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(Chest. 2005;127:965-972.)
© 2005 American College of Chest Physicians

Quantitative Analysis of Bronchial Wall Vascularity in the Medium and Small Airways of Patients With Asthma and COPD*

Midori Hashimoto, MD; Hiroshi Tanaka, MD and Shosaku Abe, MD

* From the Third Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.

Correspondence to: Hiroshi Tanaka, MD, Third Departments of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan; e-mail: tanakah{at}sapmed.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Submucosal hypervascularity is part of airway remodeling in patients with asthma; however, its existence in the small airways and its contribution to airflow limitation remain controversial.

Methods: We investigated bronchial wall vascularity and angiogenic cells between medium airways (inner diameter, 2 to 5 mm) and small airways (inner diameter, < 2 mm) in patients with asthma (n = 9) and COPD (n = 11), and in 8 control subjects. The lung specimens obtained during surgery were immunostained to detect CD31, CD34, vascular endothelial growth factor, and basic fibroblast growth factor.

Results: The number of vessels in both the medium and small airways in patients with asthma was significantly (p < 0.01) increased compared to those in patients with COPD and control subjects, and the percentage of vascularity was significantly (p < 0.01) increased in the medium airways in asthma patients and in the small airways in COPD patients. Patients with moderate asthma showed a greater increase in vascularity than those with mild asthma (p < 0.01), and the number of angiogenic factor-positive cells increased in asthma patients compared with control subjects. In asthmatic subjects, inverse correlations were found between FEV1 percentage of predicted and the number of vessels (r = –0.85; p < 0.01), or the percentage of vascularity (r = –0.72; p < 0.03) in the inner area of the medium airways, but they were not found for the small airways. In COPD patients, no correlations were demonstrated.

Conclusions: The number of vessels in the medium and small airways in asthma patients shows a greater increase than those in COPD patients, and the vascular area in the small airways is increased in COPD patients but not in asthma patients. Enhanced vascularity in the inner area of the medium airways, but not in the small airways, might contribute to airflow limitation in asthma patients.

Key Words: airway remodeling • angiogenesis • asthma • COPD • vascular endothelial growth factor


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Chronic airway inflammation and remodeling are characteristic features of patients with asthma. Airway remodeling leads to irreversible bronchial obstruction, which may make the treatment of asthma difficult. Airway wall thickening consists mainly of hypertrophy and hyperplasia of smooth muscle, an increase in mucous gland, infiltration of inflammatory cells, extracellular matrix, tissue edema, and angiogenesis in the bronchial wall.12 Even a small increase in airway wall thickening, due to edema or vascular engorgement may cause excessive narrowing of the lumen, and causes increased airway resistance.3 Hamid et al4 reported that similar but more severe inflammatory processes and remodeling are present in the small airways compared with the large airways, suggesting that the smaller airways are also critical to airflow obstruction in asthma patients. Some quantitative studies5678 using biopsy specimens obtained by fiberoptic bronchoscopy revealed an increase in the total number of vessels and vascular area in patients with asthma compared to healthy subjects. However, these studies were limited to the large airways.5678 There have been two reports910 of bronchial wall vascularity in the small airways in patients with asthma. Kuwano et al9 stained autopsy and surgical specimens with anti-factor VIII antibody to detect for vessels. Their results revealed fewer vessels or no significant increase in the number of vessels in asthmatic patients compared with COPD patients or control subjects. Carroll et al10 evaluated autopsy lung specimens and reported no differences in the number of vessels or the size of the vascular area in the small airways among the following three subject groups: patients with fatal asthma, patients with nonfatal asthma, and control subjects. Hypervascularity characterizes airway remodeling in asthma patients, but its clinical significance has not been made clear. COPD patients who smoke tobacco have airway wall thickening throughout the lung,11 which is consistent with an increase in connective tissue, smooth muscle, mucous gland, and cellular infiltration, but there have been few examinations of bronchial wall vasculature.9

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) are relevant to the angiogenic processes within the airways and stimulate endothelial cell proliferation.12 VEGF is also involved in vascular permeability leading to tissue edema. Demoly et al13 reported that levels of VEGF and VEGF normalized to IgA in BAL fluid were not different among stable patients with asthma and chronic bronchitis, and in control subjects, and they also reported no correlation between VEGF level and albumin level in subjects with asthma. However, VEGF and b-FGF are up-regulated in the airways of patients with asthma, and epithelial cells, CD34-positive cells, and many inflammatory cells were found to have a positive immunoreaction for VEGF or b-FGF,14 and VEGF levels in induced sputum were higher in asthmatic patients than in control subjects.15 Hoshino et al14 found significant correlations between the percentage of vascularity and cells positive for VEGF or b-FGF, and these angiopoietic factor-positive cells were mainly CD34-positive cells, eosinophils, and macrophages.

The aims of the present study were to assess whether airway wall hypervascularity in the large airways extends to the medium or the small airways in asthma patients, and to evaluate the clinical contribution of hypervascularity to the pathogenesis of asthma and COPD. We conducted pathologic examinations of vascular endothelial cells and their growth factors in the medium and small airways using lung specimens from patients with asthma and COPD, and from control subjects. We also evaluated the relationships between vascularity and airflow limitation, and the effect of therapy with inhaled corticosteroids (ICSs) on airway vascularity.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Twenty-eight subjects who underwent lobectomy or pneumonectomy for a solitary peripheral carcinoma, the largest of which had a diameter of < 30 mm, between 1996 and 2000, were recruited from Sapporo Medical University Hospital. No patients received presurgery chemotherapy or radiotherapy, and no subjects had intrathoracic or systemic metastasis. Nine patients with asthma defined according to the criteria of the American Thoracic Society16 (ie, episodic cough, wheezing and dyspnea with an increase of ≥ 15% in FEV1 in response to a ß2-agonist) were identified. The severity of asthma was defined by the guidelines of the Global Initiative for Asthma17 (mild: FEV1, ≥ 80% predicted; moderate: FEV1, 60 to 80% predicted). Eleven patients with moderate COPD were identified based on the guidelines of the Global Initiative for Chronic Obstructive Lung Disease,18 the definition of which is as follows: FEV1/FVC < 70%; FEV1, ≤ 30% to < 80% predicted after inhalation of a ß2-agonist. Eight control subjects had no respiratory disease and no airflow limitation. The clinical and demographic characteristics of the subjects are shown in Table 1 . Five patients with asthma were treated for > 1 year with inhaled beclomethasone dipropionate (BDP), 400 to 600 µg/d, and the other four patients were not treated with ICSs. Seven asthmatic patients were treated with oral sustained-release theophylline, and all nine patients used inhaled ß2-agonists as needed. None of the COPD subjects were treated with inhaled or oral corticosteroids. This study was approved by the local ethics committee, and subjects gave written informed consent.


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  		Table 1. Subject Characteristics*

 
Immunohistochemistry
Lung specimens were obtained from the bronchial tree of another segmental lobe in which no changes associated with lung cancer existed. The specimens were fixed with 10% formalin and were embedded in paraffin, and in each case we made three to six blocks of hilar, intermediate, and peripheral lung areas. The sections of 5-µm thickness were deparaffinized with xylene, dehydrated in ethanol, and then heated in a commercially available microwave oven (500 W) for 5 min to retrieve the antigens. Endogenous peroxidase was blocked by incubation of the sections in 1% hydrogen peroxide in methanol for 30 min. The antibodies used in this study were as follows: anti-CD31 monoclonal antibody for vessel endothelium (1:50; NeoMarkers; Fremont, CA); anti-CD34 monoclonal antibody (1:100; Becton Dickinson Immunocytometry Systems; San Jose, CA); anti-VEGF monoclonal antibody (1:100; Immuno-Biological Laboratories; Fujioka, Japan); and anti-b-FGF antibody (1:100; Santa Cruz Biotechnology; Santa Cruz, CA). The sections were incubated with biotinylated antimouse or antirabbit IgG (heavy and light chains) affinity-purified antibody for 30 min, followed by incubation (Vectastain Elite ABC kit; Vector Laboratories; Burlingame, CA) for 30 min. The sections were washed three times after each incubation with phosphate-buffered saline solution for 5 min each. For visualization, they were immersed in a 0.05% diaminobenzidine tetrahydrochloride solution containing 0.03% hydrogen peroxide for 1 to 3 min, followed by counterstaining of the nuclei with a hematoxylin solution. For specificity controls, the primary antibody was replaced by normal mouse IgG.

Airway Classification
The small airways were defined as membranous airways with an inner diameter of < 2 mm and no cartilage in the airway wall. The medium airways were defined as airway tissue that contained cartilage with an inner diameter of 2 to 5 mm.1920

Quantitation
The vascularity and numbers of positively stained cells were counted separately in the inner airway wall between the basement membrane and the outer border of smooth muscle, and in the outer wall of the tissue extending from the outer border of the smooth muscle to the parenchyma, excluding mucous glands, smooth muscle, and cartilage, which were described previously.4 Microvessels were identified by a CD31-positive vascular endothelium forming a round or spherical structure. The number of vessel and angiogenic factor-positive cells per square millimeter and the percentage of vascular area (determined by dividing the vascular area by the selected submucosal area) were examined using a light microscope with a high-power field (x400) that connected to image analyzing software (MOTIC 2000; Shimazu Rikaki; Tokyo Japan) on a personal computer (Macintosh; Apple Computers; Cupertino, CA). We traced the total area of airway wall and intravascular area manually, and the quantitative computer system was able to calculate the area of these traced irregular areas in the airway wall. To avoid observer bias, the cases were coded, and the measurements were made without knowledge of the subject characteristics, and we used the mean value of these two data by the two observers. Two observers examined five different medium airways and five different small airways in each subject. The mean coefficient of variation of the two observers in repeated measurements, using 20 different fields of the airway wall, was as follows: number of vessels, 8% and 8%; percentage of vascularity, 7% and 7%; CD34-positive cells, 10% and 9%; VEGF-positive cells, 6% and 7%; and b-FGF-positive cells, 7% and 8%.

Statistical Analysis
The values are presented as the mean ± SE. Differences among groups were analyzed by means of a nonparametric Kruskal-Wallis test, followed, where significant, by the Mann-Whitney U test for comparisons among groups. The differences among the three groups were evaluated by analysis of variance followed by the Scheffé test. Correlation between FEV1 percentage of predicted and vascularity was performed using the Spearman correlation method. A p value of < 0.05 was considered to be statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The distribution of submucosal microvessels in the inner area of the medium airways is shown in Figure 1 , top left, A, for control subjects, Figure 1, top right, B, for COPD patients, and Figure 1, bottom left, C, for patients with asthma. Microvessels were identified by CD31-positive vascular endothelium forming a round or spherical structure, and single immunopositive cells were not counted. The number of vessels was significantly increased in asthmatic patients compared with control subjects and subjects with COPD, and the percentage of vascularity was significantly increased in the inner area of the medium airways in asthmatic patients compared with control subjects (Table 2 ). The number of vessels in the inner area of the medium airways was greater (p < 0.05) than in the outer area in asthmatic patients (Table 2). In COPD patients, the number of vessels showed a tendency to increase, but not significantly, and the percentage of vascularity in the inner area of the small airways was significantly greater than that in control subjects. As shown in Figure 2 , both the number of vessels and the percentage of vascularity in the inner area of the medium airways of patients with moderate asthma (5 points for each patient, 25 points in total) were significantly greater than those in patients with mild asthma (5 points for each subject, 20 points in total). However, there was no difference between patients with mild and moderate asthma in the inner area of the small airways (Fig 3 ). In asthmatic patients, there was no difference in either the number of vessels or the percentage of vascularity in the inner area of the medium and small airways between smokers (5 points for each patient, 35 points in total) and nonsmokers (5 points for each subject, 15 points in total; data not shown).



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  		Figure 1. Photomicrographs staining with monoclonal antibody for CD31 (vessel marker) in the medium airways from control subjects (top left, A), subjects with COPD (top right, B), and patients with asthma (bottom left, C). Arrowheads indicate vessels (bar = 100 µm).

 

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  		Table 2. The Number of Vessels and Percentage of Vascularity in the Inner and Outer Areas of Airways*

 


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  		Figure 2. The number of vessels and vascularity (vascular occupying area) in the inner area of the medium airways. Each point represents one measurement (five measurements for each patient).

 


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  		Figure 3. The number of vessels and the percentage of vascularity (vascular occupied area) in the inner area of the small airways. Each point represents one measurement (five measurements for each patient).

 
The results of the distribution of angiogenic factor-positive cells and CD34-positive cell in both the medium and the small airways are shown in Table 3 . No correlation was found between the number of vessels or the percentage of vascularity and the number of CD34-positive, VEGF-positive, or b-FGF-positive cells in both patients with asthma and patients with COPD (data not shown). There were no significant differences in the number of vessels, the percentage of vascularity, the number of CD34-positive, VEGF-positive, or b-FGF-positive cells between asthmatic patients treated with ICSs and those not treated with ICSs (data not shown).


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  		Table 3. The Number of Angiogenetic Factor-Positive Cells and CD34-Positive Cells*

 
The results of the correlation between vascularity and airflow limitation in patients with asthma are shown in Figure 4 . There were inverse correlations between FEV1 percentage of predicted and the number of vessels (r = –0.85; p = 0.0024) or the percentage of vascularity (r = –0.72; p = 0.026) for the inner airway wall of the medium airways of asthmatic patients. However, no correlation was revealed for the inner airway wall of the small airways. In patients with COPD, there were no significant correlations between FEV1 percentage of predicted and the number of vessels or the percentage of vascularity in either the medium or small airways (data not shown).



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  		Figure 4. Relationship between airflow limitation and bronchial wall vascularity in nine patients with asthma. Each point represents the mean of five measurements for each patient. Negative correlations are shown between FEV1 percent predicted and the number of vessels or the percentage of vascularity in the middle inner airways, but not in the small inner airways.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found that the number of vessels and the percentage of vascularity were increased in small noncartilaginous airways in patients with asthma compared to those in control subjects. Two previous studies910 of the vascularity of the small airways in asthma patients reported either fewer vessels or no significant increase in the number of vessels. Our data extend the established finding of increased vascularity in large airways to the medium and the small airways. The different results from previous reports910 may have been caused by the difference in study population. Specimens of asthmatic patients in the previous studies were mainly obtained from autopsy, therefore the results of baseline pulmonary function tests were not shown in many cases. The mean FEV1, although only a few patients were tested, was 96% predicted (range, 83 to 111% predicted),9 or no data.10 On the other hand, mean FEV1 was 86.1% predicted in this study. And the mean ages in previous reports were 39 years9 and 35 to 44 years,10 but 60.8 years in this study. It seems that the patients in our study might have had more severe airflow limitation and been older than those in previous studies.910 Li and Wilson5 did not find any relationship between clinical parameters and airway vascularity in patients with mild and moderate asthma, although Vrugt et al6 and Salvato8 showed that subjects with severe asthma had more vessels compared with patients with mild-to-moderate asthma. Our results also demonstrated that the vascularity of the medium airways in patients with moderate asthma is more increased than that in patients with mild asthma, and the degree is more prominent in the inner area, suggesting that airway edema by plasma leakage from mucosal capillary vessels might enhance the narrowing of the bronchial lumen and consequently increase airway resistance. In our study, FEV1 percentage of predicted significantly correlated with the vascularity in the inner area of the medium airways, but not in the small airways. In this study, the medium airway contains bronchi from generations three to five (lobar bronchus is defined as generation two), the inner area of which is smallest in the total bronchial tree.21 Therefore, a small increase in airway wall thickening due to edema or vascular engorgement may directly affect airflow limitation and cause increased airway resistance. These results suggest that hypervascularity of the inner area of the medium airways, not the small airways, might contribute to airflow limitation in asthmatic patients.

In patients with COPD, the mean value of the vascularity was higher than that in control subjects, but not significantly, except for the percentage of vascularity of the small airways. Although both asthma and COPD are chronic inflammatory diseases of the bronchus, the number of vessels was not increased in the medium airways in patients with COPD. These data are consistent with the results of previous studies.9 In this study, we found no correlation between the degree of vascularity and airflow limitation in patients with COPD. In general, the loss of elastic recoil and the fibrotic thickness of the small airway wall contribute to the fixed airway obstruction in COPD patients. Reversible airway obstruction in COPD patients involves the contraction of airway smooth muscle, intraluminal mucous, and extravasation from submucosal vessels, therefore the increase in the percentage of vascularity in the inner area of the small airways found in our study might contribute to the minimal reversible change. On the other hand, Kanazawa et al22 reported that VEGF levels in sputum were decreased in patients with pulmonary emphysema, and that the VEGF levels positively correlated with the diffusing capacity of carbon monoxide, suggesting that a decrease in VEGF is associated with alveolar destruction. We recently developed23 a novel high-magnification bronchovideoscope (side-viewing type) for observation of the mucosal surface of the trachea, and we had found that submucosal vascularity in patients with COPD was not increased, although it was prominently increased in asthmatic patients. We speculated that the mechanism of angiogenesis might be different between patients with COPD and asthma. The vessel increase in COPD patients might have occurred as the result of simple tobacco-induced inflammation, and in the case of asthma patients many angiogenic factors might be secreted as an asthma-specific inflammation.

We also evaluated the effect of cigarette smoking on airway vascularity. No previous data have been published on this matter. In this study, all control patients had never smoked, and all COPD patients were smokers. The mean value for the vascularity in COPD patients was higher than that in control subjects, but not significantly, except for the percentage of vascularity of the small airways. And in asthmatic patients, there was no difference in airway vascularity between smokers and nonsmokers. Thus, we think that the effect of smoking on airway hypervascularity was minimal in this study, especially in the medium airways, and that a different mechanism of angiogenesis between asthma and COPD is suggested.

Studies713 of associations between cytokines and angiogenesis in the airway walls in asthmatic patients were few, and their results were controversial. In this study, we could not determine which cell was most involved in the formation of the vessels. The number of CD34-positive cells increased in both the medium and small airways in patients with asthma, but the increase did not correlate with the number of vessels or the percentage of vascularity. The CD34 molecule is expressed on pluripotent hematopoietic stem cells, and these cells mature into eosinophils, monocytes/macrophages and subsets of lymphocytes. Growth factors with angiogenic properties, such as VEGF and b-FGF, are quite likely to be released in excessive amounts in the airways of asthmatic patients by these cells. Hoshino et al14 found significant correlations between the percentage of vascularity and VEGF-positive or b-FGF-positive cells in the large airways, and these angiopoietic factor-positive cells may be CD34-positive cells, eosinophils, mast cells, and macrophages. We found no significant correlations between the number of angiogenic factor-positive cells and airway vascularity. The different results might have been due to the different sites of airways, the large airways in the report by Hoshino et al,14 and the medium and small airways in our study. Many angiogenic factors are released from epithelial cells and various inflammatory cells, and perhaps all of these cells might orchestrate the angiogenesis.

Treatment with BDP, 400 to 600 µg/d for > 1 year, in our study did not decrease vascularity in either the medium or the small airways. In previous reports, treatment with BDP, 800 µg/d for 6 months,24 or fluticasone propionate, 1,000 µg/d for 6 weeks,7 reduced submucosal vascularity, however, therapy with fluticasone propionate, 200 µg/d for 6 weeks7 or 3 months,25 did not decrease the hypervascularity in the large airways. Vrugt et al6 and Orsida et al26 showed a successful effect of BDP, > 800 µg/d, on airway microvessels, but no effect of treatment with BDP, 200 to 500 µg/d. For these, the reason why airway vascularity was not suppressed in asthmatic patients treated with ICSs in our study might have been due to an insufficient dose of ICSs.

In conclusion, submucosal vascularity was increased in both the medium and small airways in asthma patients, and our results extended those of previous reports of hypervascularity in the large airways to more peripheral airways. The vascularity in patients with COPD was greater than that in control subjects, but not significantly, except for the percentage of vascularity in the small airways. In asthmatic patients, the number of vessels increased in both the inner and outer areas in the medium and small airways, but only an increase in the percentage of vascularity was revealed in the inner area of the medium airways. A negative relationship between vascularity and FEV1 percentage of predicted was shown only in this inner area of the medium airways, but not in the small airways. Hypervascularity in the inner area of the medium airways, but not in the small airways, might be closely related to airflow limitation and disease severity in asthma patients.


   Footnotes
 
Abbreviations: BDP = beclomethasone dipropionate; b-FGF = basic fibroblast growth factor; ICS = inhaled corticosteroid; VEGF = vascular endothelial growth factor

Received for publication March 11, 2004. Accepted for publication September 15, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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