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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Exhaled NO is increased in patients with asthma and may reflect disease severity. We examined
whether the level of exhaled NO is related to the degree of airway obstruction induced by direct and
indirect stimuli in asthma. Therefore, we measured exhaled NO levels before and during recovery
from histamine and hypertonic saline (HS) challenge (Protocol 1) or histamine, adenosine 5'-monophosphate (AMP), and isotonic saline (IS) challenge (Protocol 2) in 11 and in nine patients with mild
to moderate asthma, respectively. The challenges were randomized with a 2-d interval. Exhaled NO
and FEV1 were measured before and at 4, 10, 20, and 30 min after each challenge. NO was measured
during a slow VC maneuver with a constant expiratory flow of (0.05 × FVC)/s against a resistance of
1 to 2 cm H2O. Baseline exhaled NO levels were not significantly different between study days in Protocol 1 (mean ± SD: 4.8 ± 1.8 ppb [histamine] versus 5.4 ± 2.1 ppb [HS], p = 0.4) or in Protocol 2 (7.9 ± 4.7 ppb [histamine], 8.3 ± 5.2 ppb [AMP], and 7.2 ± 3.7 ppb [IS], p = 0.7). A significant reduction in exhaled NO was observed directly after HS (mean ± SEM: 39.2 ± 3.9 %fall) and AMP challenge (32.3 ± 7.3 %fall) (MANOVA, p < 0.001), respectively, whereas exhaled NO levels tended to
decrease after histamine challenge. Isotonic saline challenge did not induce changes in exhaled NO
(p = 0.7). There was a positive correlation between %fall in FEV1 and the %fall in exhaled NO after
histamine, HS, and AMP challenge as indicated by the mean slope of the within-subject regression lines (p 
0.04). We conclude that acute bronchoconstriction, as induced by direct and indirect stimuli, is
associated with a reduction in exhaled NO levels in asthmatic subjects. This suggests that airway caliber should be taken into account when monitoring exhaled NO in asthma.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Recently, nitric oxide (NO) was implicated in the pathophysiology of asthma (1). Endogenous NO, which can be measured in exhaled air, appears to be increased in patients with asthma (2), and it may reflect disease severity (3). Furthermore, it has been demonstrated that the major part of the elevated exhaled NO in asthma originates from the lower respiratory tract (4, 5).
NO is generated from L-arginine by constitutive (cNOS) and inducible (iNOS) NO synthases (6). Several agonists such as histamine can stimulate the activity of cNOS, which is basically expressed in several cells within the airways. The expression of iNOS, however, can be induced by inflammatory cytokines, for instance, in epithelial cells and infiltrative cells.
Several airway stimuli such as allergen exposure (7), viral infection (8), and exercise (9), have been shown to affect exhaled NO levels in asthma, most probably because of local modification of NO synthase expression and/or activity. Although the effect of airway inflammation on exhaled NO levels has been clearly established, it is yet unknown whether exhaled NO levels can be modulated by changes in airway caliber during exacerbations of asthma.
Therefore, in this study we examined the effect of acute bronchoconstriction induced by either directly or indirectly acting stimuli on exhaled NO levels in patients with asthma. To that end we measured exhaled NO before and repetitively after inhalation challenges with histamine, hypertonic saline (HS), adenosine 5'-monophosphate (AMP), and a control challenge with isotonic saline (IS) in patients with mild to moderate asthma.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Protocol 1. Eleven nonsmoking, atopic, asthmatic subjects 19 to 28 yr
of age participated in this study. All had mild to moderate persistent
asthma, and symptoms were controlled by inhaled short-acting 
2-
agonists on demand only. Their baseline FEV1 ranged from 77 to
101% predicted, and all were hyperresponsive to inhaled histamine (PC20 range: 0.14 to 3.05 mg/ml) (10). There was no history of upper
respiratory tract infection or relevant allergen exposure during the
2 wk prior to the study. Before testing the subjects were asked to refrain from bronchodilators and caffeine-containing beverages for at
least 8 h and 4 h, respectively. In a crossover design a histamine and
hypertonic saline challenge were performed in randomized order on
2 d with an interval of 48 h.
Protocol 2. Nine other asthmatic subjects meeting the same criteria (age: 19 to 26 yr, FEV1 %predicted: 68 to 112%, and PC20 histamine: 0.14 to 4.15 mg/ml) were included into a crossover design in which histamine and AMP challenges were performed in randomized order on separate days with a 48-h interval. Furthermore, to exclude an effect by the challenge procedures per se on exhaled NO, a control challenge with IS was performed on a third day.
In each protocol, exhaled NO was measured before (baseline) and at 4, 10, 20, and 30 min after the challenge, and FEV1 was recorded before (baseline) and at 5, 15, 25, and 35 min after the provocation. For each individual patient, the challenges were performed at the same time of day (± 1 h). The protocols were approved by the Medical Ethics Committee of the Leiden University Medical Center, and all participants gave written informed consent.
Standardized challenge tests were performed using serial doubling concentrations of histamine-biphosphate (Bufa, Uitgeest, The Netherlands) in phosphate-buffered saline ranging from 0.03 to 8 mg/ml, or AMP (Sigma Chemicals, St. Louis, MO) ranging from 0.32 to 320 mg/ ml (the highest concentration was dissolved in water because of tonicity) (10). Control challenges were performed using three doses of IS only. The solutions were aerosolized using a DeVilbiss 646 nebulizer (DeVilbiss Co., Somerset, PA) (output, 0.13 ml/min), which was connected to the central chamber of an inspiratory and expiratory valve box with an expiratory aerosol filter (Pall Ultipor BB50T; Pall Biomedical Products Co., East Hills, NY). The aerosols were inhaled by tidal breathing for 2 min at 5-min intervals, with the nose clipped.
Hypertonic saline challenge was performed using sodium chloride (Merck, Darmstadt, Germany) in water. Serial doubling doses ranging from 0.9 to 14.4% were nebulized using a DeVilbiss 2000 ultrasonic nebulizer (DeVilbiss 2000 Ultraneb; DeVilbiss) (output, 2.5 ml/min) (11). The aerosols were inhaled through an inspiratory and expiratory valve box (No. 2700; Hans Rudolph, Inc., Kansas City, MO) during tidal breathing for 3 min at 7-min intervals, with the nose clipped.
The airway response to the challenge tests was recorded by FEV1 using a dry rolling-seal spirometer (Spiroflow; P.K. Morgan, Rainham, UK), before the test and at 30 and 90 s after each nebulized dose. Baseline FEV1 was determined as the mean of three reproducible values (FEV1 within 5%). The tests were discontinued when a 20% fall in FEV1 from baseline was obtained or when the highest dose was reached. The responses were expressed as the provocative concentration causing a 20% fall in FEV1 (PC20) (10).
Exhaled NO measurements were performed according to the present recommendations using a Sievers NOA 270B chemiluminescence analyzer (Sievers, Boulder, CO) with a sensitivity of < 1 ppb (8, 12). Using online visual monitoring, the subjects were asked to perform a vital capacity maneuver with a standardized expiratory flow of 0.05 times baseline FVC per second (0.05 × baseline FVC/s), resulting in an expiration time of about 20 s, into a Teflon cylinder connected to 3-mm Teflon tubing, with the nose clipped. To exclude nasal NO contamination a small expiratory resistance of 1 to 2 cm H2O was applied. Furthermore, to exclude possible influences of ambient NO, the subjects inspired "NO-free" air (< 1 ppb) during the measurements. Expired NO was continuously sampled from the center of the flow at a sample flow of 440 ml/min. The expiratory flow was measured by a pneumotachograph (Lilly principle; Jaeger GmbH., Würzburg, Germany). Mean exhaled NO concentrations were determined between 5 and 15 s after start of the expiration and expressed as parts per billion (ppb). NO concentrations were calibrated using a calibration line of NaNO2 (Merck) in distilled water as a reference. Three successive recordings at 1-min intervals were made, and the mean was used in analysis.
PC20 was log-transformed before statistical analysis and expressed as geometric mean ± SD in doubling doses (DD). Exhaled NO levels were expressed as mean ± SD, whereas changes in exhaled NO were expressed as mean %change ± SEM. Multivariate analysis of variance (MANOVA) was applied to test for the effect of induced bronchoconstriction on exhaled NO levels in general. Additionally, Student's paired t test was applied to test for significant MANOVA effects. To exclude dose-related effects of HS and/or AMP challenge on changes in NO apart from bronchoconstriction, the relationship between dose and maximal %fall in NO was examined using Pearson's correlation coefficient. Furthermore, MANOVA was used to examine the slopes of the within-subject regression lines between %fall in NO and %fall in FEV1; p values < 0.05 were considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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All subjects completed the study, although two did not reach a 20% fall in FEV1 from baseline after HS challenge, and PC20 to AMP could not be determined in one subject. The mean %fall in FEV1 and exhaled NO at each time point is presented in Table 1.
|
Protocol 1. Baseline exhaled NO did not differ between
both study days (mean ± SD: 4.8 ± 1.8 ppb [histamine] versus
5.4 ± 2.1 ppb [HS], p = 0.4) nor did baseline FEV1 (p = 0.8).
Exhaled NO levels decreased significantly after HS challenge
(MANOVA, p < 0.001), and there was a trend towards such
decrease after histamine (MANOVA, p = 0.09). The decrease
in exhaled NO was significant at 4 and 10 min after HS provocation (p 0.01) (Figure 1A). Furthermore, there was no difference in %fall in NO between histamine and HS challenge
(p = 0.5). Additionally, no relationship was found between maximal %fall in exhaled NO and the highest given dose of
hypertonic saline (r: 
0.04, p = 0.9). The mean slope of the
within-subject regression lines showed a significant correlation between %fall in FEV1 (x axis) and the %fall in exhaled
NO (y axis), both after histamine (y = 0.68x + 0.36, p = 0.02)
and HS challenge (y = 1.49x 3.12, p < 0.001) (Figure 2). This
indicates that a 10% fall in FEV1 was accompanied with a 7.2 and 11.8% fall in exhaled NO after histamine and HS challenge, respectively.
|
|
Protocol 2. Between the three study days, there was no difference in exhaled NO (mean ± SD: 7.9 ± 4.7 ppb [histamine], 8.3 ± 5.2 ppb [AMP], and 7.2 ± 3.7 ppb [IS], p = 0.7)
and FEV1 (p = 0.9) at baseline. These baseline exhaled NO
values were not significantly different from those in Protocol 1 (p = 0.8). There was a significant reduction in exhaled NO
levels after both histamine (MANOVA, p = 0.045) and AMP
challenges (MANOVA, p = 0.001). The decrease in exhaled
NO from baseline was significant at 4 min after histamine
challenge (p = 0.03), whereas a significant reduction in exhaled NO could be found at 4, 10, and 20 min after AMP challenge (p < 0.04) (Figure 1B). In the control experiment, no
changes in exhaled NO could be demonstrated after IS challenge (p = 0.7). The %fall in NO against time postchallenge
was significantly different between IS and AMP challenge
(p = 0.02), whereas it was not between IS and histamine (p = 0.3), and histamine and AMP challenges (p = 0.8). Additionally, no correlation was observed between maximal %fall and
the highest dose of AMP (r: 0.20, p = 0.7). Furthermore, the
mean slope of the within-subject regression lines showed a significant correlation between the %fall in FEV1 (x axis) and the %fall in exhaled NO (y axis) after both histamine (y = 0.97x 3.32, p = 0.01) and AMP challenge (y = 1.02x + 7.29, p = 0.04) (Figure 2). Hence, a 10% fall in FEV1 was associated with a 6.4 and 17.5% fall in exhaled NO after histamine
and AMP challenges, respectively.
| |
DISCUSSION |
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|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
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The results of the present study show that acute airway obstruction, in particular when induced by indirectly acting stimuli, leads to a rapid decrease in exhaled NO levels in patients with asthma. Furthermore, there is a significant relationship between acute changes in airway caliber and those in exhaled NO. These data suggest that exhaled NO levels are modulated by the level of airway obstruction in patients with asthma.
To our knowledge, this is the first study demonstrating the effect of acute airway obstruction on exhaled NO levels in subjects with asthma. Our results correspond to those recently reported in abstract form by Ho and colleagues (13) showing a significant reduction in exhaled NO levels after methacholine-induced airway obstruction in patients with asthma. Additionally, these investigators demonstrated increased exhaled NO levels after acute bronchodilatation in these patients. Therefore, the presently observed relationship between the reductions in FEV1 and in NO for each of the stimuli strongly suggests modulation of exhaled NO by acute changes in airway caliber in patients with asthma.
We believe that the present findings can indeed be interpreted as an effect of acute airways obstruction on exhaled NO levels. First, in the control experiment using IS no effect on exhaled NO could be demonstrated. This excludes effects of the procedures per se on exhaled NO levels. Second, since no relationship between maximal fall in NO and the highest dose given was found after both HS and AMP challenge, it seems unlikely that the changes in exhaled NO were due to dose-related factors other than bronchoconstriction. Furthermore, the exhaled NO measurements were performed using a validated procedure in which expiratory flow was standardized for each subject and kept constant during the procedures (8, 12). Additionally, a slight resistance in the expiratory flow was applied in order to exclude any possible nasal contamination of exhaled NO concentrations (12). Furthermore, subjects inspired pressurized air containing negligible NO concentrations to avoid possible influences of environmental NO on the concentrations measured. It seems unlikely that the present results can be ascribed to diurnal variation in exhaled NO since the measurements were performed at the same time of day on each study day. Finally, to exclude possible differences in NO production, we selected a homogeneous group of nonsmoking, atopic subjects with mild to moderate asthma without exposure to well-known modulators of exhaled NO such as viral infection (8) or relevant allergen exposure (7) and not using steroid medication (14) before and during the study.
How can the present results be explained? Because the airways are being considered as a major source of the elevated exhaled NO in asthma (4, 5), our findings might be due to the relative reduction of the ventilated airway surface during bronchoconstriction. Expression of iNOS and cNOS has been demonstrated in epithelial cells within the airways (15). It seems likely that NO produced by epithelial cells diffuses into the airway lumen and contributes to exhaled NO. Constriction of the airways, causing a reduction of the luminal airway surface (16, 17) may therefore lead to decreased NO levels in exhaled air. Persson and colleagues (9) have suggested that NO in exhaled air originates predominantly from the terminal and respiratory bronchioles (9). Because occlusion of the smaller airways can occur in pharmacologically induced airways obstruction (18), this may lead to an accompanied reduction in exhaled NO concentrations. Additionally, it can be speculated that trapping of NO in mucus secreted during bronchoconstriction contributes to the presently observed reductions in exhaled NO levels.
Our data seem to be inconsistent with the findings of Kharitonov and colleagues (7) showing a nonsignificant decrease in exhaled NO during the early response to allergen (EAR) and a subsequent significant increase in NO during the late reaction (LAR) in patients with asthma. However, the levels of exhaled NO measured after allergen exposure, which elicits several inflammatory reactions within the airways, may be the result of two different mechanisms. First, a reduction in exhaled NO levels caused by increased bronchoconstriction during the EAR. Second, an increase in exhaled NO caused by elevated iNOS expression and/or activity secondary to allergen-induced airway inflammation, which apparently predominates during the LAR.
It is remarkable that we observed a relatively smaller reduction in exhaled NO after histamine challenge as compared with HS and AMP, although this did not reach statistical significance. Histamine is known to stimulate (constitutive) NO synthase activity through increases in intracellular calcium levels (19). Although HS and AMP may induce bronchoconstriction partly through the secondary release of histamine by mast cells (20, 21), these local histamine levels obtained after exogenous administration might have been relatively higher (22), thereby limiting the fall in exhaled NO after histamine challenge.
In conclusion, acute airway obstruction reduces exhaled NO levels in asthmatic subjects. These data indicate that exhaled NO levels can be modulated by bronchial tone in asthma. Although it is yet unknown whether exhaled NO levels are also affected during spontaneous airway obstruction, airway caliber has to be taken into account when interpreting exhaled NO measurements in patients with asthma. In order to establish whether exhaled NO measurements are a valid and useful tool for monitoring of asthmatic patients, further research into the cellular as well as the physiologic mechanisms determining these exhaled NO levels is necessary.
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Footnotes |
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Correspondence and requests for reprints should be addressed to H. W. F. M. de Gouw, MSc., Lung Function Laboratory, C2-P-62, Leiden University Medical Centre, P. O. Box 9600, NL-2300 RC Leiden, The Netherlands.
(Received in original form March 3, 1997 and in revised form November 18, 1997).
Acknowledgments: The authors would like to thank Dr. P. S. Hiemstra for his constructive comments and his careful reading of the manuscript.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1. Barnes, P. J., and M. G. Belvisi. 1993. Nitric oxide and lung disease. Thorax 48: 1034-1043 [Medline].
2. Alving, K., E. Weitzberg, and J. M. Lundberg. 1993. Increased amount of nitric oxide in exhaled air of asthmatics. Eur. Respir. J. 6: 1368-1370 [Abstract].
3. Massaro, A. F., B. Gaston, D. Kita, C. Fanta, J. S. Stamler, and J. M. Drazen. 1995. Expired nitric oxide levels during treatment of acute asthma. Am. J. Respir. Crit. Care Med. 152: 800-803 [Abstract].
4. Kharitonov, S. A., K. F. Chung, D. Evans, B. J. O'Connor, and P. J. Barnes. 1996. Increased exhaled nitric oxide in asthma is mainly derived from the lower respiratory tract. Am. J. Respir. Crit. Care Med. 153: 1773-1780 [Abstract].
5. Massaro, A. F., S. Mehta, C. M. Lilly, L. Kobzik, J. J. Reilly, and J. M. Drazen. 1996. Elevated nitric oxide concentrations in isolated lower airway gas of asthmatic subjects. Am. J. Respir. Crit. Care Med. 153: 1510-1514 [Abstract].
6. Jorens, P. G., P. A. Vermeire, and A. G. Herman. 1993. L-arginine- dependent nitric oxide synthase: a new metabolic pathway in the lung and airways. Eur. Respir. J. 6: 258-266 [Abstract].
7. Kharitonov, S. A., B. J. O'Connor, D. J. Evans, and P. J. Barnes. 1995. Allergen-induced late asthmatic reactions are associated with elevation of exhaled nitric oxide. Am. J. Respir. Crit. Care Med. 151: 1894-1899 [Abstract].
8.
De Gouw, H. W. F. M.,
K. Grünberg,
R. Schot,
E. C. Dick, and
P. J. Sterk.
1998.
Exhaled nitric oxide (NO) increases following experimental rhinovirus 16 (RV16) infection in asthmatic subjects in vivo.
Eur.
Respir. J.
11:
126-132
9. Persson, M. G., N. P. Wiklund, and L. E. Gustafsson. 1993. Endogenous nitric oxide in single exhalations and the change during exercise. Am. Rev. Respir. Dis. 148: 1210-1214 [Medline].
10. Sterk, P. J., L. M. Fabbri, P. H. Quanjer, D. W. Cockroft, P. M. O'Bryne, S. D. Anderson, E. F. Juniper, and J.-L. Malo. 1993. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur. Respir. J. 6(Suppl. 16):53-83.
11. Sont, J. K., P. Booms, E. H. Bel, J. P. Vandenbroucke, and P. J. Sterk. 1993. The determinants of airway hyperresponsiveness to hypertonic saline in atopic asthma in vivo: relationship with subpopulations of peripheral blood leukocytes. Clin. Exp. Allergy 23: 678-688 [Medline].
12. Kharitonov, S. A., K. Alving, and P. J. Barnes. 1997. Exhaled and nasal nitric oxide measurements: recommendations Eur. Respir. J. 10: 1683-1693 [Medline].
13. Ho, C. F., C. H. Wang, C. Y. Liu, C. T. Yu, and H. P. Kuo. 1997. The effect of bronchodilators on exhaled nitric oxide (NO) in patients with bronchial asthma. Eur. Respir. J. 10: 102s .
14. Kharitonov, S. A., D. H. Yates, and P. J. Barnes. 1996. Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am. J. Respir. Crit. Care Med. 153: 454-457 [Abstract].
15.
Asano, K.,
C. B. E. Chee,
B. Gaston,
C. M. Lilly,
C. Gerard,
J. M. Drazen, and
J. S. Stamler.
1994.
Constitutive and inducible nitric oxide
synthase gene expression, regulation, and activity in human epithelial
cells.
Proc. Natl. Acad. Sci. U.S.A.
91:
10089-10093
16.
James, A. L.,
P. D. Paré, and
J. C. Hogg.
1988.
Effects of lung volume,
bronchoconstriction, and cigarette smoke on morphometric airway dimensions.
J. Appl. Physiol.
64:
913-919
17.
Yager, D.,
J. P. Bulter,
J. Bastacky,
E. Israel,
G. Smith, and
J. M. Drazen.
1989.
Amplification of airway constriction due to liquid filling of
airway interstices.
J. Appl. Physiol.
66:
2873-2884
18.
Engel, L. A.,
L. Landau,
L. Taussig,
R. R. Martin, and
G. Sybrecht.
1976.
Influence of bronchomotor tone on regional ventilation distribution at
residual volume.
J. Appl. Physiol.
40:
411-416
19. Nijkamp, F. P., and G. Folkerts. 1994. Nitric oxide and bronchial reactivity. Clin. Exp. Allergy 24: 905-914 [Medline].
20. Rodwell, L. T., S. D. Anderson, and J. P. Seale. 1991. Inhaled clemastine, an H1 antihistamine inhibits airway narrowing caused by aerosols of nonisotonic saline. Eur. Respir. J. 4: 1126-1134 [Abstract].
21. Phillips, G. D., and S. T. Holgate. 1989. The effect of oral terfenadine alone and in combination with flurbiprofen on the bronchoconstrictor response to inhaled adenosine 5'-monophosphate in nonatopic asthma. Am. Rev. Respir. Dis. 139: 463-469 [Medline].
22.
Reinheimer, T.,
D. Baumgartner,
K. D. Hohle,
K. Racke, and
I. Wessler.
1997.
Acetylcholine via muscarinic receptors inhibits histamine release from human isolated bronchi.
Am. J. Respir. Crit. Care Med.
156:
389-395
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