Published ahead of print on March 24, 2004, doi:10.1164/rccm.200401-123OC
American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 1125-1130, (2004)
© 2004 American Thoracic Society
Role of Microvascular Permeability on Physiologic Differences in Asthma and Eosinophilic Bronchitis
Hiroshi Kanazawa,
Saeko Nomura and
Junichi Yoshikawa
Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan
Correspondence and requests for reprints should be addressed to Hiroshi Kanazawa, M.D., Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abenoku, Osaka, 545–8585, Japan. E-mail: kanazawa-h{at}med.osaka-cu.ac.jp
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ABSTRACT
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Asthma and eosinophilic bronchitis are characterized by a similar type of eosinophilic inflammation. However, eosinophilic bronchitis differs from asthma in that there is no variable airflow obstruction or airway hyperresponsiveness. We evaluated the roles of vascular endothelial growth factor (VEGF) and microvascular permeability in causing these differences between the two diseases. Inflammatory indexes in induced sputum, exhaled nitric oxide levels, and vascular permeability index were examined in 11 normal control subjects, 19 beclomethasone dipropionate (BDP)-treated subjects with asthma, 20 non–BDP-treated subjects with asthma, and 17 patients with eosinophilic bronchitis. The percentage of eosinophils in sputum and exhaled nitric oxide levels were significantly higher in non–BDP-treated subjects with asthma and patients with eosinophilic bronchitis than in other two groups; however, VEGF levels and vascular permeability index were significantly higher in non–BDP-treated (VEGF: mean; 4,710 [SD; 1,150] pg/ml, p < 0.0001; vascular permeability index: 0.028 [0.009], p < 0.0001) and BDP-treated (2,560 [1,070] pg/ml, p = 0.0002; 0.016 [0.006], p = 0.004) subjects with asthma than in patients with eosinophilic bronchitis (1,120 [800] pg/ml; 0.01 [0.005]) and normal control subjects (1,390 [1,280] pg/ml; 0.008 [0.003]). We found significant correlations between the VEGF level and the airway vascular permeability index in all patient groups. Thus, interaction between airway microcirculation and VEGF may be a key element in differences in airway function between asthma and eosinophilic bronchitis.
Key Words: airway hyperresponsiveness • microvascular leakage • sputum eosinophilia • vascular endothelial growth factor • variable airflow obstruction
Bronchial asthma is physiologically characterized by variable airflow obstruction and airway hyperresponsiveness. Pathologically, asthma is a chronic inflammatory disease of the airways in which eosinophils are prominent in sputum, bronchoalveolar lavage, and mucosal biopsy samples (1). Activated eosinophils secrete granular basic proteins that damage the bronchial epithelium and membrane-derived lipid mediators, which contract airway smooth muscle, increase mucous secretion, and cause vasodilation (2). The correlation between eosinophil numbers and disease severity supports the hypothesis that the eosinophil is the central effector cell in ongoing airway inflammation in asthma. Eosinophilic bronchitis presents with chronic cough and is characterized by sputum eosinophilia similar to that seen in asthma, but unlike asthma features, has normal spirometry, no evidence of airway hyperresponsiveness, and normal peak expiratory flow variability (3). Thus, the clinical features of eosinophilic bronchitis are distinct from those of asthma; however, the etiology of eosinophilic bronchitis and the reason for the absence of variable airflow obstruction in this disease are unknown. The extent to which sputum eosinophilia and airway hyperresponsiveness in patients with asthma are related to one another remains controversial (4). In patients with eosinophilic bronchitis, there is a clear dissociation between sputum eosinophilia and airway hyperresponsiveness (5).
We have recently emphasized that airway microcirculation has the potential to contribute to the pathophysiology of asthma (6). Plasma leakage and mucosal edema formation are features of inflammatory diseases such as asthma, which is associated with edema in the airway wall and narrowing of the airway lumen. In our earlier studies, we found that mucosal edema may have a profound effect on airway function in asthma (6, 7). It has previously been reported that increased levels of vascular endothelial growth factor (VEGF) in the airway have been implicated in the pathogenesis of asthma (8). Moreover, a previous study presented evidence that VEGF increases microvascular permeability so that plasma proteins can leak into the extravascular space, leading to mucosal edema and thereby narrow airway diameters, which could amplify the effect of airway smooth muscle contraction (9). Blood vessels in asthmatic airways are in a hypervascularized, destabilized state, and this also contributes to upregulation of airway microvascular permeability (10). Therefore, we hypothesized that there may be differences in VEGF levels and the degree of microvascular permeability within the airway walls between asthma and eosinophilic bronchitis. To test our hypothesis, we compared VEGF levels in induced sputum from normal subjects and patients with asthma or eosinophilic bronchitis and examined the contribution of airway microvascular permeability to pathophysiologic differences between the two diseases. None of the results from this study has previously been reported in the form of an abstract.
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METHODS
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Subjects
Thirty-nine patients with asthma, 17 patients with eosinophilic bronchitis, and 11 normal control subjects were included in the study. All normal control subjects were healthy, lifelong, nonsmoking volunteers who had no history of lung disease. All patients with asthma were recruited from respiratory outpatient clinics at our institution and from the staff of Osaka City University Medical School Hospital. All patients with asthma were nonsmokers and satisfied the American Thoracic Society criteria for asthma (11). In short, they all had episodic cough, wheezing, dyspnea, and normal chest roentgenography results. They also exhibited reduced FEV1 during asthma attacks and an increase of 20% or greater in FEV1 in response to a bronchodilator. Methacholine inhalation challenge testing was performed for all study subjects as we previously described (12). All challenge tests were performed at 13:00 hours to eliminate the effects of diurnal variation. After baseline spirometry and inhalation of diluent to establish the stability of FEV1, the subjects were instructed to take slow inspirations in each set of inhalations. All subjects with asthma in this study demonstrated bronchial hyperreactivity to methacholine. Twenty patients with asthma were receiving neither oral nor inhaled corticosteroids. Their regular medication consisted of the ß2-agonist salbutamol on demand and theophylline. Nineteen patients with asthma were receiving inhaled beclomethasone dipropionate (BDP, 800 µg/day) for 8 weeks (BDP-treated subjects with asthma), the ß2-agonist salbutamol on demand, and theophylline. Medications were not changed during the 1-month period preceding the study and were withdrawn for at least 12 hours before the methacholine challenge test and sputum induction. All patients with asthma were clinically stable, and none had a history of respiratory infection for at least the 4-week period preceding the study. Patients with eosinophilic bronchitis had an isolated cough, no symptoms suggesting variable airflow obstruction, normal spirometric values, normal peak expiratory flow variability (maximum within-day amplitude, a percentage mean of < 20% over 2 weeks), a provocative concentration of methacholine causing a 20% drop in FEV1 of more than 10 mg/ml, a normal chest radiograph, and a sputum eosinophilia (sputum eosinophils of > 3%) (13). No patients with eosinophilic bronchitis had received oral or inhaled corticosteroids before entry into the study. Atopy in all subjects was defined as one or more positive skin prick responses to 12 common allergens. No subjects in this study were included as subjects in our previous study. Therefore, there is no overlap in the data of this study with our previous studies (14, 15). All subjects gave their written informed consent for participation in the study, which was approved by the ethics committee of Osaka City University.
Sputum Induction and Processing
Sputum induction was performed 3 days after the methacholine challenge test. Spirometry was performed before inhalation of 200 µg of salbutamol via a metered-dose inhaler. All subjects were instructed to wash their mouth thoroughly with water. They then inhaled 3% saline at room temperature, nebulized by an ultrasonic nebulizer (NE-U12; Omron Co., Tokyo, Japan) at maximum output. They were encouraged to cough deeply after 3-minute intervals thereafter. After sputum induction, spirometry was repeated. If the FEV1 fell, the subjects were required to wait until it returned to baseline value. The sputum sample diluted with phosphate-buffered solution containing dithiothreitol (a final concentration of 1 mM) was then centrifuged at 400 g for 10 minutes, and the cell pellet was resuspended. The slides were prepared using a cytospin (Cytospin 3; Shandon, Tokyo, Japan) and stained with May-Grunwald-Giemsa stain for differential cell counts. The results of differential cell counts of sputum samples were determined as the average of findings by at least two chest physicians obtained on separate occasions in a blind manner. The supernatant was stored at –70°C for subsequent assay of eosinophil cationic protein, VEGF, and albumin. The eosinophil cationic protein concentration was measured by using a radioimmunoassay kit (Pharmacia Diagnostics, Uppsala, Sweden), and the VEGF concentration was measured with an ELISA kit (R&D system Inc., Minneapolis, MN). The minimum detectable level of VEGF in this assay system is 5.0 pg/ml. Albumin concentration was measured by laser nephelometry, and then we calculated the airway vascular permeability index (the ratio of albumin concentrations in induced sputum and serum) (6). All subjects produced an adequate specimen of sputum; a sample was considered adequate if the patient was able to expectorate at least 2 ml of sputum and if on differential cell counting the slides contained less than 10% squamous cells.
Measurement of Nitric Oxide Levels in Exhaled Air
Exhaled nitric oxide (NO) was measured for all subjects with a chemiluminescence analyzer (CLM-500; Shimazu; Kyoto, Japan) with a resolution of 1 ppb in accordance with American Thoracic Society standards (16). The response time was less than 0.6 seconds, and the sampling rate was 250 ml/minute. Single-breath, online measurements for the assessment of airway NO were performed at a constant expiratory flow of 6 L/minute for each individual. The mean value of three end-expiratory NO concentrations was calculated for each subject and expressed as ppb. The NO analyzer was calibrated before each experiment with NO-free air and known concentrations of NO in nitrogen.
Statistical Analysis
All values are presented as mean [SD]. Multiple comparisons among groups were analyzed by one-way analysis of variance followed by Bonferroni's correction. The significance of correlations was evaluated by determining Spearman rank correlation coefficients. A p value of less than 0.05 was considered significant.
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RESULTS
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Baseline pulmonary function parameters, airway hyperreactivity to methacholine, and exhaled NO levels in normal control subjects and patients with asthma and eosinophilic bronchitis are shown in Table 1
. FEV1 and FEV1/FVC were significantly lower in non–BDP-treated and BDP-treated subject with asthma than in normal control subjects and patients with eosinophilic bronchitis. Airway hyperreactivity to methacholine was also exhibited in non–BDP-treated and BDP-treated subjects with asthma, but in neither normal control subjects nor patients with eosinophilic bronchitis. In contrast, exhaled NO levels were significantly higher in non–BDP-treated subjects with asthma and patients with eosinophilic bronchitis than in BDP-treated subjects with asthma and normal control subjects. Similarly, the percentage of eosinophils and the concentration of eosinophil cationic protein in induced sputum were significantly higher in non–BDP-treated subjects with asthma (percentage of eosinophils: 13.0% [4.9%], p < 0.0001; eosinophil cationic protein: 520 [230] ng/ml, p < 0.0001) and patients with eosinophilic bronchitis (12.5% [3.6%], p < 0.0001; 480 [190] ng/ml, p < 0.0001) than in normal control subjects (0.6% [0.4%]; 110 [70] ng/ml) (Figure 1)
. Moreover, these parameters in BDP-treated subjects with asthma (0.8% [0.6%]; 120 [70] ng/ml) were similar to those in normal control subjects; however, VEGF levels in induced sputum and airway vascular permeability index were significantly higher in non–BDP-treated (VEGF: 4,710 [1,150]) pg/ml, p < 0.0001; vascular permeability index: 0.028 [0.009], p < 0.0001) and BDP-treated (2,560 [1,070] pg/ml, p = 0.0002; 0.016 [0.006], p = 0.004)subjects with asthma than in patients with eosinophilic bronchitis (1,120 [800] pg/ml; 0.01 [0.005]), which levels were comparable to those in normal control subjects (1,390 [1,280] pg/ml; 0.008 [0.003]) (Figure 2)
. We found significant correlations between VEGF level and airway vascular permeability index in non–BDP-treated subjects with asthma (r = 0.80, p = 0.0005), BDP-treated subjects with asthma (r = 0.50, p = 0.04), and patients with eosinophilic bronchitis (r = 0.77, p = 0.002) (Figure 3)
. Moreover, in non–BDP-treated subjects with asthma, the percentage of eosinophils, VEGF levels, and airway vascular permeability index were negatively correlated with FEV1/FVC and airway hyperreactivity to methacholine (Table 2)
. However, in BDP-treated subjects with asthma, only VEGF levels and airway vascular permeability index were significantly correlated with these parameters of airway function, whereas the percentage of eosinophils was not. In patients with eosinophilic bronchitis, there was no correlation between VEGF levels or vascular permeability index and airway function. In addition, we also found significant correlations between VEGF level and the percentage of eosinophils in only non–BDP-treated subjects with asthma (r = 0.59, p = 0.01) but not in BDP-treated subjects with asthma and patients with eosinophilic bronchitis.
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Figure 1. Comparison of (A) percentage of eosinophils (% Eos) and (B) eosinophil cationic protein (ECP) levels in induced sputum from normal control subjects, beclomethasone dipropionate (BDP)-nontreated and BDP-treated subjects with asthma, and patients with eosinophilic bronchitis. *p < 0.01 compared with normal control subjects;  p < 0.01 compared with BDP-negative (–) subjects with asthma; #p < 0.01 compared with BDP-positive (+) subjects with asthma.
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Figure 2. A comparison of (A) vascular endothelial growth factor (VEGF) levels in induced sputum and (B) airway vascular permeability index from normal control subjects, non–BDP-treated and BDP-treated subjects with asthma, and patients with eosinophilic bronchitis. *p < 0.01 compared with normal control subjects; p < 0.01 compared with BDP-negative subjects with asthma; #p < 0.01 compared with BDP-positive subjects with asthma.
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Figure 3. Correlation between VEGF levels in induced sputum and airway vascular permeability index in induced sputum for (A) non–BDP-treated individuals with asthma, (B) BDP-treated individuals with asthma, and (C) patients with eosinophilic bronchitis.
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DISCUSSION
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We have demonstrated that the percentage of eosinophils and eosinophil cationic protein levels in induced sputum is increased in patients with eosinophilic bronchitis compared with normal subjects and BDP-treated subjects with asthma. These increases were comparable to those seen in non–BDP-treated subjects with asthma with a similar degree of eosinophilic airway inflammation; however, airflow obstruction and airway hyperresponsiveness were observed in only BDP-treated and BDP-nontreated subjects with asthma but not in patients with eosinophilic bronchitis. These findings strongly suggest that the differences in airway function between asthma and eosinophilic bronchitis are not due to the degree of eosinophilic airway inflammation.
Why then might an apparently similar and equally active airway inflammation in the two diseases be associated with different airway function? It is possible that the site of airway inflammation is different between the two diseases. It has been speculated that airway inflammation in patients with eosinophilic bronchitis is confined to the upper airway because upper airway symptoms are common in these patients; however, eosinophilic bronchitis is not typically associated with a nasal eosinophilia or upper airway hyperresponsiveness (17). Furthermore, a previous study suggested that the site of airway inflammation in eosinophilic bronchitis is mainly in the lower airways (18). Another possible reason for the differences in airway function between the two diseases is that in eosinophilic bronchitis the epithelium is intact. We found no differences in epithelial cell count between asthma and eosinophilic bronchitis that would not support this view; however, whether sputum epithelial counts reflect epithelial integrity is unclear. Airway epithelial cells are activated, as reflected by increased inducible NO synthase expression and as an increased concentration of NO in exhaled air (19). As noted before (20), we also found no differences in the concentration of exhaled NO between non–BDP-treated subjects with asthma and patients with eosinophilic bronchitis, suggesting that functional abnormalities of epithelial cells may relate more closely to the presence of eosinophilic airway inflammation than the clinical features of the two diseases. The assessment of airway epithelium by means of bronchial biopsies is confounded by variation in epithelial integrity, which may reflect a real effect of disease or an artifact (21); therefore, the biopsy material is inadequate for testing this hypothesis. An alternative explanation is that the inflammatory cell infiltration in eosinophilic bronchitis is more localized to the epithelium so that mediators released by infiltrating inflammatory cells reach airway smooth muscle in lower concentrations than in asthma. In fact, a previous study reported that vasoactive and bronchoconstrictor mediators such as cysteinyl-leukotrienes, prostanoids, and histamine are present in higher concentrations in induced sputum from patients with eosinophilic bronchitis than in that from patients with asthma (22). These observations suggest that airway inflammation might preferentially localize in the superficial airway structures in patients with eosinophilic bronchitis. In this regard, it may be that inflammatory cells localizing in the superficial structures, perhaps adjacent to sensory nerve endings, are particularly important in the genesis of heightened cough sensitivity in eosinophilic bronchitis.
VEGF is known as a vascular permeability factor. It was reported that VEGF induces fenestration in endothelial cells in both the in vivo and in vitro models (23, 24). Thus, VEGF in the airway is thought to cause leakage of the mucosal and submucosal capillary beds and induce airway wall thickness. Interestingly, this study indicates that there may be an active airway inflammation in asthma with release of VEGF. In fact, VEGF levels were increased in only individuals with asthma but not in patients with eosinophilic bronchitis. There are potential limitations in directly interpreting the degree of airway vascular permeability (25). Moreover, because plasma extravasation and airway edema are supposed to be part of an inflammatory response, it was reasonable to expect that airway vascular permeability would be affected the magnitude of inflammatory response. Therefore, we tried to find the index, which is specific to airway microvascular extravasation rather than airway inflammation. Accordingly, we did not simply evaluate albumin levels in induced sputum but a ratio of albumin concentrations in induced sputum and serum as a reliable index of airway microvascular extravasation. Although eosinophilic airway inflammation was completely inhibited by inhaled BDP therapy, VEGF levels and the airway vascular permeability index in BDP-treated individuals with asthma were still higher than those in normal control subjects and patients with eosinophilic bronchitis, resulting to sustained disordered airway function in these patients. BDP therapy in this study might be incomplete in duration or dose to control VEGF production, airway vascular permeability, and airway function. A recent study revealed that a humanized monoclonal antibody against interleukin-5, which effectively depleted eosinophils from blood and induced sputum in patients with asthma, had no effect on airway hyperresponsiveness (26). Because anti–interleukin-5 could not completely deplete bronchial mucosal eosinophils and their granule products (27), we cannot exclude the possibility of an important role for eosinophils in causing abnormal airway function in asthma. Therefore, asthmatic airway inflammation may be a heterogeneous process of which sputum eosinophilia comprises only one part, and it may be that sputum eosinophilia and VEGF-mediated microvascular hyperpermeability reflect different components of the inflammatory process. In fact, in non–BDP-treated individuals with asthma, the percentage of eosinophils, VEGF levels, and airway vascular permeability index were negatively correlated with the degree of airflow obstruction and airway hyperresponsiveness; however, in BDP-treated individuals with asthma, only VEGF levels and airway vascular permeability index were significantly correlated with these parameters of airway function, whereas the percentage of eosinophils was not. Moreover, VEGF levels were significantly correlated with the airway vascular permeability index in non–BDP-treated and BDP-treated individuals with asthma and patients with eosinophilic bronchitis. Therefore, increased airway microvascular permeability induced by accelerated production of VEGF may contribute to differences in airway function between asthma and eosinophilic bronchitis. Recently, it was reported that newly generated blood vessels in asthmatic airways are leaky, immature, and unstable and that this angiogenesis and microvascular leakage, and consequent thickening of the airway wall mucosa, lead to narrowing of the airway lumen (28). A previous study determined that the number of mast cells in the bundle of airway smooth muscle from subjects with asthma was significantly higher than that in patients with eosinophilic bronchitis and that the mast cell infiltration into airway smooth muscle is associated with the disordered airway function found in asthma (29). These findings suggest that small increases in bronchial wall thickness induced by VEGF could produce striking changes in airway responsiveness to various bronchoconstrictor mediators by infiltrating mast cells. Thus, mucosal edema induced by VEGF may have a profound effect on airway function and can explain the heightened reactivity characteristic of asthma. In contrast, mucosal edema formation is not induced in the airway walls with eosinophilic bronchitis because VEGF production is not enhanced in these patients.
In summary, we believe that there are some contributing factors to differences in airway function between asthma and eosinophilic bronchitis; however, our findings suggest that a key factor in the development of variable airflow obstruction and airway hyperresponsiveness is the increased level of VEGF but not sputum eosinophilia. Moreover, our findings support the speculation that the interaction between airway microcirculation and VEGF is a key element in the development of disordered airway function. The observations in this study have potential implications for our outstanding of the pathogenesis of asthma and eosinophilic bronchitis and the pathophysiologic role that airway microvascular permeability plays in asthma.
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Acknowledgments
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The authors thank Miss Yukari Matsuyama for her help in the preparation and editing of the article.
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FOOTNOTES
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Supported by Grant-in-Aid for Scientific Research (15590820) from the Japan Society for the Promotion of Science.
Conflict of Interest Statement: H.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; S.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; J.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this article.
Received in original form January 28, 2004;
accepted in final form March 19, 2004
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S Siddiqui, C E Brightling, A-S Jang, S-W Park, and C-S Park
Differences in airway wall remodelling in asthma and EB.
Thorax,
June 1, 2006;
61(6):
547 - 547.
[Full Text]
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A. M. O. Abdel-Rahman, S. A. F. El-Sahrigy, and S. I. Bakr
A comparative study of two angiogenic factors: vascular endothelial growth factor and angiogenin in induced sputum from asthmatic children in acute attack.
Chest,
February 1, 2006;
129(2):
266 - 271.
[Abstract]
[Full Text]
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G. Horvath and A. Wanner
Inhaled corticosteroids: effects on the airway vasculature in bronchial asthma
Eur. Respir. J.,
January 1, 2006;
27(1):
172 - 187.
[Abstract]
[Full Text]
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S-W Park, J-S Park, Y-M Lee, J-H Lee, A-S Jang, D-J Kim, Y Hwangbo, S-T Uh, Y-H Kim, and C-S Park
Differences in radiological/HRCT findings in eosinophilic bronchitis and asthma: implication for bronchial responsiveness
Thorax,
January 1, 2006;
61(1):
41 - 47.
[Abstract]
[Full Text]
[PDF]
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C. E. Mapp, P. Boschetto, P. Maestrelli, and L. M. Fabbri
Occupational Asthma
Am. J. Respir. Crit. Care Med.,
August 1, 2005;
172(3):
280 - 305.
[Abstract]
[Full Text]
[PDF]
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L. Fabbri, S. P. Peters, I. Pavord, S. E. Wenzel, S. C. Lazarus, W. MacNee, F. Lemaire, and E. Abraham
Allergic Rhinitis, Asthma, Airway Biology, and Chronic Obstructive Pulmonary Disease in AJRCCM in 2004
Am. J. Respir. Crit. Care Med.,
April 1, 2005;
171(7):
686 - 698.
[Full Text]
[PDF]
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H. Kanazawa
Effects of Pranlukast on Vascular Endothelial Growth Factor Levels in Asthma
Chest,
April 1, 2005;
127(4):
1461 - 1461.
[Full Text]
[PDF]
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N. C. Thomson and R. Chaudhuri
Why Is Eosinophilic Bronchitis not Asthma?
Am. J. Respir. Crit. Care Med.,
July 1, 2004;
170(1):
4 - 5.
[Full Text]
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Copyright © 2004 American Thoracic Society
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