 Reduce Exhaled
Nitric Oxide in Normal and Asthmatic Subjects
Irrespective of Airway Caliber Changes
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ABSTRACT |
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INTRODUCTION
METHODS
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DISCUSSION
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Cyclooxygenase products modulate the expression of nitric oxide synthase (NOS) in certain cell types.
We determined the effect of prostaglandins (PG) E2 and F2
on exhaled nitric oxide (NO) concentrations measured by chemiluminescence. Inhaled PGE2 and PGF2 significantly reduced exhaled NO. After the highest dose of PGE2 (100 µg), NO concentrations fell from 6.9 ± 0.5 ppb to 4.0 ± 0.8 ppb (p < 0.001), and from 22.9 ± 2.0 ppb to 12.3 ± 1.2 ppb (p < 0.001), whereas after PGF2, it fell from 6.5 ± 0.6 ppb to 3.0 ± 0.5 ppb (p < 0.001), and from 26.0 ± 3.4 ppb to 11.5 ± 1.4 ppb (p < 0.001) in normal (n = 7) and asthmatic (n = 8) subjects, respectively. Although the prostaglandins did not change
FEV1 in normal subjects, PGE2 caused an increase in asthmatics (from 3.6 ± 0.3 L to 3.8 ± 0.4 L, p < 0.05) and PGF2 caused a transient reduction in FEV1 from 4.0 ± 0.2 L to 3.5 ± 0.2 L (p < 0.05). To
further determine the relationship between bronchoconstriction and exhaled NO levels, we examined the effect of inhaled methacholine which did not change exhaled NO concentrations in normal
and asthmatic subjects despite a greater than 20% fall in FEV1 in asthmatics. Therefore, PGE2 and
PGF2 reduce exhaled NO, an effect not related to airway caliber changes but which may result from
an inhibition of nitric oxide synthase (NOS), particularly inducible NOS (iNOS).
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Nitric oxide (NO) is formed from L-arginine by nitric oxide synthase (NOS) in many cells within the respiratory tract and may play an important role in the pathophysiology of airway diseases (1). NO can be detected in exhaled air (5) and is increased in patients with asthma (6). Concentrations of exhaled NO are reduced by treatment with inhaled steroids (6). The source of the increase in exhaled NO in asthma is not entirely clear but could be from the airway epithelium where there is an increased expression of the inducible nitric oxide synthase (iNOS) (10, 11). Apart from the presence of iNOS which can be induced by the action of proinflammatory cytokines, other isoforms of NOS have been detected in the human respiratory tract (12) which could also contribute to exhaled NO levels. Thus, constitutive isoforms of NOS producing small amounts of NO also exist in endothelial and epithelial cells (eNOS) and in neurons (nNOS). However, their exact contribution to exhaled NO levels is not known. Nonspecific inhibitors of NOS such as N-monomethyl-L-arginine (L-NMMA) and N-nitro-L-arginine methylester (L-NAME) reduce the levels of exhaled NO in normal and asthmatic subjects, but this observation does not indicate whether the iNOS isoform is the most predominant form in asthma (16, 17).
Products of the cyclooxygenase pathway may play a role in
the pathophysiology of asthma. Prostaglandins such as PGF2
and PGE2 are known to modulate airway caliber. Thus, PGF2
induces bronchoconstriction while PGE2 causes a small degree of bronchodilatation (18, 19). In addition, PGE2 inhibits
exercise-induced bronchoconstriction (20) and allergen-induced
early- and late-phase responses (21), and also prevents aspirin-induced bronchoconstriction in aspirin-sensitive asthma. PGE2
has also been shown to prevent the induction of iNOS in certain cell lines (22).
We reasoned that prostaglandins may modulate the level of
exhaled NO by inhibiting of iNOS, particularly in patients
with asthma. Because PGE2 and PGF2 have divergent effects
on airway caliber, we determined the relationship of airway
caliber changes to those of exhaled NO. To further determine
the relationship of airway caliber to exhaled NO, we examined
the effect of methacholine-induced bronchoconstriction.
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METHODS |
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INTRODUCTION
METHODS
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DISCUSSION
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Patients
Eight (1 female) atopic asthmatic patients and seven (all male) normal subjects volunteered for this study (Table 1). None of them were
current cigarette smokers and two normal volunteers were ex-smokers of more than 5 yr. Asthmatic subjects had a history of wheezing or
chest tightness and were not taking corticosteroid therapy. Two of
them had stopped using bronchodilators for more than 3 mo; and the
other occasionally used inhaled 
2-agonists as required. None of the
patients were aspirin-sensitive. All patients had positive cutaneous responses (skin prick test > 3 mm wheal) to at least one common
aeroallergen (cat dander, house dust mite, grass pollen). All had FEV1
values > 80% of predicted normal and values of provocative concentration of methacholine required to produce a 20% fall in FEV1
(PC20) of < 4 mg/ml. There was no history of upper respiratory tract
infection for at least 4 wk prior to the study and none of the subjects
had received antibiotics in the previous week. Patients did not consume any caffeine for 2 h or inhaled 2-agonists for 8 h prior to challenge. All subjects gave their written informed consent to the study which was approved by the ethics committee of the Royal Brompton Hospital.
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Protocol
All subjects attended the laboratory on three different days separated
by at least 7 d apart in order to receive inhaled challenges in random
order with methacholine, PGE2, and PGF2. All challenges were performed between 9:00 and 12:00 h. The subject and the experimenter
who measured FEV1 and NO were not aware of the inhaled substances. Six asthmatic and five normal subjects also attended on an additional day to receive four nebulizations of 0.9% NaCl separated by
15-min intervals in order to mimic the four concentrations of prostaglandins.
Methacholine Challenge
A standard procedure was employed for bronchial challenge with methacholine. After baseline FEV1 assessment, subjects inhaled five breaths of 0.9% saline control via a hand-held nebulizer (Dosimeter MB3; MEFAR Electromedical, Bovezzo, Italy) with an output of 10 µl per breath. Aerosols were inhaled from end-tidal volume to full inspiratory capacity. Subjects were trained to take 3 s to reach full inspiratory capacity. Methacholine (Sigma Chemical Company, Poole, Dorset, UK) concentrations ranged from 0.063 to 32 mg/ml and 5 inhalations at each concentration were administered (inhalation time 1 s, breath-holding time 6 s), and FEV1 was measured 2 min after the last inhalation, until there was a fall in FEV1 of 20% compared with the control inhalation (0.9% NaCl solution) or until the maximal concentration was inhaled. The PC20 value was calculated by linear interpolation of the logarithmic dose-response curve.
Prostaglandin Challenge
Subjects were given increasing concentration of PGE2 (ProstinE2; Upjohn SA, Puurs, Belgium) or PGF2 (Prostin F2; Upjohn SA) aerosols
at 25-min intervals. After a 15-min rest, three baseline measurements
of FEV1 were made at intervals of 1 min followed by inhalation of
0.9% NaCl and three FEV1 measurements were repeated with 1-min
interval in between. Exhaled NO was measured before and after saline inhalations, and the mean of the two measurements was taken as
baseline value. Provided FEV1 had not fallen by > 10% of the baseline value, PGE2 or PGF2 challenge was performed with doubling
concentrations of freshly prepared PGE2 or PGF2 at concentrations
of 6 µg/ml, 12.5 µg/ml, 25 µg/ml, and 50 µg/ml. Prostaglandins (2 ml)
were delivered continuously from a nebulizer giving doses of 12 µg,
25 µg, 50 µg, and 100 µg (23). FEV1 was measured every 5 min up to
15 min after each dose and every 5 min for the following 15 min during spontaneous recovery.
Measurement of Exhaled NO
Exhaled NO was measured by chemiluminescence analyzer (Model LR2000; Logan Research, Rochester, Kent, UK), with sensitivity from 1 part per billion (ppb) to 5,000 ppb of NO, accuracy ± 0.3 ppb, and response time of < 2 s to 90% of full scale. In addition, the analyzer also measured CO2 (range 0 to 10% CO2, accuracy ± 0.1%, response time 200 ms to 90% of full scale), expiration flow and pressure, and exhaled volume in real-time. The analyzer was fitted with a biofeedback display unit to provide a visual guidance for the subject to maintain the pressure and exhalation flow within a given range (3 ± 0.4 mm Hg and 5 to 6 L/min) for end-exhaled NO measurements, hence, improving test repeatability and enhancing patient cooperation. Pressure created in the mouthpiece, and subsequently in the reaction chamber, varied insignificantly and therefore caused negligible change (< 0.1 ppb) in NO readings. The sampling rate through the reaction chamber of the analyzer was 250 ml/min for all measurements. The analyzer was calibrated daily using NO-free certified compressed air to set absolute zero and then a certified concentration of NO in nitrogen of 90 ppb and 500 ppb (BOC Special Gases, Surrey Research Park, Guildford, UK), and certified 5% CO2 (BOC). Ambient air NO level was recorded and the absolute zero was adjusted prior to all measurements. For the end-exhaled NO measurements, subjects exhaled slowly from TLC over 15 to 20 s at an exhalation flow rate 5 to 6 L/min. NO was sampled from a side-arm attached to the mouthpiece. The mean value of the last 100 measurements, acquired at 0.04-s intervals, was taken from the point corresponding to the plateau of end-exhaled CO2 reading (5 to 6% CO2), and representing the lower respiratory tract sample. Results of the analyses were computed and graphically displayed on a plot of NO and CO2 concentrations, pressure, and flow against time.
Statistics
Results were expressed as means ± SEM, apart from PC20 results which were expressed as geometric means and geometric SEM. Comparisons between groups were made by repeated measured two-way analysis of variance (ANOVA) with Bonferroni's correction for multiple comparisons. A p value < 0.05 was considered significant.
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RESULTS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Effect of Methacholine Challenge in Normal and Asthmatic Subjects
There was no change in exhaled NO and FEV1 during and after methacholine challenge in normal subjects. Despite the reduction in FEV1 induced by a PC20 concentration of methacholine, there was no change in exhaled NO in patients with asthma (Figure 1).
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Effect of PGE2 and PGF2 Inhalation in Normal Subjects
Inhalation of 0.9% NaCl prior to PGE2 or PGF2 inhalation
did not change either exhaled NO concentrations or FEV1 values (Figure 2). In addition, four consecutive nebulizations of
0.9% NaCl separated by 15-min intervals had no effect on exhaled NO.
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All subjects experienced a short-lasting episode of cough associated with retrosternal soreness after the first inhalation of prostaglandins. Exhaled NO levels were significantly (p < 0.001) reduced after PGE2 inhalation (from 6.9 ± 0.5 ppb to 5.2 ± 0.6 ppb 15 min after 12 µg and to 4.0 ± 0.8 ppb after 100 µg) and remained low for up to 25 min during the recovery period (4.4 ± 0.7 ppb, p < 0.001). There was a nonsignificant increase in FEV1 after PGE2 inhalation.
PGF2 inhalation also caused a significant reduction in exhaled NO from 6.5 ± 0.6 ppb to 4.0 ± 0.4 ppb at 15 min after 12 µg, and to 3.0 ± 0.5 ppb after 100 µg. Exhaled NO remained low for up to 30 min during the recovery period (4.3 ± 0.7 ppb, p < 0.001). There was no change in FEV1 throughout
the study.
Effect of PGE2 and PGF2 Inhalation in Asthmatic Subjects
Inhalation of 0.9% NaCl prior to PGE2 or PGF2 inhalations
did not change either exhaled NO concentrations or FEV1
(Figure 3). In addition, four consecutive nebulizations of 0.9%
saline did not change exhaled NO.
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Patients with asthma also experienced a short-lasting episode of cough (associated with retrosternal soreness and tightness of the chest after the first inhalation of prostaglandins). NO levels were significantly (p < 0.001) reduced after PGE2 inhalation (from 22.9 ± 2.0 ppb to 16.0 ± 1.8 ppb 15 min after 12 µg and to 13.3 ± 1.2 ppb after 100 µg), an effect that persisted for up to 30 min during the recovery period (16.6 ± 2.0 ppb, p < 0.001). There was a small but significant (p < 0.05) increase in FEV1 from 3.6 ± 0.3 L at baseline to 3.8 ± 0.4 L at 15 min after 25 µg, with no further increase after the 50 µg and 100 µg doses of PGE2. FEV1 remained significantly elevated for up to 25 min after the last dose of PGE2.
There was also a significant reduction in exhaled NO after
PGF2 inhalation (from 26.0 ± 3.4 ppb to 14.1 ± 3.0 ppb 15 min after 12 µg and to 11.5 ± 1.4 ppb after the dose of 100 µg). Exhaled NO remained low for up to 30 min after inhalation (14.9 ± 1.9 ppb, p < 0.001). Although there was a significant reduction in FEV1 at 5 to 10 min after the initial doses of
PGF2, there was no further change.
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DISCUSSION
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We have shown that inhaled prostaglandins PGE2 and PGF2
rapidly reduce exhaled NO concentrations in both normal and asthmatic subjects while causing bronchodilatation and bronchoconstriction respectively in patients with asthma. Taken
together with the finding that bronchoconstrictor doses of
methacholine did not alter exhaled NO levels, we conclude
that PGE2- and PGF2-induced changes of airway caliber are
independent of changes in concentrations of exhaled NO.
The fall in exhaled NO induced by both prostaglandins occurred in both normal and asthmatic subjects. Although the
percentage fall from baseline values of exhaled NO were similar in both groups, there was a greater absolute fall in asthmatics because they started from a higher basal value of exhaled
NO. The increased concentrations of exhaled NO in asthmatics may result from an increased expression of the iNOS in airway epithelial cells and possibly alveolar macrophages (10, 13,
24, 25). Analogues of L-arginine such as L-NMMA and L-NAME
induce a fall in exhaled NO in both normal and asthmatic subjects (6, 16, 17) but these inhibitors of NOS are not specific for
any particular NOS. However, the more specific inhibitor of
iNOS, aminoguanidine, only inhibits the higher levels of exhaled NO in patients with asthma but not in normal subjects
(17). Because PGE2 and PGF2 inhibited exhaled NO in both
normal subjects and asthmatics, it is likely that these prostaglandins were inhibiting both inducible and endogenously expressed NOS.
It is unlikely that the changes in exhaled NO we observed
are linked to or are the consequence of changes in airway caliber. Bronchoconstriction induced by methacholine in asthmatic patients did not result in significant changes in the levels
of exhaled NO. Conversely, bronchodilatation with a -adrenergic agonist also does not affect exhaled NO levels (26). Furthermore, the effects of PGE2 and of PGF2 on airway caliber
in the asthmatic subjects were divergent, with PGE2 causing
bronchodilatation and PGF2 bronchoconstriction, whereas
both prostaglandins induce a fall in exhaled NO concentrations. In both normal and asthmatic subjects, we observed significant decreases in exhaled NO at the lowest dose of prostaglandins that we used (12 µg), indicating that the sensitivity
of exhaled NO to the prostaglandins was unlikely to be different in the two groups despite the airway caliber responses in
the asthmatics. Conversely, our data also do not link changes in exhaled NO concentrations to airway caliber, which is in
agreement with studies in which breathing up to 80 parts per
million of exogenous NO did not affect specific airway conductance in normal subjects (27) and had only a very weak
bronchodilatory effect in asthmatic subjects (28). Thus, in contrast to the pulmonary vascular smooth muscle, airway smooth
muscle is less responsive to inhaled NO.
The functional consequences of lowering endogenous NO production, particularly in patients with asthma, are unknown. Although this may not modulate airway caliber directly, other effects may occur such as changes in bronchial mucosal blood flow and reduction of airway microvascular leakage (29).
The mechanism by which the prostaglandins E2 and F2 inhibit NOS activity, hence leading to a fall in exhaled NO, is not known. In studies of renal mesangial cells, inhibition of endogenous products of the cyclooxygenase pathway by indomethacin led to an increase in NO production induced by
interleukin-1 (IL-1) stimulation, whereas exogenous PGE2
reversed this effect (30). These observations indicate that
PGE2 is an inhibitor of iNOS. The changes in exhaled NO that
we observed in vivo were very rapid, occurring within a few
minutes of inhalation, indicating that the effects of the prostaglandins are likely to occur through a direct effect on the
NO synthases, reflecting an enzyme induction. Our current
data indicate that both PGE2 and PGF2 had similar effect in
reducing the level of exhaled NO, possibly an effect occurring
through stimulation of similar prostaglandin receptors.
Interactions between NO and prostaglandins have been described in various inflammatory models (31). NO has been
shown to be able to directly activate both the constitutive and
inducible forms of cyclooxygenase enzyme, thus leading to the
overproduction of prostaglandins (32, 33). Conversely, inhibitors of NOS such as L-NMMA and aminoguanidine can attenuate PGE2 production through inhibition of inducible cyclooxygenase (33, 34). Our data indicate that prostaglandins E2
and F2 can in turn inhibit the production of NO. Taken with
the previous observations, a potential self-regulating mechanism for NO production may occur in inflammation through
the production of PGE2 and PGF2.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Professor K. Fan Chung, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK.
(Received in original form July 15, 1997 and in revised form September 24, 1997).
Acknowledgments: Supported in part by the British Lung Foundation (UK).
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References |
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METHODS
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REFERENCES
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S. A. KHARITONOV and P. J. BARNES Exhaled Markers of Pulmonary Disease Am. J. Respir. Crit. Care Med., June 1, 2001; 163(7): 1693 - 1722. [Full Text] [PDF]
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A. J. MACFARLANE, R. DWORSKI, J. R. SHELLER, I. D. PAVORD, A. BARRY KAY, and N. C. BARNES Sputum Cysteinyl Leukotrienes Increase 24 Hours after Allergen Inhalation in Atopic Asthmatics Am. J. Respir. Crit. Care Med., May 1, 2000; 161(5): 1553 - 1558. [Abstract] [Full Text]
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