G. M. GAUVREAU, L. J. WOOD, R. SEHMI, R. M. WATSON, S. C. DORMAN, R. P. SCHLEIMER, J. A. DENBURG, and P. M. O BYRNE

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1 The Effects of Inhaled Budesonide on Circulating Eosinophil Progenitors and Their Expression of Cytokines after Allergen Challenge in Subjects with Atopic Asthma G. M. GAUVREAU, L. J. WOOD, R. SEHMI, R. M. WATSON, S. C. DORMAN, R. P. SCHLEIMER, J. A. DENBURG, and P. M. O BYRNE Asthma Research Group, St. Joseph s Hospital and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada; and Johns Hopkins Allergy and Asthma Research Center, Baltimore, Maryland Allergen inhalation by dual responder subjects with atopic asthma is associated with an increase in circulating eosinophil/basophil colony-forming units (Eo/B CFU) and granulocyte macrophage colonystimulating factor (GM-CSF) immunolocalization in Eo/B colony cells grown in vitro. The current study examined the effect of the inhaled corticosteroid, budesonide, on the number of allergeninduced circulating eosinophils and Eo/B CFU, and immunolocalization of GM-CSF and interleukin-5 (IL-5) in Eo/B colony cells grown in vitro. Sixteen subjects with mild atopic asthma were treated for either 7 or 8 d with 200 g inhaled budesonide or placebo twice a day. Peripheral blood was collected before and 24 h after allergen inhalation challenge and nonadherent mononuclear cells (NAMC) were grown in methylcellulose culture. Eo/B CFU were enumerated after 14 d in culture, and prepared on slides for immunocytochemistry. Budesonide attenuated the allergen-induced increase in circulating eosinophils ( /ml versus /ml, p ), circulating Eo/B CFU ( /10 6 NAMC versus /10 6 NAMC, p 0.05), and immunolocalization of GM-CSF in Eo/B colony cells ( % positive versus %, p 0.01) but not immunolocalization of IL-5 ( % versus %, p 0.05). Inhaled budesonide attenuated the number of allergen-induced circulating eosinophils and their progenitors grown in the presence of GM-CSF, which may partially be a result of regulating eosinophil progenitor expression of the autocrine growth factor GM-CSF. Asthma is a disease characterized by peripheral blood eosinophilia and eosinophilic infiltration of the airways, which is enhanced in association with the allergen-induced late airway bronchoconstrictor response (1, 2). Eosinophils and basophils arise from common progenitor cells, the eosinophil/basophil colony-forming unit (Eo/B CFU) (3, 4) that circulate at higher levels in peripheral blood of atopic compared with nonatopic individuals (5, 6). Peripheral blood Eo/B CFU are also elevated during asthma exacerbations (7) and fall after an initial rise after seasonal exposure to allergen (8). Allergen inhalation challenge resulting in airway hyperresponsiveness and inflammation is also associated with increased levels of Eo/B CFU in peripheral blood (9, 10) and bone marrow of subjects with atopic asthma (11). Granulocyte macrophage colony-stimulating factor (GM- CSF) is an important growth factor for eosinophils. Infusions (Received in original form January 31, 2000 and in revised form July 14, 2000) This study was supported by an operating grant from the Medical Research Council of Canada. Dr. O Byrne is a Medical Research Council of Canada Senior Scientist. Correspondence and requests for reprints should be addressed to Dr. P. M. O Byrne, Firestone Chest & Allergy Unit, Room R113, St. Joseph s Hospital, 50 Charlton Avenue East, Hamilton, ON, L8N 4A6 Canada. Am J Respir Crit Care Med Vol 162. pp , 2000 Internet address: of GM-CSF increase numbers of circulating myeloid progenitors cultured from human blood (12). GM-CSF is important for the proliferation and differentiation of eosinophils, which has been proposed to occur in an autocrine fashion (4). Expression of GM-CSF by eosinophil progenitors is enhanced in response to local stimuli, such as allergen inhalation (10). Inhaled glucocorticosteroids are a first line therapy for the control of allergic asthma (13). Steroids down-regulate production of proinflammatory cytokines, such as GM-CSF (14), through direct binding to a glucocorticoid receptor (15). The inhaled glucocorticoid, budesonide, has been shown to suppress levels of circulating (16) and airway eosinophils (2), and to significantly attenuate allergen-induced increases in peripheral blood and airway eosinophils (2, 17). Withdrawal of inhaled corticosteroids in subjects with allergic asthma results in increased circulating Eo/B CFU in association with asthma exacerbations (7). Budesonide has recently been shown to suppress baseline eosinophil bone marrow progenitor levels in subjects with atopic asthma but had no effect on allergen-induced increases of progenitors (17). This study examined the hypothesis that regular treatment with the inhaled glucocorticoid, budesonide, would reduce the numbers of allergen-induced peripheral blood Eo/B CFU, and furthermore, that this effect may be related to a reduction in the expression of hematopoietic factors by eosinophil progenitors in the blood of subjects with atopic asthma. The overall goal was to investigate the mechanisms by which regular treatment with inhaled budesonide attenuates allergen-induced peripheral blood and airway eosinophilia. METHODS Subjects Twenty subjects with mild atopic asthma participated in two studies approved by the Ethics Committee of the McMaster University Health Sciences Centre. The samples for this present study were collected during the two studies as the study designs were identical aside from the duration of treatment with inhaled budesonide. Ten subjects were randomized to inhale budesonide or placebo for 7 d, and 10 subjects were randomized to inhale budesonide or placebo for 8 d. Subjects were considered atopic with a positive skin prick test ( 2 mm wheal) to at least one of 21 common allergens. Subjects with documented allergen-induced early (EAR) and late (LAR) asthmatic response of at least a 15% fall in forced expiratory volume in 1 s (FEV 1 ) were selected for the study and gave signed consent to participate. Subjects did not have asthma exacerbations or respiratory tract infections and were not exposed to sensitizing allergens for at least 4 wk prior to entering the study because airway responses and colony formation by progenitors are altered by allergen exposure (7, 8, 10). All subjects had stable asthma with baseline FEV 1 greater than 70% of predicted normal on all study days before allergen inhalation. Subjects used no medication other than inhaled 2 -agonist as required to treat their symptoms, and 2 -agonists were withheld for at least 8 h before each

2 2140 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL visit. Subjects were instructed to refrain from rigorous exercise, tea, or coffee in the morning before visits to the laboratory. A sample size of more than eight subjects per group was considered to be sufficient to observe treatment effects on the LAR, as a previous study using the same methodology has demonstrated that eight or more subjects can demonstrate a 50% change in the LAR with a power of 90% (18). Three subjects were excluded from study 1 and one from study 2; two experienced deterioration of their asthma, one was unable to inhale the same dose of allergen during the two challenges, and one was unable to complete the second allergen challenge. Study Design The studies were carried out with a double-blind, placebo-controlled, randomized, crossover design. In the first study, subjects were randomized to complete two treatment periods inhaling 200 g budesonide or placebo twice a day for 7 d (n 7), and in the second study, subjects completed two treatment periods inhaling 200 g budesonide or placebo twice a day for 8 d (n 9). Each treatment period consisted of four visits to the laboratory. Baseline measurements of FEV 1, the provocative concentration of methacholine causing a 20% fall in FEV 1 (PC 20 ), induced sputum differentials and peripheral blood differentials were determined before treatment, and on treatment Day 7, and on Day 9 at 24 h following allergen challenge. Peripheral blood Eo/B CFU were measured before and 24 h following allergen challenge. Allergen inhalation challenges were carried out on the morning of Day 8, and spirometry was measured until 7 h after allergen inhalation (Figure 1). Treatment periods were separated by a washout period of at least 3 wk. Laboratory Procedures Methacholine inhalation test. Methacholine inhalation challenge was performed as described by Cockcroft (19). Subjects inhaled normal saline, then doubling concentrations of methacholine phosphate from a Wright nebulizer (Roxon Medi-Tech Ltd., Montreal, QC, Canada) via a Hans Rudolph valve (Hans Rudolph, Inc., Kansas City, MO) for 2 min. FEV 1 was measured at 30, 90, 180, and 300 s after each inhalation. Spirometry was performed with a Collins water-sealed spirometer and kymograph (Warren Collins, Braintree, MA). The test was terminated when a fall in FEV 1 of 20% of the baseline value occurred, and the PC 20 was calculated. Allergen inhalation challenge. Allergen challenge was performed as described by O Byrne and coworkers (20). Allergen extracts were stored at 70 C and diluted in phosphate-buffered saline with 1.5% benzyl alcohol for skin tests and diluted in physiological saline for allergen inhalation on the day of use. The allergen extract was selected and diluted for inhalation at a concentration determined from a formula using the results from the skin test and the methacholine PC 20 (21). Allergen inhalation challenges were performed using a Wright nebulizer pressurized by air at 50 psi and at a flow rate that gave an output of 0.13 ml/min and aerodynamic mass median diameter of m. Concentrations of allergen were inhaled by tidal breathing (nose clipped) for 2 min, with FEV 1 measured 10 min after each inhalation. Subjects inhaled the same concentration of allergen for both challenges. The starting allergen concentration for both challenges was two doubling concentrations lower than the third and final concentration, which was found to result in a 15% EAR and LAR during a previous screening period; inhalations were increased by doubling concentrations until the final concentration was inhaled. FEV 1 was subsequently measured at 20, 30, 45, 60, 90, and 120 min and at hourly intervals up to 7 h postallergen inhalation. FEV 1 was measured using a water-sealed spirometer, with triplicate FEV 1 measurements at baseline and single FEV 1 measurements postallergen inhalation; volumes were recorded at body temperature, atmospheric pressure, saturated with water vapor. The diluent inhalation challenge was performed in the same manner as the allergen inhalation challenge, with subjects inhaling physiological saline (three inhalations of 2 min) instead of allergen. The EAR was taken to be the largest fall in FEV 1 within 2 h after allergen inhalation, and the LAR was taken to be the largest fall in FEV 1 between 3 and 7 h after allergen inhalation. Sputum analysis. Sputum was induced and processed using the method described by Pizzichini and coworkers (22). Sputum cell plugs were mixed with a bench rocker, in four times their volume of 0.1% dithiothreitol (Sputolysin; Calbiochem Corp., San Diego, CA) and four times their volume of Dulbecco s phosphate-buffered saline (DPBS; Gibco BRL, Life Technologies, Grand Island, NY). The cell suspension was filtered through a 52- m nylon gauze (BNSH Thompson, Scarborough, ON, Canada) to remove debris, then centrifuged at 1,500 rpm for 10 min. Cells were resuspended in DPBS at /ml, and cytospins were prepared on glass slides using 50 l 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 (American Scientific Products, McGaw Park, IL). Peripheral blood collection and differential counts. Blood was collected into heparinized tubes by direct venipuncture, and blood smears were made for differential staining (Diff-Quik). 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 milliliter blood by dividing by the total number of cells counted, and multiplying by the total leukocyte count. Peripheral blood Eo/B CFU assay. Methylcellulose assays for peripheral blood CFU were performed as previously described (8). Mononuclear cells were separated from whole peripheral blood using Percoll density gradients (Pharmacia, Uppsala, Sweden), then adherent cells were removed by a 2-h incubation at 37 C in plastic flasks. Nonadherent mononuclear cells (NAMC) were cultured in 0.9% methylcellulose (Sigma Chemical Co., St. Louis, MO) at per mm tissue culture dish (Falcon Plastics, Oxnard, CA) in Iscove s modified Dulbecco s medium and 20% fetal calf serum (Gibco, Burlington, ON, Canada) supplemented with 1% penicillin-streptomycin and mol/l of 2-mercaptoethanol. To evaluate the effects of budesonide on baseline Eo/B CFU and allergen-induced Eo/B CFU, cells were grown in vitro under four different growth conditions: (1) 10 ng/ml rhgm-csf (Pharmingen, Markham, ON, Canada), (2) 10 ng/ml rhil-3 (Genzyme, San Diego, CA) plus 0.5 ng/ml stem cell factor (SCF) (Amgen, Thousand Oaks, CA), (3) 10 ng/ml rhil-3 (Genzyme, San Diego, CA), and (4) 10 ng/ml rhil-5 (Pharmingen). Cultures were incubated for 14 d at 37 C and 5% CO 2. Day 14 Eo/B type granulocyte colonies were enumerated in two replicate methylcellulose plates under inverted microscopy, and expressed as Eo/B CFU per NAMC plated. The Eo/B colonies were identified by Figure 1. Study schematic.

3 Gauvreau, Wood, Sehmi, et al.: Budesonide and Eosinophil Progenitors 2141 morphology, as previously described, as tight, granulated, compact, round refractile cell aggregations (3, 5). Immunocytochemical staining. Day 14 Eo/B colony cells grown from peripheral blood stimulated with SCF plus IL-3 were randomly selected under inverted microscopy, washed in 0.5 ml Dulbecco s phosphate buffered saline (DPBS; Gibco), and resuspended in DPBS at a concentration of /ml. Cytospins were prepared on aptex-coated glass slides using 50 l of cell suspension and a Shandon III cytocentrifuge at 300 rpm for 5 min (Shandon Southern Instruments). Cytospins were fixed for 10 min in periodate lysine paraformaldehyde, then 10 min in 15% sucrose, and stored at 70 C. Immunopositive cells for GM-CSF and IL-5 were detected by the alkaline phosphatase antialkaline phosphatase method (23). Cytospins were incubated for 60 min with 75% human AB serum (Sigma Chemical Co.) and for 30 min with 25% normal rabbit serum (Sigma Chemical Co.) to block nonspecific binding of the first and second antibodies, respectively. Cytospins were then incubated overnight with mouse monoclonal anti-human GM-CSF antibody at 10 g/ml (Genzyme, Cambridge, MA) or mouse monoclonal anti-human IL-5 antibody at 30 g/ ml (R&D Systems, Minneapolis, MN), followed by 45-min incubations with rabbit anti-mouse secondary and mouse APPAP tertiary antibodies (Dako, Glostrop, Denmark). All antibodies were diluted in 1.0% bovine serum albumin (BSA; Sigma Chemical Co.) and wash buffer made up of DPBS, 0.01 M HEPES buffer, and 0.01% saponin (Sigma Chemical Co.). Mouse IgG 1 (Sigma Chemical Co.) was used as a negative control. Positive control slides for GM-CSF consisted of peripheral blood monocytes stimulated with lipopolysaccharide (LPS); for IL-5, peripheral blood eosinophils were stimulated with calcium ionophore. The percentage of cells immunolocalizing GM-CSF and IL-5 was determined from a count of 400 cells under light microscopy. Statistical Analyses Budesonide treatment for 7 d and 8 d had the same effects on allergen-induced airway physiology, airway inflammation, and peripheral blood eosinophils, thus data from the two studies were pooled together to increase the statistical power of measurements of Eo/B CFU. Summary statistics of the combined data are expressed as mean and SEM. Methacholine PC 20 measurements, which are made by linear interpolation of log dose response curves, are expressed as the mean log 10 values and the SEM of log 10 values. Repeated measurements of blood, sputum, and methacholine PC 20 were analyzed for the effects of allergen and budesonide (main effects), and for the effects of budesonide on the allergen-induced changes (interaction effect) using a two-way repeated measures ANOVA. Single timepoint comparisons of allergen-induced percentage fall in FEV 1 were analyzed using two-tailed Student s paired t test. RESULTS Allergen inhalation challenge during placebo treatment caused an EAR of %, which was significantly attenuated during budesonide treatment to % (p 0.002) (Figure 2). The allergen-induced LAR during placebo treatment of % was significantly attenuated during budesonide treatment to % (p ) (Figure 2). There was a decrease in methacholine PC 20 from mg/ml at baseline to mg/ml at 24 h following allergen challenge during placebo treatment (p 0.003). Budesonide treatment significantly attenuated the allergen-induced shift in methacholine PC 20, being mg/ml at baseline and mg/ml at 24 h following allergen challenge (p 0.003). The preallergen baseline percentage sputum eosinophils were not different after 1 wk of treatment with budesonide compared with placebo ( % versus , p 0.05). There was an allergen-induced increase in percentage sputum eosinophils with placebo treatment to % at 24 h following challenge (p ), and this was significantly attenuated to % by budesonide (p ). The baseline number of peripheral blood eosinophils did not change during treatment with budesonide, being /ml after placebo and /ml after budesonide (p 0.05). The number of circulating eosinophils increased significantly at 24 h following allergen challenge, being /ml (p ); this increase was suppressed to /ml by budesonide (p ). Budesonide treatment also significantly attenuated the allergen-induced shift in the percentage sputum eosinophils from baseline compared with placebo treatment (p 0.001). There was no effect of budesonide treatment on baseline numbers of Eo/B CFU grown in the presence of GM-CSF, IL-3, plus SCF, IL-3 or IL-5 (p 0.05) (Table 1). At 24 h following allergen challenge, there was a significant increase in the number of circulating Eo/B CFU grown in the presence of GM- CSF (p 0.05), but the changes were not significant with IL-3 plus SCF (p 0.07), IL-3 (p 0.06), or IL-5 (p 0.32) (Table 1). Budesonide treatment significantly suppressed the allergen-induced increase in Eo/B CFU grown in the presence of TABLE 1 COMPARISON OF EOSINOPHIL/BASOPHIL COLONY-FORMING UNITS (Eo/B CFU) FROM PERIPHERAL BLOOD COLLECTED AT BASELINE AND 24 h AFTER ALLERGEN INHALATION CHALLENGE FOLLOWING TREATMENT WITH BUDESONIDE 200 g TWICE A DAY OR PLACEBO* Placebo Budesonide Baseline 24 h Postallergen Baseline 24 h Postallergen Stimulation (Eo/B CFU/10 6 NAMC) (Eo/B CFU/10 6 NAMC) GM-CSF IL-3 SCF IL IL Figure 2. Percentage change in FEV 1 (mean and SEM) following diluent challenge (open circles), and allergen challenge (solid circles) with placebo (solid line) and budesonide (dotted line) treatment. There were significant early (0 2 h) and late (3 7 h) allergen-induced asthmatic responses (*p 0.05) that were significantly reduced with budesonide treatment ( p 0.05). Definition of abbreviations: Eo/B CFU eosinophil/basophil colony-forming units; GM- CSF granulocyte macrophage colony-stimulating factor; IL interleukin; NAMC nonadherent mononuclear cells; SCF stem cell factor. * Colony-forming units were enumerated after 14 d in culture in the presence of GM- CSF, IL-3 SCF, IL-3, and IL-5. Values shown are mean SEM (n 16 subjects). p 0.05 for difference from baseline. p 0.05 for difference from placebo. p 0.10 for difference from baseline. p 0.10 for difference from placebo. n 9 subjects.

4 2142 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 3. Allergen-induced expression of interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by peripheral blood eosinophil/basophil (Eo/B) colony cells. Percentage Eo/B colony cells immunopositive for IL-5 (top panel) and GM-CSF (bottom panel) measured at baseline and 24 h following allergen challenge with placebo (open symbols) and budesonide (solid symbols) treatment. There was a significant increase in percentage IL-5-positive cells with budesonide treatment ( p 0.007) with no effect of allergen. There was an allergen-induced increase in percentage GM-CSF-positive cells (*p 0.01), which was suppressed by budesonide ( p 0.01). GM-CSF (p 0.05), but not IL-3 plus SCF (p 0.07) or IL-3 (p 0.56) (Table 1). There was no effect of budesonide or allergen on the number of GM (granulocyte macrophage) colonies grown from peripheral blood. Budesonide treatment significantly increased the percentage Eo/B colony cells immunopositive for IL-5 at baseline (p 0.007), but had no effect on the percentage Eo/B colony cells immunopositive for GM-CSF at baseline (p 0.63) (Figure 3). There was a significant allergen-induced increase in the percentage Eo/B colony cells immunopositive for GM-CSF (p 0.01), which was significantly suppressed by budesonide (p 0.01) (Figure 3). There was no effect of allergen on the percentage Eo/B colony cells immunopositive for IL-5 (p 0.05). DISCUSSION This study has confirmed previous observations showing that when subjects with atopic asthma are challenged with high dose allergen inhalation resulting in a dual airway asthmatic response, airway hyperresponsiveness, and inflammation, there are associated increases in circulating eosinophils and Eo/B progenitors grown in the presence of GM-CSF (9, 10), and enhanced expression of GM-CSF by Eo/B colony cells (10). In addition, the study demonstrated down-regulation of allergeninduced peripheral blood Eo/B progenitor responses by the inhaled glucocorticoid, budesonide, and examines a possible mechanism underlying this effect. Allergen-induced increases in peripheral blood progenitors most likely occur as a consequence of allergen-induced elaboration of hematopoietic signals acting on bone marrow progenitors (24). The number of bone marrow Eo/B CFU responsive to both GM-CSF and IL-5, as well as CD34 progenitors expressing receptors for these cytokines, have previously been shown to increase after allergen inhalation challenge (11, 17, 25). Levels of myeloid (eosinophil or neutrophil) progenitors in the peripheral blood and bone marrow can be shown to be enhanced at a time after release of systemic or local hemopoietins or chemokines (24, 26, 27), suggesting that allergen-induced increases in airway levels of hemopoietins and, in particular, the C C chemokine eotaxin, may play an important role in the mobilization of progenitors from the bone marrow into the circulation, and their subsequent differentiation. We have shown a higher number of GM-CSF-stimulated, but not IL-5 or IL-3- stimulated peripheral blood Eo/B CFU following allergen challenge compared with before challenge. GM-CSF may therefore be an important growth factor for stimulation of the peripheral blood compartment of eosinophil progenitors in allergic eosinophilia. By contrast, bone marrow eosinophil progenitors are more responsive to IL-5 than to GM-CSF or IL-3 after allergen challenge (11). This suggests that IL-5 may be an important feedback signal between the airway and the bone marrow compartment, needed for acute expansion and/or mobilization of eosinophil progenitors from the bone marrow. Indeed, recent studies have shown a cooperative role for IL-5 and eotaxin in this regard (27). It is possible that progenitors that have migrated from the bone marrow compartment into circulation after allergen challenge may no longer be responsive to IL-5 but acquire or maintain responsiveness to GM-CSF. Studies of specific cytokine receptors and the kinetics of their appearance on eosinophil progenitors in different compartments may help clarify this. Eosinophil progenitors may also be capable of autoregulation through expression of growth factors (4). We have demonstrated that peripheral blood eosinophil progenitor-derived colony cells (i.e., differentiating eosinophils) synthesize both GM-CSF and IL-5, and that the expression ex vivo of GM- CSF in these cells is enhanced following in vivo allergen inhalation challenge (10). Other immunoregulatory cytokines and chemokines, such as IL-4 and RANTES, have recently been demonstrated in the granules of differentiating eosinophils (28). The GM-CSF in these eosinophils may, in an autocrine fashion, stimulate further proliferation and differentiation of eosinophil progenitors. Both IL-5 and GM-CSF can be detected at the mrna level at sites of allergic inflammation (26, 29 31), supporting a microenvironmental differentiation hypothesis of allergic inflammation; local (in the marrow or airway) generation of GM-CSF and/or IL-5 could contribute to the hematopoietic inductive environment (HIM), and influence both bone marrow and tissue progenitors (32, 33), and thus differentiation of lineage-committed progenitors (34). The increased expression of IL-5 observed following budesonide treatment may be the result of a steroid-induced TH2 shift, which has been reported in CD4 T lymphocytes (35). Budesonide has been reported to regulate the production of proinflammatory cytokines in alveolar macrophages of subjects with mild asthma (36), and therefore may also regulate production of proinflammatory cytokines by other cells. The present study has demonstrated that the allergen-induced increase in the expression of GM-CSF by peripheral blood Eo/B colony cells is inhibited by budesonide, which may contribute to down-regulation of eosinophil differentiation and proliferation. Whether this is a direct inhibitory effect on the progenitor, or a secondary effect by inhibition of another cell type needs to be further studied. It is possible that budesonide could be regulating the HIM by inhibiting the production of hematopoietic growth factors by structural cells known to support Eo/B colony growth (37) or by T cells in the airway or bone marrow itself (26). We have demonstrated that 7 8 d treatment with a low dose of the inhaled steroid, budesonide, effectively inhibits the allergen-induced increases in circulating levels of eosinophils and their progenitors. The results of this study support the previous observation that resolution of asthma exacerbations

5 Gauvreau, Wood, Sehmi, et al.: Budesonide and Eosinophil Progenitors 2143 with inhaled corticosteroid is accompanied by reduced levels of circulating eosinophils and Eo/B CFU and that withdrawal of inhaled steroids leads to an immediate rise in these progenitors in blood (7, 9). There are several sites where budesonide may act that would result in suppression of allergen-induced eosinophil progenitors, including production of growth factors in the airway, or activation and migration of eosinophil progenitors in the blood and bone marrow compartments. Budesonide may suppress Eo/B CFU levels in peripheral blood by downregulating the expression of the hematopoietic factor(s) produced in the airways following allergen inhalation. Studies of allergic dogs have demonstrated evidence for a serum hematopoietic factor that regulates allergen-induced increases in bone marrow granulocyte progenitors (24). Corticosteroids have been found to suppress allergen-induced levels of GM-CSF and IL-5 in nasal secretions (38), with inhibition of the eosinophil-promoting effects of epithelial-derived GM- CSF (14). Inhibiting production of these stimulatory growth factory may suppress migration and differentiation of progenitors from bone marrow and peripheral blood. Early studies from our laboratory used a dog model of allergen-induced airway hyperresponsiveness to demonstrate an effect of budesonide on bone marrow progenitor cells both in vivo (39) and in vitro (40), suggesting the bone marrow could be an important target for regulation of the allergen-induced hematopoietic response. Wood and coworkers (17) have recently reported that inhaled budesonide suppressed baseline levels of bone marrow Eo/B CFU grown from donors with asthma, confirming glucocorticoids have a suppressive effect on human bone marrow eosinophil progenitors. In this same study, however, budesonide did not prevent the allergeninduced increase in bone marrow Eo/B CFU. This is in contrast to the effects of budesonide in the present study on peripheral blood eosinophil progenitors, where baseline levels of peripheral blood Eo/B CFU remained unaffected by budesonide treatment, but the allergen-induced increase of progenitors grown in the presence of GM-CSF was suppressed. Budesonide may therefore prevent the allergen-induced release of bone marrow cells into the peripheral blood compartment, which has previously been shown in a murine model (41). That we observe attenuation of allergen-induced Eo/B CFU in the peripheral blood following allergen challenge but not in the bone marrow suggests that eosinophil progenitor expansion continues in the bone marrow compartment despite the levels of corticosteroids achieved in the latter. A specific effect of budesonide treatment on factors that are elevated in the blood of individuals with asthma (42) and contribute to the migration of eosinophils progenitors from the bone marrow into the peripheral blood, for example, eotaxin (27), is a candidate mechanism that needs to be explored. This study demonstrates protective effects of inhaled budesonide on allergen-induced airway eosinophilia, which are accompanied by inhibition of allergen-induced levels of circulating eosinophils and their progenitors grown in the presence of GM-CSF. Regulation of allergen-induced increases in circulating eosinophil progenitors by budesonide may occur as a result of several events. Suppression of hematopoietic or chemokinetic signals generated in the airway may reduce proliferation/ differentiation and alter migration of eosinophil progenitors from the bone marrow into the circulation. Budesonide may also regulate eosinophil progenitor proliferation by regulating their expression of and sensitivity to the hematopoietic growth factor GM-CSF. Down-regulation of eosinophil hematopoiesis at multiple regulatory sites by glucocorticoids may be a strategy providing effective control of allergen-induced eosinophilia. References 1. Aalbers R, Kauffman HF, Vrugt B, Keoter GH, De Monchy JGR. Allergen-induced recruitment of inflammatory cells in lavage 3 and 24h after challenge in allergic asthmatic lungs. Chest 1993;103: Gauvreau GM, Doctor J, Watson RM, Jordana M, O Byrne PM. Effects of inhaled budesonide on allergen-induced airway responses and airway inflammation. Am J Respir Crit Care Med 1996;154: Denburg JA, Telizyn S, Messner H, Jamal BLN, Ackerman SJ, Gleich GJ, Bienenstock J. Heterogeneity of human peripheral blood eosinophil-type colonies: evidence for a common basophil-eosinophil progenitor. Blood 1985;66: Boyce JA, Friend D, Masumoto R, Austen KF, Owen WF. Differentiation in vitro of hybrid eosinophil/basophil granulocytes: autocrine function of an eosinophil developmental intermediate. J Exp Med 1995;182: Denburg JA, Telizyn S, Belda A, Dolovich J, Bienenstock J. Increased numbers of circulating basophil progenitors in atopic patients. J Allergy Clin Immunol 1985;76: Sehmi R, Howie K, Sutherland DR, Schragge W, O Byrne PM, Denburg JA. Increased levels of CD34 hemopoietic progenitor cells in atopic subjects. Am J Respir Cell Mol Biol 1996;15: Gibson PG, Dolovich J, Girgis-Girbado A, Morris M, Anderson M, Hargreave FE, Denburg JA. The inflammatory response in asthma exacerbation: changes in circulating eosinophils, basophils and their progenitors. Clin Exp Allergy 1990;76: Otsuka H, Dolovich J, Befus D, Telizyn S, Bienenstock J, Denburg JA. Basophilic cell progenitors, nasal metachromatic cells, and peripheral blood basophils in ragweed-allergic patients. 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