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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Increased numbers of eosinophils and mast cells in the bronchial mucosa are characteristic features in subjects with aspirin-sensitive asthma. Interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are involved in the activation, maturation, and perpetuation of survival of eosinophils. Immunohistochemical techniques were therefore used to study the expression of IL-5 and GM-CSF on frozen bronchial biopsies from 13 aspirin-sensitive asthmatic (ASA) and 8 non-ASA (NASA) subjects. Aspirin sensitivity was diagnosed by lysine-aspirin inhalation provocation. ASA airways demonstrated a significant 2-fold increase in the total number of submucosal inflammatory cells expressing IL-5 (p = 0.03) and approximate 4 - and 2-fold increases in the numbers of mast cells expressing IL-5 and GM-CSF (p = 0.02 and p = 0.04, respectively). There was also a 4-fold increase in the number of eosinophils expressing IL-5 (p = 0.004). These results suggest a central role for the mast cell and eosinophil in regulation of the inflammatory cell infiltrate of ASA airways by secretion of the hemopoietic cytokines IL-5 and GM-CSF.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Patients with bronchial asthma and aspirin sensitivity form a distinct clinical subpopulation of patients with asthma. These patients may have accompanying symptoms of rhinorrhea, nasal congestion, anosmia, loss of taste, and recurrent severe nasal polyposis (1). Upon ingestion of aspirin, cysteinyl leukotrienes are released and this results in worsening of asthmatic symptoms (2). These features do not occur in aspirin-tolerant asthmatic individuals.
There is accumulating evidence to support a central role for leukotrienes as mediators of aspirin-induced airway obstruction (7). Leukotrienes have been recovered from various body fluids in increased concentrations after aspirin challenge (2, 6, 8, 9). In addition, baseline urinary leukotriene E4 concentrations are significantly increased in aspirin-sensitive asthmatic subjects (2, 8). Leukotrienes are produced from arachidonic acid through the action of the 5-lipoxygenase enzyme when inflammatory cells, including eosinophils and mast cells, are activated (10, 11).
We have previously demonstrated that the numbers of mast cells and eosinophils, but not macrophages, T cells, or neutrophils, are increased in the airways of aspirin-sensitive asthmatic subjects (12, 13). Since the cytokines interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) appear to be essential cytokines for the maturation, recruitment, and survival of eosinophils (14), we have tested the hypothesis that the expression of these two cytokines may be enhanced in aspirin-sensitive asthma.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Twenty-one asthmatic patients were studied, of whom 13 were aspirin-sensitive asthmatic (ASA) and eight were non-ASA (NASA) subjects. The diagnosis of aspirin sensitivity was made on the basis of history and confirmed by a 20% or greater fall in FEV1 following lysine-aspirin inhalation challenge as previously described (12). The NASA group also underwent lysine-aspirin challenge and, if negative, this was confirmed by incremental oral aspirin challenge to 600 mg of aspirin. These subjects are the same as those reported previously (12), except for one additional new ASA individual (Subject 13).
The ASA subjects (seven males, eight atopic) had an age of 42 ± 4.0 yr (mean ± SEM) with an FEV1 of 91.6 ± 4.3% (mean ± SEM), and the eight NASA subjects (six males, seven atopic) had an age of
36 ± 3.6 yr (mean ± SEM) with an FEV1 of 90.2 ± 10.2% (mean ± SEM). Of the 13 ASA subjects, three were taking prednisolone orally,
twelve were taking regularly inhaled corticosteroids, and five were using
regular nasal corticosteroids (Table 1). Of the eight NASA subjects,
one was using prednisolone orally, five were using regular inhaled corticosteroids, and one was taking regular nasal corticosteroids (Table 2).
All asthmatic subjects were using inhaled or oral 
2-agonists as required. All subjects were skin-prick tested to common aeroallergens, and
atopy was defined as the presence of at least two positive reactions
(wheals of 3 mm or greater than saline control) in skin-prick tests with cat fur, dog hair, grass pollen, and Dermatophagoides pteronyssinus.
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Bronchoscopy and airway mucosa biopsy was performed as previously described (12) at least 1 mo after aspirin provocation. Bronchial
biopsies were immediately snap-frozen in embedding medium and
stored at 
80° C until analyzed. All subjects provided written and informed consent, and the study was approved by the Hochgesbirgsklinik, Davos-Wolfgang Ethics Committee.
Immunohistochemistry
Frozen tissue sections of bronchial biopsies from ASA and NASA were initially single-stained for expression of IL-5 and GM-CSF. To determine which cells were expressing IL-5 and GM-CSF, sections were also double stained for IL-5 and mast cells, IL-5 and eosinophils, IL-5 and T cells, GM-CSF and mast cells, GM-CSF and eosinophils, GM-CSF and T cells, and GM-CSF and macrophages.
Single immunostaining for the expression of IL-5 and GM-CSF was performed by means of the ABC technique, as previously described (12). Double staining was performed by the ABC technique combined with the alkaline phosphatase technique as previously described (7), using a polyclonal antibody to either IL-5 or GM-CSF, concurrently with one monoclonal antibody to each cell type: macrophages (EBM11); eosinophils (BMK13), mast cells (AA1), or T lymphocytes (anti-CD3).
Affinity-purified goat polyclonal anti-GM-CSF (R&D Systems, Minneapolis, MN) or anti-IL-5 (R&D Systems) were used at concentrations of 2 and 10 µg/ml, respectively. Specificity of these antibodies has been checked by R&D Systems by means of neutralization assays, direct ELISA, and Western blot analysis. All the primary antibodies used for cell identification were mouse monoclonal IgG1 antibodies and comprised of the following: AA1 (DAKO, High Wycombe, UK), a mast cell tryptase marker used at 1:50 dilution; EBM11 (DAKO), a pan-macrophage marker recognizing CD68 used at 1:100 dilution; anti-CD3 (DAKO), a pan-T lymphocyte marker used at 1:50 dilution; and BMK13 (Cymbus Bioscience Ltd, Chilworth, UK), a pan-eosinophil marker recognizing major basic protein used at 1:40 dilution. The secondary antibodies were the following: swine anti-rabbit biotinylated antibody (DAKO) used at 1:200 dilution and rabbit anti-mouse alkaline phosphatase-conjugated antibody (DAKO) also used at 1:200 dilution, to develop single staining for the rabbit and the goat polyclonals, respectively; and rabbit anti-mouse alkaline phosphatase-conjugated antibody (DAKO) at 1:200 dilution together with rabbit anti-goat biotinylated antibody (DAKO) at 1:400 dilution, to develop double staining for the goat polyclonals and the cell markers.
Endogenous biotin, alkaline phosphatase, and peroxidase activity was abolished as previously described (12). The immunoperoxidase color reaction was developed by incubation with diaminobenzidine, which produces a brown precipitate, and 5-bromo-4-chloro-3-indolyl phosphate/nitroblue tetrazolium (Sigma Chemical Co., Poole, Dorset, UK), which produces a blue precipitate. A positive control using inflamed tonsil tissue and a negative control without primary antibody were included in each staining run.
Image Analysis
Immunoperoxidase detection on bronchial epithelium. The hue-saturation-intensity (HSI) method of color image analysis was adopted for detection of the brown immunoperoxidase reaction product, as previously described (18). This was performed on an image analyzer consisting of a PC computer containing DT2871 frame-grabber and DT2858 frame-processor boards (Data Translation, MA), with Colour Freelance software (Foster-Findlay Associates, Newcastle on Tyne, UK).
Color detection for a specific application was programmed by first determining the hue and saturation values of the color properties to be detected (in this case, the brown color of the immunoperoxidase reaction product) and then manually drawing around the epithelium via the computer mouse and a drawing facility in the software. Automatic detection of tissue was performed by intensity thresholding within this manually defined zone, thus excluding from analysis any gaps in the epithelium. The program then selected those pixels within the appropriate range of hue and saturation values for the brown-colored reaction product within the chosen tissue area and calculated the percentage of pixels detected within the area, i.e., percentage of area stained. With each biopsy, the total epithelial area present was measured. The procedures were written into an image-analysis program to facilitate the analysis of multiple specimens.
Submucosal cell count. The numbers of specific cells were counted on the entire submucosal biopsy area by a blinded investigator. The total section area was measured using the image analyzer, and all cell counts were expressed as cells/mm2.
Statistical Analysis
Statistical analysis of the data was performed by the Mann-Whitney U test, using Minitab Software (Minitab Inc.). Results are expressed as mean ± SEM.
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RESULTS |
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DISCUSSION
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Expression of IL-5 and GM-CSF in Bronchial Epithelium
There was no significant difference between the ASA and NASA subjects in the epithelial expression of IL-5 and GM-CSF. There was negligible IL-5 epithelial expression in both ASA and NASA. For GM-CSF, 19.9 ± 3.9% and 25.7 ± 5.2% of the epithelium was stained in ASA and NASA, respectively (p = 0.37).
Expression of IL-5 in Bronchial Submucosa
Single immunostaining. There was a significant mean 2-fold increase in the total number of IL-5-positive cells in ASA subjects as compared with NASA subjects (295.4 ± 47.9 cells/ mm2 and 135.2 ± 20.8 cells/mm2, respectively, p = 0.03) (Figure 1).
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Double immunostaining. The IL-5-positive cells were composed mainly of mast cells, eosinophils, and T cells being on average 32.0% (239.6 ± 45.8 cells/mm2), 39.9% (277.6 ± 58.0 cells/mm2), and 27.4% (294.1 ± 56.8 cells/mm2), respectively, in ASA and 26.6% (61.4 ± 16.7 cells/mm2), 29.7% (95.3 ± 18.1 cells/mm2), and 29.9% (118.1 ± 28.0 cells/mm2), respectively, in NASA (Figure 2).
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There was a significant mean 4-fold increase in the number of mast cells expressing IL-5 (p = 0.02) in ASA subjects as compared with NASA subjects (73.1 ± 14.2 versus 18.5 ± 8.0 cells/mm2, respectively) (Figure 3).
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There was a significant mean 4-fold increase in the number of eosinophils expressing IL-5 (p = 0.004) between ASA and NASA subjects (114.9 ± 26.6 versus 32.2 ± 10.3 cells/mm2, respectively) (Figure 4).
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The number of T cells expressing IL-5 in ASA and NASA were 92.3 ± 29.1 and 35.7 ± 9.4 cells/mm2, respectively. The higher value for ASA was due to one outlier, and there was no statistical significant difference (p = 0.06).
There was also a significant mean 6-fold increase in the percentage of mast cells expressing IL-5 between ASA and NASA subjects (54.4 ± 5.5 versus 31.5 ± 6.4 cells/mm2, respectively; p = 0.04). The percentage of eosinophils expressing IL-5 was also raised in ASA subjects but the difference failed to reach statistical significance (46.6 ± 3.9 versus 36.9 ± 2.9 cells/mm2, respectively; p = 0.07).
Expression of GM-CSF in Bronchial Submucosa
Single immunostaining. There was no significant difference between the total number of cells in the submucosa of ASA and NASA subjects that were positive for GM-CSF (287.7 ± 45.3 and 371.7 ± 44.6 cells/mm2, respectively; p = 0.13) (Figure 5).
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Double immunostaining. There was a significant mean 1.7-fold increase in the numbers of mast cells expressing GM-CSF (p = 0.04) between ASA and NASA subjects (53.6 ± 7.1 versus 31.0 ± 6.8 cells/mm2, respectively) (Figure 6).
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No significant difference was observed in the number of eosinophils, T cells, or macrophages expressing GM-CSF (p = 0.47, p = 0.24, and p = 0.74, respectively) (Table 3).
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No significant difference was observed in the percentage of mast cells or eosinophils expressing GM-CSF (p = 0.06 and p = 0.08, respectively).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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A number of novel observations have been made in this study. We have shown that mast cell and eosinophil IL-5 and mast cell GM-CSF expression is significantly increased in ASA airways, suggesting that these hemopoietic cytokines may be responsible for the augmented eosinophilic infiltration observed in the condition. There is abundant evidence to support the role of cysteinyl leukotrienes in ASA and, as the eosinophil is a rich source of these mediators, the increased expression of IL-5 provides a pathophysiologic mechanism for recruitment of a critical effector cell in ASA. We have demonstrated that the significantly increased expression of IL-5 and GM-CSF was uniquely restricted to the mast cell and eosinophil, but not the T cell, emphasizing the central paracrine and autocrine function of these two cell types in the disease. The increased expression of IL-5 cannot be explained only by increased numbers of cells as the percentage of mast cells expressing IL-5 was also significantly elevated in ASA subjects. For GM-CSF, however, the percentage of mast cells expressing this cytokine was not significantly increased in ASA subjects. Thus, we cannot exclude the possibility that the enhanced expression of GM-CSF was due simply to increased numbers of this cell type. Our findings cannot be explained by the presence of more severe asthma since there was no significant difference between the baseline FEV1 between the ASA and control asthmatic subjects studied.
Aspirin intolerance is marked by the development of bronchospasm, naso-ocular symptoms, urticaria, angioedema, and anaphylaxis after ingestion of nonsteroidal anti-inflammatory drugs. These symptoms may occur in isolation or in any combination (1). Symptoms generally appear after the third decade of life and are frequently associated with chronic rhinitis, sinusitis, and nasal polyposis. These subjects often have persistent asthma, requiring regular treatment with either inhaled or oral corticosteroids (19, 20). In the subjects used in this study, there were no significant differences in the age, baseline lung function, or the usage of medication, between ASA and NASA subjects. The diagnosis of aspirin sensitivity was confirmed by lysine-aspirin bronchoprovocation, whereas the NASA subjects were proven to be aspirin-tolerant by both inhalation and oral aspirin challenge.
There is indirect evidence that mast cells and eosinophils
are central to the pathology of ASA. Sladek and coworkers
found increased eosinophils and eosinophil cationic protein
release in bronchoalveolar lavage fluid of subjects with ASA
as compared with control subjects (6). In a study of seven subjects with ASA, Yoshimi and associates reported an increased
peripheral blood eosinophilia and increased numbers of activated eosinophils in nasal polyps of these patients (21). In another study, immunohistochemical examination of ASA nasal
polyps demonstrated abundant eosinophils and degranulated
mast cells (22). The possibility that mast cells may be involved
in the pathogenesis of ASA and rhinitis is supported by a
number of studies. Bosso and colleagues demonstrated increased serum histamine and tryptase levels after aspirin ingestion in three of 17 ASA subjects manifesting moderate to
severe respiratory reactions associated with aspirin-induced
reactions in other organ systems (23). Similarly, Ferreri and
coworkers found increased levels of leukotriene C4 and histamine in nasal secretions associated with decreases in FEV1 in
three of four ASA subjects who had naso-ocular and bronchospastic reactions to aspirin (4). Treatment with cromolyn sodium in 20 subjects with ASA has been reported to lead to a
17% improvement in FEV1 50 min after inhalation (24). Furthermore, pretreatment with cromolyn sodium either prevented or delayed asthmatic responses to aspirin ingestion
(25). The demonstration that a high molecular weight neutrophil chemotatic factor was released into the serum of half of 22 subjects following aspirin-induced asthmatic reactions lends
further support to the concept of mast cells as the source of
mediators responsible for reactions in ASA (26). In a recent
study, Fischer and colleagues demonstrated a significant rise
in nasal lavage tryptase levels following aspirin ingestion in
ASA subjects (27). Further support to the hypothesis that pulmonary mast cells are activated during aspirin-induced airway
obstruction was given by O'Sullivan and associates who have
shown that urinary excretion of the prostaglandin D2 metabolite 9
,11-prostaglandin F2 was increased in ASA subjects on
bronchial challenge with inhaled lysine-aspirin (28). The increase in urinary 9,11-prostaglandin F2 was not observed
when bronchoconstriction was induced by histamine challenge.
In recent studies, we have shown that the numbers of mast cells and eosinophils, but not macrophages, T cells, or neutrophils, are increased in the airways of ASA subjects (12, 13). We have also shown previously that although the expression of the inducible pro-inflammatory cyclooxygenase isoenzyme 2 (COX-2) is not significantly different between ASA and NASA subjects, there is an increase in the numbers of mast cells and eosinophils expressing COX-2 in ASA subjects. The percentage of mast cells staining for COX-2 and the percentage of COX-2-containing cells that are mast cells are also increased in ASA subjects (13). These studies emphasize the potential role of the eosinophil and the mast cell in orchestrating the inflammatory pathology of ASA airways.
In order to provide insight into the possible signals for eosinophilic recruitment, we have now evaluated the expression of IL-5 and GM-CSF, since these cytokines may be essential for
the maturation and recruitment of eosinophils into the airways
of asthmatic patients (14). We have shown that there is an
increase in the total number of airway submucosal inflammatory cells expressing IL-5 in ASA subjects. The IL-5-positive
cells were composed mainly of mast cells, eosinophils, and
T cells in approximately equal proportions. The expression of
both IL-5 and GM-CSF in mast cells was elevated as was the
expression of IL-5 in eosinophils of ASA subjects. The production of IL-5 by infiltrating eosinophils in this unique syndrome may provide an autocrine amplification mechanism for
further recruitment, priming, and prolonged survival of this cell type. This eosinophilic autocrine cytokine expression (production and excretion) mechanism has been previously shown
by groups such as Walsh and colleagues who proved that fibronectin-dependent survival was significantly inhibited by
anti-IL-3, anti-GM-CSF, and anti-IL-5 monoclonal antibodies.
These three cytokines could also be detected in supernatants
from eosinophils cultured for 3 d on tissue fibronectin (29). In
addition to IL-5, GM-CSF, and IL-3, eosinophils are also
known to express a variety of cytokines and growth factors
such as interferon-
and IL-10 (30, 31). The present data extends previous work in coeliac disease, asthma, eosinophilic
cystitis, hypereosinophilic syndromes, eosinophilic heart diseases, and lesional atopic dermatitis (32), demonstrating the in vivo potential of the eosinophil to produce hemopoietic cytokines. In asthma, IL-5 challenge had been shown to not
only cause an increase in the number of eosinophils in both
bronchial mucosa and BAL, but also these eosinophils were in
a greater state of activation, as assessed by secretion of eosinophil cationic protein (36).
These results emphasize the central role of the mast cell and eosinophil in ASA by their capacity to regulate cellular infiltration, survival, and pro-inflammatory functions through the production of IL-5 and GM-CSF.
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Footnotes |
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Correspondence and requests for reprints should be addressed to T. H. Lee, Department of Allergy and Respiratory Medicine, 4th Floor, Hunts House, Guy's Hospital, London SE1 9RT, UK.
(Received in original form February 19, 1997 and in revised form May 15, 1997).
Acknowledgments: Supported in part by the National Asthma Campaign, UK.
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References |
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DISCUSSION
REFERENCES
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