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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Although eotaxin causes selective infiltration of eosinophils into the lung, its role in airway hyperresponsiveness remains unclear. We studied the effects of local administration of eotaxin on airway inflammation and hyperresponsiveness in guinea pigs in vivo. Airway responsiveness to inhaled histamine and differential cell counts in bronchoalveolar lavage fluid (BALF) were evaluated 12 h, 24 h, 3 d, and 7 d after intratracheal instillation of eotaxin. Significant eosinophilia in BALF was observed between 6 h and 7 d after eotaxin administration. Histologically, eosinophil accumulation was observed in the airways but not in the alveoli. In contrast, eotaxin did not affect airway responsiveness between 12 h and 7 d after its administration. We then studied the effects on airway responsiveness of subthreshold doses of interleukin 5, leukotriene D4 (LTD4), and platelet-activating factor (PAF) combined with eotaxin. Neither interleukin 5 nor LTD4 affected airway responsiveness. After eotaxin treatment, PAF significantly enhanced airway responsiveness without further increases in eosinophil counts. Eotaxin plus PAF significantly increased in eosinophil peroxidase activity in BALF compared with control and with eotaxin alone. These data indicate that eotaxin alone causes eosinophil accumulation in the airways but not hyperresponsiveness, and that additional factors such as PAF are needed to activate eosinophils for the development of airway hyperresponsiveness.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Airway hyperresponsiveness and eosinophilic airway inflammation are characteristic features of asthma (1, 2). The precise mechanisms of inflammatory cell accumulation and hyperresponsiveness are unknown but are considered to be dependent on the generation of various inflammatory mediators including prostaglandins, leukotrienes, and cytokines (3). The recruitment of eosinophils into sites of airway inflammation is a complex process that potentially is regulated by various chemokines including eotaxin.
Eotaxin is a C-C chemokine purified from the bronchoalveolar lavage fluid (BALF) of actively sensitized guinea pigs after aerosol allergen challenge (4), and it has been cloned in guinea pigs (5), mice (6), and humans (7, 8). Eotaxin is a potent eosinophil chemoattractant in the lung and skin (4, 9). Eotaxin couples with C-C chemokine receptor 3 (CCR3) expressed on eosinophils, causing a selective recruitment of eosinophils to the sites of inflammation (8, 12, 13). Eotaxin is expressed on bronchial epithelial cells, T lymphocytes, macrophages, and eosinophils in individuals with asthma (14, 15). It has been suggested that its increased production in response to antigen stimulation may play a key role in regulating eosinophil accumulation at the site of inflammation (16). However, its effects on airway inflammation and hyperresponsiveness are not fully understood. Therefore, we studied the effects of eotaxin on airway inflammation and hyperresponsiveness in guinea pigs in vivo.
Here we report that eotaxin causes accumulation of eosinophils in the airways, but it does not induce airway hyperresponsiveness. On the basis of these results, we hypothesized that other factors that activate eosinophils, such as platelet- activating factor (PAF) (17, 18), interleukin 5 (IL-5) (19, 20), or leukotriene D4 (LTD4) (21), might be involved in the development of airway hyperresponsiveness after eotaxin-induced local accumulation of eosinophils. We show that PAF, but not IL-5 or LTD4, is able to cause airway hyperresponsiveness after eotaxin-induced airway eosinophilia.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Animal Experiments
Experimental protocol 1. Two groups (n = 8 for each group) of male
Hartley-strain guinea pigs (450 to 550 g) were used in this protocol. The
control group received an intratracheal instillation of vehicle solution.
The experimental group received an intratracheal instillation of human
eotaxin solution (10
10 to 106 M, 200 µl). Human eotaxin was generated
as described previously (8). Eotaxin was dissolved in Hanks' balanced
salt solution (HBSS) with 0.1% bovine serum albumin (BSA); 0.1%
BSA in HBSS was used as vehicle. Animals were anesthetized with diethyl ether and instilled intratracheally with vehicle or eotaxin solution. Twelve hours, 24 h, 3 d, and 7 d after instillation, measurement of airway
responsiveness to histamine aerosol, bronchoalveolar lavage (BAL), and
histological assessment of airway and lung tissues were performed.
To examine the interaction between eotaxin and IL-5, LTD4, and
PAF, the highest dose of each factor that did not affect airway responsiveness (subthreshold dose) was used in combination with eotaxin. In
the preliminary dose-ranging studies, IL-5 (108 or 107 M in each animal) was administered by instillation and airway responsiveness to
inhaled histamine was measured 24 h after treatment. LTD4 (1010,
109, 108, or 107 M) or PAF (0.5, 5, or 50 ng/ml) was administered
by inhalation and airway responsiveness was measured 30 min after
inhalation. From these dose-ranging studies, IL-5 at 107 M, LTD4 at
107 M, and PAF at 50 ng/ml increased airway responsiveness compared with control (n = 2 to 4). Each subthreshold dose (108 M IL-5,
108 M LTD4, or PAF at 5 ng/ml) did not affect airway responsiveness and eosinophil counts in BALF. On the basis of these studies, we used 108 M IL-5, 108 M LTD4, and PAF at 5 ng/ml to examine
the interaction with eotaxin.
Experimental protocol 2. To examine the interaction between eotaxin and IL-5, we tested four groups (n = 5 for each group) of guinea
pigs with (1) an intratracheal instillation of vehicle solution (control),
(2) an intratracheal instillation of IL-5 (108 M, 200 µl), (3) an intratracheal instillation of eotaxin (108 M), or (4) an intratracheal instillation of both IL-5 and eotaxin. Twenty-four hours after treatment,
airway responsiveness was measured, and BAL fluid was collected.
Experimental protocol 3. To study the interaction between eotaxin
and LTD4 or PAF, we used six groups (n = 5 or 6 for each group) of
guinea pigs treated with (1) an intratracheal instillation of vehicle solution and inhalation of saline (control), (2) an intratracheal instillation of vehicle solution and inhalation of LTD4 (108 M), (3) an intratracheal instillation of vehicle solution and inhalation of PAF (5 ng/
ml), (4) an intratracheal instillation of eotaxin (108 M) and inhalation
of saline, (5) an intratracheal instillation of eotaxin and inhalation of
LTD4, or (6) an intratracheal instillation of eotaxin and inhalation of
PAF. Inhalation of LTD4 or PAF was performed 24 h after instillation
of eotaxin. Thirty minutes after inhalation, airway responsiveness was
measured, and BAL fluid was collected.
Eotaxin and IL-5 were dissolved in HBSS with 0.1% BSA; 0.1% BSA in HBSS was used as vehicle. LTD4 and PAF were dissolved in saline for inhalation.
Measurement of airway responsiveness. Airway responsiveness to inhaled histamine was assessed as previously described (22). Animals were anesthetized with sodium pentobarbital (50 mg/kg, intraperitoneal), and the trachea was cannulated via tracheostomy. The animals were then ventilated mechanically with a respirator (7 ml/kg tidal volume, 60 breaths/min) (model 680; Harvard Apparatus, South Natick, MA). The animals were placed supine in a body plethysmograph. Plethysmograph airflow was measured with a Fleisch pneumotachograph (TV-132T; Nihon Kohden, Tokyo, Japan) and a differential pressure transducer (TP-602T; Nihon Kohden). To evaluate pleural pressure, a fluid-filled catheter was introduced into the esophagus so that the maximal amplitude of pressure was obtained. Transpulmonary pressure was estimated from the difference between pleural and airway opening pressures, as measured by a differential pressure transducer (TP-603T; Nihon Kohden). Total pulmonary resistance (RL) was calculated from the transpulmonary pressure and plethysmograph airflow. Airway responsiveness was assessed by changes in RL after inhalation of increasing concentrations of histamine (0.017 to 5.0 mg/ml). Histamine aerosols were generated by an ultrasonic nebulizer (20 µl/min, output at the port of the tracheal cannula) (TUR-3200; Nihon Kohden) placed in line with the ventilator. The provocative concentration of histamine aerosol (PC200) was the concentration required to increase RL to 200% of its baseline value, and it was calculated by log-linear interpolation from individual animals. A decrease in PC200 represented an increase in airway responsiveness.
Bronchoalveolar lavage. Guinea pigs were killed with an overdose of pentobarbital, and BAL was performed as previously described (22). Both lungs were gently lavaged three times with 0.9% saline at a pressure of 25 cm H2O via the tracheal cannula. Total cell counts were determined by light microscopy, using a standard hemacytometer. The lavage fluid was centrifuged at 800 rpm for 5 min at 4° C. The cell pellet was resuspended in saline, and cytospin preparations (Cytospin 3; Shandon, Pittsburgh, PA) were made. Differential counts on 200 cells were performed by light microscopy, using a single-blind method after application of a modified Wright-Giemsa stain (Diff-Quik; Baxter, McGaw Park, IL).
Histological assessment. Twenty-four hours after instillation of eotaxin, the lungs were removed, fixed in 10% formalin under 25 cm H2O for 24 h at 4° C, embedded in paraffin, sectioned at 3 µm, and stained with hematoxylin and eosin. Eosinophil accumulations in the airway and lung tissues were evaluated by light microscopy.
Eosinophil peroxidase activity. The eosinophil peroxidase (EPO) activity in the supernatant of BALF was measured as described previously (23), which is based on the oxidation of o-phenylenediamine (OPD) by EPO in the presence of hydrogen peroxide (H2O2). The substrate solution consisted of 10 mM OPD in 0.05 M Tris-HCl buffer (pH 8) and 4 mM H2O2. Substrate solution (100 µl) was added to BAL supernatant samples (50 µl) in a 96-well microplate and incubated at room temperature for 30 min before stopping the reaction by addition of 50 µl of 4 M sulfuric acid. The absorbance was then measured at 490 nm with an ImmunoMIni NJ-2300 (System Instrumental, Tokyo, Japan). Duplicate incubations were carried out in the absence or presence of the EPO inhibitor 3-amino-1,2,4-triazole (AMT, 2 mM). Serial dilutions of horseradish peroxidase (200 ng/ml) were used to quantitate the amount of peroxidase in the samples. Results are expressed as nanograms of peroxidase activity per milliliter and were corrected for the activity of other peroxidases that were not inhibitable by AMT.
In Vitro Chemotaxis and Intracellular Ca2+ Concentration in Eosinophils
Because human eotaxin was used in these experiments, we examined in vitro chemotaxis and intracellular Ca2+ concentration of guinea pig eosinophils after eotaxin administration to confirm that these cells were responsive to the human protein.
Guinea pig eosinophils were obtained as reported previously (24). Briefly, 2 ml of horse serum was injected intraperitoneally into guinea pigs twice each week for 2 wk. Twenty-four hours after the final injection, 100 ml of saline was administered intraperitoneally and collected. Eosinophils in the peritoneal lavage fluid were purified over a discontinuous Percoll gradient to yield eosinophil preparations of 95 to 100% purity.
In vitro chemotaxis was performed with a 96-well chamber (MBB
96; NeuroProbe, Gaithersburg, MD) and migrated cells were measured with a fluorescence-based assay (25). Calcein AM (5 µg/ml) was added to eosinophil suspension and cells were incubated for 30 min at
37° C. Eosinophils were washed twice with phosphate-buffered saline
(PBS), counted, and resuspended in RPMI. The bottom wells in the
microplate were filled with human eotaxin solution (1011 to 106 M,
30 µl) diluted in PBS with 0.1% BSA. To determine the total fluorescence of the eosinophils added to the origin side of the filter, cell suspension was placed directly in three wells in the bottom chamber. A
standard 5-µm pore polycarbonate filter (PRD 5/A; NeuroProbe) was
positioned on the loaded microplate. Eosinophils (1.0 × 106 cells/ml,
40 µl) were placed directly onto the filter sites and the chamber was
incubated for 30 min (37° C and 5% CO2). The nonmigrated cells on
the origin side of the filter were removed by gently wiping the filter.
The chemotaxis chamber was placed in a multiwell fluorescence plate
reader (CytoFluor II; PerSeptive Biosystems, Framingham, MA) and
cells that migrate into the bottom chamber were measured by the calcein fluorescence signal (excitation, 450 nm; emission, 530 nm). Eosinophil migration was expressed as the percentage of total cells placed.
Intracellular Ca2+ concentrations in guinea pig eosinophils were measured with an Attofluor digital fluorescence microscopy system (Atto Instruments, Rockville, MD). Eosinophils were loaded with Fura-2 by incubating with Fura-2/AM (Dojindo, Kumamoto, Japan) for 20 min at room
temperature and then for an additional 20 min at 37° C. Extra Fura-2/AM
was removed by centrifugation. The Fura-2-loaded cells were placed in a
chamber of 0.5-ml volume and mounted on an inverted microscope
(Axiovert135; Carl Zeiss GmbH, Jena, Germany). Fura-2 was excited at
two different wavelengths (340 and 380 nm), and the Fura-2 fluorescence
images emitted at 510 nm were recorded with a rewritable optical disk recorder (LQ-4100A; Panasonic, Osaka, Japan) at a rate of approximately
1 Hz. Human eotaxin (107 M) in Ca2+-free Krebs solution (132.2 mM
NaCl, 5.9 mM KCl, 1.2 mM MgCl2, 11.5 mM glucose, 11.5 mM HEPES-
NaOH, and 0.92 mM EGTA-Na) was then applied to the eosinophils. Fluorescence images were used to calculate fluorescence ratios individually
for each cell, and the ratio (R) was converted into apparent Ca2+ concentration with the equation [Ca2+]i = Keff · (R 
Rmin)/(Rmax R), where
Keff is the effective binding constant, Rmin is the fluorescence ratio at zero
calcium, and Rmax is the fluorescence ratio at high Ca2+. All experiments
were performed at room temperature (20 to 25° C).
Reagents
Sodium pentobarbital was purchased from Abbott (North Chicago, IL). BSA, horse serum, histamine dihydrochloride, and PAF were from Sigma (St. Louis, MO). HBSS was from GIBCO-BRL (Grand Island, NY). LTD4 was from Salford Ultrafine Chemicals and Research (Manchester, UK). IL-5 was from Biosource International (Camarillo, CA). Percoll was from Pharmacia Biotech AB (Uppsala, Sweden). OPD, H2O2, AMT, and horseradish peroxidase were from Wako Pure Chemical Industries (Osaka, Japan). Calcein AM was from Molecular Probes (Eugene, OR).
Statistical Analysis
PC200 values are expressed as geometric means and standard errors (GSEM), and other data are expressed as arithmetic means ± SEM. The effects of eotaxin on PC200 values and BALF cell counts were compared by analysis of variance (ANOVA), and the significance of differences between values was assessed with the Bonferroni correction for multiple comparisons. p Values of less than 0.05 were considered significant.
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RESULTS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Effect of Eotaxin on Airway Eosinophil Infiltration and Responsiveness
Intratracheal administration of eotaxin caused significant, dose-dependent increases in eosinophil counts in BALF 24 h after instillation (Figures 1A). The effect of eotaxin reached a plateau at 108 M, and eosinophil counts remained at high levels
for at least 7 d after instillation (Figure 1A and 1B). Histologically, eosinophil accumulation was observed predominantly in
the trachea and the bronchi but not in the alveoli 24 h after instillation of eotaxin. The effect of eotaxin was selective for eosinophils, as shown in Table 1. Despite eosinophil accumulation
in the airways, airway responsiveness to inhaled histamine was
not affected between 12 h and 7 d after instillation of eotaxin
(Figure 2). There were no significant differences in baseline values of RL between groups. Because eotaxin-induced eosinophil accumulation was maximal at 24 h after instillation, airway
responses to histamine were assessed from this time point to examine the interaction between eotaxin and other mediators.
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Effect of Eotaxin and IL-5 on Airway Eosinophil Infiltration and Responsiveness
Instillation of a subthreshold dose of IL-5 alone did not affect either airway responsiveness or eosinophil counts in BALF. Simultaneous instillation of IL-5 and eotaxin caused eosinophil accumulation in BALF, the level of which was not significantly different from that observed with eotaxin alone (Figure 3A). Simultaneous instillation of IL-5 and eotaxin did not change the number of macrophages, neutrophils, and lymphocytes in BALF compared with eotaxin alone. There were no significant differences in baseline values of RL between groups. IL-5 plus eotaxin instillation did not significantly affect the PC200 value compared with vehicle instillation alone (Figure 3B).
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Effects of Eotaxin and LTD4 or PAF on Airway Eosinophil Infiltration and Responsiveness
Significant eosinophil accumulation in BALF was observed after eotaxin instillation with or without LTD4 inhalation but not after LTD4 inhalation alone. Eosinophil counts for LTD4 inhalation after eotaxin administration were not increased when compared with counts for saline inhalation after eotaxin administration (Figure 4A). There were no significant differences in the number of macrophages, neutrophils, and lymphocytes in BALF between the group inhaling LTD4 after eotaxin instillation and the group receiving eotaxin alone. There were no significant differences in baseline RL values between groups. LTD4 inhalation after eotaxin instillation did not affect PC200 values compared with instillation of saline or eotaxin alone (Figure 4B).
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Significant eosinophil accumulation in BALF was observed after eotaxin instillation with or without PAF inhalation but not after vehicle instillation with PAF inhalation. Eosinophil counts were not significantly increased with PAF inhalation after eotaxin instillation in comparison with those inhaling saline after eotaxin instillation (Figure 5A). After PAF plus eotaxin, the number of macrophages, neutrophils, and lymphocytes in BALF were not significantly different from that observed with eotaxin alone. Histologically, eosinophils were observed frequently in the mucosa of the airways after eotaxin instillation with or without PAF. In contrast, eosinophils were scarce in the alveoli of animals with eotaxin alone and with eotaxin plus PAF. However, inhalation of PAF after instillation of eotaxin significantly decreased PC200 values in comparison with saline inhalation after eotaxin instillation (Figure 5B).
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Eotaxin instillation alone induced airway eosinophilia but did not enhance EPO activity. After eotaxin instillation plus PAF inhalation, EPO activity was increased significantly compared with control and with eotaxin instillation alone (Figure 6).
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In Vitro Chemotaxis and Intracellular Ca2+ Concentration
To confirm that human eotaxin can stimulate guinea pig eosinophils, in vitro chemotaxis and intracellular Ca2+ concentrations in guinea pig eosinophils were measured. Human eotaxin
(109 to 106 M) had potent chemotactic activity for guinea pig
eosinophils. The concentration dependence produced a characteristic bell-shaped profile (Figure 7A). Human eotaxin transiently
induced a marked elevation of intracellular Ca2+ concentration
(Figure 7B).
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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In this study, we demonstrated that eotaxin induces eosinophil infiltration in the airways but not hyperresponsiveness in guinea pigs in vivo. We also demonstrated that PAF, but not IL-5 or LTD4, causes airway hyperresponsiveness after eotaxin-induced local eosinophil accumulation. These findings suggest that eotaxin and PAF play an important role in the development of eosinophilic airway inflammation and airway hyperresponsiveness in vivo.
Intratracheal instillation of eotaxin increased eosinophil counts in BALF. Histologically, eosinophils were observed predominantly in the airways, but not in the alveoli, which indicates that the effects of eotaxin are localized to the airways where it is administered. This observation is consistent with previous reports (9, 10).
Despite eosinophil accumulation in the airways caused by eotaxin, airway hyperresponsiveness did not occur. This observation suggests that eotaxin may function only as chemotactic factor for eosinophils and that other factors are needed to activate accumulated eosinophils and to cause airway hyperresponsiveness. To evaluate this possibility, we assessed the interaction between eotaxin and other factors that may be linked to eosinophilic inflammation and airway hyperresponsiveness.
In previous studies, it has been shown that PAF causes airway inflammation and hyperresponsiveness through recruitment of eosinophils (17, 18). PAF, as well as eotaxin, induces migration of eosinophils through the basement membrane in the presence of IL-5 (26). It has also been shown that PAF activates eosinophils (27). In the present study, inhalation of PAF developed airway hyperresponsiveness after eotaxin- induced eosinophil accumulation. EPO activity in BALF was significantly increased after eotaxin instillation and PAF inhalation but not after eotaxin alone. These results suggest that the development of airway hyperresponsiveness by inhalation of subthreshold dose of PAF occurs through activation of recruited eosinophils after eotaxin in our model.
IL-5 causes eosinophil accumulation, activation, and airway hyperresponsiveness (19, 20). We used a subthreshold dose of IL-5 to examine the interaction between IL-5 and eotaxin, but IL-5 did not cause airway hyperresponsiveness even when combined with eotaxin. It has been reported that intravenous administration of IL-5 causes recruitment of eosinophils from bone marrow into circulating blood (28), and this markedly enhances eotaxin-induced eosinophil accumulation in the skin of guinea pigs (11, 28, 29). In the present study, however, IL-5 did not enhance eotaxin-induced eosinophil accumulation. These observations suggest that the failure to enhance eotaxin-induced eosinophilia and to develop airway hyperresponsiveness after simultaneous administration of IL-5 and eotaxin may be due to the intratracheal administration of IL-5. Thus, systemic administration of IL-5 with local administration of eotaxin may activate eosinophils and may lead to airway hyperresponsiveness.
LTD4, which has been shown to be produced by asthmatic lung tissues in vitro (30) and in vivo (31), is one of the most potent bronchoconstrictors (32). It was reported that inhalation of LTD4 induces eosinophil recruitment to the airway (21). In the present study, however, inhalation of the subthreshold dose of LTD4 after eotaxin did not lead to either airway hyperresponsiveness or enhanced eosinophil accumulation. These results suggest that LTD4 does not directly activate eosinophils despite its various physiological actions.
Eosinophil accumulation after eotaxin administration was maintained for at least 7 d. It has been reported that eotaxin induces rapid accumulation of eosinophils, and the duration of action in vitro is short (8). The reason for the prolonged local eosinophilia after eotaxin instillation is not clear. It is possible that locally accumulated eosinophils in the airways are prevented from apoptosis. Another possibility is that recruited eosinophils release PAF or another eotaxin that promotes further accumulation of eosinophils.
Human eotaxin was instilled into guinea pig trachea in the present study. Eotaxin interacts with its specific receptor CCR3. At the amino acid level, human eotaxin is 61.8% identical to guinea pig eotaxin (7). We confirmed that human eotaxin stimulates guinea pig eosinophils by measuring the in vitro chemotactic response and the intracellular Ca2+ concentration in guinea pig eosinophils after application of human eotaxin. The dose-response profile of in vitro chemotaxis is similar to that found for human eotaxin acting on human eosinophils. Intracellular Ca2+ concentrations were significantly elevated immediately after administration of human eotaxin to guinea pig eosinophils.
In the present study, animals treated with vehicle or eotaxin demonstrated high levels of neutrophil counts in BALF compared with untreated animals (3.0 ± 1.9% of total cells). Neutrophils were increased in all groups and the differences among the groups were only in eosinophil counts. Therefore, it is considered that neutrophilia is due to nonspecific inflammation associated with the procedure of intratracheal instillation and that neutrophils did not influence airway hyperresponsiveness observed in this study.
The clinical relevance of the PAF results in this study is still unclear. However, PAF causes eosinophilic airway infiltration and hyperresponsiveness in humans (33, 34). It has also been reported that a PAF antagonist suppresses airway hyperresponsiveness in patients with asthma (35). Taken together, these findings suggest an important role for PAF in bronchial asthma.
In conclusion, we show that eotaxin causes eosinophil recruitment into the airways but not airway hyperresponsiveness. These data suggest that other factors, such as PAF, are needed for activation of recruited eosinophils and development of airway hyperresponsiveness. Further studies of eosinophilic airway inflammation induced by eotaxin and PAF may clarify the precise mechanisms of bronchial asthma.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Hisamichi Aizawa, M.D., Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: aizawah{at}fukuokae.hosp.go.jp
(Received in original form May 11, 1999 and in revised form October 25, 1999).
* Present address: Clinical Research Center, Fukuoka-higashi National Hospital, 1-1-1 Chidori, Koga 811-3195, Japan.
Present address: Department of Bacteriology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
Acknowlegement :
Acknowledgments: The authors thank Dr. Hironori Sagara of Dokkyo University School of Medicine for technical assistance.
Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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