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Departments of 1Biomedical Engineering, 2Chemical Engineering and Materials Science, and 4Pediatrics, 3General Clinical Research Center, and 5Center for Statistical Consulting, University of California, Irvine, California 92697-2575
Submitted 2 June 2003 ; accepted in final form 28 August 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONAPPENDIX A: ASTHMA CONTROL...APPENDIX B: MATHEMATICAL...ACKNOWLEDGMENTSREFERENCES |
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model; airways; alveoli; inflammation
E) (2, 29). However, a single measurement of CNO,plat cannot distinguish airway and alveolar contributions and thus may not be the optimal parameter to describe pulmonary NO exchange. The potential for greater clinical insight is accompanied by the need for new and robust analytic approaches to characterize NO in the exhaled breath. Because NO is produced throughout the respiratory tract, factors like expiratory flow rate substantially influence the NO concentration in the exhaled breath (Cexh) (21, 47, 54). To account for this and other determinants of NO concentration, we and others have described NO exchange using a biologically relevant two-compartment model (airway and alveolar compartments) and a series of flow-independent NO exchange parameters (20, 42, 48, 52). The flow-independent parameters potentially provide clinically relevant information about NO exchange. For example, the alveolar NO concentration is elevated in allergic alveolitis (alveolar inflammation), whereas airway wall NO flux is elevated in asthma (bronchial inflammation) (37).
Inflammation is characteristic of asthma and induces the expression of several steroid-sensitive enzymes, such as NO synthase (NOS) and glutaminase, which impact NO metabolism (3, 23, 43). Consequently, corticosteroids, which attenuate the inflammatory process, also reduce the concentration of NO in the exhaled breath (31, 41). This feature of corticosteroid therapy may be useful in monitoring the inflammatory status of the airways, but, by reducing the concentration of NO in the exhaled breath to near normal, may mask steroid-independent alterations in airway NO physiology that are of potential clinical significance.
The airway diffusing capacity of NO (Daw,NO) is the conductance for the transfer of NO between the airway wall and the gas stream (48, 52, 53). It depends on both the physical features of the airway wall (e.g., airway surface area or tissue thickness) and the rate of chemical consumption (4, 53), both of which may be altered in asthma. Recently, Silkoff et al. (48) demonstrated that Daw,NO was elevated in asthma independent of steroid therapy by measuring multiple CNO,plat at small flow rates (<50 ml/s). However, values for the flow-independent NO exchange parameters may depend on the breathing maneuver and analytic technique utilized. Thus the goal of the present study was to apply our alternate breathing and analytic technique (20-s preexpiratory breath hold followed by a decreasing flow-rate maneuver) in asthma to confirm the results of Silkoff et. al. and potentially provide additional insight into the pathophysiology that marks chronic asthma.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX A: ASTHMA CONTROL...APPENDIX B: MATHEMATICAL...ACKNOWLEDGMENTSREFERENCES |
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Experimental protocol. Each subject performed two types of exhalation maneuvers: one necessary to estimate the flow-independent NO exchange parameters, and the other according to the ATS guidelines (2). The first maneuver was five repetitions of a 20-s preexpiratory breath hold followed by a decreasing flow rate (from 
6 to 1% of vital capacity per second) maneuver (53) to estimate several flow-independent NO exchange parameters. A positive pressure of >5 cmH2O was maintained to prevent nasal contamination during the breath hold (2), and a Starling resistor (Hans Rudolph, Kansas City, MO) with a variable resistance was used to progressively decrease the flow rate during the exhalation. After breath hold, the exhalation valve was opened, allowing the patient to expire. A schematic of the experimental apparatus has been previously presented (53). The second maneuver was a vital capacity maneuver performed in triplicate to collect plateau NO concentration based on the ATS guidelines (2). We also included an exhalation flow rate of 250 ml/s (ATS guideline is 50 ml/s) consistent with the guidelines of the ERS (29). After measuring the indexes of NO exchange dynamics, general spirometry, such as FVC, and FEV1 normalized by FVC (FEV1/FVC) were measured in all subjects (Vmax229; Sensormedics, Yorba Linda, CA) by using the best performance (see Table 1) from three consecutive maneuvers.
Airstream analysis. A chemiluminesence NO analyzer (NOA280, Sievers, Boulder, CO) was used to measure the Cexh. The instrument was calibrated on a daily basis by using a certified NO gas (45 parts/million in N2; Sievers, Boulder, CO). The zero-point calibration was performed with a NO filter (Sievers) immediately before the collection of a profile. The flow rate and pressure signals were measured by using a pneumotachometer (RSS100, Hans Rudolph, Kansas City, MO). The pneumotachometer was calibrated daily and was set to provide the flow in units of STPD.
Data analysis and parameter estimation. Experimental single-exhalation profiles with the 20-s preexpiratory breath hold were characterized by the peak concentration in phases I and II (CNO,peak); the peak width (W50) in phases I and II, defined as the exhaled volume in which the NO concentration was >50% of CNO,peak; and the total volume of phases I and II (VI,II), defined as the point of zero slope (dCexh/dV = 0, where V is volume) in the exhalation profile (53) (Fig. 1). The constant-flow-rate single exhalations were characterized by the CNO,plat, as previously described by the ATS and the ERS (2, 29).
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A previously described two-compartment model was used to estimate four flow-independent NO exchange parameters: 1) maximum flux of NO from the airways (
; pl/s); 2)Daw,NO [pl·s-1·parts per billion (ppb)-1]; 3) steady-state alveolar concentration (Calv,ss; ppb); and 4) mean airway tissue NO concentration (Caw,NO; ppb; equal to the ratio of to Daw,NO). A simple schematic of the two-compartment model and flow-independent parameters is presented in Fig. 2, and a detailed description of the mathematical estimation of the parameters has been previously described (53).
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The source of NO from the airways can be described by the instantaneous flux of NO from the airways (Jaw,NO; pl/s). Jaw,NO depends on the flow-independent parameters and is expressed as a linear function of the airway gas-phase concentration (Cair) by the following
 | (1) |
 | (2) |
is equal to the product Daw,NO * Caw,NO (Eq. 2). Conceptually, approaches Jaw,NO as the product Daw,NO * Cair approaches zero. Daw,NO is the conductance for mass transfer (transfer factor or airway diffusing capacity) of NO between the airway tissue and the gas phase. The alveolar region is characterized by Calv,ss, which is equivalent to the alveolar tissue concentration (25, 52). Fig. 3 illustrates the independent (i.e., all other parameters are held constant) impact of Daw,NO, , and Calv,ss on the single-exhalation profile with a 20-s preexpiratory breath hold and a decreasing exhalation flow rate.
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Once the flow-independent parameters are known, the two-compartment model can be used to predict CNO,plat at any constant exhalation flow, and thus there is no loss of information in characterizing NO exchange with the flow-independent NO parameters (53)
 | (3) |
is the plateau concentration of NO predicted by the model using the flow-independent parameters. Our laboratory (44, 53) has previously demonstrated that is not different than the experimentally measured CNO,plat in healthy adults, with the advantage that intersubject and interpopulation variations in flow rate can be accounted for by calculating CNO,plat at a precise desired flow rate (e.g., 50 ml/s). Statistics. To detect differences among the three groups of subjects, data were analyzed by using ANOVA and post hoc paired comparisons of treatment means. In those instances in which Levene's test rejected homogeneity of variance, tests for group differences relied on Welch's ANOVA or Satterthwaite's method to adjust the test to account for this problem. To detect significant relationships between the parameters that characterize NO exchange and either asthma symptoms or standard indexes of lung function (e.g., FEV1), we utilized first- and second-order partial correlation coefficients, respectively. For example, to determine the relationship between NO parameters and lung function for all subjects, the second-order partial correlation coefficient factors out the effect of having asthma or being treated with steroids by subtracting the group mean from each individual score. As to the question of normality, in addition to screening variables for excessive skewness, all tests of group differences were rerun by using a log transformation of the dependent variables. Because the log transformation of each variable did not impact the results, all statistical tests were reported by using the untransformed data. Finally, a P value <0.05 was considered statistically significant, and all results were produced by using the GLM procedure of SAS.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX A: ASTHMA CONTROL...APPENDIX B: MATHEMATICAL...ACKNOWLEDGMENTSREFERENCES |
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Of the 20 subjects with asthma, three of the steroid treated (subjects 2, 10, and 12) were not able to complete the 20-s breath hold, and thus we utilized a 10-s breath hold, which may increase the confidence interval of Daw,NO (44, 53). To highlight differences among groups in exhaled concentrations, a composite exhalation profile for each group was attained (Fig. 4) by taking the mean exhaled concentration at equivalent exhaled volume intervals for each of the three groups. The three asthmatic subjects who were not able to complete the 20-s breath hold were excluded from the composite exhalation profile. Steroid-naive subjects with asthma had an increased concentration of NO in all phases of the exhalation profile compared with both steroid-treated subjects with asthma and healthy controls. Although the NO exhalation profile for steroid-treated subjects with asthma and healthy controls is similar (Fig. 4B), there are important differences that reflect alterations in the flow-independent NO parameters. Steroid-treated subjects with asthma have elevated NO in phase III that is reflected in a steeper phase III slope. This steeper slope reflects a greater airway wall flux () as opposed to an elevated Calv,ss, which would cause a uniform increase in NO concentration over phase III (52, 53). The elevated would result in a much larger CNO,peak than actually observed, and this results in an elevated Daw,NO as described below.
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Mean (±SD) CNO,peak for steroid-naive, steroid-treated, and healthy subjects was 192 ± 127, 82 ± 42, and 67 ± 29 ppb, respectively. CNO,peak for steroid-naive subjects with asthma was statistically larger than that for the other two groups. W50 for steroid-naive, steroid-treated, and healthy subjects was 189 ± 60, 171 ± 49, and 190 ± 51 ml, respectively, and was not different among groups. VI,II for steroid-naive, steroid-treated, and healthy subjects was 657 ± 98, 604 ± 127, and 668 ± 142 ml, respectively, and was also not different among the groups.
As shown in Fig. 5, and Daw,NO are elevated in steroid-naive subjects with asthma relative to healthy controls. The use of corticosteroids does not impact Daw,NO, but is associated with a significantly lower and Caw,NO that are equivalent to those in healthy adults. Calv,ss is not different among the three groups.
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The experimental values of CNO,plat at the target flow rates of 50 and 250 ml/s, respectively, are presented in Table 3 (for healthy adults and subjects with asthma) along with the model-predicted CNO,plat (Eq. 3, ) at exhalation flow rates of exactly 50 and 250 ml/s. and CNO,plat were not statistically different from each other, with the exception of the steroid-naive group of asthmatic subjects at 250 ml/s (see Table 3). Statistical differences between the groups did not depend on the choice of CNO,plat or . Thus, to control for small variations in the exhalation flow rate between groups (e.g., mean exhalation flow rate at the target of 50 ml/s was 62 ml/s and 55 ml/s for steroid-naive and steroid-treated groups, respectively), statistical differences between groups are presented by using (Fig. 6). was 13.0 ± 5.97 and 5.17 ± 2.97 ppb for healthy adults, 53.9 ± 33.0 and 16.1 ± 9.46 ppb for steroid-naive adults with asthma, and 23.2 ± 14.3 and 7.76 ± 5.34 ppb for steroid-treated adults with asthma at flow rates of 50 and 250 ml/s, respectively. at 50 ml/s is significantly higher for both groups of subjects with asthma compared with healthy controls (Fig. 6), whereas only the steroid-naive subjects with asthma have a higher at 250 ml/s.
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Daw,NO was inversely correlated with both FEV1 (%predicted) and FVC (%predicted) (Fig. 7, A and B). In contrast, Caw,NO was positively correlated with FVC (%predicted). and Calv,ss were not correlated with any lung function indexes. at either E was not correlated with indexes of lung function, but CNO,plat was inversely correlated with FEV1/FVC (%predicted) (Fig. 8). The asthma control questionnaire composite score was not correlated with any of the NO exchange parameters.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX A: ASTHMA CONTROL...APPENDIX B: MATHEMATICAL...ACKNOWLEDGMENTSREFERENCES |
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and Caw,NO, respectively). In contrast, Daw,NO was elevated in both groups of asthmatic subjects and was independent of the use of corticosteroids. These findings are in good agreement with previously published data by Silkoff et al. (48), despite using a different breathing maneuver and analytic technique to estimate the flow-independent NO exchange parameters. In addition, we found that Daw,NO is inversely correlated with both FEV1 and FVC (%predicted), independent of the presence of asthma and steroid use. Thus we confirm that Daw,NO may reflect physiological changes in the lungs that impact lung function independent of the use of corticosteroids. Because the initial reports that FENO in asthma was elevated (1, 30), subsequent studies have focused on exploring the correlation between Cexh and other inflammatory markers (i.e., eosinophils), clinical interventions such as corticosteroids, and standard indexes of lung function (i.e., FEV1/FVC). Corticosteroid treatment significantly decreases CNO,plat in subjects with asthma (31, 40, 41), and the dose of steroid is inversely related to CNO,plat (32). In addition, an increase in CNO,plat has recently been shown to be equally effective as sputum eosinophils and airway hyperresponsiveness to hypertonic saline as a predictor for loss of asthma control (26). However, the present study, as well as that of Silkoff et al. (48), demonstrates the presence of steroid-independent factors (i.e., Daw,NO) that can also contribute to the elevated levels of NO in the exhaled breath of asthmatic subjects.
We are also now aware of disease states in which exhaled concentration of NO is in the normal range only because abnormalities in the flow-independent determinants of NO concentration balance each other. For example, in scleroderma, the alveolar concentration of NO is elevated, whereas the airway wall flux of NO is reduced (15). In cystic fibrosis, the Daw,NO (transfer factor) is elevated, but the airway wall concentration is reduced, leading to an Cexh that is similar to that of healthy controls (45).
Silkoff et al. (48) first reported that Daw,NO is fourfold higher in subjects with asthma and that this increase is independent of steroid treatment, whereas decreases. Lehtimaki et al. (38) then demonstrated that steroid treatment reduces in newly diagnosed asthma subjects (previously steroid naive) by utilizing multiple constant-flow rate maneuvers (52, 54). Most recently, Hogman et al. (22) also recently demonstrated that Daw,NO is increased 1.5-fold in a group of atopic asthmatic subjects. Although we utilized a different breathing maneuver and technique to estimate the flow-independent NO parameters, our results are consistent with previously reported trends (22, 38, 48) and also demonstrates that Daw,NO is inversely correlated with FEV1 and FVC (%predicted) and Caw,NO is positively correlated with FVC. The positive correlation of Caw,NO with FVC is likely due to the fact that it is inversely related to Daw,NO (i.e., Caw,NO = /Daw,NO). Of note is the fact that Silkoff et al. (48) reported that values of , Daw,NO, and Caw,NO after steroid use in asthmatic subjects were all positively correlated with FEV1/FVC (%predicted). These important differences may be due to differences in study design and the technique used to estimate the flow-independent NO parameters. Nonetheless, future studies will need to continue to investigate the relationship between NO flow-independent parameters and lung function.
Cexh necessarily reflects both the chemical and physical properties of the airway wall and alveoli, as well as the endogenous production rate from NOS isoforms in the airway and alveoli. Our ability to estimate the flow-independent NO parameters, which depend on these properties from the exhaled concentration signal, can be illustrated by using the composite exhalation profile (Fig. 4A). Our laboratory (53) has previously demonstrated that only phases I and II are sensitive to changes in Daw,NO (if Daw,NO increases, less NO is exhaled in phases I and II), only phase III is sensitive to Calv,ss (if Calv,ss increases, there is a uniform increase across exhaled volume in phase III), and all three phases are sensitive to (if increases, there is more NO exhaled in all phases, and the impact on phase III is a steeper slope) (see Fig. 3). Thus the observed changes in the composite profile of each group are consistent with our reported values of the flow-independent parameters. For example, steroid-treated subjects with asthma have a steeper slope in phase III and a higher concentration (necessitating a larger ), yet a similar amount of NO in phases I and II (necessitating a larger Daw,NO to balance the increased ). Of note is the fact that, among the parameters characterizing phases I and II of the exhalation profile, only CNO,peak differs among the groups (W50 and VI,II are not different among the three groups). This is consistent with altered NO production and transport in the airway wall during the breath hold, but also suggests that the volume accumulating NO during the breath hold and subsequently eliminated during exhalation is similar among the three groups.
Our laboratory has previously reported analytic expressions for the flow-independent parameters that approximate the functional dependence on the surface area emitting NO [Ai, where i is either airways (aw) or alveoli (alv); cm2], solubility [partition coefficient (
t:air)], molecular diffusion [molecular diffusivity (Dt,NO); cm2/s], chemical consumption (lumped first-order rate reaction constant k; s-1), thickness of the tissue layer (Lt,i; cm), and chemical production [airway (Saw,NO) and alveolar (Salv,NO) production rate per unit volume; ml NO·s-1·cm-3] (45, 52). The analytic expressions are summarized in APPENDIX B and provide a level of quantitative insight into the mechanism of the observed changes in the flow-independent parameters.
Daw,NO is independent of Saw,NO; is a positive function of total surface area of airway space (Aaw), t:air, Dt,NO, and k; and is an inverse function of the thickness of the airway tissue layer (Lt,aw) (Eq. B2 in APPENDIX B). Thus the increase in Daw,NO may be due to alterations in any of these parameters. The airway wall in asthma is generally considered to be thicker than in healthy controls due to remodeling processes, such as subepithelial fibrosis and increased mucous production (56). The thicker airway wall would tend to increase the diffusion distance for NO, and the mucus tends to be more viscous, which would decrease the "ease" at which NO can diffuse (i.e., decrease Dt,NO) (4). Both of these observations would decrease Daw,NO and contrast with our experimental observation, as well as that of Silkoff et al. (48), of an elevated Daw,NO. Enhanced chemical consumption, primarily with superoxide (9), can increase Daw,NO due to an increase in the radial concentration gradient (4, 45). However, Daw,NO remains elevated after steroid treatment, which has been reported to suppress super-oxide release (10).
An increase in Aaw is a plausible mechanism for the increase in Daw,NO. Silkoff et al. (48) postulated that extension of the NO-producing nonadrenergic noncholinergic nerves from the large airways into the small airways may increase the Ai, which is supported both directly and indirectly by several studies (6, 7, 16, 17, 39, 55). Expression of inducible NOS (iNOS) in the airways of subjects with asthma has been demonstrated (12, 36, 50), which could potentially increase Aaw; however, this possible mechanism would likely be sensitive to corticosteroid therapy, which is not the observation.
has a similar functional dependence on the physical and chemical parameters of the airways (Aaw, Dt,NO, and Lt,aw) (see APPENDIX B) as Daw,NO. However, in contrast to Daw,NO, is inversely related to k and is a positive function of an additional parameter, Saw,NO. An increase in Saw,NO by an increase in neuronal NOS expression from nonadrenergic noncholinergic nerves (6, 7, 16, 17, 39, 55) or prokaryotic denitrification (13) may increase the exhaled concentration of NO and thus contribute to the observed increase in for both steroid-naive and steroid-treated subjects with asthma. Other enzymatic and nonenzymatic chemical events in the airways, such as increased iNOS expression in the epithelium (18), nitrite reduction to NO at lower pH (23, 24, 35), and S-nitrosoglutathione catabolism (5, 11, 14, 49), could also increase Saw,NO and contribute to the increase in for steroid-naive subjects with asthma.
Steroid treatment dramatically decreases the Cexh (see Fig. 5), which corresponds to observed decreases in and Caw,NO as well as CNO,plat at both 50 and 250 ml/s flow rates. As previously discussed, steroid therapy decreases superoxide production, which would correspond to a reduced consumption rate and an increase in , which is not observed. The decrease in in steroid-treated subjects with asthma may be related to 1) the reduced iNOS activity in the epithelial and inflammatory cells in the airways (12, 34, 36, 50, 57); 2) reduced nitrite to NO reduction due to normalized airway pH (23, 24, 35); 3) decreased prokaryotic colonization (13); and 4) inhibition of arginase upregulation (33). The decrease in Caw,NO (a ratio of over Daw,NO) for steroid-treated subjects with asthma is due to the decrease in , whereas Daw,NO is not changed.
In summary, we have estimated both flow-independent NO exchange parameters and plateau Cexh following ATS guidelines, in subjects with low FEV1/FVC and a clinical history of asthma. Daw,NO is elevated independent of corticosteroid use, whereas , Caw,NO, and CNO,plat (at both 50 and 250 ml/s) are all reduced by the use of steroids. In addition, Daw,NO is inversely correlated with pulmonary function, independent of the presence of asthma and steroid use. In agreement with Silkoff et al. (48), we conclude that Daw,NO may reflect changes in the lungs that impact function and that are not impacted by steroid therapy and thus may provide clinical information not available from Cexh alone.
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APPENDIX A: ASTHMA CONTROL QUESTIONNAIRE |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX A: ASTHMA CONTROL...APPENDIX B: MATHEMATICAL...ACKNOWLEDGMENTSREFERENCES |
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Each question is answered by the subject on a scale of 0-6, representing the absence of symptoms (score of 0) to severe symptoms (score of 6). The composite score is then the mean of the six scores. Thus a higher composite score reflects more asthmatic symptoms. The questionnaire has been shown to have improved discriminative and evaluative measurement properties than an asthma control diary (27).
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APPENDIX B: MATHEMATICAL DESCRIPTION OF FLOW-INDEPENDENT NO PARAMETERS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX A: ASTHMA CONTROL...APPENDIX B: MATHEMATICAL...ACKNOWLEDGMENTSREFERENCES |
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, Daw,NO, and Calv,ss have been previously derived (52) and presented in a slightly different form (45, 51)
 | (B1) |
 | (B2) |
 | (B3) |
, where k (s-1) is the first-order rate constant that characterizes the rate of chemical consumption by substrates such as superoxide. The 
i represents the ratio of the rate of chemical consumption (k; s-1) to the rate of molecular diffusion (Dt,NO/L2; s-1) for NO. The hyperbolic tangent (tanh) is bounded between -1 and 1 and is a monotonically increasing function of its argument. Eq. B1 provides units of milliliters per second for Daw,NO that are equivalent in magnitude to picoliters per second per ppb. |
ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX A: ASTHMA CONTROL...APPENDIX B: MATHEMATICAL...ACKNOWLEDGMENTSREFERENCES |
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GRANTS
This work was supported by National Institutes of Health Grants HL-60636, HD-23969, and RR-00827.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIX A: ASTHMA CONTROL...APPENDIX B: MATHEMATICAL...ACKNOWLEDGMENTSREFERENCES |
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) and ST (
) asthma subjects and HA (
). The mean ± SD 
, Difference between the individual score of each subject and the group mean value to which each subject belongs. +, HA (n = 24); 