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Published ahead of print on June 30, 2004, doi:10.1164/rccm.200403-408OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 737-741, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200403-408OC

Original Article

Alveolar and Airway Sites of Nitric Oxide Inflammation in Treated Asthma

Arthur F. Gelb, Colleen Flynn Taylor, Eliezer Nussbaum, Carlos Gutierrez, Aaron Schein, Chris M. Shinar, Mark J. Schein, Joel D. Epstein and Noe Zamel

Departments of Pharmacy Services and Radiology, and Pulmonary Division, Department of Medicine, Lakewood Regional Medical Center, Lakewood; University of California at Los Angeles, Geffen School of Medicine, Los Angeles; Department of Pediatrics, Miller Children's Hospital at Long Beach Memorial Hospital, Long Beach; University of California at Irvine, School of Medicine, Irvine, California; and University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Arthur F. Gelb, M.D., 3650 East South Street, Suite 308, Lakewood, CA 90712. E-mail: afgelb{at}msn.com


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The goal of this study was to identify airway and alveolar site(s) of inflammation using exhaled nitric oxide (NO) as a marker in treated patients with asthma, including response to oral corticosteroids, and correlate these sites with expiratory airflow limitation. In 53 (24 male) patients with asthma, age 43 ± 23 years (mean ± SD) and all on inhaled corticosteroids, post 180 µg aerosolized albuterol, FEV1 was 74 ± 23% predicted and FEV1/FVC was 68 ± 11%. Exhaled NO at 100 ml/second was 27 ± 23 ppb (p < 0.001 compared with normal, 12 ± 15 ppb). Bronchial NO maximal flux was 2.4 ± 3.1 nl/second (p < 0.001 compared with normal, 0.85 ± 0.55). Alveolar NO concentration was 7.0 ± 7.4 ppb (p = 0.01 compared with the normal value, 3.2 ± 2.0 ppb). There was no significant correlation between FEV1 % predicted or lung elastic recoil and NO bronchial flux or alveolar concentration. However, there was a weak but significant correlation between NO bronchial flux and alveolar concentration (Spearman r = 0.50, p < 0.001). In 10 subjects with asthma on inhaled corticosteroids, 5 days of 30 mg prednisone resulted in isolated significant decreases in NO alveolar concentration, from 13 ± 10 to 4 ± 4 ppb (p = 0.002). Despite treatment, including inhaled corticosteroids, patients with asthma may have ongoing separate airway and alveolar sites of NO inflammation, the latter responsive to oral corticosteroids.

Key Words: alveolitis • asthma • exhaled nitric oxide • inflammation

Measurement of exhaled nitric oxide (NO) is a relatively simple, reproducible (1) noninvasive test for monitoring endogenous inflammatory signals in asthma and the response to inhaled corticosteroids and montelukast (2–7). The currently accepted method (8, 9) of measuring exhaled NO at a single constant expiratory flow rate is incapable of separating whether the source of increased NO is originating from the airway versus alveolar site or both in asthma. Therefore, several investigators have developed newer techniques to discriminate NO gas exchange between airway and alveolar compartments (10–14). Lehtimaki and colleagues (15) have used the two-compartment model described by Tsoukias and George (13, 14), and found elevated alveolar NO concentration but normal bronchial NO flux in subjects without asthma with alveolitis. However, inhaled corticosteroid-naive individuals with intermittent mild asthma and normal FEV1 % predicted, but abnormal methacholine challenge test, had normal alveolar but elevated airway NO flux that was responsive to inhaled corticosteroids (15, 16). Alternatively, steroid-naive individuals with asthma with normal FEV1 % predicted and nocturnal symptoms had elevated bronchial NO flux and increased alveolar NO concentration (17).

This cross-sectional and prospective study measured exhaled NO using the two-compartment model of Tsoukias and George (13, 14) in clinically stable individuals with asthma with varying expiratory airflow limitation and treatment. Our goal was to evaluate bronchial and alveolar sites of inflammation using NO as the signal and the response to oral corticosteroids.

Some of the results of these studies have been previously reported in the form of an abstract (18).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
We measured exhaled NO in 53 nonsmoking, clinically stable individuals with asthma (24 males), age 43 ± 23 years (mean ± SD), who were regularly followed in a tertiary referral outpatient clinic for management of mild-to-severe persistent asthma (19). They were all on inhaled corticosteroids.

We also studied 13 nonsmoking, clinically stable individuals with asthma (6 males), age 39 ± 23 years (mean ± SD), who, by their choice, were inhaled corticosteroid naive.

We modified the classification of asthma (19) to include treated individuals with asthma, and stratification was determined after administration of 180 µg albuterol sulfate by metered-dose inhaler. Mild refers to an FEV1 greater or equal to 80% predicted, moderate to an FEV1 of 79 to 61% predicted, and severe to an FEV1 of less than 61% predicted (19).

All individuals with asthma studied had given informed consent for participation. This study was approved by the Institutional Review Board.

Individuals with asthma were not on oral corticosteroids or leukotriene inhibitors within 2 months of measurement of exhaled NO. Optimal medical therapy was confirmed by evaluating clinical status and serial spirometry obtained during routine outpatient clinic visits every 1–2 months over 3–5 years in each patient with asthma.

Normal Control Subjects
Normal values for exhaled NO were obtained from 34 subjects (13 males), age 40 ± 17 years (mean ± SD), who were asymptomatic, healthy nonsmokers with normal lung function.

Measurement of Exhaled NO Gas Exchange
Exhaled NO was measured at three separate constant expiratory flow rates: 100, 150, and 200 ml/second in triplicate, and the mean of three values obtained within 10% of each other is reported using a Sievers NOA 280 chemiluminescence analyzer with varying expiratory airflow resistors (Ionics, Boulder, CO). We chose 100 ml/second for the lowest expiratory flow rate rather than 50 ml/second, as previously recommended (8, 9), because reproducible data could not be obtained at 50 ml/second in subjects with asthma with FEV1 less than 80% predicted. We also could not obtain reproducible data using flow rates greater than 200 ml/second. More importantly, Tsoukias and George (13, 14) and George and colleagues (21) have shown the relationship between steady-state alveolar NO concentration (CANO) and expiratory flow is linear above a threshold of 50 ml/second. To avoid nasal NO contamination, a mouth pressure of greater than 5 cm H2O was used, as previously recommended (20). The NO analyzer was calibrated at minimum daily with a known NO concentration (45 ppm) and before each patient or control subject with NO-free air. The technique of Tsoukias and George (13, 14) was used to calculate bronchial NO maximal flux (J'awNO) and CANO.

Spirometry and CANO measurements were repeated in 16 subjects with asthma on inhaled corticosteroids chosen at random at least 10 days after the initial study to evaluate reproducibility.

Lung Computed Tomography Studies
High-resolution, thin-section computed tomography scan of the lung was obtained in 28 of the 33 subjects with asthma (5 refused) age greater than 21 years with moderate-to-severe persistent asthma (19), and scored by a radiologist (M.J.S.) for emphysema (0–100, 100 being the worst) using picture templates, as previously validated (22).

Lung Function Studies
When clinically stable for at least 3 months, patients with asthma were instructed to continue all their medications, except to withhold inhaled albuterol sulfate and ipratropium bromide 6 hours before testing. Techniques for measuring spirometry, thoracic gas volumes, and airway resistance using plethysmography, and diffusing capacity have been previously published (23).

Clinical Status
Patients with asthma were divided into two groups: "difficult" versus "not difficult" to clinically manage. "Difficult" comprised patients who required two or more hospitalizations for control of asthma during the past 2 years or three or more 7–14 day tapering courses of oral corticosteroids during the past year.

We also divided daily inhaled fluticasone dosage into low, less than 500 µg daily, or high, 500 µg or greater daily during the preceding year.

Statistical Methods
We compared values between normal controls and patients with asthma using analysis of variance on the ranks (nonparametric analysis of variance, Kruskal-Wallis test). Alternatively, Wilcoxon rank sum test was used. Additionally, Spearman's correlation coefficient and chi-square were used. Statistical significance was p < 0.05. SAS version 8.02 for Windows was used for analysis (SAS Institute, Cary, NC). Figures include median, 1 and 3 quartile, 5 and 95%, and all outlier values.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Lung Function
Results of lung function studies in normal control subjects and cohorts with asthma, with and without maintenance inhaled corticosteroids, are described in Table 1. The cohorts with mild-to-severe persistent asthma (n = 66) had normal diffusing capacity and mild hyperinflation at total lung capacity; 6.5 ± 1.4 L (mean ± SD), 118 ± 16% predicted.


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  		TABLE 1. Results of lung function in normal control subjects versus patients with asthma

 
Lung Computed Tomography
High-resolution, thin-section lung CT obtained in 28 of the 33 adults with moderate-to-severe persistent asthma (FEV1 < 80% predicted) revealed no or trivial emphysema with a score of 10 or less (22).

NO in Patients with Asthma on Inhaled Corticosteroids
Results of total exhaled NO (FENO (ppb) at 100 ml/second, CANO (ppb), and J'awNO (nl/second) are described in Table 2 and Figures 1– 3. Compared with normal control values, 53 patients with mild-to-severe persistent asthma on inhaled corticosteroids had significantly abnormal FENO, J'awNO, CANO, and spirometry. However, there was no significant correlation between either FENO at any expiratory flow rate, CANO, or J'awNO versus expiratory airflow limitation using FEV1 % predicted as the signal (Spearman's r < 0.06, p > 0.7). There was a significant but weak correlation between J'awNO and CANO (Spearman's r = 0.50, p < 0.001).


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  		TABLE 2. Results of total exhaled nitric oxide, bronchial nitric oxide maximal flux, and steady-state alveolar nitric oxide concentration in normal controls versus patients with asthma

 


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  		Figure 1. Measurement of total exhaled nitric oxide (FENO) at 100 ml/second, including median, 1st and 3rd quartile, and 5th and 95th percentile in normal controls and patients with asthma on and off inhaled corticosteroids (IC). Solid circles refer to outliers and asterisks (*) to p < 0.05 compared with normal.

 


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  		Figure 2. Measurement of bronchial nitric oxide maximal flux (J'awNO) in normal controls and in patients with asthma on and off inhaled corticosteroids. Solid circles refer to outliers and the asterisk (*) to p < 0.05 compared with normal.

 


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  		Figure 3. Measurement of steady-state alveolar nitric oxide concentration (CANO) in normal controls and in patients with asthma on and off inhaled corticosteroids. Solid circles refer to outliers and the asterisk (*) to p < 0.05 compared with normal.

 
Reproducibility of Alveolar NO Measurements
In 16 patients with asthma, aged 55 ± 18 years (mean ± SD), CANO and FEV1 (L) were obtained 76 ± 39 days after the initial study. Eight of the 16 patients with asthma were classified as difficult to treat. The initial FEV1 was 2.1 ± 0.9 L, (71 ± 22% predicted) and not significantly different (p = 0.3) from the subsequent FEV1 of 2.0 ± 0.9 L (68 ± 24% predicted). The initial CANO was 7.1 ± 5.5 ppb, and the subsequent CANO was 5.8 ± 5.2 ppb, p = 0.46. These results suggest good reproducibility for measurements of FEV1 and CANO.

NO and Inhaled Corticosteroids
There was no significant relationship between daily low versus high fluticasone dosage and FENO at 100 ml/second: median 31 (18, 45) (first, third quartile) versus 21 (13, 29) ppb (Wilcoxon, p = 0.11); J'awNO: median 2.3 (1.1, 3.7) versus 1.4 (0.6, 2.4) nL/second (p = 0.16); CANO: median 5.8 (4.1, 9.1) versus 4.2 (2.1, 7.7) ppb (p = 0.29), and FEV1 % predicted: 74 (60, 99) versus 66 (57, 80) % (p = 0.30).

Difficult Versus Not Difficult to Treat and NO
A significantly greater proportion of patients with asthma categorized as clinically "difficult to manage" had abnormally elevated FENO at 100 ml/second: 79 versus 41% (chi-square p = 0.02), CANO: 49 versus 17% (p = 0.008), and J'awNO: 59 versus 31% (p = 0.06) when compared with patients with asthma categorized as "not difficult to manage." Eight of 17 patients less than 21 years of age with asthma were labeled difficult to treat, and 6 of these 8 had persistent FEV1 less than 80% predicted. No patients with asthma who were not difficult to treat had FEV1 less than 80% predicted. Alternatively, 29 of 49 patients older than age 21 with asthma were difficult to treat and 24 of 29 had FEV1 less than 80% predicted. Only 7 of 20 patients with asthma who were not difficult to treat had persistent FEV1 less than 80% predicted.

NO and Lung Elastic Recoil
In 23 (10 males) patients age 54 ± 17 years (mean ± SD) with asthma with FEV1 65 ± 16%, the static lung elastic recoil pressure at 100% predicted TLC was 11 ± 4 cm H2O, 53 ± 23% predicted. There was no correlation between static lung elastic recoil and CANO; r = 0.05, p = 0.10.

NO in Patients with Asthma Not on Inhaled Corticosteroids
In the 13 inhaled corticosteroid-naïve patients with asthma, only FENO was significantly elevated compared with normal subjects (p = 0.009).

Effect of Oral Corticosteroid Treatment on CANO and J'awNO
Five days of 30 mg prednisone in 10 (6 female) patients (age 59 ± 15 years [mean ± SD]) with asthma on inhaled corticosteroids resulted in a significant (p = 0.002) decrease only in CANO, from 13 ± 10 ppb (mean ± SD) to 4 ± 4 ppb, with no significant change in FENO at 100 ml/second, J'awNO, and expiratory spirometry (Table 3).


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  		TABLE 3. Results of lung function and expired nitric oxide before and after 30 mg daily prednisone for 5 d in 10 patients with asthma age 59 ± 19 yr (mean ± sd)

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
As reported herein, significantly increased CANO in adults with asthma may reflect increased or nonsuppressed inflammatory signals originating in very distal gas exchanging respiratory bronchioles and/or alveoli. This unexpected finding in clinically stable patients with asthma without isolated nocturnal symptoms, and with varying mild-to-severe expiratory airflow limitation, was noted despite treatment, including inhaled corticosteroids. There was a significant but weak correlation between J'awNO and CANO, but not between J'awNO and CANO and expiratory airflow obstruction using either FEV1 % predicted as the signal or lung elastic recoil.

The observation of significantly increased CANO compared with control subjects in the present study is consistent with previously obtained results in steroid-naive patients with mild intermittent asthma with minimal expiratory airflow limitation and presence of nocturnal symptoms (17). The present results also complement the observations of Mahut and coworkers (24) who noted similarly increased CANO in children with mild symptomatic asthma on inhaled corticosteroids but with normal or near-normal spirometry. Previous studies by Hogman and colleagues (10) noted normal values for CANO in adults and children with asthma.

However, the novel observation was the significant reduction in abnormally increased CANO in patients with asthma on inhaled corticosteroids after 5 days of 30 mg prednisone. The failure to concomitantly reduce bronchial NO flux was unexpected, and based on the work of Ricciardolo (25) it may reflect broncho-protective constitutive NO synthase in the larger airways. Alternatively, broncho-reactive inducible NO synthase in the distal airways and/or alveoli is responsive to oral corticosteroids. The inhaled corticosteroids are probably able to suppress inducible NO synthase in the larger airways but not penetrate beyond smaller distal airways.

Shin and coworkers (26) evaluated 20 individuals with asthma with both similar extent of expiratory airflow limitation and techniques to measure bronchial and alveolar NO, as in the present study. Consistent with the present results, they noted significantly elevated bronchial NO levels in 12 subjects with asthma despite treatment with inhaled corticosteroids (26). However, in contrast to the present results, despite a moderate increase in alveolar NO, it did not reach statistical significance (26).

Shin and coworkers (26–28) and Van Muylem and coworkers (29) noted that an increase in alveolar NO concentration could reflect a primary increase in alveolar NO production or secondary axial contamination from very small airway radial diffusion of NO. Because there was a weak correlation between bronchial NO flux and alveolar NO in subjects with asthma on inhaled corticosteroid in the present study, axial contamination seems unlikely as a contributing factor. Furthermore, there were nine patients with asthma with normal bronchial NO flux yet abnormal CANO and 14 patients with asthma with the reverse observation.

Normal control values for airway and alveolar NO in the present study were similar to normal values previously obtained by Mahut and coworkers (24), Shin and coworkers, (26) and George and coworkers (21), but higher than results of Lehtimaki and coworkers (17) and Hogman and coworkers (10). This discrepancy may in part be related to differences in equipment, but probably is more reflective of varying techniques. Lehtimaki and colleagues (17) and Hogman and colleagues (10) used expiratory flow rates up to 370 ml/second and 500 ml/second, respectively, compared with 200 ml/second in the present study and 250 ml/second by Shin and colleagues (26). Higher expiratory flow rates lead to lower alveolar NO in normal individuals and patients with asthma (21).

Chronic asthma is presumably due to a cascade of circulating cytokines and mediators of inflammation, responsible for airway remodeling in both the large and small airways of individuals with asthma (30, 31). It has been suspected, but never proven, that these changes are responsible for persistent clinical symptoms as well as persistent expiratory airflow limitation, due to uncontrolled smooth muscle bronchoconstriction and hyperreactivity in refractory asthma (30, 31). However, there is accumulating biopsy and autopsy data to suggest that some characteristics of airway remodeling, especially epithelial abnormalities and thickening of the reticular basement membrane, may reflect the presence of asthma but not the duration or extent of physiologic impairment in asthma (32–36).

Preliminary evidence suggests there may be a concomitant lung parenchymal component in persistent asthma. This includes the presence of inflammatory cells in the lung parenchyma obtained by fiberoptic bronchoscopy biopsy in patients with nocturnal asthma (37). Moreover, we recently reported unexpected and unexplained loss of lung parenchymal elastic recoil properties not due to emphysema in stable, nonsmoking, patients with chronic persistent asthma with abnormal expiratory airflow limitation (23, 38). These physiologic observations also challenge the prevailing concept that intrinsic small and large airway remodeling is solely responsible for expiratory airflow limitation in chronic, persistent asthma.

The current observation of increased bronchial and alveolar NO levels in individuals with chronic asthma on inhaled corticosteroids suggests concurrent, separate, incompletely or nonsuppressed inflammatory sites. In particular, the elevated alveolar NO may reflect smoldering inflammatory signals distal to membranous bronchioles that may be suppressed with oral prednisone. The relationship between increased alveolar NO, an inflammatory marker, and its role in asthma pathobiology, including persistent expiratory airflow limitation, will need to be further defined.


   Acknowledgments
 
The authors thank Steven C. George, M.D., Ph.D., for helpful suggestions, critical review, and discussion of the manuscript, Christy Kirkendall and Michelle Curry for patient scheduling, and Aia White-Podue for manuscript preparation.


   FOOTNOTES
 
Supported in part by the Mary Decker Foundation.

Conflict of Interest Statement: A.F.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; C.F.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; E.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; C.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; C.M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; M.J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; J.D.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; N.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this article.

Received in original form March 24, 2004; accepted in final form June 28, 2004


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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