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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Treatment with inhaled 
2-agonists immediately before allergen inhalation inhibits allergen-induced
early, but not late asthmatic responses (LAR). By contrast, 2 wk treatment with inhaled albuterol increases airway responses to inhaled allergen. We examined the effects of regular albuterol treatment
on allergen-induced increases in inflammatory cells in blood and induced sputum. Ten mild, stable allergic asthmatics inhaled albuterol (800 µg/day) or placebo for 7 d in a controlled, randomized, double-blind, crossover study. Allergen inhalation was performed 12 h after the final dose. Methacholine airway responsiveness and blood samples were analyzed before and 24 h after, and induced sputum
was obtained before, 7 h and 24 h after allergen. Allergen significantly reduced methacholine PC20,
increased blood eosinophil numbers, and numbers of sputum neutrophils, EG2 positive and metachromatic cells (p < 0.05), without significant differences between treatments. Albuterol treatment
significantly increased the LAR compared to placebo treatment (p = 0.003) and significantly enhanced
the number of sputum eosinophils (p = 0.009) and sputum ECP (p = 0.04) at 7 h but not 24 h post-allergen (p > 0.05). We conclude that regular use of inhaled albuterol significantly increases the LAR
to inhaled allergen, in association with an increase in the number of sputum eosinophils and the release of ECP, suggesting albuterol increases the late response by increasing eosinophil influx into the
airways.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Airway inflammation is an important characteristic in patients with current symptomatic asthma. This has been demonstrated by increased numbers of inflammatory cells, particularly eosinophils, mast cells and lymphocytes present in bronchial biopsies (1) bronchoalveolar lavage fluid (BAL) (2) and sputum (3) from asthmatics when compared to nonasthamtics. Allergen challenge is a valuable laboratory model for the study of the pathogenesis of airway inflammation in asthma. Allergen inhalation results in acute bronchoconstriction in sensitized subjects, and in 50-60% of adult subjects, this is followed by a late bronchoconstrictor response (LAR), which is associated with the development of allergen-induced airway hyperresponsiveness (4), and increases in the number of airway inflammatory cells, particularly eosinophils and metachromatic cells (MCC), in bronchial biopsies (5), BAL (6), and induced sputum (7, 8). Sputum induction is a safe, noninvasive method of directly obtaining repeated samples of airway secretions (3). Measurements of inflammatory cells from sputum are repeatable (9), demonstrate changes associated with airway responses after inhaled allergen (8), and has been shown to demonstrate the effects of a therapeutic intervention with inhaled corticosteroids (10).
Inhaled 2-adrenoceptor agonists are the most effective bronchodilator agents for the symptomatic treatment of asthma.
2-agonists reverse airway obstruction primarily by relaxing
airway smooth muscle (11). In addition, 2-agonists are potent
inhibitors of the release of histamine and newly synthesized
mediators from activated mast cells (12) in vitro, and 2-adrenoceptors have been found on other immune cells including macrophages, eosinophils, neutrophils and lymphocytes,
and may modulate adhesion of inflammatory cells through a
cAMP-dependant kinase (13). Thus, these in vitro studies suggest that 2-agonists may have some anti-inflammatory properties for the treatment of asthma.
However, recent studies have demonstrated that regular
treatment with 2-agonists increase airway responsiveness to
nonallergic stimuli (14, 15), and enhance allergen-induced late
bronchoconstrictor responses (16, 17). Regular treatment with
albuterol is also associated with increased levels of activated
eosinophils in bronchial biopsies (18). Given the association
between allergen-induced airway responses and airway eosinophilia (3, 6, 7, 10), we hypothesized that regular treatment
with inhaled 2-agonist might also enhance the allergen-induced
airway eosinophilia. Therefore, the purpose of this study was
to determine whether regular treatment with the inhaled
2-agonist, albuterol, administered for 1 wk, a duration of treatment known to enhance the allergen-induced late bronchoconstrictor responses (17), influences allergen-induced changes in
inflammatory cells, particularly eosinophils, in blood and in
the airways as assessed by changes in induced sputum.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Fourteen nonsmoking subjects (Table 1) with mild atopic asthma
(eight female, six male), were selected for the study because of a previously documented allergen-induced early and late bronchoconstrictor response of at least 15% reduction in the forced expiratory volume in 1 s (FEV1) during a screening period, and gave signed consent to
participate in the study. Inhalation challenge with the allergen diluent,
0.9% saline, was completed during the screening period in order to
correct the allergen-induced fall in FEV1 for normal airflow variability during the allergen challenge day. Four of the subjects dropped out
of the study due to protocol violations. Two of these subjects were unable to inhale the same three doses of allergen at all three allergen inhalation challenges, because of marked bronchoconstriction at the
lowest inhaled dose of allergen during the albuterol treatment period.
Two subjects were excluded from the study because their diary cards
indicated they had used albuterol instead of the medication provided
as a rescue medication during the study. The statistical analysis was
performed on results from the remaining 10 subjects. This sample size
was considered sufficient, as a previous study has shown that eight
or more subjects can demonstrate a 50% change in the LAR with a
power of > 90%, using the same methodology employed in this study
(19). The study was approved by the Ethics Committee of McMaster
University Health Sciences Center. Subjects were not exposed to sensitizing allergens and did not have asthma exacerbations or respiratory tract infections for at least four weeks prior to entering the study.
All subjects had stable asthma with FEV1 greater than 70% of predicted normal on all study days before allergen inhalation. Subjects
used no regular medication other than infrequent (< twice weekly)
inhaled 2-agonist as required to treat their symptoms. Ipratropium
bromide replaced 2-agonists as a rescue medication during the study
period. All medications were withheld for at least 8 h before each
visit, and subjects were instructed to refrain from rigorous exercise,
tea, or coffee in the morning before visits to the laboratory.
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Study Design
The study was carried out with a double blind, placebo-controlled,
randomized, two-period cross-over design (Figure 1). During each period, subjects were treated with either inhaled albuterol 200 µg (2 puffs) four times daily (Ventolin; Glaxo Canada, Toronto, Ontario),
or an identical placebo 2 puffs four times daily for 1 wk. Each treatment period consisted of four visits to the laboratory. Baseline measurements of FEV1, the provocative concentration of methacholine
causing a 20% fall in FEV1 (PC20), blood and induced sputum differential and total cell counts were determined before treatment and on
the 7th day of treatment with albuterol or placebo. Allergen challenges were carried out the following morning, 12 h after treatment
was discontinued, and FEV1 was measured for the next 7 h. Sputum
samples were obtained during the late response, 7 h after allergen inhalation, 19 h after treatment was discontinued. Sputum could not be
induced earlier than 7 h, because of the requirement of pretreatment
with inhaled 2-agonists before sputum induction, which would interfere with subsequent measures of allergen-induced airway responses.
Blood was not obtained 7 h after allergen because allergen-induced
eosinophilia has not been shown to occur at this time after allergen inhalation (20). Methacholine PC20, blood and sputum samples were obtained 24 h post-allergen, 36 h after treatment was discontinued. Each
treatment period was separated by a washout period of at least 3 wk.
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Laboratory Procedures
Methacholine inhalation test. Methacholine inhalation challenge was performed as described by Cockcroft (21). Subjects inhaled normal saline, then doubling concentrations of methacholine phosphate from a Wright nebulizer for 2 min. FEV1 was measured at 30, 90, 180, and 300 s after each inhalation. Spirometry was measured with a Collins water-sealed spirometer and kymograph. The test was terminated when a fall in FEV1 of 20% of the baseline value occurred, and the methacholine PC20 was calculated.
Allergen Inhalation Test
Allergen challenge was performed as described by O'Byrne and coworkers (22). The allergen producing the largest skin wheal diameter was diluted in normal saline. The concentration of allergen extract for inhalation was determined from a formula described by Cockcroft and coworkers (23) using the results from the skin test and the methacholine PC20. The starting concentration of allergen extract for inhalation was two doubling concentrations below that predicted to cause a 20% fall in FEV1. The same doses of allergen were administered during each treatment period, and the FEV1 was measured at 10, 20, 30, 40, 50, 60, 90, and 120 min post allergen inhalation, then each hour until 7 h after allergen inhalation. The early bronchoconstrictor response was taken to be the largest fall in FEV1 within 2 h after allergen inhalation, and the late response was taken to be the largest fall in FEV1 between 3 h and 7 h after allergen inhalation. The area under the curve was determined during the early (0-2 h) and late (3-7 h) response by plotting the response using graphics software (Fig P.; Fig P Software Corporation, Durham, NC), which calculated the area of the FEV1-time response. All allergen challenges were performed with the same allergen dose utilized during the screening challenge.
Differential blood counts. Blood was collected into heparinized tubes by direct venipuncture, and blood smears were made for differential staining (Diff Quik; American Scientific Products, McGaw Park, IL). Differential cell counts were obtained from the mean of two slides with 300 cells counted per slide. Total leukocyte count was determined using a hemocytometer (Neubauer Chamber; Hausser Scientific, Blue Bell, PA), and cell populations were expressed as the number per ml blood by dividing by the total number of cells counted, and multiplying by the total leukocyte count.
Sputum analysis. Sputum was induced and processed using the
method described by Popov and coworkers (24). Subjects inhaled 3%,
4%, then 5% saline for 7 min each. The induction was stopped when
an adequate sample was obtained, or if the FEV1 dropped 20% from
baseline. Cell plugs with little or no squamous epithelial cells were selected from the sample using an inverted microscope, separated from
saliva, and weighed. Samples were aspirated in two times their volume
of 0.1% dithiothreitol (Sputolysin, Calbiochem Corp., San Diego, CA)
and two times their volume of Dulbecco's phosphate buffered saline
(Gibco, Grand Island, NY). The cell suspension was filtered through a
52 µm nylon gauze (BNSH Thompson, Scarborough, ON, Canada) to
remove debris, then centrifuged at 1,500 rpm for 10 minutes. Supernatants were collected and stored at 
70° C for fluid phase measurements
of eosinophil cationic protein (ECP) by radioimmunoassay (Pharmacia, Uppsala, Sweden). The total cell count was determined using a
hemocytometer (Neubauer Chamber) and expressed as the number of
cells per ml sputum. Cells were resuspended in Dulbecco's phosphate
buffered saline (DPBS) at 0.75-1.0 × 106/ml. Cytospins were prepared
on glass slides using 50 µl of cell suspension and a Shandon III cytocentrifuge (Shandon Southern Instruments, Sewickly, PA), at 300 rpm
for 5 min. Differential cell counts were obtained from the mean of two
slides with 400 cells counted per slide stained with Diff Quik. The
same observer counted all study slides, and the reproducibility of the
cell counts using these methods is excellent (9). For example, the interclass correlation coefficient is 0.97 for sputum eosinophils. Metachromatic cell (MCC) (mast cells and basophils) counts on slides stained
with toluidine blue, were obtained from the mean of two slides with
5,000 cells observed on each slide. Cell types were enumerated by dividing by the total number of cells counted, and multiplying by the total cell count per milliliter of sputum. If possible, cytospins were also
prepared on apex coated slides and fixed for 10 min in periodate-lysine-paraformaldehyde for immunocytochemical staining for ECP.
Slides were stained with a mouse monoclonal antihuman antibody directed against cleaved ECP (EG2) (Kabi Pharmacia, Uppsala, Sweden) which was diluted in 1.0% BSA (Sigma Chemical Co.) and wash
buffer made up of DPBS, 0.01 M HEPES buffer (Boehringer Mannheim Canada Ltd., Burlington, ON) and 0.01% saponin (Sigma
Chemical Co.), and were incubated overnight at a concentration of 1 µg/ml. Labeling of EG2 was detected by the alkaline phospatase antialkaline phosphatase method (25). Mouse IgG1 (Sigma Chemical Co.)
was used as a negative control. The percentage of EG2 positive cells
was determined from a count of 500 cells under light microscopy, and
were expressed as the number of EG2 positive cells per ml of sputum.
These slides were also double stained with 10 µg/ml FITC for 10 min,
which is a specific stain for eosinophils (26). The level of eosinophil activation was determined by examination of 100 fluorescent cells for appearance of immunolocalization of the EG2 antibody, and expressed as the number of EG2 positive/100 eosinophils.
Statistical Analysis
Methacholine PC20 measurements are made by linear interpolation of log dose response curves resulting in logarithmic values for PC20, which are then subjected to statistical analysis. Summary statistics for methacholine PC20 are expressed as geometric mean and geometric standard error of the mean (GSEM). All other summary statistics are expressed as mean and SEM. Two-tailed Students t test for paired observations was used to compare the early and late airway responses to allergen. The effects of 7 d treatment with placebo and albuterol treatment on airway and blood cellular and log transformed sputum cellular changes were analyzed, using a one-way repeated measured ANOVA, for the effects of treatment. The effects of placebo and albuterol treatment on allergen-induced airway and blood cellular and log transformed sputum cellular changes from post treatment baseline, were analyzed using a two-factor repeated measures ANOVA, for the effects of time and treatment (29). As not all subjects had an adequate number of sputum slides for EG2 staining, complete sets of slides were only available from six subjects to compare the effects of 7 d albuterol treatment on baseline activated eosinophils, and from three subjects to compare the effects of albuterol in allergen-induced increases in activated eosinophils. All sputum cellular data were log transformed prior to analysis.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The allergen-induced late bronchoconstrictor response was significantly enhanced after albuterol treatment when compared to placebo (Figure 2). The maximal % fall in FEV1 during the late response was 28.3 ± 3.1% after albuterol treatment and 18.2 ± 3.6% after placebo treatment (p = 0.003) and the area under the curve was also significantly increased (p = 0.04) (Table 2). The early bronchoconstrictor response was not significantly changed after albuterol treatment versus placebo (Figure 2). The maximal % fall in FEV1 during the early response was 32.2 ± 3.8% after albuterol treatment and 34.2 ± 3.7% after placebo treatment (Table 2). Rescue medication with ipratropium bromide was rarely required during either of the treatment periods (Table 1).
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The methacholine PC20 decreased significantly 24 h after allergen inhalation after albuterol treatment from 1.55 mg/ml (GSEM 1.37) to 0.44 mg/ml (GSEM 1.32) (p = 0.002) and after placebo treatment from 1.62 mg/ml (GSEM 1.54) to 0.51 mg/ml (GSEM 1.38) (p = 0.002) (Figure 3), however, there was no difference in the magnitude of the allergen-induced increase in airway responsiveness between albuterol and placebo treatments (Table 2).
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Allergen inhalation increased the number of eosinophils per milliliter in sputum both at 7 h after allergen, during the late bronchoconstrictor response, and 24 h after allergen when methacholine airways responsiveness was increased (p = 0.01). Albuterol treatment, however, significantly enhanced the numbers of eosinophils per milliliter in sputum 7 h after allergen to 220 ± 156 × 104/ml when compared to 91 ± 62 × 104/ml after placebo treatment (p = 0.009) (Figure 4). This difference was no longer present in sputum 24 h after allergen, the number of eosinophils being 75 ± 22 × 104/ml after albuterol treatment and 166 ± 78 × 104/ml after placebo treatment (p = 0.31) (Table 3, Figure 4). The absolute change in the number of allergen-induced eosinophils at 7 h was greater after albuterol treatment in nine subjects, as compared with the change after placebo treatment, and decreased in one subject (Figure 5).
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Significant allergen-induced change
from post-treatment baseline. *Significant allergen-induced difference between albuterol and placebo
treatments.
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The concentration of ECP increased significantly after allergen inhalation from 1.1 ± 0.6 µg/ml during placebo to 1.8 ± 0.6 µg/ml at 7 h and 8.1 ± 3.5 µg/ml at 24 h after allergen (p = 0.00001). During albuterol treatment, the concentration of fluid phase sputum ECP increased from 0.8 ± 0.4 µg/ml to 4.3 ± 1.8 µg/ml at 7 h and 5.1 ± 2.3 µg/ml at 24 h after allergen (Table 3, Figure 4). As with the number of sputum eosinophils, the allergen-induced increase in the concentration of sputum ECP was significantly enhanced by albuterol at 7 h after allergen inhalation (p = 0.045). The allergen-induced changes in the number of eosinophils was correlated with the concentration of fluid phase ECP (p = 0.00004, r = 0.62). The number of EG2 positive eosinophils significantly increased after allergen inhalation during placebo, from 18 ± 7 × 104/ml to 223 ± 188 × 104/ml at 7 h and 127 ± 50 × 104/ml at 24 h after allergen, and during albuterol treatment, from 10 ± 5 × 104/ml to 258 ± 207 × 104/ml at 7 h and 91 ± 32 × 104/ml at 24 h after allergen (p = 0.004) (Table 3, Figure 4). However, we did not observe a significant effect of albuterol treatment on allergen-induced increases in EG2 positive cells (p = 0.29).
There was a significant correlation between the magnitude of the LAR (expressed as area under the curve) and the increase in sputum fluid phase ECP (r = 0.67, p = 0.002), and between the maximal fall in FEV1 and the increase in sputum ECP (r = 0.56, p = 0.015). There was no significant correlation between the allergen-induced increase in the number of sputum eosinophils and the magnitude of the LAR (r = 0.18), or maximal fall in FEV1 (r = 0.18).
Allergen inhalation also increased the numbers of sputum neutrophils (p = 0.04) and the numbers of MCC (p = 0.02) measured 7 and 24 h after allergen inhalation, however there was no significant difference between albuterol and placebo treatments either at 7 or 24 h (Table 3).
The number of blood eosinophils increased significantly 24 h after allergen inhalation after albuterol treatment from 35.1 = 7.5 × 104/ml to 56.1 ± 6.4 × 104/ml (p = 0.001) and after placebo treatment from 38.9 ± 7.4 × 104/ml to 57.7 ± 9.5 × 104/ml (p = 0.001). This increase was the same magnitude for placebo and albuterol treatment periods (Table 3). The number of blood neutrophils measured 24 h after allergen inhalation did not change significantly after 7 d of albuterol treatment, and there was no difference in allergen-induced changes between albuterol and placebo (Table 3).
Regular use of albuterol for 7 d did not significantly alter the baseline FEV1, being 3.3 ± 0.2 L after albuterol treatment and 3.5 ± 0.2 L after placebo treatment, or the baseline methacholine PC20, being 1.55 mg/ml (GSEM 1.37) after albuterol treatment, and 1.62 mg/ml (GSEM 1.54) after placebo. Also, regular albuterol treatment for 7 d did not significantly change the numbers of baseline blood eosinophils or neutrophils, nor the number of sputum inflammatory cells; eosinophils or activated eosinophils, MCC or neutrophils, nor the concentration of ECP measured in sputum (Table 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study confirms previous reports which have demonstrated that regular treatment with inhaled albuterol increases allergen-induced late responses (16, 17). Use of ipratropium bromide as a rescue medication was infrequent and similar during both treatment periods, and should not bias the results. The allergen-induced late response is associated with airway inflammation, particularly increases in airway eosinophils and MCC (8). We have previously demonstrated that the number of eosinophils and the number of EG2 positive cells in sputum increase by 7 h after allergen inhalation, and remain elevated at 24 h (10). We therefore hypothesised that the increase in allergen-induced late responses may be caused by albuterol- induced increases in allergen-induced airway inflammation, as measured by changes in induced sputum.
Consistent with this hypothesis, albuterol enhanced allergen-induced sputum eosinophils and ECP at 7 h after allergen inhalation, during the late response, but there were no significant increases in the number of sputum neutrophils or MCC. This suggests the albuterol-enhanced late response may be associated with increased numbers of eosinophils rather than neutrophils or MCC, and is supported by the observation that sputum ECP levels in the present study, and sputum eosinophils in other studies of patients with asthma (30, 31) correlate with parameters of airflow obstruction.
We did not confirm the observations of Maestrelli and coworkers (31), who demonstrated a significant correlation between the magnitude of bronchoconstriction after isocyanate inhalation and the increase in sputum eosinophil counts. It is possible that this lack of correlation is because of different mechanisms involved. The lack of correlation is more likely due to large intersubject variability in the magnitude of allergen-induced eosinophilia, which has previously been described (8), and suggests the need for a larger subject sample size to further investigate the relationship between airway responses and airway eosinophilia. However, the level of ECP in sputum correlated well with airway responses, supporting the relationship between eosinophil activation and airflow obstruction.
The allergen inhalation was started 12 h after the last dose of albuterol, which is longer than its duration of pharmacological action. This suggests that the increases in allergen-induced late responses and eosinophil influx during the late response are a consequence of events in the airways which persist for 8-12 h after the pharmacological effects of albuterol are over. In addition, there was no difference in allergen-induced airway hyperresponsiveness measured at 24 h, between albuterol and placebo treatments, which was 36 h after the last dose of albuterol. This suggests that the untoward effects of albuterol on allergen-induced responses are short-lived. We did not observe a difference in blood or sputum eosinophils measured 24 h after allergen inhalation, suggesting albuterol may locally enhance allergen-induced eosinophilia in the airways, 7 h after allergen-inhalation, by altering the kinetics of eosinophil influx across the airway. The time course of the changes in allergen-induced airway eosinophils after albuterol treatment also suggests that the rate of trafficking of eosinophils through the airway may be increased. Thus, regular treatment with albuterol may lead to a faster onset of the appearance of eosinophils in the airways, as well as a faster resolution, as sputum eosinophils were slightly but not statistically lower 24 h following allergen, without altering the trafficking of other inflammatory cells. However, there is no direct evidence, as yet, to support any of these hypotheses.
Measurement of induced sputum is a sensitive indicator of eosinophilic airway inflammation, and it can be used to distinguish between different types of airway inflammation (32). Using induced sputum, we have recently demonstrated that treatment with inhaled steroid therapy for 7 d caused a significant reduction of sputum eosinophils and EG2 positive cells (activated eosinophils) (10) associated with complete attenuation of the late response and significant reduction of allergen-induced airway hyperresponsiveness. In the present study, we also found an allergen-induced increase in both the number of eosinophils and the number of activated eosinophils. Quantification of eosinophils dual stained with FITC and EG2 demonstrated that the ratio of eosinophils localizing EG2 did not change after allergen inhalation (Table 3). This indicates that the allergen-induced increase in activated eosinophils into sputum is due to an influx of eosinophils into the airways rather than an increased level of activation of airway eosinophils. These results support our earlier observations with allergen-induced eosinophilia (10). Furthermore, albuterol may be enhancing the influx of eosinophils into the airway without affecting their level of activation.
The mechanism of the albuterol-induced increases in allergen-induced airway eosinophils was not investigated in this
study. Short term treatment with albuterol has been reported
to down-regulate pulmonary 2-receptors in vivo in humans
(33). Down-regulation of 2-receptors on immune cells may
render these cells more easily activated to participate in airways
inflammation due to overexpression of adhesion molecules.
Finally, it is also possible that the enhanced late bronchoconstrictor response with albuterol treatment is not only associated with increased influx of eosinophils into the airways,
but also may be associated with tolerance to the broncho-protective effect of the inhaled 2-agonist (34). Desensitization of
2-adrenoceptor-induced cAMP formation has been observed
in cultured airway smooth muscle cells (36), and this response
in vivo may render subjects less able to respond to endogenous catecholamines.
In this study, one week regular treatment with albuterol
did not have an effect on baseline FEV1, methacholine PC20,
allergen-induced early responses, or baseline numbers of inflammatory cells measured in peripheral blood or sputum.
Studies with longer term regular treatment of 2-agonist have
shown increased airway hyperresponsiveness to nonallergic
stimuli (14, 15), and increased EG2 positive cells in bronchial
biopsies (18). It may require a similar length of albuterol treatment to demonstrate increased indices of inflammation in peripheral blood or sputum in this group of mild asthmatics.
The clinical consequences of the effect of regular albuterol
use on allergen-induced airway responses and inflammation
are not known. However, it is a concern that one reason for
asthmatics to increase their usage of inhaled 2-agonists is
during allergen exposure, when asthma symptoms increase.
Whether or not this repeated use of an inhaled 2-agonist during regular and repeated allergen inhalation, rather than the
single, high dose allergen inhalation used in this study to elicit
late responses, further enhances allergen-induced responses
and eosinophil influx requires further study.
In conclusion, this study confirms previous observations
that regular treatment with inhaled 2-agonist enhances the allergen-induced late bronchoconstrictor response. In addition,
this study demonstrates an enhancement of allergen-induced
eosinophil influx into the airways with regular albuterol treatment, suggesting that albuterol enhances the late bronchoconstrictor response to inhaled allergen by increasing the rate of
influx of airway eosinophils.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. P. M. O'Byrne, Department of Medicine, Rm 3U-1 Health Sciences Center, McMaster University, 1200 Main St West, Hamilton, ON, L8N 3Z5 Canada.
(Received in original form August 13, 1996 and in revised form May 7, 1997).
Dr. Jordana is a Career Scientist of the Ontario Ministry of Health and Dr. O'Byrne is a Medical Research Council of Canada Senior Scientist.Acknowledgments: The authors thank T. Rerecich for technical assistance, J. Otis for help in the preparation of the manuscript, and Dr. G. Norman for statistical advice.
This study was supported by an operating grant from the Medical Research Council of Canada.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Panettieri, R. A. Jr.,
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