Modeling pulmonary nitric oxide exchange.

Nitric oxide (NO) was first detected in the exhaled breath more than a decade ago and has since been investigated as a noninvasive means of assessing lung inflammation. Exhaled NO arises from the airway and alveolar compartments, and new analytical methods have been developed to characterize these sources. A simple two-compartment model can adequately represent many of the observed experimental observations of exhaled concentration, including the marked dependence on exhalation flow rate. The model characterizes NO exchange by using three flow-independent exchange parameters. Two of the parameters describe the airway compartment (airway NO diffusing capacity and either the maximum airway wall NO flux or the airway wall NO concentration), and the third parameter describes the alveolar region (steady-state alveolar NO concentration). A potential advantage of the two-compartment model is the ability to partition exhaled NO into an airway and alveolar source and thus improve the specificity of detecting altered NO exchange dynamics that differentially impact these regions of the lungs. Several analytical techniques have been developed to estimate the flow-independent parameters in both health and disease. Future studies will focus on improving our fundamental understanding of NO exchange dynamics, the analytical techniques used to characterize NO exchange dynamics, as well as the physiological interpretation and the clinical relevance of the flow-independent parameters.     

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

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 = 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 Ca(NO) (range 1-5 ppb); however, the trumpet model predicts a positive slope of 0.4-2.1 ppb despite a zero Ca(NO) 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.     

Characterizing airway and alveolar nitric oxide exchange during tidal breathing using a three-compartment model.

Exhaled nitric oxide (NO) may be a useful marker of lung inflammation, but the concentration is highly dependent on exhalation flow rate due to a significant airway source. Current methods for partitioning pulmonary NO gas exchange into airway and alveolar regions utilize multiple exhalation flow rates or a single-breath maneuver with a preexpiratory breath hold, which is cumbersome for children and individuals with compromised lung function. Analysis of tidal breathing data has the potential to overcome these limitations, while still identifying region-specific parameters. In six healthy adults, we utilized a three-compartment model (two airway compartments and one alveolar compartment) to identify two potential flow-independent parameters that represent the average volumetric airway flux (pl/s) and the time-averaged alveolar concentration (parts/billion). Significant background noise and distortion of the signal from the sampling system were compensated for by using a Gaussian wavelet filter and a series of convolution integrals. Mean values for average volumetric airway flux and time-averaged alveolar concentration were 2,500 +/- 2,700 pl/s and 3.2 +/- 3.4 parts/billion, respectively, and were strongly correlated with analogous parameters determined from vital capacity breathing maneuvers. Analysis of multiple tidal breaths significantly reduced the standard error of the parameter estimates relative to the single-breath technique. Our initial assessment demonstrates the potential of utilizing tidal breathing for noninvasive characterization of pulmonary NO exchange dynamics.     

Airway diffusing capacity of nitric oxide and steroid therapy in asthma.

Exhaled nitric oxide (NO) concentration is a noninvasive index for monitoring lung inflammation in diseases such as asthma. The plateau concentration at constant flow is highly dependent on the exhalation flow rate and the use of corticosteroids and cannot distinguish airway and alveolar sources. In subjects with steroid-naive asthma (n = 8) or steroid-treated asthma (n = 12) and in healthy controls (n = 24), we measured flow-independent NO exchange parameters that partition exhaled NO into airway and alveolar regions and correlated these with symptoms and lung function. The mean (+/-SD) maximum airway flux (pl/s) and airway tissue concentration [parts/billion (ppb)] of NO were lower in steroid-treated asthmatic subjects compared with steroid-naive asthmatic subjects (1,195 +/- 836 pl/s and 143 +/- 66 ppb compared with 2,693 +/- 1,687 pl/s and 438 +/- 312 ppb, respectively). In contrast, the airway diffusing capacity for NO (pl.s-1.ppb-1) was elevated in both asthmatic groups compared with healthy controls, independent of steroid therapy (11.8 +/- 11.7, 8.71 +/- 5.74, and 3.13 +/- 1.57 pl.s-1.ppb-1 for steroid treated, steroid naive, and healthy controls, respectively). In addition, the airway diffusing capacity was inversely correlated with both forced expired volume in 1 s and forced vital capacity (%predicted), whereas the airway tissue concentration was positively correlated with forced vital capacity. Consistent with previously reported results from Silkoff et al. (Silkoff PE, Sylvester JT, Zamel N, and Permutt S, Am J Respir Crit Med 161: 1218-1228, 2000) that used an alternate technique, we conclude that the airway diffusing capacity for NO is elevated in asthma independent of steroid therapy and may reflect clinically relevant changes in airways.     

Examining axial diffusion of nitric oxide in the lungs using heliox and breath hold.

Exhaled nitric oxide (NO) is highly dependent on exhalation flow; thus exchange dynamics of NO have been described by multicompartment models and a series of flow-independent parameters that describe airway and alveolar exchange. Because the flow-independent NO airway parameters characterize features of the airway tissue (e.g., wall concentration), they should also be independent of the physical properties of the insufflating gas. We measured the total mass of NO exhaled (A(I,II)) from the airways after five different breath-hold times (5-30 s) in healthy adults (21-38 yr, n = 9) using air and heliox as the insufflating gas, and then modeled A(I,II) as a function of breath-hold time to determine airway NO exchange parameters. Increasing breath-hold time results in an increase in A(I,II) for both air and heliox, but A(I,II) is reduced by a mean (SD) of 31% (SD 6) (P < 0.04) in the presence of heliox, independent of breath-hold time. However, mean (SD) values (air, heliox) for the airway wall diffusing capacity [3.70 (SD 4.18), 3.56 pl.s(-1).ppb(-1) (SD 3.20)], the airway wall concentration [1,439 (SD 487), 1,503 ppb (SD 644>)], and the maximum airway wall flux [4,156 (SD 2,502), 4,412 pl/s (SD 2,906)] using a single-path trumpet-shaped airway model that considers axial diffusion were independent of the insufflating gas (P > 0.55). We conclude that a single-path trumpet model that considers axial diffusion captures the essential features of airway wall NO exchange and confirm earlier reports that the airway wall concentration in healthy adults exceeds 1 ppm and thus approaches physiological concentrations capable of modulating smooth muscle tone.     

Effect of heterogeneous ventilation and nitric oxide production on exhaled nitric oxide profiles.

Elevated exhaled nitric oxide (NO) in the breath of asthmatic subjects is thought to be a noninvasive marker of lung inflammation. Asthma is also characterized by heterogeneous bronchoconstriction and inflammation, which impact the spatial distribution of ventilation in the lungs. Since exhaled NO arises from both airway and alveolar regions, and its level in exhaled breath depends strongly on flow, spatial heterogeneity in flow patterns and NO production may significantly affect the exhaled NO signal. To investigate the effect of these factors on exhaled NO profiles, we developed a multicompartment mathematical model of NO exchange using a trumpet-shaped central airway segment that bifurcates into two similarly shaped peripheral airway segments, each of which empties into an alveolar compartment. Heterogeneity in flow alone has only a minimal impact on the exhaled NO profile. In contrast, placing 70% of the total airway NO production in the central compartment or the distal poorly ventilated compartment can significantly increase (35%) or decrease (-10%) the plateau concentration, respectively. Reduced ventilation of the peripheral and acinar regions of the lungs with concomitant elevated NO production delays the rise of NO during exhalation, resulting in a positive phase III slope and reduced plateau concentration (-11%). These features compare favorably with experimentally observed profiles in exercise-induced asthma and cannot be simulated with single-path models. We conclude that variability in ventilation and NO production in asthmatic subjects impacts the shape of the exhaled NO profile and thus impacts the physiological interpretation.     

A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide (NO) have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which may reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways, (ii) the concentrations in the tracheo-bronchial lining fluid, (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, the model illuminates the discrepancies between observed and theoretically predicted blood-breath ratios of acetone during resting conditions, i.e., in steady state. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases and thus is expected to have general relevance for a wider range of blood-borne inert gases. The chief intention of the present modeling study is to provide mechanistic relationships for further investigating the exhalation kinetics of acetone and other water-soluble species. This quantitative approach is a first step towards new guidelines for breath gas analyses of volatile organic compounds, similar to those for nitric oxide.     

Low levels of nitric oxide and carbon monoxide in alpha 1-antitrypsin deficiency.

Quantitations of exhaled nitric oxide (NO) and carbon monoxide (CO) have been proposed as noninvasive markers of airway inflammation. We hypothesized that exhaled CO is increased in individuals with alpha(1)-antitrypsin (AT) deficiency, who have lung inflammation and injury related to oxidative and proteolytic processes. Nineteen individuals with alpha(1)-AT deficiency, 22 healthy controls, and 12 patients with non-alpha(1)-AT-deficient chronic obstructive pulmonary disease (COPD) had NO, CO, CO(2), and O(2) measured in exhaled breath. Individuals with alpha(1)-AT deficiency had lower levels of NO and CO than control or COPD individuals. Alpha(1)-AT-deficient and COPD patients had lower exhaled CO(2) than controls, although only alpha(1)-AT-deficient patients had higher exhaled O(2) than healthy controls. NO was correlated inversely with exhaled O(2) and directly with exhaled CO(2), supporting a role for NO in regulation of gas exchange. Exhaled gases were not significantly related to corticosteroid use or lung function. Demonstration of lower than normal CO and NO levels may be useful as an additional noninvasive method to evaluate alpha(1)-AT deficiency in individuals with a severe, early onset of obstructive lung disease.     

A new and more accurate technique to characterize airway nitric oxide using different breath-hold times.

Exhaled nitric oxide (NO) arises from both airway and alveolar regions of the lungs, which provides an opportunity to characterize region-specific inflammation. Current methodologies rely on vital capacity breathing maneuvers and controlled exhalation flow rates, which can be difficult to perform, especially for young children and individuals with compromised lung function. In addition, recent theoretical and experimental studies demonstrate that gas-phase axial diffusion of NO has a significant impact on the exhaled NO signal. We have developed a new technique to characterize airway NO, which requires a series of progressively increasing breath-hold times followed by exhalation of only the airway compartment. Using our new technique, we determined values (means +/- SE) in healthy adults (20-38 yr, n = 8) for the airway diffusing capacity [4.5 +/- 1.6 pl.s(-1).parts per billion (ppb)(-1)], the airway wall concentration (1,340 +/- 213 ppb), and the maximum airway wall flux (4,350 +/- 811 pl/s). The new technique is simple to perform, and application of this data to simpler models with cylindrical airways and no axial diffusion yields parameters consistent with previous methods. Inclusion of axial diffusion as well as an anatomically correct trumpet-shaped airway geometry results in significant loss of NO from the airways to the alveolar region, profoundly impacting airway NO characterization. In particular, the airway wall concentration is more than an order of magnitude larger than previous estimates in healthy adults and may approach concentrations (approximately 5 nM) that can influence physiological processes such as smooth muscle tone in disease states such as asthma.     

Airway nitric oxide release is reduced after PBS inhalation in asthma.

Exhaled nitric oxide (NO) is elevated in asthma, but the underlying mechanisms remain poorly understood. Recent results in subjects with asthma have reported a decrease in exhaled breath pH and ammonia, as well as altered expression and activity of glutaminase in both alveolar and airway epithelial cells. This suggests that pH-dependent nitrite conversion to NO may be a source of exhaled NO in the asthmatic airway epithelium. However, the anatomic location (i.e., airway or alveolar region) of this pH-dependent NO release has not been investigated and could impact potential therapeutic strategies. We quantified airway (proximal) and alveolar (peripheral) contributions to exhaled NO at baseline and then after PBS inhalation in stable (mild-intermittent to severe) asthmatic subjects (20-44 yr old; n = 9) and healthy controls (22-41 yr old; n = 6). The mean (SD) maximum airway wall flux (pl/s) and alveolar concentration (ppb) at baseline in asthma subjects and healthy controls was 2,530 (2,572) and 5.42 (7.31) and 1,703 (1,567) and 1.88 (1.29), respectively. Compared with baseline, there is a significant decrease in the airway wall flux of NO in asthma as early as 15 min and continuing for up to 60 min (maximum -28% at 45 min) after PBS inhalation without alteration of alveolar concentration. Healthy control subjects did not display any changes in exhaled NO. We conclude that elevated airway NO at baseline in asthma is reduced by inhaled PBS. Thus airway NO may be, in part, due to nitrite conversion to NO and is consistent with airway pH dysregulation in asthma.     

Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry

Exhaled nitric oxide (NO) is altered in asthmatic subjects with exercise-induced bronchoconstriction (EIB). However, the physiological interpretation of exhaled NO is limited because of its dependence on exhalation flow and the inability to distinguish completely proximal (large airway) from peripheral (small airway and alveolar) contributions. We estimated flow-independent NO exchange parameters that partition exhaled NO into proximal and peripheral contributions at baseline, postexercise challenge, and postbronchodilator administration in steroid-naive mild-intermittent asthmatic subjects with EIB (24-43 yr old, n = 9) and healthy controls (20-31 yr old, n = 9). The mean +/- SD maximum airway wall flux and airway diffusing capacity were elevated and forced expiratory flow, midexpiratory phase (FEF(25-75)), forced expiratory volume in 1 s (FEV(1)), and FEV(1)/forced vital capacity (FVC) were reduced at baseline in subjects with EIB compared with healthy controls, whereas the steady-state alveolar concentration of NO and FVC were not different. Compared with the response of healthy controls, exercise challenge significantly reduced FEV(1) (-23 +/- 15%), FEF(25-75) (-37 +/- 18%), FVC (-12 +/- 12%), FEV(1)/FVC (-13 +/- 8%), and maximum airway wall flux (-35 +/- 11%) relative to baseline in subjects with EIB, whereas bronchodilator administration only increased FEV(1) (+20 +/- 21%), FEF(25-75) (+56 +/- 41%), and FEV(1)/FVC (+13 +/- 9%). We conclude that mild-intermittent steroid-naive asthmatic subjects with EIB have altered airway NO exchange dynamics at baseline and after exercise challenge but that these changes occur by distinct mechanisms and are not correlated with alterations in spirometry.     

Assessment of exhaled nitric oxide kinetics in healthy infants.

Exhaled nitric oxide (Fe(NO)) measurements provide a noninvasive approach to the evaluation of airway inflammation. Flow-independent NO exchange parameters [airway NO transfer factor (D(NO)) and airway wall NO concentration (Cw(NO))] can be estimated from Fe(NO) measurements at low flows and may elucidate mechanisms of disturbances in NO exchange. We measured Fe(NO) in sedated infants by using an adaptation of a raised lung volume rapid thoracic compression technique that creates forced expiration through a mass-flow controller that lasts 5-10 s, at a constant preset flow. We measured Fe(NO) at expired flows of 50, 25, and 15 ml/s in five healthy infants (7-31 mo). Median Fe(NO) increased [24, 40, and 60 parts per billion (ppb)] with decreasing expiratory flows (50, 25, and 15 ml/s). Group median (range) for D(NO) and Cw(NO) were 12.7 (3.2-37) x 10(-3) nl. s(-1). ppb(-1) and 108.9 (49-385) ppb, respectively, similar to values reported in healthy adults. Exhaled NO is flow dependent; flow-independent parameters of exhaled NO kinetics can be assessed in infants and are similar to values described in adults.     

Biomarkers of some pulmonary diseases in exhaled breath

Analysis of various biomarkers in exhaled breath allows completely non-invasive monitoring of inflammation and oxidative stress in the respiratory tract in inflammatory lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), bronchiectasis and interstitial lung diseases. The technique is simple to perform, may be repeated frequently, and can be applied to children, including neonates, and patients with severe disease in whom more invasive procedures are not possible. Several volatile chemicals can be measured in the breath (nitric oxide, carbon monoxide, ammonia), and many non-volatile molecules (mediators, oxidation and nitration products, proteins) may be measured in exhaled breath condensate. Exhaled breath analysis may be used to quantify inflammation and oxidative stress in the respiratory tract, in differential diagnosis of airway disease and in the monitoring of therapy. Most progress has been made with exhaled nitric oxide (NO), which is increased in atopic asthma, is correlated with other inflammatory indices and is reduced by treatment with corticosteroids and antileukotrienes, but not (β₂-agonists. In contrast, exhaled NO is normal in COPD, reduced in CF and diagnostically low in primary ciliary dyskinesia. Exhaled carbon monoxide (CO) is increased in asthma, COPD and CF. Increased concentrations of 8-isoprostane, hydrogen peroxide, nitrite and 3-nitrotyrosine are found in exhaled breath condensate in inflammatory lung diseases. Furthermore, increased levels of lipid mediators are found in these diseases, with a differential pattern depending on the nature of the disease process. In the future it is likely that smaller and more sensitive analysers will extend the discriminatory value of exhaled breath analysis and that these techniques may be available to diagnose and monitor respiratory diseases in the general practice and home setting.     

Impact of axial diffusion on nitric oxide exchange in the lungs.

Nitric oxide (NO) appears in the exhaled breath and is a potentially important clinical marker. The accepted model of NO gas exchange includes two compartments, representing the airway and alveolar region of the lungs, but neglects axial diffusion. We incorporated axial diffusion into a one-dimensional trumpet model of the lungs to assess the impact on NO exchange dynamics, particularly the impact on the estimation of flow-independent NO exchange parameters such as the airway diffusing capacity and the maximum flux of NO in the airways. Axial diffusion reduces exhaled NO concentrations because of diffusion of NO from the airways to the alveolar region of the lungs. The magnitude is inversely related to exhalation flow rate. To simulate experimental data from two different breathing maneuvers, NO airway diffusing capacity and maximum flux of NO in the airways needed to be increased approximately fourfold. These results depend strongly on the assumption of a significant production of NO in the small airways. We conclude that axial diffusion may decrease exhaled NO levels; however, more advanced knowledge of the longitudinal distribution of NO production and diffusion is needed to develop a complete understanding of the impact of axial diffusion.     

Ozone-induced increase in exhaled 8-isoprostane in healthy subjects is resistant to inhaled budesonide

The aim of this study was to quantify lung oxidant stress after short-term ozone exposure as reflected by 8-isoprostane concentrations in exhaled breath condensate (EBC) and to investigate the effects of inhaled budesonide on this response. 8-Isoprostane is a prostaglandin-F(2 alpha) isomer that is formed in vivo by free radical-catalyzed peroxidation of arachidonic acid. EBC is a noninvasive method to collect airway secretions. We undertook a double-blind, randomized, placebo-controlled, crossover study with inhaled budesonide (800 microg) or placebo twice daily for 2 weeks prior to ozone exposure (400 parts per billion) for 2 h in nine healthy nonsmokers. Exhaled 8-isoprostane was measured by an enzyme immunoassay. 8-Isoprostane was increased 4 h after ozone exposure compared to pre-exposure values in both placebo (36.9 +/- 3.9 pg/ml, mean +/- SEM, vs. 16.9 +/- 0.7 pg/ml; p <.001) and budesonide groups (33.4 +/- 2.6 pg/ml vs. 15.8 +/- 0.3 pg/ml; p <.001). Pretreatment with budesonide did not affect the increases in 8-isoprostane (mean differences 3.4 pg/ml, 95% CI -8.9 to 15.7, p =.54). Short-term ozone exposure causes acute increase in lung oxidative stress as reflected by exhaled 8-isoprostane. This increase is resistant to pretreatment with a high dose of inhaled budesonide.     

Fractionated breath condensate sampling: H2O2 concentrations of the alveolar fraction may be related to asthma control in children

Background

Asthma is a chronic inflammatory disease of the airways but recent studies have shown that alveoli are also subject to pathophysiological changes. This study was undertaken to compare hydrogen peroxide (H₂O₂) concentrations in different parts of the lung using a new technique of fractioned breath condensate sampling.

Methods

In 52 children (9-17 years, 32 asthmatic patients, 20 controls) measurements of exhaled nitric oxide (FE_NO), lung function, H₂O₂ in exhaled breath condensate (EBC) and the asthma control test (ACT) were performed. Exhaled breath condensate was collected in two different fractions, representing mainly either the airways or the alveoli. H₂O₂ was analysed in the airway and alveolar fractions and compared to clinical parameters.

Results

The exhaled H₂O₂ concentration was significantly higher in the airway fraction than in the alveolar fraction comparing each single pair (p = 0.003, 0.032 and 0.040 for the whole study group, the asthmatic group and the control group, respectively). Asthma control, measured by the asthma control test (ACT), correlated significantly with the H₂O₂ concentrations in the alveolar fraction (r = 0.606, p = 0.004) but not with those in the airway fraction in the group of children above 12 years. FE_NO values and lung function parameters did not correlate to the H₂O₂ concentrations of each fraction.

Conclusion

The new technique of fractionated H₂O₂ measurement may differentiate H₂O₂ concentrations in different parts of the lung in asthmatic and control children. H₂O₂ concentrations of the alveolar fraction may be related to the asthma control test in children.     

Nitric oxide in the breath of bottlenose dolphins: Effects of breath hold duration,feeding, and lung disease

Breath analysis, including measurement of nitric oxide (NO), is a noninvasive diagnostic tool that may help evaluate cetacean health. This is the first report on the effects of breath hold duration, feeding, and lung disease on NO in dolphin exhaled breath. Three healthy dolphins were trained to hold their breath for 30, 60, 90, and 120 s and then exhale into an underwater funnel. Exhaled NO values from 157 breath samples were compared among three healthy dolphins by breath hold time and after fasting and feeding. Exhaled NO values were also measured in two dolphins with pulmonary disease. NO in dolphin breath was higher compared to ambient air; healthy dolphins had higher NO concentrations in their breath after feeding compared to after overnight fasting; and there were no significant differences in exhaled NO levels by breath hold duration. A dolphin with Mycoplasma‐associated pneumonia and chronic gastrointestinal disease had higher postprandial exhaled NO levels compared to healthy controls. This study demonstrates, contrary to previous publications, that dolphins exhale NO. Given the high standard deviations present in exhaled breath NO values, future studies are needed to further standardize collection methods or identify more reliable samples (e.g., blood).     

Lipoteichoic acid induces surfactant protein-A biosynthesis in human alveolar type II epithelial cells through activating the MEK1/2-ERK1/2-NF-κB pathway

Background

Asthma is a chronic inflammatory disease of the airways but recent studies have shown that alveoli are also subject to pathophysiological changes. This study was undertaken to compare hydrogen peroxide (H₂O₂) concentrations in different parts of the lung using a new technique of fractioned breath condensate sampling.

Methods

In 52 children (9-17 years, 32 asthmatic patients, 20 controls) measurements of exhaled nitric oxide (FE_NO), lung function, H₂O₂ in exhaled breath condensate (EBC) and the asthma control test (ACT) were performed. Exhaled breath condensate was collected in two different fractions, representing mainly either the airways or the alveoli. H₂O₂ was analysed in the airway and alveolar fractions and compared to clinical parameters.

Results

The exhaled H₂O₂ concentration was significantly higher in the airway fraction than in the alveolar fraction comparing each single pair (p = 0.003, 0.032 and 0.040 for the whole study group, the asthmatic group and the control group, respectively). Asthma control, measured by the asthma control test (ACT), correlated significantly with the H₂O₂ concentrations in the alveolar fraction (r = 0.606, p = 0.004) but not with those in the airway fraction in the group of children above 12 years. FE_NO values and lung function parameters did not correlate to the H₂O₂ concentrations of each fraction.

Conclusion

The new technique of fractionated H₂O₂ measurement may differentiate H₂O₂ concentrations in different parts of the lung in asthmatic and control children. H₂O₂ concentrations of the alveolar fraction may be related to the asthma control test in children.     

Role of exhaled nitric oxide in asthma

Nitric oxide (NO), an evanescent atmospheric gas, has recently been discovered to be an important biological mediator in animals and humans. Nitric oxide plays a key role within the lung in the modulation of a wide variety of functions including pulmonary vascular tone, nonadrenergic non-cholinergic (NANC) transmission and modification of the inflammatory response. Asthma is characterized by chronic airway inflammation and increased synthesis of NO and other highly reactive and toxic substances (reactive oxygen species). Pro- inflammatory cytokines such as TNFalpha and IL-1beta are secreted in asthma and result in inflammatory cell recruitment, but also induce calcium- and calmodulin-independent nitric oxide synthases (iNOS) and perpetuate the inflammatory response within the airways. Nitric oxide is released by several pulmonary cells including epithelial cells, eosinophils and macrophages, and NO has been shown to be increased in conditions associated with airway inflammation, such as asthma and viral infections. Nitric oxide can be measured in the expired air of several species, and exhaled NO can now be rapidly and easily measured by the use of chemiluminescence analysers in humans. Exhaled NO is increased in steroid-naive asthmatic subjects and during an asthma exacerbation, although it returns to baseline levels with appropriate anti-inflammatory treatment, and such measurements have been proposed as a simple non-invasive method of measuring airway inflammation in asthma. Here the chemical and biological properties of NO are briefly discussed, followed by a summary of the methodological considerations relevant to the measurement of exhaled NO and its role in lung diseases including asthma. The origin of exhaled NO is considered, and brief mention made of other potential markers of airway inflammation or oxidant stress in exhaled breath.     

呼出气温度的研究现状

呼出气温度是一种新的呼吸系统疾病监测手段。从被发现开始,呼出气温度就引起了众多学者的兴趣。人们发现在哮喘等呼吸系统疾病患者身上测出的呼出气温度较正常健康人的呼出气温度要高。大量的研究结果表明呼出气温度的变化与患者肺部的炎症改变有关,学者们研究推断肺部的炎症改变使得肺部病变部位局部血管增生及血流量增加因而导致了肺部气道热量交换和损失的改变,最终导致患者呼出气温度的改变。这一发现在呼吸系统疾病中有着重要意义,科学家们认为呼出气温度可以作为一种非侵入性的新监测手段。