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ABSTRACT |
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ABSTRACT
INTRODUCTION
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Allergen-induced late airway responses are associated with increased numbers of airway eosinophils and basophils. The purpose of this study was to compare and contrast the effects of inhaled cysteinyl leukotrienes LTD4 and LTE4, which are released during allergen- induced airway responses, and allergen, on airway inflammatory cells. Fifteen subjects with atopic, mild asthma inhaled diluent, LTD4, LTE4, and allergen. Spirometry was performed for 7 h, and sputum inflammatory cells were measured before, 7 h, and 24 h after challenges. The maximum early percent fall in FEV1 was 23.6 ± 1.4%, 21.6 ± 2.3%, 29.3 ± 2.4%, and 4.0 ± 1.1% after LTD4, LTE4, allergen, and diluent, respectively. Only inhaled LTE4 and allergen significantly increased sputum eosinophils at 7 h and 24 h, and sputum basophils at 7 h. Six additional subjects underwent airway biopsies 4 h after inhalation. There were significantly more eosinophils in the lamina propria after inhalation of LTE4 compared with LTD4 and diluent (p < 0.05). These results suggest cysteinyl leukotrienes play a role in eosinophil migration into the airways in allergic asthma, and for the same degree of bronchoconstriction, inhaled LTE4 causes more tissue and airway eosinophilia than LTD4.
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Keywords: airway inflammation; allergen inhalation; cysteinyl leukotrienes; eosinophil; mediators
Allergen inhalation by sensitized subjects with atopic asthma results in the development of bronchoconstriction, which can be accompanied by airway hyperresponsiveness and an increased number of airway inflammatory cells, including eosinophils, basophils, and mast cells (1, 2). These cells are sources of the cysteinyl leukotrienes LTC4, LTD4, and LTE4 (3), which are lipid mediators known to cause bronchoconstriction in human airways (4) and play a role in the pathogenesis of asthma (7). Endogenous cysteinyl leukotrienes produced after allergen inhalation (8) are partly responsible for allergen- induced bronchoconstriction, as leukotriene synthesis inhibitors or cysteinyl LT1-receptor antagonists inhibit both allergen- induced early responses and late responses (9).
The role of cysteinyl leukotrienes in the development of allergen-induced airway hyperresponsiveness and airway inflammation is less well understood. Only a limited number of studies have described the effects of inhaled cysteinyl leukotrienes on airway inflammatory cells. Inhaled LTD4 has been shown to increase sputum eosinophils in subjects with asthma in one study (12), but not in another (13). Inhaled LTE4 has been shown to elevate the numbers of eosinophils measured in bronchial biopsies (14, 15), and treatment with a cysteinyl LT1-receptor antagonist reduced both eosinophils and basophils in BAL after segmental allergen challenge (16).
To date, there is no direct comparison of inhaled LTD4, LTE4, or allergen in their ability to cause airway inflammation and airway hyperresponsiveness. This randomized, cross-over study has compared the effects of inhaled LTD4 and LTE4 and allergen on the recruitment of airway eosinophils, mast cells, and basophils measured in induced sputum and bronchial biopsies, and on airway hyperresponsiveness in a group of subjects with mild, stable allergic asthma.
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INTRODUCTION
METHODS
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DISCUSSION
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Study Design
Twenty-one nonsmoking subjects with mild atopic asthma with a
forced expiratory volume in 1 s (FEV1) greater than 70% of predicted (> 70%pred) were recruited for the study (Table 1). These subjects were selected because they had previously demonstrated that they were able to develop allergen-induced early airway responses of at
least a 15% fall in FEV1, and allergen-induced increase in sputum
eosinophils at 7 and 24 h after challenge. Subjects used no medication
other than inhaled 
2-agonists in the last 4 wk before and during the
study. Medication was 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. Subjects did not
have asthma exacerbations or respiratory tract infections for at least
4 wk before entering the study, and were studied out of season for
their allergies. The study was approved by the ethics committee of the
McMaster University Health Sciences Center (Hamilton, ON, Canada), and subjects gave signed consent.
Clinical Methods
The study was double-blinded, diluent-controlled, randomized, with a
cross-over design. Subjects underwent skin testing and allergen challenge (13) to document allergen-induced responses. Fifteen subjects
were randomized to 3 treatment periods for inhalation of diluent,
LTD4, and LTE4 (Cayman Chemical, Ann Arbor, MI) (13), using a
Wright nebulizer, with 7 d between inhalations. If methacholine responsiveness or sputum eosinophils had not returned to baseline value, the washout period was extended. LTD4 and LTE4 were supplied in ethanol, stored at 
70° C, and diluted in physiological saline in 2-fold concentrations immediately before use. Challenges were started at a concentration of leukotriene chosen on the basis of methacholine responsiveness, and the concentration of leukotriene was increased in doubling concentrations until at least a 20% fall in FEV1
from preinhalation baseline was achieved (Table 1). Diluent challenge consisted of inhaling three doubling concentrations of ethanol
diluted to the highest concentration used for leukotriene challenges.
Spirometry was performed for 7 h after inhalation, and then sputum
was induced and processed (17). Sputum could not be induced earlier
because pretreatment with bronchodilator would interfere with subsequent measurement of FEV1. The methacholine PC20 (provocative
concentration causing a 20% fall in FEV1) (18) and sputum cells were
measured 1 d before and 24 h after challenge. Sputum cell differential
counts and immunostaining for mast cells, basophils, and the activated
form of human eosinophil cationic protein (ECP), EG2, were performed (2). Six subjects were randomized as described above, and underwent three bronchoscopic procedures 14 d apart. Biopsies were
obtained 4 h after inhalation, as a previous report demonstrated significant increases in tissue eosinophils after inhalation of LTE4 at this
time point (14). Fiberoptic bronchoscopy was carried out with an
Olympus (Lake Success, NY) 1T20D fiberoptic bronchoscope according
to a standardized protocol (19). Specimens were fixed in 4% paraformaldehyde, mounted in paraffin, and stained with Congo red for eosinophils and toluidine blue for mast cells and basophils. Cells were enumerated in the lamina propria, to a depth of 115 µm. The area and depth of
lamina propria in which the counts were performed were measured by
computerized image analysis (microscope: Olympus BX40; camera,
Sony 3CCD Power HAD video camera; software, Northern Eclipse;
Empix Imaging, Mississauga, ON, Canada), and results are expressed as
the number of cells per millimeter squared of lamina propria.
Statistical Analysis
Summary statistics for measurements of FEV1 are expressed as means and SEM. Values of methacholine PC20 and inflammatory cells were log-transformed before analysis and are reported as geometric means (+geometric SEM [GSEM]). Two-way repeated measures analysis of variance (ANOVA) was used to examine the effects of leukotriene and time. Because allergen inhalation was not randomized into the study design, its effect was not included in the ANOVA. Provocation data were not analyzed with regard to sequence effects. Statistical analyses were performed with computer software (Statistica 4.5; StatSoft, Tulsa, OK).
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RESULTS |
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Inhaled LTD4 and LTE4 caused bronchoconstriction, which began to resolve by 10 min after inhalation, and returned to within 10% of baseline by 1 h (Figure 1). The maximum percent fall in FEV1 and the area under the curve at 0-1 h (AUC0-1h) after LTD4 and LTE4 inhalation were not different from each other (p < 0.17). A 40-fold higher concentration of LTE4 (median) was required to elicit the same degree of bronchoconstriction as with LTD4 (Table 1). Allergen-induced bronchoconstriction demonstrated a slower onset than LTD4 and LTE4, was maximal at 20 min, and more prolonged returning to only 14% of the baseline value by 1 h (Figure 1). The percent fall in FEV1 between 3 and 7 h after LTD4 and LTE4 was 3.1 ± 0.8 and 4.0 ± 1.0%, respectively, which was significantly smaller than the allergen-induced maximum late percent fall in FEV1 of 18.8 ± 3.1% (p < 0.0002) (Figure 1).
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There was no effect of inhaled diluent, LTD4, or LTE4 on methacholine PC20 measured 24 h after inhalation challenge (p = 0.79) (Figure 2). By contrast, inhaled allergen caused a fall in methacholine PC20 from 2.1 mg/ml (+GSEM, 1.0) before allergen inhalation to 0.5 mg/ml (+GSEM, 0.3) 24 h after allergen inhalation (p < 0.00004).
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There was no significant difference in the number of sputum eosinophils at baseline before inhalation of diluent, LTD4, and LTE4 (Figure 3). The number of sputum eosinophils increased from 2.6 × 104/ml (+GSEM, 1.4) at baseline, to 14.7 × 104/ml (+GSEM, 5.8) 7 h after inhalation of LTE4 (p = 0.004), and to 19.1 × 104/ml (+GSEM, 5.3) at 24 h after inhalation of LTE4 (p = 0.005). This increase in sputum eosinophils was significantly higher than after diluent or LTD4 (p < 0.05). There was no significant difference in the number of sputum eosinophils between diluent and LTD4 inhalation challenge (Figure 2). The number of eosinophils in the lamina propria of the airway biopsies 4 h after inhaled LTE4 was higher than after inhaled LTD4 or diluent (p < 0.05) (Figures 4 and 5). There was no statistically significant change in the number of activated sputum eosinophils (EG2-positive cells) after inhalation of LTD4 or LTE4 (Table 2).
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p < 0.05 compared with preinhalation baseline (solid triangles); *p < 0.05 compared with diluent control, 
p < 0.05 compared with LTD4
(open triangles). Allergen was not compared with diluent, LTD4, or LTE4.
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Inhalation of LTE4 increased the number of sputum basophils at 7 h (p = 0.048) but not at 24 h compared with diluent (p > 0.05) (Table 2). There was no increase in the number of sputum mast cells after inhalation of diluent, LTD4, or LTE4 (p > 0.05). The number of metachromatic cells (mast cells and basophils) measured in the lamina propria was significantly greater 4 h after inhalation of LTE4 compared with LTD4 and diluent (p = 0.05); however, there was no effect of diluent or LTD4 on the number of metachromatic cells measured in the lamina propria (p > 0.05) (Figure 5).
The sputum total cell count increased after inhalation challenge with diluent, LTD4, and LTE4 (p = 0.01), leading to a significant effect of time on the number of sputum mast cells (tryptase-positive cells) (p < 0.0009) despite no change in the mast cell differential (p = 0.15). The number of sputum neutrophils also increased after inhaled diluent, LTD4, and LTE4 (p < 0.005) as a result of an increase in the neutrophil differential (p = 0.0007) and sputum total cell count (p = 0.01). There was, however, no difference in the number of sputum neutrophils or mast cells between any of the inhalation challenges (p = 0.07 and p = 0.16).
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DISCUSSION |
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We have demonstrated that inhalation of LTE4 by subjects with mild asthma increases the number of airway eosinophils measured in bronchial lamina propria 4 h after challenge, and in sputum 7 and 24 h after challenge, suggesting that inhaled LTE4 induces a prolonged inflammatory event. However, inhaled LTD4, causing the same degree of bronchoconstriction as inhaled LTE4, did not cause sputum or tissue eosinophilia. The magnitude of the effect of inhaled LTE4 was significantly less than the sputum eosinophilia caused by inhaled allergen in the same subjects, and it was not associated with the development of methacholine airway hyperresponsiveness, as occurred after inhaled allergen.
Increased numbers of inflammatory cells, including eosinophils and neutrophils, have been found in bronchial biopsies performed 4-6 h after LTE4 inhalation (14, 15), and small increases in sputum eosinophils have been measured in 50% of subjects with asthma 4 h after LTE4 inhalation (20). The results from this study, demonstrating increased numbers of both eosinophils and basophils in sputum after LTE4 inhalation, support the current concept that the cysteinyl leukotrienes may be a cause of the airway eosinophilia in asthma. There have been few studies investigating the effects of antileukotrienes on allergen-induced airway inflammation. Pretreatment with a cysteinyl LT1 antagonist has been shown to significantly inhibit allergen-induced lymphocytes and basophils, but not eosinophils, measured in bronchoalveolar lavage (BAL) 48 h after segmental allergen challenge (21). However, when higher doses of cysteinyl LT1 antagonist were administered, these investigators were able to demonstrate a partial effect on eosinophils (16). In a separate study, Diamant and coworkers were unable to see any effect of cysteinyl LT1 antagonist on allergen-induced sputum eosinophils or other inflammatory cells measured in sputum, despite significant inhibition of the early and late asthmatic responses (22). This lack of effect may have been a result of additional mechanisms leading to accumulation of inflammatory cells after allergen inhalation.
The cysteinyl leukotrienes are thought to be the main cause of allergen-induced bronchoconstriction, as inhibitors of leukotriene synthesis or cysteinyl LT1-receptor antagonists have produced almost complete inhibition of allergen-induced early responses and partial inhibition of the late response (9). Although cysteinyl leukotrienes have been shown to be the main cause of allergen-induced early bronchoconstriction, histamine, and possibly neural reflexes, also contribute to the early phase of bronchoconstriction. Despite a similar degree of bronchoconstriction to inhaled LTE4 to theoretically achieve approximately the same airway levels of leukotrienes as after allergen inhalation (at least on the cysteinyl LT1 receptor on airway smooth muscle), other mediators/neural reflexes as well as prolonged leukotriene generation may contribute to the enhanced responses observed after allergen inhalation. We induced a similar degree of bronchoconstriction to inhaled allergen, LTD4, and LTE4; there were different effects of LTD4 and LTE4, and both were different than allergen inhalation. The early airway response to allergen was more prolonged than to LTD4 or LTE4, and neither inhaled LTD4 nor LTE4 caused a late response. The degree of sputum eosinophilia after LTE4 was approximately one-quarter of that measured after allergen challenge (Figure 3) and considerably fewer sputum basophils and mast cells were detected than previously measured after allergen challenge (2). The LTE4-induced airway inflammation was not associated with the development of methacholine airway hyperresponsiveness, which was measured 24 h after challenge. Subjects may have developed LTE4-induced airway hyperresponsiveness to methacholine earlier than 24 h, as earlier studies have shown airway hyperresponsiveness peaks 3 to 7 h after inhalation of LTE4 (23). Our experiments, however, cannot explain this apparent discrepancy between the presence of eosinophilic inflammation without the concurrent airway hyperresponsiveness 24 h after LTE4 inhalation. It is possible that LTE4-induced sputum eosinophilia and basophilia is not sufficient to cause the same magnitude of airway inflammation that is observed in association with allergen-induced late responses. On the other hand, allergen inhalation resulting in airway hyperresponsiveness induces the release of many proinflammatory mediators. Upregulation of the eosinophilic cytokines after allergen inhalation (24) may enhance (i.e., interleukin 5 [IL-5] and eotaxin) or prolong (i.e., granulocyte-macrophage colony-stimulating factor [GM-CSF]) the allergen-induced airway eosinophilia and basophilia, resulting in late airway responses and methacholine airway hyperresponsiveness.
This study has confirmed previous observations that inhaled LTD4 resulting in submaximal (13) or maximal (12) bronchoconstriction does not increase sputum eosinophils in asthmatic airways when compared with control challenge (diluent or methacholine). The results of this study, that inhaled LTE4, but not LTD4, caused significant increases in the number of sputum eosinophils, was a surprising finding, because it is thought that both LTD4 and LTE4 act on the cysteinyl LT1 receptor. Studies using allergic guinea pigs have demonstrated eosinophil influx into the airway after LTD4 challenge (25), and LTD4 appears to be a chemoattractant for isolated human peripheral blood eosinophils in vitro (26). We have also shown a direct, albeit small, chemotactic effect of LTD4 and LTE4 on peripheral blood eosinophils (27). There are, however, other mechanisms whereby leukotrienes may cause elevated airway eosinophil levels, such as leukotriene-induced survival of eosinophils (28), and leukotriene-induced production of eosinophil chemoattractants such as eotaxin (29).
Different effects of LTD4 and LTE4 may be explained by the stability of each metabolite, as well as the relative concentration of each leukotriene that was inhaled. It has been shown that LTC4, and presumably LTD4, are quickly metabolized in the airway, as more than half of the LTC4 instilled into the asthmatic airway is converted to LTE4 within 15 min (30). This suggests that inhalation of LTD4 may actually supply LTE4, as well, to the airways. If inhalation of LTD4 is indirectly supplying LTE4 to the airways through rapid metabolism, higher concentrations of inhaled LTD4 may reproduce what has been observed after inhalation of LTE4. This is supported by observations that both LTD4 and LTE4 have direct effects on eosinophil accumulation in vivo (31) and cause eosinophil migration in vitro (32). We chose to deliver leukotrienes into the airways at concentrations resulting in a physiological response that could be immediately measured. We were unable to match the concentration of inhaled LTD4 to the concentration of inhaled LTE4 causing a physiological response, as this would result in severe bronchoconstriction, given the greater potency of LTD4 than LTE4 on airway smooth muscle. LTE4, being a less potent bronchconstrictor agent than LTD4, was delivered at a 40-fold higher concentration to achieve the same degree of bronchoconstriction. If LTD4 and LTE4 share a common cysteinyl LT1 receptor (33), as suggested by the inhibitory effects of an LT-receptor antagonist to LTE4-induced responses in vivo (15), the relative potency of the two cysteinyl leukotrienes may be different in their effects on airway smooth muscle and eosinophils, or any other upstream event leading to eosinophil accumulation. Evidence that LTE4 is less potent than LTD4 in causing changes in vascular permeability despite similar contractile potencies when tested in vitro (34) supports the hypothesis that differences in both vascular responses and cellular responses may contribute to the different bronchoconstrictor potencies observed in vivo.
There is, however, evidence of selective binding of LTE4 to only a subset of LTD4 receptors (35). Although it has been generally thought that LTD4 and LTE4 act on the same receptors, pharmacological reversal has been found to be different between the two leukotrienes, suggesting these leukotrienes may not necessarily bind the same receptors (31). In agreement, molecular dynamics simulations have demonstrated that LTE4 conformation spans the LTD4 and LTC4 types and therefore may occupy both of these receptors (36).
Whether cysteinyl leukotrienes contribute to cell activation is unclear, as we did not observe a statistically significant increase in EG2-positive cells (activated eosinophils). In another study of LTD4- and LTE4-challenged conjunctiva, there was no observed tissue damage despite a dose-dependent eosinophilia (25). The primary action of leukotrienes, therefore, may be amplification of inflammation rather than activation of inflammatory cells. The increase in sputum neutrophils observed after all the inhalation challenges is likely a result of the sputum induction procedure, as repeated induction of sputum has been shown to cause elevations of sputum neutrophils (13). The increase in sputum mast cells observed after all the inhalation challenges is a result of an effect of time on the total sputum cell count, and a low between-subject variability in sputum mast cell numbers. In contrast to the sputum neutrophil differential, the sputum mast cell differential was not affected by time (p = 0.15).
We have provided evidence that inhaled LTE4, but not inhaled LTD4, administered in concentrations to match the bronchoconstriction achieved with inhaled allergen, attracts eosinophils into the airways of subjects with atopic asthma. This accumulation of eosinophils was relatively small when compared with that after allergen inhalation, and this effect did not result in the development of late responses or methacholine airway hyperresponsiveness. These studies suggest that the cysteinyl leukotrienes are important not only in causing allergen-induced bronchoconstriction, but may also directly contribute to accumulation of airway eosinophils. The magnitude of eosinophil accumulation in vivo and in vitro is small. We suggest that although cysteinyl leukotrienes may induce primary effects on eosinophils, their role as priming agents may have a greater overall effect on eosinophil accumulation during an allergic event such as allergen inhalation.
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Correspondence and requests for reprints should be addressed to P. M. O'Byrne, M.D., Firestone Institute for Respiratory Health, St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada. E-mail: obyrnep{at}mcmaster.ca
(Received in original form February 7, 2001 and accepted in revised form July 16, 2001).
Acknowledgments: The authors thank T. Rerecich, J. Otis, and E. Baswick for help in the preparation of this manuscript, and Dr. A. Irani and Dr. L. Schwartz for their generous gift of the 2D7 antibody.
Supported by the Canadian Institutes of Health Research.
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References |
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REFERENCES
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