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INTRODUCTION
METHODS
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DISCUSSION
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Increased exhaled nitric oxide (NO) may reflect respiratory tract inflammation in untreated asthmatics. We compared exhaled NO and bronchoalveolar lavage (BAL) nitrate/nitrite (NO3
/NO2) in 10 patients who had untreated, active pulmonary sarcoidosis with those of normal control subjects. Exhaled NO concentrations, determined by chemiluminescence, were similar in patients and control
subjects (peak NO concentration of patients [mean ± SD]: 13.6 ± 5.9 parts per billion [ppb], peak NO
concentration of control subjects: 11.2 ± 5.7 ppb, p = 0.32; mean alveolar NO concentration of patients: 7.8 ± 4.4 ppb, mean alveolar NO concentration of control subjects: 7.1 ± 4.2 ppb, p = 0.70;
end-tidal NO concentration of patients: 6.9 ± 4.5 ppb, end-tidal NO concentration of control subjects: 6.6 ± 4.0 ppb, p = 0.60). BAL NO2 was assayed using a modified Griess reaction after reduction of NO3 to NO2. There was no significant difference in mean BAL NO2 concentrations, expressed
as nanomoles per milliliter of epithelial lining fluid (patients: 544 nmol/ml, control subjects: 579 nmol/ ml, p = 0.81) or as nanomoles per milliliter of BAL fluid (patients: 6.7 nmol/ml, control subjects: 5.7 nmol/ml, p = 0.41). These data suggest that excess NO generation does not accompany the respiratory tract inflammation of pulmonary sarcoidosis. O'Donnell DM, Moynihan J, Finlay GA, Keatings
VM, O'Connor CM, McLoughlin P, Fitzgerald MX. Exhaled nitric oxide and bronchoalveolar
lavage nitrite/nitrate in active pulmonary sarcoidosis.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Nitric oxide (NO) is produced endogenously in the human
respiratory tract, where it can act as a dilator of bronchial and vascular smooth muscle, a neurotransmitter, and an immune
response mediator. It is generated by the enzyme nitric oxide
synthase through the oxidation of L-arginine and reacts readily
with O2 to form the stable bio-active oxidation end products
nitrate (NO3) and nitrite (NO2) (1). It has been proposed
that the increased NO in the exhaled air of untreated asthmatic patients (2) reflects induction of the inducible form of
nitric oxide synthase (iNOS) in the inflammatory microenvironment of the asthmatic respiratory tract (3). This view is
supported by the immunocytochemical detection of iNOS in
the airway epithelium of asthmatic patients (4) and by its in
vitro induction in alveolar macrophages and epithelial cells after the addition of pro-inflammatory stimuli, including cytokines such as interferon-
(IFN-), tumor necrosis factor-
(TNF-), and interleukin-1 (5, 6).
Whether increased exhaled NO is unique to asthma or is a nonspecific result of many forms of pulmonary inflammation is not clear. Although some studies have reported increased exhaled NO among subjects with bronchiectasis (7), values are normal or low in patients with cystic fibrosis (8, 9). The interpretation of the cystic fibrosis results is complicated by the presence of copious airway secretions that might absorb or degrade any excess NO produced by the inflammatory process.
No published studies to date have investigated exhaled NO in
interstitial lung disease although alveolar macrophages are a potential source of iNOS (10). In the alveolitis of active pulmonary sarcoidosis, alveolar macrophages are present in increased absolute numbers along with the characteristic increase
in activated T lymphocytes. Furthermore, the iNOS-inducing
cytokines mentioned previously, i.e., IFN- and TNF-, have
been associated with the inflammatory milieu of sarcoid alveolitis (11, 12). We therefore hypothesized that respiratory
tract NO production and detectable exhaled NO might be elevated in this disorder. The aim of this study was to examine
exhaled NO and the concentration of its stable metabolites
NO3 and NO2 in bronchoalveolar lavage fluid (BALF) in a
group of untreated sarcoidosis patients with active alveolitis.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Study protocols were approved by the local ethics committee, and all subjects gave written informed consent. Ten patients (eight male) were studied at the time of their first evaluation for suspected active pulmonary sarcoidosis. All were Irish (Caucasian), and the mean age of the group was 35.5 yr (range: 22 to 63 yr). All subjects were symptomatic at the time of entry into the study. The major presenting complaint in six patients was dyspnea or cough; in two patients, granulomatous uveitis; in one patient, nonspecific chest pain with fatigue, fever, and weight loss; and in one patient, wheeze and progressive peripheral lymphadenopathy. In all cases, the chest X-ray (CXR) was abnormal (4 = Siltzbach Stage 1, 3 = Stage 2, 2 = Stage 3, 1 = Stage 4). Six patients had an elevated serum angiotensin converting enzyme (sACE) concentration1 (mean sACE for the group: 50 U/ml; range: 31 to 220 U/ml). None had hypercalcemia or renal or hepatic impairment. No patient had ever received oral or inhaled glucocorticoid or other systemic immune-suppressive therapy. In all cases, the diagnosis of sarcoidosis was confirmed by transbronchial or lymph node biopsy.
Control subjects for the exhaled NO measurement (n = 12; 8 male; mean age: 28.2 yr; range: 22 to 44 yr; all Irish) were healthy nonsmokers with no history of asthma or allergic rhinitis and who had no upper or lower respiratory tract symptoms during the month before testing. Control BAL samples were obtained from nonsmokers (n = 5; all male; mean age: 47.8 yr; range: 40 to 58 yr; all Irish) with no history of respiratory disease and a normal CXR who were undergoing elective surgery. Pulmonary function tests of all subjects are displayed in Table 1.
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Exhaled NO Measurement
Exhaled NO was measured using a rapidly responding chemiluminescence analyzer (LR 2000; Logan Research, Medway, UK), which has an infrared CO2 analyzer in sequence and is accurate to within 1 part per billion (ppb) NO. Ambient NO on all occasions was < 3 ppb. Subjects exhaled with maximal effort via a narrow-bore TeflonTM tube against a fixed resistance. During this maneuver, a sample of exhaled gas was aspirated continuously into the analyzer at a rate of 250 ml/ min through a side-port on the Teflon tube close to the subject's mouth. NO, CO2, mouth pressure, and cumulative volume signals (25 Hz per channel) were digitized and stored directly on a computer hard disk for later analysis. Each subject performed three consecutive tests.
The difference between the response times of the NO and CO2 analyzers was examined by presenting abruptly to the instrument a gas mixture containing CO2 and NO in O2 and N2. The time taken to reach 90% of the steady-state value for CO2 and NO was determined, and the difference computed. The mean difference in response times was 2.44 s. Before analyzing the data from all patients, the NO and CO2 records were realigned by delaying the CO2 record by 2.44 s. This allowed the delineation of three exhaled NO parameters (see Figure 1 and its legend for definitions) based on the phase of expiration. The final value for each parameter in each subject represents the mean of the values obtained in the three tests performed.
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Bronchoalveolar Lavage
BAL was performed using a flexible fiberoptic bronchoscope wedged
in a segmental bronchus of the right middle or right lower lobe. In the
sarcoidosis patients, local anesthesia and intravenous sedation were
used. In the control subjects, BAL was performed immediately after
intubation for an elective surgical procedure. Three 60-ml aliquots of
normal saline were instilled and withdrawn in turn. The returned fluid
was stored on ice and processed immediately. It was centrifuged at
1,000 rpm for 6 min at 4° C, and the supernatant stored at 
70° C. The
cell pellet was resuspended in RPMI medium (Life Technologies,
Paisley, Scotland) and reserved for differential cell counting. When an
increased percentage of lymphocytes was present, samples were incubated with fluorochrome-conjugated monoclonal antibodies to CD4
and CD8 (Becton Dickinson, Oxford, UK) and the ratio of CD4 to
CD8 lymphocytes was determined using flow cytometry (FACScan®;
Becton Dickinson).
Measurement of BAL NO3/NO2
Total concentration of NO3 and NO2 was determined in thawed
BAL supernatant by a modified Griess reaction method (13). Triplicate samples of BAL were incubated for a minimum of 3 h at 20° C
with glucose-6-phosphate (500 µmol/L), glucose-6-phosphate dehydrogenase (160 U/L), NADPH (1 µmol/L), and nitrate reductase (20 U/L) in phosphate buffer (80 mmol/L, pH 7.5). The Griess reaction
was then initiated by addition of sulfanilamide to a final concentration of 0.5% (wt/vol), orthophosphoric acid (1.25%, vol/vol), and N-(1 naphthyl)ethylenediamine hydrochloride (0.05%, wt/vol). All reagents were
obtained from Sigma (Poole, Dorset, UK). After a further incubation
at 20° C for 10 min, the absorbance of each sample mixture was measured at 540 nm and corrected for opacity by measuring the absorbance at 750 nm. The corrected absorbance was interpolated in a standard curve of absorbance plotted versus concentration in order to find
the concentration of NO2 in the sample. As all NO3 had already
been reduced to NO2 by the use of nitrate reductase, this represented
the combined concentration of NO3 and NO2 in the BALF. Results
of the NO2 assay were expressed as NO2 concentration in nanomoles
per milliliter of BALF.
The volume of epithelial lining fluid (ELF) recovered was determined (14) as follows:
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and NO2 was also expressed as NO2 concentration in nanomoles
per milliliter of ELF. A suitable plasma sample for this determination was not available in one of the 10 patients studied.
Statistical Analysis
Data for exhaled NO parameters and BALF NO3/NO2 (expressed
as nanomoles of NO2 per milliliter of BALF or nanomoles of NO2
per milliliter of ELF) were expressed as either mean value ± SD or as
mean value (range). Comparisons between patient and control groups
were made using an unpaired Student's t test. Correlation was examined using standard linear regression. A p value < 0.05 was accepted
as statistically significant.
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RESULTS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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BAL Total and Differential Cell Counts
All BAL samples from sarcoidosis patients were highly cellular and contained a significantly higher percentage of lymphocytes than those from control subjects. Control BAL samples displayed absolute and relative cell counts within the normal range (Table 2).
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Exhaled NO
The scatter of values and the mean ± SD of each group for the 10 patients and 12 control subjects are shown in Figure 2. Peak exhaled NO, mean alveolar NO, and end-tidal NO concentrations were not significantly different in the sarcoidosis patients compared with the values recorded in the normal subjects. There was no significant correlation between any exhaled NO parameter and the sACE value, BAL leukocyte counts, or DLCO (data not shown). Peak NO values for the six patients with interstitial infiltration on CXR (14.0 ± 5.1 ppb) were no higher than those in the patients with hilar adenopathy only (13.0 ± 8.0 ppb, p = 0.80). Similarly, there was no significant difference for mean alveolar NO (6.8 ± 2.5 versus 9.2 ± 6.6 ppb, p = 0.44) or end-tidal NO (6.7 ± 2.4 versus 8.9 ± 6.8 ppb, p = 0.46) between these two subgroups of patients. Comparing each of the two subgroups separately with the control group for every parameter again showed no significant differences (p > 0.4 for all comparisons).
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Although peak exhaled NO values were higher than mean alveolar and end-tidal values in all subjects, there was a strong correlation between all parameters (peak versus end-tidal NO, r = 0.88; peak versus mean alveolar NO, r = 0.86; mean alveolar versus end-tidal NO, r = 0.99).
BALF NO2
The scatter of these values is shown in Figure 3. The concentration of NO2 in the BALF of the patients expressed as nanomoles of NO2 per milliliter of BALF or as nanomoles of
NO2 per milliliter of ELF was not significantly different from
that of control subjects. There was no statistically significant
correlation between the BALF NO2 concentrations and the
sACE values, BAL leukocyte counts, or DLCO. BALF NO2
concentrations did not differ significantly between the group of patients with radiographic interstitial infiltration and those without (7.2 ± 2.8 versus 7.1 ± 2.8 nmol/ml BALF, p = 0.96)
or between either of those two subgroups and control values
(p > 0.4 for all such comparisons).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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No difference was observed between patients with active pulmonary sarcoidosis and normal subjects for any measure of
exhaled NO or BALF NO2. Factors that might influence the
results are patients' smoking habits, disease activity at time of
testing, and the methods used to measure exhaled NO. One of
our patients was a regular smoker, but analysis performed
omitting her results did not change our findings. It is clear
from the total and differential cell counts in BAL that all patients had active sarcoid alveolitis at the time of exhaled NO
testing. Exhaled NO values may vary according to the technique used for measurement, the maneuver performed by the
subject, and the parameters used for analysis. On-line measurement of a sample continuously aspirated into the analyzer, as in our study, is the technique generally used in recently
published clinical studies (8, 15) as it causes less NO loss than
the collection of expired air into a reservoir for later analysis (3). Our use of the maximal effort maneuver, made possible by the relatively rapid analyzer response time, was based on a twofold rationale. First, we found in preliminary studies that it
was a maneuver easily understood and reproduced by patients and normal subjects alike. Second, we wished to minimize
contamination of measured NO by nasal NO (16, 17). Closure
of the soft palate is the most straightforward method of reducing diffusion of nasal NO into the pharynx and thus into expired air. It occurs involuntarily when mouth pressure during
expiration exceeds 4 cm H2O, as always occurred during the
forced vital capacity maneuver against resistance performed
by our subjects. This simple, reproducible maneuver therefore
minimizes nasal contamination. It did not interfere with the
detection of increased exhaled NO. Testing untreated asthmatics using our protocol, we have obtained high peak NO
values (range: 32 to 84 ppb).
The most usually reported parameter in other studies is the peak NO, a value that in normal and asthmatic subjects is usually observed in the early part of the expiratory curve. Conscious that increases in exhaled NO in patients with alveolitis might be detectable only in gas arising from the alveoli, we analyzed two other NO values (see Figure 1) occurring during the plateau phase of the CO2 curve, i.e., mean alveolar and end-tidal NO. In fact, these "alveolar" values correlated very closely with the peak NO (see RESULTS) and, even using these indices, values obtained in the patient group were not significantly different from those recorded in control subjects (see Figure 2).
There are two possible reasons why patients with active
pulmonary sarcoidosis have normal exhaled NO concentrations. The first is that excess NO production and, by inference,
iNOS induction, does not accompany the alveolar inflammation of sarcoidosis; the second, that excess NO, though produced, is not detectable in the exhaled air. The latter explanation is certainly possible, as alveolar NO would react readily
with heme in the red blood cells of the pulmonary capillaries.
However, in biologic systems, the half-life of NO is between
0.1 and 5 s and the presence of NO at air-aqueous interfaces
results in the generation of intermediate nitrogen oxides and
the stable end products of NO metabolism, i.e., NO3 and
NO2 (1). Thus, increased alveolar NO production, even if not
reflected in exhaled air, would be likely to cause some detectable increase in BALF NO3/NO2. However, we found no
difference in their concentration in the BALF of patients with
sarcoidosis when compared with normal values. Furthermore,
the range of values obtained among the sarcoidosis patients
corresponds to that reported by other investigators in normal
BALF (18). The absence of a detectable increase in either exhaled NO or BALF NO3/NO2 in active sarcoidosis suggests
that excess NO production does not accompany the pulmonary inflammation in this disorder.
Before discussing the implications of these findings, the limitations of this study must be considered. First, our patients were
all Irish. Therefore, we cannot answer the question whether excess NO generation occurs in black sarcoidosis patients,
whose disease tends to follow a course with much more frequent
end-organ damage than that of Caucasian patients (19). Second, despite the presence of a high percentage of lymphocytes
in BAL, not all our patients had radiologic evidence of interstitial pulmonary disease. The question thus arises whether there
is any difference in pulmonary NO generation between those
patients with hilar adenopathy alone and those with interstitial shadowing. Although we did not find any significant difference in exhaled NO or BALF NO3/NO2 between these
two subgroups, the numbers in each (n = 4 and n = 6, respectively) are small and a study of larger groups is required to test
that specific hypothesis. A third issue is whether respiratory tract concentrations of NO and its metabolites continue to be low among patients who progress to long-term pulmonary inflammation and tissue damage. As we examined our patients
at a single time-point, this question remains.
Nonetheless, the overall results suggest that excess NO
generation is not part of the respiratory tract inflammation
that occurs in pulmonary sarcoidosis. The reasons why this
might be so are not immediately apparent. Both airway epithelial cells (4, 10, 20) and alveolar macrophages (AMs) (10,
21) from humans can express iNOS. The granulomatous response to several infectious agents in animal species includes
iNOS induction in macrophages (22, 23), although there is less
evidence for this in human disease. We are not aware of any
studies in humans addressing the question of exhaled NO concentrations in histoplasmosis or brucellosis or the role of
iNOS in these infections. However, one study has clearly demonstrated increased expression of active iNOS in AMs from
patients with clinically active Mycobacterium tuberculosis infection (21), and a recent abstract reported that exhaled NO
concentrations were higher in patients with tuberculosis than
in control subjects (24). In addition, excess NO is generated in
the gastrointestinal tract of patients with Crohn's disease, a
noninfectious granulomatous disorder (25). Taken together, these lines of evidence suggest that iNOS would be expressed
in the human airway in the granulomatous inflammation of
sarcoidosis. Furthermore, TNF- (11, 26) and IFN- (12, 27),
both of which promote iNOS expression, are part of the inflammatory alveolar milieu of sarcoidosis.
Perhaps some other mechanism, specific to sarcoidosis, is
preventing AM iNOS expression in this apparently favorable
cytokine milieu. One possibility is the additional presence of
transforming growth factor-
, which has recently been described (28) in macrophages from patients with sarcoidosis and
which in a murine system (29) blocks TNF--mediated amplification of IFN--induced iNOS expression. Another is that
iNOS expression is highest in fully mature AMs (30), whereas
in sarcoidosis many macrophages display a phenotype intermediate between monocytes and mature AMs (31) and hence may not yet be capable of NO production.
Several animal studies suggest that NO has a lymphocytostatic as well as a pro-inflammatory function. NO produced by AMs seems to be one mediator contributing to suppression of T-cell proliferative responses to antigens in the lung (30). NO inhibits the expansion of cloned T-helper 1 (Th1) lymphocytes (32) and iNOS knockout mice develop a preferential Th1 expansion following antigen challenge (23). In this context, our finding of apparently normal respiratory tract NO production in association with a lymphocytic alveolitis in which T lymphocytes display a Th1 polarization (27) is even more intriguing. Perhaps low respiratory tract NO generation in a pro-inflammatory environment itself favors the development of an inappropriate lymphocytic alveolitis.
The control of iNOS expression and activity and the exact
role of NO in the human respiratory tract are not fully understood. We have shown that exhaled NO and BALF NO2/
NO3 are normal in sarcoidosis despite the presence of active
alveolitis. These results suggest that excess NO generation is
not a universal by-product of chronic cytokine-mediated pulmonary inflammation but depends upon the precise inflammatory milieu and the nature of the inflammatory stimulus.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Paul McLoughlin, Department of Physiology, University College Dublin, Earlsfort Terrace, Dublin 2, Ireland.
(Received in original form May 6, 1997 and in revised form July 29, 1997).
1 Laboratory reference range for sACE: 0 to 85 U/ml.Acknowledgments: This study was assisted by the Health Research Board of Ireland. The writers wish to thank Geraldine Lawless and Carol Delahunty for performing the pulmonary function tests.
Supported by a grant from the Health Research Board of Ireland.
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References |
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ABSTRACT
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METHODS
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DISCUSSION
REFERENCES
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J. A. DE ANDRADE, J. P. CROW, L. VIERA, C. BRUCE ALEXANDER, K. RANDALL YOUNG, D. C. MCGIFFIN, G. L. ZORN, S. ZHU, S. MATALON, and R. M. JACKSON Protein Nitration, Metabolites of Reactive Nitrogen Species, and Inflammation in Lung Allografts Am. J. Respir. Crit. Care Med., June 1, 2000; 161(6): 2035 - 2042. [Abstract] [Full Text]
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