Late-phase Asthmatic Reaction to Inhaled Allergen Is Associated with Early Recruitment of Eosinophils in the Airways1-3

GIOVANNI A. ROSSI, EMANUELE CRIMI, SABINA LANTERO, PIERO GIANIORIO, SUSANNA ODDERA, PAOLO CRIMI, and VITO BRUSASCO

T he

Introduction

late-phase asthmatic response (LAR) to an allergen is associated with airways inflammation (1-3). Studies performed with inhalation or local instillation of allergens have shown a collection of inflammatory cellsin the airways comprised of polymorphonuclear leukocytes in the first hours after challenge; later, a mild increase in the proportion of lymphocytes was observed (4-8). De Monchy and colleagues (4) demonstrated that an increased number of eosinophils and increased levels of eosinophil-derived cationic protein were present 6 h after allergen inhalation challenge in the bronchoalveolar lavage (BAL) fluid of patients with LAR but not in patients without LAR. Diaz and coworkers (8), in a similar group of patients, provided evidence of an increased number of bronchoalveolar lavagelymphocytes and neutrophils, in addition to eosinophils, during the late-phase response. Based on the observation that eosinophils were also increased after allergen challenge in the BAL of most patients with a single earlyphase response, these authors suggested that the accumulation of eosinophils may not be the only prerequisite for the development of the late-phase response. In planning this study, wehypothesized that the development of the late-phase response may depend not only on the type of cell recruited in the airways but also on the intensity and/or the time at which this recruitment occurs. To verify this hypothesis we evaluated the celltypes in BAL at different times after allergen inhalation challenge in patients with or without aLAR. Methods

Patients The study was performed on 54 outpatients (52 men and 2 women), 16 to 38 yr of age, allergic to house dust mite, with a history of

SUMMARY To determine whether a link exists between the recruitment of Inflammatory cells In the airways and the development of the late-phase asthmatic reaction, we studied with bronchoalveolar lavage 54 asthmatic patients either at baseline (10 patients) or 4 h (11 patients), 24 h (13 patients), and 72 h (20 patients) after allergen Inhalation challenge. Among the patients studied 4 h after allergen challenge, five were known to have a late-phase asthmatic response and showed a significant Increase In the number and percentage of eoslnophlls In bronchoalveolar lavage compared with either patients without late-phase response (p < 0.05) or unchallenged patients (p < 0.01). Both the number and the percentage of eoslnophlls In bronchoalveolar lavage were also Increased (p < 0.05) In patients without a late-phase asthmatic reaction studied 24 h but not In those studied 4 h after allergen. challenge. The numbers and the percentages of macrophages, neutrophlls, or lymphocytes did not differ significantly among the different groups of patients. Of the patients studied 4 and 24 h after allergen challenge, only those with a late-phase asthmatic response showed an Increased airway responsiveness to methacholine 1 h before bronchoalveolar lavage. Weconclude that the development of the late-phase asthmatic response to allergen Inhalation challenge and the allergen-Induced Increase In airway responsiveness are associated with an early recruitment of eoslnophlls In the airways. AM REV RESPIR DIS 1991; 144:379-383

perennial asthma with or without rhinitis lasting for 2 yr or longer. Allergic sensitization was demonstrated by skin prick test or radioallergosorbent test. To be included in the study, all patients wererequired to be asymptomatic, not to have suffered from respiratory infections for the previous 4 wk, and to have an FEV 1 larger than 70070 of predicted (9). None of the patients took antiasthmatic treatment other than p2-stimulants on an asnecessary basis, which were discontinued at least 12 h before study. All patients were informed of the nature and the scope of the study and gave written consent. Four groups of patients were studied: 10 patients (control group) underwent BAL 1 h after recovery from a nonspecifically (methacholine) induced bronchospasm. The remaining 44 patients underwent BAL 4 h (11 patients, 4-h group), 24 h (13 patients, 24-h group), or 72 h (20 patients, 72-h group) after allergen inhalation challenge.The patients in each group were further divided into two subgroups depending on whether they did (LAR +) or did not (LAR-) develop a latephase asthmatic response either on the study day (24-h group and 72-h group) or on a preceding occasion (control group and 4-h group).

Bronchial Challenges Forced expiratory maneuvers were recorded by a wedge spirometer (Vitalograph, Ltd.,

Buckingham, UK), and the highest FEV1 from three technically acceptable maneuvers was retained for analysis. Methacholine or allergen aerosols were delivered by an ampule dosimeter device (MEFAR, Brescia, Italy) according to a method previously described (10). Control measurements of FEV 1 were determined after inhalation of saline. Methacholine challengewas started from a dose of 10 ug (methacholine chloride in saline) with twofold increments until the FEV 1 measured 1 min after inhalation was decreased below 80070 of control. The maximum dose at which methacholine challenge was stopped if patients did not respond was 5,000 ug, The provocative dose causing a 15070 fall in the FEV 1 (PD 1S ) was calculated by interpolation of the dose-responsecurves. A singledose of inhaled

(Received in original form December 12, 1990) 1 From the First Division ofPneumonology, Hospital San Martino, the Institute of Sports Medicine, School of Physiopathology, and the Institute of Hygiene, School of Community Medicine, University of Genoa, Italy. 2 Supported in part by grant Nos. 87.00560.56 and SP2 FATMAfrom the National ResearchCouncil, Rome. 3 Correspondence and requests for reprints should be addressed to Giovanni A. Rossi, M.D., Instituto Giannina Gaslini, Largo G. Gaslini, 5 16147 Genova, Italy.

379

380 salbutamol (200 J.1g) was given immediately after methacholine challenge to relievebronchospasm. Methacholine responsiveness was determined on the day before allergen challenge and, in patients in the 4-h group and the 24-h group, also 1 h before HAL. Allergen bronchial challenge was performed by using scalar solutions of Dermatophagoides pteronyssinus reconstituted from predosed (arbitrary units, AU) dried allergen (Pharmacia, Uppsala, Sweden). A 15min period was allowed between allergen inhalations and FEV I measurements. The allergen bronchial challenge was started from a dose of 4 AU, with twofold increments until FEV I fell below 80070 of control, or up to a maximum dose of 500 AU. FEV I was measured 30 and 60 min after challenge and then hourly for 8 h to detect the occurrence of the LAR defined as a decrease of 15% or more in the FEV I during the 3- to 8-h period after initial early-phase reaction. Bronchoalveolar Lavage BAL was performed as described previously (11). Patients were premedicated with intramuscular atropine (0.5 mg) and diazepam (10mg) 5 min before the procedure. After local anesthesia of the nostrils with 2% lidocaine solution followed by injection of epinephrine solution 0.1:1,000 (l ml each side), the fiberoptic bronchoscope (Olympus HF, 1YPe PI0; Lorenzatto, Turin, Italy) was passed through the nose. After local anesthesia of pharynx and airways, the tip of the instrument was wedged into a subsegmental branch of the right middle lobe. BAL was performed by infusing 100ml sterile saline, fractionated in fivealiquots of 20 mIeach, which wereaspirated at a negative pressure of 50 to 120mm Hg. HAL fluid was filtered through two layers of sterile gauze, and cells were separated from the supernatant by centrifugation at 250 x g for 5 min. A small sample of the cell suspension was used to count the number of cells per ml. The residual cell pellet was washed once and resuspended in Hanks' balanced salt solution, without Ca 2 + or Mg2+, at a concentration of 1()6 cellsper ml, Differential cell count was done using a cytocentrifuge (Cytospirr"; Shandon Southern Instruments, Sewickley, PA), spinning approximately 100,000cellsat 500 rpm for 5 min onto a glass slide. The cytocentrifuge preparations were air dried and stained with Diff-Quick'" (Merz & Dade A. G., Dudingen, Switzerland). The percentages of the different cell types were obtained by counting at least 30 cellsper slide, using a light microscope (Carl Zeiss, Oberkochen, Germany). Inhaled salbutamol (200 J.1g) was given to patients who experienced respiratory symptoms after HAL. Patients left the hospital 1 h after completion of HALwith a contact telephone number they could call at any time.

Statistical Analysis Two-factor analysis of variance (ANOVA) was used to compare differences in baseline data among patient groups and between subgroups

ROSSI, CRIMI, LANTERO, GIANIORIO, ODDERA, CRIMI, AND BRUSASCO

TABLE 1 PATIENT CHARACTERISTICS*

Subgroup Control LARLAR+ 4-h LARLAR+ 24-h LARLAR+ 72-h LARLAR+

n

Mean (Range) Age (yr)

Mean ± SEM FEV l (% predicted)

Geometric Mean MCh POlS (pg)

5 5

22 (16-25) 24 (19-27)

98 ± 1 90 ± 3

6 5

22 (18-27) 19 (18-21)

6 7 12 8

Mean ± SEM Maximum FEVl Fall (%) Early

Late

1,038 [1] 97 [0]

19 ± 3 [1] 28 ± 2 [0]

2 ± 1 31 ± 3

96 ± 4 85 ± 4

299 [0] 64 [0]

15 ± 2 [3] 29 ± 4 [0]

3±2 37 ± 3

20 (17-26) 22 (17-38)

100 ± 7 102 ± 4

596 [2] 52 [0]

20 ± 4 [2] 28 ± 2 [0]

3 ± 1 31 ± 4

23 (17-47) 23 (17-28)

101 ± 4 103 ± 4

334(3] 86 [0]

17 ± 3 [4] 36 ± 4 [1]

6 ± 1 27 ± 3

Definition of abbreviations: SEM = standard error of the mean; MCh = methacholine. * The number of patients who did not respond to the maximum doses of 5 mg methacholine or 500 arbitrary units of allergen is indicated in brackets.

TABLE 2 NUMBERS OF CELLS IN BRONCHOALVEOLAR LAVAGE*

Subgroup Control LARLAR+ 4-h LARLAR+

Mean ± SEM BAL Recovered (ml)

91 ± 2 62 ± 12

65 ± 4 61 ± 3

24-h LAA-

70 ± 3

LAR+

58 ± 4

72-h LAR-

65 ± 3

LAR+

63 ± 6

Total

Macrophages

Lymphocytes

Neutrophils

Eosinophils

87 (67-104) 54 (53-64)

75.7 (65-95) 48 (48-60)

7.4 (2-9) 4.6 (3-5)

0 (0-1) 1 (0-1)

0.6 (0-1) 0.5 (0-0.5)

229 (95-285) 129 (113-159)

221 (91-270) 120 (102-133)

4.1 (1-6) 7.4 (3-10)

0 (0-0) 0.5 (0-1)

(0-1) 4* (2.5-5)

201 (185-254) 96 (71-113)

181 (172-236) 77 (67-92)

6 (2-9) 4 (2-19)

0 (0-2.5) 0 (0-1)

5§ (2-7.7) 2 (0-4.5)

106 (50-128) 120 (77-153)

99 (47-124) 114 (61-139)

3.3 (1-5) 6 (2-12)

0.5 (0-0.5) 0.6 (0-1.5)

0.5 (0-2.5) 1.3 (0.5-1.5)

ot

* Results are expressed as 10' cellslml. median values with the range from lower to upper quartiles in parentheses.

t p < 0.05 versus 24-h group, LAR- subgroup

and versus 4-h group, LAR+ subgroup. :j: p < 0.01 versus control, LAR+subgroup. § p < 0.05 versus control, LAR- subgroup and versus 72-h group, LAR- subgroup.

with different types of bronchial response to allergen. To control the per experiment error rate, Kruskal-Wallis ANOVAwas used to assess the significance of differences in the percentage and the number of each cell type among groups. When this preliminary test was significant at the 5% level, multiple comparisons between groups were carried out by the Mann-Whitney-Wilcoxon test. P values less than 0.05 were considered statistically significant.

Results

Baseline Data The age of the patients and the baseline lung function were similar in the control

group and in the three groups that underwent allergen inhalation challenge, independently of the type of bronchial response to the allergen (table 1). Methacholine PD1S was not different among groups (p >0.05) but was significantly lower in the LAR+ subgroups compared with the LAR- subgroups (p < 0.01). The early maximum FEV 1 fall was also not different among groups (p > 0.05) but was significantly larger in the LAR + subgroups compared with the LAR- subgroups (p < 0.(01).

Bronchoalveolar Lavage Studies BAL was performed in all subjects with-

BRONCHOALVEOLAR LAVAGE, EOSINOPHILS, AND THE LATE ASTHMATIC REACTION

381

TABLE 3 PERCENTAGES OF INFLAMMATORY AND IMMUNOEFFECTOR CELLS IN BRONCHOALVEOLAR LAVAGE· Subgroup Control LARLAR+ 4-h LARLAR+ 24-h LARLAR+ 72-h LARLAR+

Macrophages

Lymphocytes

Neutrophils

Eosinophils

92 (87-97) 89 (87-91)

7.1 (2-10) 9 (6-12)

0 (0-1) 1 (1-2)

1 (0-1) 0.5 (0-1)

98t (96-98) 91 (86-93)

2 (2-3) 3 (2-11)

0 (0-0) 0.5 (0-1)

0.5:1: (0-1) 2.S§ (2-3)

93 (91-96) 92 (78-96)

3 (2-5) 3 (2-17)

0 (0-1) 0 (0-1)

211 (1-3) 3 (0.5-5)

95 (92-96.5) 91 (86.5-96)

3.5 (1-5) 7 (2-8)

0.5 (0-1) 0.5 (0-1.5)

0.5 (0-2.5) 1 (0.5-6.5)

• Results are expressed as percentage of cells, median values with the range from lower to upper quartiles in parentheses. t p < 0.01 versus 4-h group, LAR+ SUbgroup. :j: p < 0.05 versus 24-h group, LAR- subgroup and versus 4-h group, LAR+ subqroup, § p < 0.01 versus control, LAR+ subgroup. . II p < 0.05 versus control, LAR- SUbgroup.

out complications. The bacteriologic cultures of the recovered fluid were sterile in all cases except for the occasional growth of microorganisms of the oral flora. 3 Eosinophils (10 / ml)

8f sf:

8 Eosinophile (10 3 / ml)

*

LAR-

6

**

2

fi

o CON=;O;OLS

4 h

4

LAR+

BAL data, expressed as cell numbers per ml fluid recoveredand as percentages of inflammatory and immune effector cells recovered, are shown in tables 2 and 3, respectively. The total number of bron-

4

-B24 h

72 h

LAR+

7EosinoPhiis (% of SAL cells)

6

2

:ri.

o CONTROLS

4 h

24 h

72 h

LAR-

(~ of BAL ~)

5 4

3 2

o CONTROLS

**

-B4h

24 h

72 h

~~

o CONTROLS

*

B 4h

B 24 h

II 72 h

Fig. 1. Numbers (top) and percentages (bottom) of eosinophils in subgroups of patients with (LAR+)or without (LAR-) a late-phase asthmatic reaction to allergen inhalation challenge. Horizontal lines are medians; bars indicate the lower and upper quartiles. • Significantly different (p < 0.05) from all other groups.•• Significantly different (p < 0.01) from controls.

choalveolar cells recovered was not significantly different between LAR - and LAR+ subgroups (p > 0.05, all comparisons). Both the number (table 2) and the percentage (table 3) of macrophages, lymphocytes, and neutrophils weresimilar in the LAR- and in the LAR + subgroups belonging to the various groups (p > 0.05, all comparisons). In contrast, both the total numbers and the percentages of eosinophils were significantly higher in the LAR+subgroup than in the LAR- subgroup of the 4-h group (p < 0.05), but not of the control, the 24-h, or the 72-h groups (p > 0.05, all comparisons). The number and the percentage of eosinophils found in the different groups of patients with or without LAR response are shown in figure 1. Within the 4-h group, only the subgroup of patients with a late-phase response showed a significantly (p < 0.01) higher number and percentage of eosinophils than control subjects. In the LAR- subgroup of the 24-h group, both the number and the percentage of eosinophils were increased (p < 0.05)compared with control subjects and patients studied at 4 or 72 h after allergen challenge. Neither numbers nor percentages of macrophages, lymphocytes, and neutrophils showed significant differences among groups (p > 0.05,all comparisons). Airway Responsiveness The results of methacholine inhalation challenges performed 1 h before BAL studies are shown in figure 2. In the LAR+ subgroup of the 4-h group, but not in the LAR - subgroup, methacholine PD lS was significantly decreased 3 h after allergen challenge from 64 to 19 J.1g (p < 0.005). Similarly, in the LAR+ subgroup of the 24-h group, but not in the LAR - subgroup, methacholine PDIS was significantly decreased 23 h after allergen challenge from 52 to 31 J.1g (p < 0.02). Discussion

The main findings of this study, in which stable asthmatic patients were evaluated by BAL at different times after inhalation challenge with house dust mite, are that (1) the inflammatory reaction of the airways to allergen is characterized by a selective recruitment of eosinophils, and (2) the major difference in bronchial inflammatory response between patients with and patients without the late-phase reaction appears to be the time at which eosinophil accumulation in the airway lumen occurs. In our patients without a late-phase

382

'0000 Mch

ROSSI, CRIMI, LANTERO, GIANIORIO, ODDERA, CRIMI, AND BRUSASCO

Pel,. ' meg

LAR+

'0000 Mch

'000

'000

'00

'00

'0

10

'0000 Mch

Baseline

3 h post allergen

Pd,. ' meg

LAR+

----=

Baseline

'0000 Meh

LAR-

Pd,. ' meg

3 h Post allergen

LAR-

'000

'000

'00

Pel,. ' meg

=::: +s;

'0

Baseline

100

-=::::

23 h Post allergen

10

Baseline

23 h Post allergen

Fig. 2. Allergen-induced changes in methacholine (MQh) responsiveness in LAR+and LAR- subgroups of the 4-h (top) and the 24-h (bottom) groups. p < 0.005 (top left panel); p < 0.02, (bottom left panel).

response, the accumulation of eosinophils in the airway lumen was observed only 24 h after allergen challenge and was not associated with changes in methacholine sensitivity.. In contrast, in patients with LAR, the bronchial recruitment of eosinophils was already present 4 h after allergen challenge, that is, before the time at which they wereexpected to have a latephase reaction, and was associated with increased methacholine sensitivity. We could not monitor the late-phase reaction on the study day in patients evaluated 4 h after challenge because they underwent bronchoscopy and were treated with atropine and J3z-agonists. However, methacholine responsiveness after allergen challenge was increased in the subgroup known to havea late-phase response in a fashion similar to that observed in the subgroup of patients evaluated 24 h after challenge who developed LAR. Based on this observation and on previous reports (12, 13) of increased airway responsiveness preceding the development of the late-phase response, we can reasonably assume that these patients would also have developed the late-phase response on the study day. The bronchial inflammatory response that we have observed after allergen inhalation challenge appears to be similar, in many respects, to that reported by De Monchy and coworkers (4) and by Metzger and coworkers (6). These authors found that in patients known to have a

late-phase reaction the number of eosinophils after inhalation challenge (4) or the number of both eosinophils and neutrophils after local antigen deposition (6) was significantly increased in the first few hours after challenge compared with baseline values. These findings suggest that the expression of a late-phase response may result from an interaction between various types of inflammatory and immune effector cells. It is possible that in patients with a late-phase response the early recruitment of eosinophils depends on an early and intense allergen-induced stimulation of cells, such as mast cells (14)and macrophages (15), able to release specific chemotactic peptides. Eosinophils, which possess surface receptors for IgE antibodies (16), can be activated in the airways by antigen-IgE immune complexes to release a variety of products (17), including free oxygen radicals (18)highly cytotoxicto bronchial epithelial cells. Support for this hypothesis is given by the finding of higher levels of antigen-specific IgE antibodies in bronchial lavage of patients with a latephase response followinginhalation challenge (19).In a previous series of patients we have shown that the severity of the late reaction was correlated with the dose provoking the early-phase response but not with the intensity of the early reaction (10). In the present study patients with a late-phase response had more severe early-phase responses than patients

without late-phase responses. The apparent correlation observed in this series of patients between the severity of the early reaction and the occurrence of the late reaction was because in less sensitive patients the target decrease of a 20070 early fall in FEV 1 was not reached. We therefore think it unlikely that the occurrence of the late-phase response depended on the intensity of the obstructive response during the early phase. An important point that emerges from the present study is that in patients without a late-phase asthmatic response there is also an increase in the number and percentage of bronchoalveolar eosinophils, but their recruitment into the airway lumen occurs at a later time after allergen challenge.This observation confirms and extends what has been reported by Diaz and coworkers (8), who evaluated asthmatic patients 6 h after inhalation challenge and found a clear trend, although not statistically significant, for an increase in BAL eosinophils in patients without the late-phase response.The later accumulation of eosinophils in the bronchial lumen of our patients without a late-phase response was not associated with changes in methacholine responsiveness. Thus, it is possible that the bronchial recruitment of eosinophils in patients without a late-phase response occurs when the stimuli able to activate these cells, that is, immune complexes or other factors released in response to inflammatory and immune processes, are no longer present or activein the airways. In the present study, control patients underwent methacholine challenge and other patients underwent both methacholine and allergen challenge. There are no data showing whether methacholine challenge, by itself or in combination with allergen challenge, interferes with cell recruitment. We think it unlikely, however, that an effect of methacholine on BAL cells can explain the differences in the timing of eosinophil recruitment between patients with and without a latephase reaction. Recent data support a link between T lymphocyte function and the occurrence of the late-phase response to allergen (8, 20). Although we could not demonstrate any statistically significant difference in lymphocyte numbers or percentages after challenge between patients with and without LAR, we have shown in a separate report that lymphocytes migrated into the airways may contribute to the development of hyperresponsiveness (21). The lack of neutrophilic inflammation

BRONCHOALVEOLAR LAVAGE, EOSINOPHILS, AND THE LATE ASTHMATIC REACTION

in all patient subgroups that underwent allergen challengesuggeststhat these cells likely do not contribute to the bronchial response to an inhaled allergen. In conclusion, by evaluating asthmatic patients at different times after allergen inhalation challenge, we have demonstrated that the late-phase response is characterized by an early recruitment of eosinophils in the airways. The temporal association of eosinophil influx in the bronchial lumen with an increased responsiveness to methacholine supports the hypothesis of a pathogenetic role of these cells in the development of latephase bronchial obstruction in asthma. References 1. Abraham WM, Perruchoud AP, Sielczak MW, YergerLD, Stevenson JS. Airwayinflammation during antigen-induced late bronchial obstruction. Prog Respir Res 1985; 19:48-55. 2. O'Byrne PM, Dolovich J, Hargreave FE. Late asthmatic response. Am Rev Respir Dis 1987; 136:740-51. 3. Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989; 139:806-17. 4. De Monchy JGR, Kauffman HF, Venge P, et 0/. Bronchoalveolar eosinophilia during allergeninduced late-phase asthmatic reactions. Am Rev Respir Dis 1985; 131:373-6.

5. Metzger WJ, Richerson HB, Worden K, Monick M, Hunninghake GW. Bronchoalveolar lavage of allergic asthmatic patients following allergen bronchoprovocation. Chest 1986; 89:477-83. 6. Metzger WJ, Zavala D, Richerson HB, et 0/. Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs. Am Rev Respir Dis 1987; 135:433-40. 7. Fick RB Jr, Richerson HB, Zavala DC, Hunninghake GW. Bronchoalveolar lavage in allergic asthma. Am Rev Respir Dis 1987; 135:1204-9. 8. Diaz P, Gonzalez MC, Galleguillos FR, et 0/. Leukocytes and mediators in bronchoalveolar lavage during allergen-induced late-phase asthmatic reactions. Am Rev Respir Dis 1989; 139:1383-9. 9. Quanjer PH. Standardized lung function testing. Report of war king party on standardization of lung function tests - European Community for Coal and Steel. Bull Eur Physiopathol Respir 1983; 19(5uppl:I-94). 10. Crimi E, Brusasco V, Losurdo E, Crimi P. Predictive accuracy of late asthmatic reaction to Dermatophagoides pteronyssinus. J Allergy Clin Immunol 1986; 78:908-13. 11. Rossi GA, Sacco 0, Cosulich E, Risso A, Balbi B, Ravazzoni C. Helper T lymphocytes in pulmonary sarcoidosis: functional analysis of a lung T-cellsubpopulation in patients with active disease. Am Rev Respir Dis 1986; 133:1086-90. 12. Thorpe JE, Steinberg D, Bernstein IL, Murlas CG. Bronchial reactivity increases soon after the immediate response in dual responding asthmatic subjects. Chest 1987; 91:21-5. 13. Durham SR, Craddock CF, Cookson WO, Benson MK. Increases in airway responsiveness to histamine precede allergen-induced late asthmatic responses. J Allergy Clin Immunol1988; 82:764-70.

383 14. Tomioka M, Ida S, Shindoh Y, Ishihara T, Takishima T. Mast cell in bronchoalveolar lumen of patients with bronchial asthma. Am Rev Respir Dis 1984; 129:1000-5. 15. Tonnel AB, Gosset P, Joseph M, Fourier G, Capron A. Stimulation of alveolar macrophages in asthmatic patients after local provocation test. Lancet 1983; 1:1406-8. 16. Capron M. Eosinophils: receptors and mediators in hypersensitivity. Clin Exp Allergy 1989; 19(5uppl:3-8). 17. Gleich GJ, Flavahan NA, Fujisawa T, Vanhoutte PM. The eosinophils as a mediator of damage to respiratory epithelium: a model for bronchial hyperreactivity. J Allergy Clin Immuno11988; 81:776-81. 18. Rossi GA, Sacco 0, Vassallo F, et 0/. Oxidative metabolism of human peripheral blood eosinophils and neutrophils: H10 1 production after stimulation with phorbol myristate acetate and immune complexes. Eur Respir J 1989; 6(Suppl: 435-40). 19. Crimi E, Rossi GA, Lantero S, et 01. Late asthmatic response is associated with elevated concentration of specific IgE in the respiratory tract. Am Rev Respir Dis 1989; 139:A461. 20. Gonzalez C, Diaz P, Galleguillos F, Ancic P, Cromwell 0, Kay AB. Allergen-induced recruitment of bronchoalveolar helper T-eells(OKT4), and suppressor Tcells (OKT8) in asthma: relative increases in OKT8 cells in single early- compared with latephase responses. Am Rev Respir Dis 1987; 136: 600-4. 21. Brusasco V, Crimi E, Gianiorio P, Lantero S, Rossi GA. Allergen induced increase in airway responsiveness and inflammation in mild asthma. J Appl Physiol 1990; 69:2209-14.

Late-phase asthmatic reaction to inhaled allergen is associated with early recruitment of eosinophils in the airways.

To determine whether a link exists between the recruitment of inflammatory cells in the airways and the development of the late-phase asthmatic reacti...
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