Exhaled Nitric Oxide after  β<sub>2</sub>-agonist Inhalation and  Spirometry in Asthma

Silkoff, Philip E.; Wakita, Suguru; Chatkin, José Miguel; Ansarin, Khalil; Gutiérrez, C.; Caramori, Marlova Luzzi; McClean, Patricia; Slutsky, Arthur S.; Zamel, Noé; Chapman, Kenneth R.

doi:10.1164/ajrccm.159.3.9805044

Cited by 145 publications

(134 citation statements)

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“…The findings of this study support and extend published results on the effect of airway calibre on exhaled NO levels [7,11,12]. This study is the first to demonstrate the distinct relationship between FEV1 and exhaled NO levels in a cross-section of subjects with different airway diameters.…”

Section: Discussionsupporting

confidence: 89%

“…Control studies: possible confounding effects of repeated spirometry and nebulized salbutamol Repeated spirometric manoeuvres (as would occur during histamine challenge) have been shown to cause a reduction in NO levels [7,8] and b 2 -agonists may induce NO production [7,9]. In order to address whether the observed findings were purely related to these factors, 10 subjects in protocol 2 returned for the following studies.…”

Section: Study Design and Subjectsmentioning

confidence: 99%

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The current single exhalation method of measuring exhaled nitric oxide is affected by airway calibre

Wood

Robson

et al. 2000

Eur Respir J

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The current single exhalation method of measuring exhaled nitric oxide is affected by airway calibre. L.P. Ho, F.T. Wood, A. Robson, J.A. Innes, A.P. Greening. #ERS Journals Ltd 2000. ABSTRACT: The authors have observed that some patients with acute exacerbations of asthma do not have substantially higher levels of exhaled nitric oxide (NO). The study examined whether this could be explained by the effect of airway calibre on exhaled NO.Exhaled NO, height and forced expiratory volume in one second (FEV1) were measured in 12 steroid-naive asthmatics and 17 normal subjects. For comparison, another group of patients with airways disease (34 cystic fibrosis patients) were also studied. In 20 asthmatics (on various doses of inhaled steroids, 0±3,200 mg . day -1 ), exhaled NO was measured before and after histamine challenge (immediately after reaching the provocative concentration causing a 20% fall in FEV1) and in 12 of these patients, also after nebulized salbutamol to restore FEV1 to baseline. Studies were also conducted to examine possible confounding effects of repeated spirometry (as would occur in histamine challenge) and nebulized salbutamol alone in exhaled NO levels. Exhaled NO was measured using a single exhalation method with a chemiluminescence analyser at a constant flow rate and mouth pressure.There was a significant correlation between FEV1 and exhaled NO in steroid naive asthmatics (r=0.9, p<0.001) and cystic fibrosis patients (r= -0.48, p<0.05) but not in normal subjects (r= -0.13, p=0.61). Exhaled NO decreased significantly after histamine challenge and returned to baseline after bronchodilation by nebulized salbutamol (meanSEM: 23.63.6 parts per billion (ppb) (prehistamine), 18.22.7 ppb (posthistamine) and 23.63.8 ppb (postsalbutamol) p=0.001). Repeated spirometry and nebulized salbutamol did not affect exhaled NO measurements significantly.Exhaled nitric oxide levels appear to be lower in circumstances of smaller airway diameter. Hence, within a subject nitric oxide levels may be artefactually decreased during bronchoconstriction. This may be caused by increased airflow velocity in constricted airways when the exhalation rate is kept constant.

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Section: Discussionsupporting

confidence: 89%

Section: Study Design and Subjectsmentioning

confidence: 99%

The current single exhalation method of measuring exhaled nitric oxide is affected by airway calibre

Wood

Robson

et al. 2000

Eur Respir J

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“…To determine the potential impact of nitrogen in the residual volume, each subject also performed the preexpiratory breath hold maneuver with a 20-s breath hold in the presence of heliox without tidal breathing heliox before the maneuver. After measurement of the indexes of NO-exchange dynamics (4,5,25), general spirometry such as FVC, FEV 1, and FEV1 by FVC were measured in all subjects (Vmax229; Sensormedics, Yorba Linda, CA) by using the best performance (see Table 1) from three consecutive maneuvers.…”

Section: Methodsmentioning

confidence: 99%

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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“…Samples were collected into a specially constructed Tyvek bag from the cannulated mice. This 5-minute sample was adequate for the measurement of NO concentration in the expired air, using a Sievers Nitric Oxide analyzer (Sievers Inst., Boulder, CO) (Silkoff et al, 1999). Nitrate and nitrite in the previously isolated lavage samples were measured as an indicator of NO production through reduction with acidified vanadium III using the Sievers NO Analyzer (Sievers, Boulder, CO).…”

Section: Measurement Of Exhaled No and Of Nitrate/nitrite In Lung Lavmentioning

confidence: 99%

Arginases I and II in lungs of ovalbumin-sensitized mice exposed to ovalbumin: Sources and consequences

Kenyon

Bratt

Linderholm

2008

Toxicology and Applied Pharmacology

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Arginase gene expression in the lung has been linked to asthma both in clinical studies of human patients and in the well-studied mouse model of ovalbumin-induced airway inflammation. Arginase is thought to regulate NO levels in the lung by its ability to divert arginine, the substrate for nitric oxide synthases that produce citrulline and NO, into an alternative metabolic pathway producing ornithine and urea. In the present study arginase I and arginase II concentrations were measured in isolated microdissected airway preparations from sensitized Balb/c mice exposed to ovalbumin aerosol. We found that arginase II was constitutively expressed in the airways of normal mice, whereas arginase I was undetectable in normal airways, while its expression was increased in airways of mice exposed to ovalbumin. The expression of arginase I strongly correlated with the presence of lung inflammation, as quantified by differential cell counts in lung lavage, suggesting that most, or all, of the arginase I in lungs of mice exposed to ovalbumin is present in the inflammatory cells rather than in the airway epithelium. There was also a significant correlation between increased expression of arginase I in the isolated airways and decreased lung compliance. On the other hand, while we found arginase II expression to also be significantly increased in airways from mice exposed to ovalbumin as compared with normal airways, the relative increase was much less than that observed for arginase I, suggesting that there was a smaller contribution of inflammatory cells to the arginase II content of the airways in mice exposed to ovalbumin. There was no apparent correlation between the content of arginase in isolated airways and exhaled NO concentration in the expired air from mice exposed to ovalbumin. However, there was a correlation between exhaled NO concentration from mice exposed to ovalbumin and the lymphocyte content of the lung lavage.The concentration of arginine found in isolated airways from Balb/c mice exposed for 2 weeks to ovalbumin was about half of the value found in isolated microdissected airways from normal mice. Treatment of mice systemically with an arginase inhibitor significantly increased the amount of NO produced, as measured as the amount of nitrite + nitrate (NOx) in lung lavage supernatant prepared from mice exposed to ovalbumin. Our results are consistent with the hypothesis that the response of the lung to ovalbumin challenge includes an adaptive response in the large airways regulating the concentration of arginine within cells of the airway epithelium and subepithelial layer, by shunting of arginine into the metabolic pathway for increased synthesis of NO.

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

Cited by 145 publications

References 14 publications

The current single exhalation method of measuring exhaled nitric oxide is affected by airway calibre

The current single exhalation method of measuring exhaled nitric oxide is affected by airway calibre

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

Arginases I and II in lungs of ovalbumin-sensitized mice exposed to ovalbumin: Sources and consequences

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

Cited by 145 publications

References 14 publications

The current single exhalation method of measuring exhaled nitric oxide is affected by airway calibre

The current single exhalation method of measuring exhaled nitric oxide is affected by airway calibre

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

Arginases I and II in lungs of ovalbumin-sensitized mice exposed to ovalbumin: Sources and consequences

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