity of NO is increased 2.3-fold relative to air) in healthy adults (21-38 yr old, n ϭ 9). Heliox decreased the plateau concentration of exhaled NO by 45% (exhalation flow rate of 50 ml/s). In addition, the total mass of NO exhaled in phase I and II after a 20-s breath hold was reduced by 36%. A single-path trumpet model that considers axial diffusion predicts a 50% increase in the maximum airway flux of NO and a near-zero alveolar concentration (CA NO) and source. Furthermore, when NO elimination is plotted vs. constant exhalation flow rate (range 50 -500 ml/s), the slope has been previously interpreted as a nonzero CANO (range 1-5 ppb); however, the trumpet model predicts a positive slope of 0.4 -2.1 ppb despite a zero CANO because of a diminishing impact of axial diffusion as flow rate increases. We conclude that axial diffusion leads to a significant backdiffusion of NO from the airways to the alveolar region that significantly impacts the partitioning of airway and alveolar contributions to exhaled NO. gas exchange; model; exhaled breath NITRIC OXIDE (NO) performs many important functions in the lungs and has been regarded as a potential noninvasive marker of lung inflammation (2). The characteristics of NO gas exchange are unique compared with other endogenous gases because exhaled NO is thought to have a significant alveolar and airway source (6,8,15,22). A two-compartment model is commonly used to characterize NO exchange dynamics for healthy and diseased lungs (9,11,13,20,21,23,24,27,29), by partitioning exhaled NO into airway and alveolar contributions using three flow-independent NO exchange parameters: maximum flux of NO from the airways (JЈaw NO ), the diffusing capacity of NO in the airways (Daw NO ), and the steady-state alveolar concentration (CA NO ). However, the two-compartment model considers only convection of NO in the airways as a transport mechanism and has neglected axial diffusion of NO in the gas phase to preserve mathematical simplicity.Recently, our laboratory (17) and others (31) separately demonstrated theoretically that axial diffusion may play an important role in NO transport. During exhalation, the concentration of NO is higher in the airways compared with the alveoli, creating a gradient for diffusion of NO from the air...

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“…The two-compartment model separates the lung into a rigid trumpet-shaped airway region characterized by a constant NO production (or flux of NO from the airway wall surface) and an expansile distal airway/alveolar region characterized by a steady-state NO concentration. This model has been used to estimate proximal and distal NO sources in healthy subjects as well as numerous disease states, including asthma (13,27,(35)(36)(37)(38)(39)42).…”

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confidence: 99%

Quantifying proximal and distal sources of NO in asthma using a multicompartment model

Shelley

Puckett

George

2010

Journal of Applied Physiology

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Shelley DA, Puckett JL, George SC. Quantifying proximal and distal sources of NO in asthma using a multicompartment model. J Appl Physiol 108: 821-829, 2010. First published January 21, 2010 doi:10.1152/japplphysiol.00795.2009 is detectable in exhaled breath and is thought to be a marker of lung inflammation. The multicompartment model of NO exchange in the lungs, which was previously introduced by our laboratory, considers parallel and serial heterogeneity in the proximal and distal regions and can simulate dynamic features of the NO exhalation profile, such as a sloping phase III region. Here, we present a detailed sensitivity analysis of the multicompartment model and then apply the model to a population of children with mild asthma. Latin hypercube sampling demonstrated that ventilation and structural parameters were not significant relative to NO production terms in determining the NO profile, thus reducing the number of free parameters from nine to five. Analysis of exhaled NO profiles at three flows (50, 100, and 200 ml/s) from 20 children (age 7-17 yr) with mild asthma representing a wide range of exhaled NO (4.9 ppb Ͻ fractional exhaled NO at 50 ml/s Ͻ 120 ppb) demonstrated that 90% of the children had a negative phase III slope. The multicompartment model could simulate the negative phase III slope by increasing the large airway NO flux and/or distal airway/alveolar concentration in the well-ventilated regions. In all subjects, the multicompartment model analysis improved the leastsquares fit to the data relative to a single-path two-compartment model. We conclude that features of the NO exhalation profile that are commonly observed in mild asthma are more accurately simulated with the multicompartment model than with the two-compartment model. The negative phase III slope may be due to increased NO production in well-ventilated regions of the lungs. nitric oxide; heterogeneity; sensitivity; phase III slope NITRIC OXIDE (NO) is a free radical present in exhaled breath and is thought to be a marker of inflammation in the lungs (3, 21). Exhaled NO can be elevated in inflammatory diseases, such as asthma, and is reduced after treatment with inhaled corticosteroids (ICS) (17). These observations have generated significant interest in the clinical use of exhaled NO as a noninvasive marker to diagnose and monitor the progression of inflammatory diseases.Elevated NO in asthma has been traditionally attributed to inflammation in the proximal airways; however, recent evidence highlights the importance of peripheral regions (e.g., respiratory bronchioles) in inflammation (13,18,19). Elevated peripheral NO has been associated with increased symptoms and can be resistant to ICS (13). When NO is measured at the mouth during exhalation, the only way to distinguish between the proximal and peripheral NO sources is through a mathematical model. The two-compartment model of NO exchange is a relatively simple, yet powerful, tool to partition the NO signal into proximal (large airways) and distal (small airways and alve...

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Flow-independent nitric oxide exchange parameters in healthy adults

Cited by 27 publications

References 32 publications

Exhaled nitric oxide from lung periphery is increased in COPD

Exhaled nitric oxide from lung periphery is increased in COPD

Probing the impact of axial diffusion on nitric oxide exchange dynamics with heliox

Quantifying proximal and distal sources of NO in asthma using a multicompartment model

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