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Published ahead of print on January 23, 2004, doi:10.1164/rccm.200312-1645OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 915-920, (2004)
© 2004 American Thoracic Society

Original Article

The Effect of Pranlukast on Allergen-induced Bone Marrow Eosinophilopoiesis in Subjects with Asthma

Krishnan Parameswaran, Richard Watson, Gail M. Gauvreau, Roma Sehmi and Paul M. O'Byrne

Firestone Institute for Respiratory Health, St. Joseph's Healthcare; and Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Correspondence and requests for reprints should be addressed to Paul M. O'Byrne, M.B., F.R.C.P.I., F.R.C.P.(C), Department of Medicine, McMaster University, Health Sciences Centre, Room 3W10, 1200 Main Street West, Hamilton, ON, L8N 3Z5 Canada. E-mail: obyrnep{at}mcmaster.ca


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We investigated the mechanisms by which leukotriene receptor antagonists decrease airway eosinophil number. In a randomized, double-blind crossover study, we examined the effects of 2 weeks of treatment with pranlukast 300 mg twice a day or placebo on allergen-induced changes in airway eosinophil number and bone marrow eosinophil progenitors in 15 subjects with mild asthma. Pranlukast treatment for 2 weeks decreased mean sputum eosinophil count from 0.15 x 106/g (5.3% of cells) before treatment to 0.02 x 106/g (0.7% of cells) after treatment (p < 0.05), whereas placebo did not. Pranlukast also decreased the eosinophil count (5.6% at 7 hours and 7.5% at 24 hours) (p < 0.05) after allergen inhalation compared with placebo (13.8% at 7 hours and 15.3% at 24 hours). There was a similar trend for sputum cells immunostaining for EG2, eotaxin, interleukin-5, and regulated upon activation, normal T cell expressed and secreted. Pranlukast also significantly attenuated the allergen-induced increase in the number of bone marrow eosinophil/basophil cfu (mean 0.3) at 24 hours compared with placebo (mean 6.2). The proportion of CD34+ cells expressing the eotaxin receptor CC chemokine receptor 3, 24 hours after allergen inhalation, was also reduced by pranlukast. We conclude that, the cysteinyl leukotriene receptor antagonist, pranlukast, attenuates allergen-induced increase in airway eosinophils by decreasing bone marrow eosinophilopoiesis and airway chemotactic and eosinophilopoietic cytokines.

Key Words: leukotriene receptor antagonist • allergen • sputum eosinophil • eosinophil progenitor

Allergen inhalation by patients with asthma causes, within 7 hours, an increase in the number of inflammatory cells in the airway, notably eosinophils and basophils (1). Eosinophilic inflammation, which is a hallmark of allergic inflammation, is associated with the late asthma response and an increase in airway hyperresponsiveness (2, 3). This cellular infiltration is facilitated by a number of cytokines such as interleukin (IL)-5, chemokines such as eotaxin and regulated upon activation, normal T cell expressed and secreted (RANTES), and mediators such as cysteinyl leukotriene C4, D4, and E4. Whereas IL-5 promotes eosinophil proliferation, differentiation, priming, and survival (4), eotaxin (5) and RANTES (6) induce chemotaxis of eosinophils to the airway and their activation.

There is strong evidence to suggest that the bone marrow plays an important role in the allergen-induced eosinophilic airway inflammation (7). After an allergen inhalation, eosinophil lineage–committed progenitor cells expressing the membrane-bound isoform of IL-5 receptor {alpha}-subunit (CD34+IL5-R{alpha}+) and the IL-5–responsive eosinophil/basophil cfu (Eo/B cfu) increase in the bone marrow (8–10) and in peripheral blood (11). Progenitor cells are also observed in the airway mucosa of subjects with asthma (12). It is likely that allergen inhalation increases the number of eosinophil progenitors in the bone marrow, which migrate to the airways either as mature eosinophils or as immature cells and undergo local differentiation. An increase in the eotaxin receptor, CC chemokine receptor 3 (CCR3), on the bone marrow progenitor cells after an allergen inhalation may facilitate the progenitor cell mobilization from the bone marrow to the peripheral circulation (13).

Cysteinyl leukotrienes promote airway eosinophilic inflammation. Inhalation of LTD4 and LTE4 causes sputum and tissue eosinophilia (14), and cysteinyl leukotriene receptor antagonists can decrease sputum eosinophilia (15). Cysteinyl leukotrienes can cause airway eosinophilia by a number of possible mechanisms (16). They can promote eosinophil chemotaxis into the airway (17), increase the surface expression of adhesion molecules on eosinophils and blood vessels facilitating their migration (18), prolong eosinophil survival (19), and upregulate gene expression of various cytokines/chemokines such as IL-4, IL-5, IL-13, eotaxin, and granulocyte–macrophage colony-stimulating factors that can promote eosinophil production and survival (20). We have shown previously that bone marrow Eo/B cfu cultures grown in the presence of IL-5 were significantly increased by LTD4 and this was inhibited by montelukast (21). We therefore hypothesized that one of the mechanisms by which cysteinyl leukotrienes promote airway eosinophilia is by promoting eosinophilopoiesis in the bone marrow.

We investigated this by studying the effect of a cysteinyl leukotriene-1 receptor antagonist, pranlukast, on allergen-induced changes in bone marrow–derived eosinophil lineage–committed CD34+ cells and IL-5–responsive Eo/B cfu. In addition, we studied the effect of treatment on CCR3 receptor expression on the progenitor cells. We also studied the effect of pranlukast treatment on the numbers of total and activated eosinophils in sputum and the immunoreactivity in sputum cells for EG2+, IL-5, eotaxin, and RANTES.

Some of the results of these studies have been reported previously in the form of an abstract (22).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The subjects were 16 nonsmokers with atopy and mild asthma (Table 1) using short-acting ß-agonists infrequently. All subjects gave written informed consent, and the Research Ethics Committee of Hamilton Health Sciences Corporation approved the study.


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  		TABLE 1. Baseline subject characteristics

 
Design
This was a randomized, double-blind, crossover, two-period study comparing 2 weeks of treatment with pranlukast, 300 mg tablet twice a day, or matching placebo, with at least 2 weeks of washout period between the treatment periods. The subjects underwent a screening allergen inhalation to identify those with a dual asthma response (greater than 15% fall in FEV1 within 120 minutes, followed by a similar drop between 3 and 7 hours after allergen inhalation). After 2 to 4 weeks, they had spirometry, sputum induction, and a methacholine inhalation test. They were then randomized to one of the two treatment arms using computer-derived codes that were maintained off-site by an independent third-party pharmacist. The medications were taken at 8 P.M. and 8 A.M. The first dose was in the evening of Day 1, and the last dose was on the morning of Day 15. On Day 8 (± 2 days), they visited the laboratory for a physical examination to evaluate for adverse effects and to evaluate compliance. On Day 13 (± 2 days), subjects attended the laboratory for spirometry, sputum induction, and an iliac bone marrow aspiration. The next day, an allergen inhalation test was performed. At 7 hours after allergen inhalation, sputum was induced. The next day, approximately 24 hours after allergen inhalation, subjects attended the laboratory for spirometry, sputum induction, and another bone marrow aspiration. Compliance was evaluated weekly by pill counting. Any adverse effect was evaluated by self-reported symptoms, physical examination, blood chemistry, and urine examination.

Allergen Inhalation
FEV1 was measured using a Collins water-sealed spirometer (Warren E. Collins, Braintree, MA) and kymograph according to the American Thoracic Society recommendations (23). Allergen inhalation was performed as described previously (2, 24).

Sputum Induction and Processing
Sputum was induced with hypertonic saline, separated from saliva, and processed as described by Pizzichini and coworkers (25).

Sputum Cytochemistry
Sputum cytospins were prepared on Aptex-coated slides (Sigma Chemical Co., Mississauga, ON, Canada), fixed for 10 minutes in periodate–lysine–paraformaldehyde, and stained as described by Gauvreau and coworkers (1).

Bone Marrow Progenitor Culture
Five milliliters of bone marrow sample was aspirated into heparinized (1,000 U/ml) syringes from the iliac crests after freezing the skin and periosteum with 2% lidocaine. Low-density mononuclear cells were isolated by sedimentation on Percoll density gradients (specific gravity 1.08) and cultured in the presence of IL-5 (1 ng/ml) as described previously (8–10).

Immunofluorescence Staining
Nonadherent mononuclear cells were stained with saturating amounts of biotin-conjugated anti–IL-5R{alpha}, and anti-CCR3, or the isotype-control antibody in 100 µl of ice-cold, fluorescence-activated, cell-sorter staining buffer for 30 minutes at 4°C (8, 9, 12, 13).

Flow Cytometry
The stained nonadherent mononuclear cells were analyzed using a FACScan flowcytometer equipped with an argon laser (Becton Dickinson Instrument Systems, Mississauga, ON, Canada) using the CELLQUEST program. CD34+ blast cells were identified as described previously (8, 13).

Analysis
Demographic data were summarized using descriptive statistics. Sputum eosinophil counts, expressed in absolute terms and as a percentage of the total cell count, and the immunopositive cells were analyzed using repeated measures analysis of variance. Treatment (pranlukast or placebo), time (baseline, preallergen, 7 hours postallergen, 24 hours postallergen), and period (first or second treatment) were the within-subject factors. The differences between pranlukast and placebo on allergen-induced changes in bone marrow progenitor colony counts and receptor expression were analyzed using paired t test. All analyses were performed using the Statistical Package for Social Sciences, version 10 (SPSS Inc., Chicago, IL). p Values less than 0.05 were considered to be statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
One subject developed a facial urticaria after one dose of the study medication and was withdrawn from the study. Fifteen subjects completed the study. One subject had transient, mild, and reversible elevation of liver enzymes that was not attributed to pranlukast treatment. The overall compliance with treatment was 90%.

Sputum Cell Counts
Two weeks of treatment with pranlukast decreased mean sputum eosinophil count from 0.15 x 106/g (± 0.24) before treatment to 0.02 x 106/g (± 0.02) after treatment (p < 0.05) (Figure 1) , whereas placebo did not (0.11 x 106/g [± 0.16] before treatment and 0.10 x 106/g [± 0.15] after treatment).



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  		Figure 1. Changes in sputum eosinophil count. Two weeks of placebo treatment did not have any effect on the eosinophil count (expressed as a percentage of total cell count), whereas treatment with pranlukast decreased it significantly. The increase in eosinophil count at 7 and 24 hours after allergen inhalation was also significantly decreased by pranlukast treatment but not by placebo (*p < 0.05).

 
Allergen inhalation increased sputum eosinophil numbers, and this effect was attenuated by pranlukast. After placebo treatment, sputum eosinophils increased to 0.72 x 106/g (± 1.04) at 7 hours and 0.54 x 106/g (± 0.59) at 24 hours. After pranlukast treatment, the increase in sputum eosinophil was significantly less (0.21 x 106/g at 7 hours [± 0.38] and 0.33 x 106/g [± 0.38] at 24 hours) (p < 0.05) (Figure 1). There were no significant changes in the total sputum cell counts or other cell counts with either allergen inhalation or pranlukast treatment (data not shown).

Sputum Cytochemistry
Similar to the effect on eosinophil counts, 2 weeks of treatment with pranlukast decreased EG2+ cells and attenuated the allergen-induced increase in EG2+ cells (Table 2) . The effect at 7 hours was statistically significant compared with the placebo treatment. A similar pattern was observed on sputum cells stained for IL-5, RANTES, and eotaxin. Whereas placebo pretreatment caused a 2.4-fold increase in IL-5–positive cells and a 1.7- and 2-fold increase in RANTES and eotaxin-positive cells, respectively, at 7 hours after allergen challenge, the corresponding numbers after pranlukast treatment were 1.5-, 1.0-, and 1.2-fold, respectively. However, this difference was not statistically significant (Table 2).


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  		TABLE 2. Changes in sputum cells immunostaining for cytokines

 
Bone Marrow Eo/B cfu
After 2 weeks of treatment with pranlukast, the number (mean ± SD) of IL-5–responsive Eo/B cfu in the bone marrow was 17.3 ± 6.3. This was not different from placebo treatment (17.3 ± 6.1). Allergen inhalation increased the bone marrow Eo/B cfu during placebo treatment to 23.6 ± 6.2. This effect was significantly decreased during pranlukast treatment to 17.7 ± 7.4 (p < 0.05) (Figure 2) .



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  		Figure 2. Changes in eosinophil/basophil cfu (Eo/B cfu) in the bone marrow. Allergen inhalation after 2 weeks of treatment with placebo caused a significant increase in the number of cfu (per 2.5 x 105 nonadherent mononuclear cells in the bone marrow). This was completely attenuated by 2 weeks of treatment with pranlukast (*p < 0.05). However, pranlukast treatment did not have an effect on the baseline number of cfu.

 
Bone Marrow Progenitor Cell Receptor Expression
We examined the numbers of bone marrow cells expressing CD34 and the numbers of CD34+ cells expressing CCR3. Allergen inhalation preceded by 2 weeks of placebo treatment did not cause a significant increase in CD34+ cells. However, pranlukast significantly reduced the allergen-induced increase in CD34+CCR3+ cells compared with placebo (p < 0.05) (Table 3) .


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  		TABLE 3. Changes in bone marrow progenitor cells

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study confirms previous findings that treatment with a leukotriene receptor antagonist, pranlukast, decreases the number of total and activated eosinophils in the airway and attenuates their increase after an allergen inhalation. The study also showed for the first time that this was associated with a decrease in the numbers of IL-5–responsive eosinophil cfu and CD34+CCR3 cells in the bone marrow. This suggests that one of the mechanisms by which leukotriene antagonists decrease allergen-induced airway eosinophil number is by a direct effect on allergen-induced eosinophilopoiesis in the bone marrow.

The ability of specific antagonists of the Cys-LT1 receptor to decrease airway eosinophil number is well recognized. Six weeks of treatment with montelukast decreased sputum eosinophil number in patients with mildly uncontrolled asthma (14). Four to six weeks of treatment with pranlukast (26), montelukast (27), and zafirlukast (28) decreased allergen-induced increase in airway eosinophil number. We observed a similar effect on eosinophil number and activation after 2 weeks of treatment with pranlukast and after an allergen inhalation. We hypothesized, for a number of reasons, that one of the mechanisms would be a direct effect on eosinophilopoeisis and egress of the progenitor cells from the bone marrow. First, allergen inhalation results in increased production of cysteinyl leukotrienes in the airway (29). Second, CD34+ granulocytic precursors express Cys-LT1 receptors on their surface (30). Third, we had demonstrated previously, in vitro, an increase in IL-5–responsive Eo/B cfu when nonadherent mononuclear cells from bone marrow of subjects with atopy were treated with LTD4 (21). Finally, LTD4 evoked calcium fluxes and actin polymerization in CD34+ cells derived from bone marrow of normal subjects and promoted chemotaxis toward it that was inhibited by a Cys-LT1 receptor antagonist (31).

Consistent with our hypothesis, we observed two novel effects of the Cys-LT1 receptor antagonist, pranlukast, on eosinophil progenitor cells. First, the increase in the number of IL-5–responsive cfu after an allergen inhalation was significantly decreased by 2 weeks of treatment with pranlukast, which did not seem to have an effect on the baseline number compared with the placebo treatment arm. The study did not investigate the mechanism of this effect. The effect of a leukotriene receptor antagonist may be direct or indirect. Because cysteinyl leukotrienes may be involved in mediating some of the biological effects of IL-5 (32), pranlukast may interfere with the ability of IL-5 to promote eosinophilopoiesis. This seems unlikely in this study because the nonadherent mononuclear cells from the pranlukast-treated subjects were grown in vitro in the presence of optimal concentration of IL-5, unless pranlukast is able to modulate IL-5 signal transduction pathways and make the cells unresponsive or less responsive to the effect of IL-5. There are two major signaling pathways of IL-5 in eosinophils. IL-5 activates Lyn, Syk, and JAK2 and propagates signals through the Ras–mitogen-activated protein kinase and Janus kinase-signal transducer and activator transcription factor pathways (33). It is not known whether cysteinyl leukotrienes are involved in either of these pathways. On the basis of recent evidence that they may be upstream of STAT6 signaling in the IL-13 signaling mechanism (34), this is a likely possibility that needs further investigation. The effect of pranlukast on eosinophilopoiesis may also be indirect. Because IL-5 can upregulate Cys-LT1 receptor expression on HL-60 cells that differentiated into eosinophils (35), they may also increase the expression of Cys-LT1 receptors on CD34+ cells. Pranlukast may directly prevent IL-5–responsive eosinophil differentiation of the CD34+ cells with increased Cys-LT1 receptor expression.

The second novel observation in this study was that pranlukast attenuated the allergen-increased increase in the number of CD34+ cells in the bone marrow expressing the eotaxin receptor, CCR3. We confirmed previous observation of CCR3 expression on CD34+ cells (13); however, we did not examine the localization of CCR3 to CD34+ cells that also express IL-5R{alpha}. The CD34+ cells expressing CCR3 show increased chemotaxis toward eotaxin (13), and this is augmented in the presence of IL-5. It is likely, therefore, that the allergen-induced increase in the levels of IL-5 and eotaxin in the airways of patients with dual asthma response causes the migration of pluripotent undifferentiated hemopoeitic cell from the bone marrow to the airway (36), where it can undergo local maturation into eosinophils. Our results suggest that cysteinyl leukotrienes are involved in the expression of CCR3 receptors on the progenitor cells. The mechanism was not investigated in this study. Because IL-5 is known to increase CCR3 expression on leukemic cell lines (37) and because treatment with leukotriene receptor antagonists can decrease airway IL-5 levels in murine models of asthma (38, 39), we postulate that the effect of pranlukast may be indirect by decreasing airway or perhaps bone marrow IL-5 levels. Indeed, airway and bone marrow IL-5 levels increase after an allergen inhalation (40), and in the present study, pranlukast treatment caused nearly 50% attenuation in the number of sputum cells staining positive for IL-5, 7 hours after an allergen inhalation, compared with placebo. Two weeks of treatment with pranlukast (preallergen) also seemed to cause a trend toward increasing the number of CD34+ cells and CD34+CCR3+ cells. Because the bone marrow contains a dynamic progenitor cell pool and because we did not perform bone marrow aspiration before the start of treatment, it is difficult to interpret whether this increase represents an increase in bone marrow production or whether it is a reflection of the ability of pranlukast to prevent them from exiting the bone marrow. The latter seems to be the likely possibility.

The effect of pretreatment with a leukotriene antagonist on allergen-induced bone marrow responses seems to be different from that of pretreatment with an inhaled corticosteroid. Seven days of treatment with budesonide decreased IL-5–responsive Eo/B cfu in subjects with asthma; however, unlike in this study, it did not prevent the allergen-induced increase in the numbers of cfu (41). In other words, although an allergen inhalation was able to overcome the inhibitory effect of inhaled corticosteroids in the growth of IL-5–responsive bone marrow progenitor cells, a leukotriene antagonist seems to be able to prevent it. The most logical explanation is that cysteinyl leukotriene levels increase significantly after an allergen inhalation and may contribute to the stimulation of the bone marrow. It is also possible that allergen may increase the expression of Cys-LT1 receptor on the progenitor cells making them more responsive to a leukotriene antagonist. The lack of significant effect of 2 weeks of treatment on preallergen Eo/B cfu was surprising considering that the sputum eosinophil counts were decreased with 2 weeks of treatment. It is possible that the role of cysteinyl leukotrienes in eosinophilopoiesis is modest in patients with mild, stable asthma and that other mechanisms such as eosinophil chemoattraction and effect of cytokines are more pronounced. Although it is known that leukotrienes are produced in the bone marrow (42), it is not known whether their levels are increased after an allergen inhalation. We did not measure cysteinyl leukotrienes in the bone marrow in this study, but we plan to do it in future studies. Similar to the previous study (41), we did not find the total number of CD34+ cells to change significantly with allergen inhalation or with treatment.

We also examined the effects of pranlukast treatment on three cytokines/chemokines that are relevant in causing airway eosinophil infiltration. Compared with placebo, pranlukast treatment attenuated the increase in sputum cells staining for IL-5, RANTES, and eotaxin 7 hours after an allergen inhalation. The difference, however, was not statistically significant. One of the reasons is that this was not a primary outcome measure and the study was not powered to show this difference. Second, the variability in the total cell counts in sputum was high, similar to previous reports (1), increasing the noise to signal ratio. However, our observations are consistent with previous reports that have shown leukotriene receptor antagonists to decrease airway IL-5 (38, 39, 43) and RANTES (44) levels in murine models of allergic sensitization.

In summary, the cysteinyl leukotriene receptor antagonist, pranlukast, decreases allergen-induced increase in airway eosinophil by decreasing both eosinophil progenitor cells in the bone marrow and the levels of eosinophilopoietic and chemotactic cytokines in the airway. The reduction in the numbers of IL-5–responsive eosinophil cfu and CD34+ cells expressing CCR3 in the bone marrow suggests a role for cysteinyl leukotrienes in IL-5 signal transduction pathway.


   Acknowledgments
 
The authors thank the subjects who participated in this study. The authors are grateful to A. Fanat, T. Rerecich, T. Strinich, S. Behmann, and J. Otis, McMaster University, for their excellent technical assistance; F. Denning, Cato Research Ltd., NC, and M. Katayama, Ono Pharma USA, Inc., NJ, for monitoring the study; and G. Sobhi, McMaster University, for assistance with dispensing the study medications.


   FOOTNOTES
 
Supported by a grant-in-aid from Ono Pharmaceutical Co., Ltd. K.P. is a postdoctoral fellow of the Canadian Institutes of Health Research.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: K.P. has received honoraria for lectures from Merck ($5,000 CAD), Altana ($5,000 CAD), 3-M ($2,000 CAD), and GlaxoSmithKline ($1,500 CAD), has provided consulting for Sepracor ($6,000 USD), and is coapplicant on a grant from AstraZeneca ($100,000 CAD); R.W. has no declared conflict of interest; G.M.G. has no declared conflict of interest; R.S. has received research grants from GlaxoSmithKline and AstraZeneca; P.M.O. is a consultant and sits on advisory boards for AstraZeneca, Altana, Bristol-Meyers Squibb, GlaxoSmithKline, Topigen, Roche, and Merck, has received lecture fees from these companies and holds sponsored grants from Altana, AstraZeneca, Dynavax, GlaxoSmithKline, Ono, and Merck.

Received in original form December 3, 2003; accepted in final form January 17, 2004


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Gauvreau GM, Watson RM, O'Byrne PM. Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am J Respir Crit Care Med 1999;160:640–647.[Abstract/Free Full Text]
  2. O'Byrne PM, Dolovich J, Hargreave FE. Late asthmatic response. Am Rev Respir Dis 1987;136:740–756.[Medline]
  3. O'Byrne PM, Inman MD, Parameswaran K. The trials and tribulations of IL-5, eosinophils, and allergic asthma. J Allergy Clin Immunol 2001;108:503–508.[CrossRef][Medline]
  4. Clutterback EJ, Sanderson CJ. Human eosinophil hematopoiesis studied in vitro by means of murine eosinophil differentiation factor (IL-5): production of functionally active eosinophils from normal human bone marrow. Blood 1988;71:646–651.[Abstract/Free Full Text]
  5. Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, Celestin J, Leder P, Luster AD. Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med 1996;2:449–456.[CrossRef][Medline]
  6. Kameyoshi Y, Dorschner A, Mallet AI, Christophers E, Schroder JM. Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. J Exp Med 1992;176:587–592.[Abstract/Free Full Text]
  7. Denburg JA, Sehmi R, Saito H, Pil-Seob J, Inman MD, O'Byrne PM. Systemic aspects of allergic disease: bone marrow responses. J Allergy Clin Immunol 2000;106:S242–S246.[CrossRef][Medline]
  8. Sehmi R, Woods L, Watson RM, Foley R, Hamid Q, O'Byrne PM, Denburg JA. Allergen-induced increases in IL-5{alpha}-subunit expression on bone marrow derived CD34+ cells from asthmatic subjects: a novel marker of progenitor cell commitment towards eosinophil differentiation. J Clin Invest 1997;100:2466–2475.[Medline]
  9. Sehmi R, Howie K, Sutherland DR, Shragge W, O'Byrne PM, Denburg JA. Increased levels of CD34 progenitor cells in atopic subjects. Am J Respir Cell Mol Biol 1996;15:645–654.[Abstract]
  10. Wood LJ, Inman MD, Watson RM, Denburg JA, Foley R, O'Byrne PM. Bone marrow inflammatory progenitor cells after allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 1998;157:99–105.[Abstract/Free Full Text]
  11. Gauvreau GM, Wood LJ, Sehmi R, Watson RM, Dorman SC, Schleimer RP, Denburg JA, O'Byrne PM. The effects of inhaled budesonide on circulating eosinophil progenitors and their expression of cytokines after allergen challenge in subjects with atopic asthma. Am J Respir Crit Care Med 2000;162:2139–2144.[Abstract/Free Full Text]
  12. Robinson DS, Damia R, Zeibecoglou K, Molet S, North J, Yamada T, Kay AB, Hamid Q. CD34+/interleukin-5R{alpha} messenger RNA+ cells in the bronchial mucosa in asthma: potential airway eosinophil progenitors. Am J Respir Cell Mol Biol 1999;20:9–13.[Abstract/Free Full Text]
  13. Sehmi R, Dorman S, Baatjes A, Watson R, Foley R, Ying S, Robinson DS, Kay AB, O'Byrne PM, Denburg JA. Allergen-induced fluctuation in CC chemokine receptor 3 expression on bone marrow CD34+ cells from asthmatic subjects: significance for mobilization of haemopoietic progenitor cells in allergic inflammation. Immunology 2003;109:536–546.[CrossRef][Medline]
  14. Gauvreau GM, Parameswaran KN, Watson RM, O'Byrne PM. Inhaled leukotriene E4, but not leukotriene D4, increased airway inflammatory cells in subjects with atopic asthma. Am J Respir Crit Care Med 2001;164:1495–1500.[Abstract/Free Full Text]
  15. Pizzichini E, Leff JA, Reiss TF, Hendeles L, Boulet LP, Wei LX, Efthimiadis AE, Zhang J, Hargreave FE. Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J 1999;14:12–18.[Abstract]
  16. Peters-Golden M. Do anti-leukotriene agents inhibit asthmatic inflammation? Clin Exp Allergy 2003;33:721–724.[CrossRef][Medline]
  17. Spada C, Nieves A, Krauss A, Woodward D. Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro. J Leukoc Biol 1994;55:183–191.[Abstract]
  18. Fregonese L, Silvestri M, Sabatini F, Rossi G. Cysteinyl leukotrienes induce human eosinophil locomotion and adhesion molecule expression via a Cys-LT1 receptor-mediated mechanism. Clin Exp Allergy 2002;32:745–750.[CrossRef][Medline]
  19. Lee E, Roberston T, Smith J, Kilfeather S. Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals. Am J Respir Crit Care Med 2000;161:1881–1886.[Abstract/Free Full Text]
  20. Peters-Golden M, Sampson A. Cysteinyl leukotriene interactions with other mediators and with glucocorticoids during airway inflammation. J Allergy Clin Immunol 2003;111:S37–S48.[CrossRef][Medline]
  21. Braccioni F, Dorman SC, O'Byrne PM, Inman MD, Denburg JA, Parameswaran K, Baatjes AJ, Foley R, Gauvreau GM. The effect of cysteinyl leukotrienes on the growth of eosinophil progenitors from peripheral blood and bone marrow of atopic subjects. J Allergy Clin Immunol 2002;110:96–101.[CrossRef][Medline]
  22. Parameswaran K, Watson R, Rerecich T, Otis J, Strinich T, O'Byrne PM. The CysLT1 receptor antagonist, pranlukast, attenuates allergen-induced increase in airway eosinophils and bone marrow derived eosinophil/basophil progenitors in subjects with atopic asthma [abstract]. Eur Respir J 2003;22:349s.
  23. American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med 1995;152:1107–1136.[Medline]
  24. Cockcroft DW, Murdock KY, Kirby J, Hargreave FE. Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine. Am Rev Respir Dis 1987;135:264–267.[Medline]
  25. Pizzichini E, Pizzichini MMM, Efthimiadis A, Hargreave FE, Dolovich J. Measurement of inflammatory indices in induced sputum: effects of selection of sputum to minimize salivary contamination. Eur Respir J 1996;9:1174–1180.[Abstract]
  26. Obase Y, Shimoda T, Tomari SY, Mitsuta K, Kawano T, Matsuse H, Kohno S. Effects of pranlukast on chemical mediators in induced sputum on provocation tests in atopic and aspirin-intolerant asthmatic patients. Chest 2002;121:143–150.[Abstract/Free Full Text]
  27. Leigh R, Vethanayagam D, Yoshida M, Watson RM, Rerecich T, Inman MD, O'Byrne PM. Effects of montelukast and budesonide on airway responses and airway inflammation in asthma. Am J Respir Crit Care Med 2002;166:1212–1217.[Abstract/Free Full Text]
  28. Calhoun WJ, Lavins BJ, Minkwitz MC, Evans R, Gleich GJ, Cohn J. Effect of zafirlukast (Accolate) on cellular mediators of inflammation: bronchoalveolar lavage fluid findings after segmental antigen challenge. Am J Respir Crit Care Med 1998;157:1381–1389.
  29. Macfarlane AJ, Dworski R, Sheller JR, Pavord ID, Kay AB, Barnes NC. Sputum cysteinyl leukotrienes increase 24 hours after allergen inhalation in atopic asthmatics. Am J Respir Crit Care Med 2000;161:1553–1558.[Abstract/Free Full Text]
  30. Figueroa DJ, Breyer RM, Defoe SK, Kargman S, Daugherty BL, Waldburger K, Liu Q, Clements M, Zeng Z, O'Neill GP, et al. Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am J Respir Crit Care Med 2001;163:226–233.[Abstract/Free Full Text]
  31. Bautz F, Denzlinger C, Kanz L, Mohle R. Chemotaxis and transendothelial migration of CD34+ hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1. Blood 2001;97:3433–3440.[Abstract/Free Full Text]
  32. Underwood DC, Osborn RR, Newsholme SJ, Torphy TJ, Hay DW. Persistent airway eosinophilia after leukotriene D4 administration in the guinea pig: modulation by the LTD4 receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody. Am J Respir Crit Care Med 1996;154:850–857.[Abstract]
  33. Adachi T, Alam R. The mechanism of IL-5 signal transduction. Am J Physiol Cell Physiol 1998;44:C623–C633.
  34. Elias JA, Lee CG, Zheng T, Shim Y, Zhu Z. Interleukin-13 and leukotrienes: an intersection of the pathogenetic schema. Am J Respir Cell Mol Biol 2003;28:401–404.[Free Full Text]
  35. Thivierge M, Doty M, Johnson J, Stankova J, Pleszczynski MR. IL-5 up-regulates cysteinyl leukotriene 1 receptor expression in HL-60 cells differentiated into eosinophils. J Immunol 2000;165:5221–5226.[Abstract/Free Full Text]
  36. Palframan RT, Collins PD, Williams TJ, Rankin SM. Eotaxin induces a rapid release of eosinophils and their progenitors from the bone marrow. Blood 1998;91:2240–2248.[Abstract/Free Full Text]
  37. Tiffany HL, Alkhatib G, Combadiere C, Berger EA, Murphy PM. CC chemokine receptors 1 and 3 are differentially regulated by IL-5 during maturation of eosinophilic HL-60 cells. J Immunol 1998;160:1385–1392.[Abstract/Free Full Text]
  38. Wu AY, Chik SC, Chan AW, Li Z, Tsang KW, Li W. Anti-inflammatory effects of high-dose montelukast in an animal model of acute asthma. Clin Exp Allergy 2003;33:359–366.[CrossRef][Medline]
  39. Eum S-Y, Maghni K, Hamid Q, Campbell H, Eidelman DH, Martin JG. Involvement of the cysteinyl-leukotrienes in allergen-induced airway eosinophilia and hyperresponsiveness in the mouse. Am J Respir Cell Mol Biol 2003;28:25–32.[Abstract/Free Full Text]
  40. Wood LJ, Sehmi R, Dorman S, Hamid Q, Tulic MK, Watson RM, Foley R, Wasi P, Denburg JA, Gauvreau G, et al. Allergen-induced increases in bone marrow T lymphocytes and interleukin-5 expression in subjects with asthma. Am J Respir Crit Care Med 2002;166:883–889.[Abstract/Free Full Text]
  41. Wood LJ, Sehmi R, Gauvreau GM, Watson RM, Foley R, Denburg JA, O'Byrne PM. An inhaled corticosteroid, budesonide, reduces baseline but not allergen-induced increases in bone marrow inflammatory cell progenitors in asthmatic subjects. Am J Respir Crit Care Med 1999;159:1457–1463.[Abstract/Free Full Text]
  42. Lindgren JA, Stenke L, Mansour M, Edenius C, Lauren L, Nasman-Glaser B, Ericsson I, Reizenstein P. Formation and effects of leukotrienes and lipoxins in human bone marrow. J Lipid Mediat 1993;6:313–320.[Medline]
  43. Hojo M, Suzuki M, Maghni K, Hamid Q, Powell WS, Martin JG. Role of cysteinyl leukotrienes in CD4(+) T cell-driven late allergic airway responses. J Pharmacol Exp Ther 2000;293:410–416.[Abstract/Free Full Text]
  44. Kawano T, Matsuse H, Kondo Y, Machida I, Saeki S, Tomari S, Mitsuta K, Obase Y, Fukushima C, Shimoda T, et al. Cysteinyl leukotrienes induce nuclear factor kappa b activation and RANTES production in a murine model of asthma. J Allergy Clin Immunol 2003;112:369–374.[CrossRef][Medline]



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