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(Chest. 2002;122:166-170.)
© 2002 American College of Chest Physicians

Vascular Involvement in Exercise-Induced Airway Narrowing in Patients With Bronchial Asthma*

Hiroshi Kanazawa, MD; Kazuhisa Asai, MD; Kazuto Hirata, MD and Junichi Yoshikawa, MD

* From the Department of Respiratory Disease, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Correspondence to: Hiroshi Kanazawa MD, Department of Respiratory Disease, 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


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: The bronchial microcirculation has the potential to contribute to the pathophysiologic mechanisms of exercise-induced bronchoconstriction (EIB) in asthmatic patients. This study was designed to determine whether increase in airway vascular permeability is associated with the severity of EIB in asthmatic patients.

Design: Cross-sectional analysis.

Setting: University hospital. Participants: Twenty-five asthmatic patients and 12 normal control subjects.

Interventions: All asthmatics performed an exercise test, and the percentage of maximal fall in FEV1 and the area under the curve of the percentage fall in FEV1 plotted against time for 30 min (AUC0–30) were determined.

Measurements and results: The inflammatory indexes, NO levels, and airway vascular permeability index (ratio of albumin concentrations in induced sputum and serum) were examined in all subjects. The airway vascular permeability index was significantly higher in EIB-positive asthmatics (0.031 ± 0.009) than in EIB-negative asthmatics (0.020 ± 0.005, p = 0.0011) and normal control subjects (0.008 ± 0.003, p < 0.0001). We also found that there was a significant correlation between NO levels in induced sputum and the airway vascular permeability index (r = 0.525, p = 0.0101). Moreover, the airway vascular permeability index was significantly correlated with the severity of EIB (percentage of maximal fall in FEV1 [r = 0.761, p = 0.0002], AUC0–30 [r = 0.716, p = 0.0005]). However, this index was not significantly correlated with magnitude of eosinophilic inflammation.

Conclusion: Our findings suggest that increased airway vascular permeability due to excessive production of NO correlates with the severity of EIB in asthmatics, and that assessment of albumin flux in airway lining fluid stimulated by hypertonic saline solution is a sensitive predictor of the severity of EIB.

Key Words: bronchial asthma • bronchial circulation • exercise-induced bronchoconstriction • nitric oxide • vascular permeability


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Exercise-induced bronchoconstriction (EIB) is the term used to describe the increase in airway resistance that follows vigorous exercise in most asthmatic patients. Despite the wide prevalence and clinical significance of EIB, its mechanism has not been elucidated. Two major hypotheses have been put forward to explain the mechanism whereby water and heat loss by hyperventilation with exercise causes airway narrowing. One hypothesis suggests that evaporative water loss associated with exercise causes a transient increase in osmolarity of the fluid interface of the mucosal surface in the airways, resulting in mast cell degranulation.1 The second hypothesis is that EIB is a mechanical event in which the airways are rapidly rewarmed by reactive hyperemia of the bronchial circulation with subsequent edema of the airway wall.2 However, since mast cell-derived mediators, such as histamine and leukotrienes, may cause not only airway smooth-muscle contraction but also airway edema, it is possible that both of these hypotheses are related to the airway narrowing following exercise in asthmatics. Therefore, EIB is, at least in part, due to bronchial microvascular phenomena such as vascular engorgement and plasma leakage that could thicken the mucosa and thereby narrow airway diameters, which could in turn amplify the effects of airway smooth-muscle contraction.

There is increasing evidence that nitric oxide (NO) plays an important role in physiologic regulation of the airways, and is implicated in the pathophysiology of airway disease.3 We found that excessive production of NO in the airways correlates with the severity of EIB in asthmatic patients.4 However, identification of the target tissue of excessively produced NO would be important for the understanding of the precise mechanism of EIB. Therefore, this study was designed to determine whether increase in airway vascular permeability via excessive production of NO correlates with the severity of EIB in asthmatic patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
The normal controls consisted of 12 subjects (mean age, 32.9 years; mean FEV1, 107.3%). All normal control subjects were healthy, lifelong nonsmoking volunteers who had no history of lung disease. All asthmatic patients satisfied the American Thoracic Society criteria for asthma.5 The clinical characteristics of these patients are shown in Table 1 . The 25 asthmatics included in this study were all nonsmokers. Methacholine inhalation challenge testing was performed for all asthmatics. All challenge tests were performed at 1 PM to eliminate the effect of diurnal variation. Following 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 asthmatics in this study demonstrated bronchial hyperreactivity to methacholine. Their regular medication consisted of ß2-agonists and theophylline, and none were receiving oral or inhaled corticosteroids. Medications were not changed for a 1-month period preceding the study, and were withdrawn for at least 12 h before the methacholine challenge test and exercise test. All patients were in clinically stable condition, and none had a history of respiratory infection for at least the 4-week period preceding the study. All subjects gave their written informed consent for participation in the study, which was approved by the Ethics Committee of Osaka City University.


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  		Table 1. Clinical Characteristics of Study Subjects*

 
Sputum Induction and Processing
Spirometry was performed prior to inhalation of 200 µg of albuterol via a metered-dose inhaler. All subjects were instructed to wash their mouths thoroughly with water. They then inhaled 3% saline solution at room temperature, nebulized by an ultrasonic nebulizer (NE-U12; Omron; Tokyo, Japan) at maximum output. They were encouraged to cough deeply after 3-min 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 samples were kept at 4°C for not more than 2 h before further processing. The portion of the sample was diluted with phosphate-buffered saline solution containing 10 mmol/L dithiothreitol (Sigma Chemical; St Louis, MO) and gently vortexed at room temperature. They were then centrifuged at 400g for 10 min, and the cell pellet was resuspended. Total cell counts were performed with a hemocytometer, and slides were made by using a cytospin (Cytospin 3; Shandon; Tokyo, Japan) and stained with May-Grunwald-Giemsa stain for differential cell counts. The supernatant was stored at - 70°C for subsequent assay for albumin, NO, and eosinophil cationic protein (ECP). ECP concentration was measured by using a radioimmunoassay kit (Pharmacia Diagnostics; Uppsala, Sweden), and albumin concentration was measured by laser nephelometry. We calculated the airway vascular permeability index (ratio of albumin concentrations in induced sputum and serum). For the first time, the term airway vascular permeability index was used in this study. There are the potential limitations in directly interpreting the degree of airway vascular permeability. 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. However, we tried to find the index, which is specific to the bronchial vasculature rather than airway inflammation. Therefore, we did not simply evaluate albumin levels in induced sputum, but a ratio of albumin concentrations in induced sputum and serum as a most reliable index of extravasation.

NO Derivatives Assay
NO derivatives (nitrate plus nitrite) in induced sputum were assayed colorimetrically after the Griess reaction, as previously described.6 Two hundred microliters of sputum sample or standard was deproteinated by adding 20 µL of NaOH (1.0 mol/L, 4°C; Wako Chemical; Osaka, Japan) and 30 µL of ZnSO4 (1.3 mol/L, 4°C). Samples were mixed and allowed to stand on ice for 15 min. After centrifugation (5 min, 4°C, 2,600g), 100 µL of supernatant was mixed with 5 x 10-2 U of nitrate reductase, 20 µL 0.2 mol/L N-tris (hydroxymethyl) methylamino enthanesulphonic acid (pH 7.0, Sigma Chemical) and 20 µL of 0.5 mol/L sodium formate. After anaerobic incubation at room temperature for 20 min, 1.0 mL of water was added to the samples, and nitrite was assayed in supernatants obtained by centrifugation (5 min, 260g). Deproteinated samples or standards (200 µL) were mixed with 20 µL of 1% sulfanilamide in 15% phosphoric acid. After 10 min, 20 µL of 0.1% N-(1-naphtyl) ethylenediamine was added, and the absorption at 540 nm was determined.

Exercise Challenge Testing
Three days after sputum induction, the exercise test was performed at approximately 1 PM to eliminate the effects of diurnal variation. Exercise challenge testing was performed on an electrically driven treadmill (Q55xt, Series 90; Quinton Instrument; Seattle, WA) for 6 min with a fixed workload adjusted to increase the cardiac frequency to 90% of the maximum predicted for the age of the patient.7 All subjects breathed unconditioned room air (temperature, 22 to 25°C) and were coached to overcome hyperventilation during testing. A single-lead ECG and pulse oximetry (502-US; CSI; Tokyo, Japan) were monitored continuously. The criteria for exclusion were the presence of coronary artery disease or cardiac arrhythmia. A spirometer (Chestac - 25F; Chest; Tokyo, Japan) was used to obtain spirometric measurements before and after exercise challenge. The higher of two measurements of FEV1 obtained before exercise challenge was taken as the baseline value. Single measurements of FEV1 were obtained 1, 3, 5, 10, 15, 20, 25, and 30 min after completion of the exercise challenge. The response to exercise challenge was taken to be the maximum percentage fall in FEV1 after exercise:

percentage fall in FEV1 = ([FEV1 at baseline - FEV1 after]/FEV1 at baseline) x 100

Those patients whose maximum decrease in FEV1 was > 20% were considered to be EIB-positive asthmatics. In addition, the bronchoconstrictor response was also assessed as the area under the curve of the percentage fall in FEV1 plotted against time for 30 min (AUC0–30). The AUC0–30 was calculated using trapezoidal integration as described by Makker et al.8

Statistical Analysis
When multiple comparisons were made between groups, significant intergroup variability was first established using the Kruskal-Wallis test. The Mann-Whitney U test was then used for intergroup comparisons. The significance of correlation was evaluated by determining Spearman’s rank correlation coefficients. A p value < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Thirteen EIB-positive asthmatics and 12 EIB-negative asthmatics were well matched with respect to age, baseline lung function, and hyperreactivity to methacholine (Table 1) . There were also no significant differences in temperature or humidity during the exercise test between EIB-positive asthmatics and EIB-negative asthmatics. However, the percentage of eosinophils and the concentration of ECP in induced sputum in EIB-positive asthmatics (% eosinophils, 20.6 ± 7.1%; ECP, 871 ± 187 ng/mL) were significantly higher than in EIB-negative asthmatics (% eosinophils, 14.2 ± 6.8%, ECP, 549 ± 270 ng/mL) and normal control subjects (% eosinophils, 0.7 ± 0.5%, ECP, 120 ± 67 ng/mL). The concentration of NO derivatives in induced sputum was also significantly higher in EIB-positive asthmatics (1,401 ± 234 µmol/L) than in EIB-negative asthmatics (1,057 ± 163 µmol/L) and normal control subjects (603 ± 148 µmol/L).

The airway vascular permeability index was significantly higher in EIB-positive asthmatics (0.031 ± 0.009) than in EIB-negative asthmatics (0.020 ± 0.005, p = 0.0011) and normal control subjects (0.008 ± 0.003, p < 0.0001; Fig 1 ). We also found that there was a significant correlation between the concentration of NO derivatives in induced sputum and airway vascular permeability index (r = 0.525, p = 0.0101; Fig 2 ). Moreover, airway vascular permeability index was significantly correlated with the severity of EIB (percentage of maximal fall in FEV1 [r = 0.761, p = 0.0002], AUC0–30 [r = 0.716, p = 0.0005]; Fig 3 ). However, though it tended to increase, airway vascular permeability index was not significantly correlated with magnitude of eosinophilic inflammation (percentage of eosinophils [r = 0.400, p = 0.0502], ECP [r = 0.365, p = 0.0741]; Fig 4 ).



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  		Figure 1. Comparison of airway vascular permeability index in normal control subjects and asthmatics with or without EIB.

 


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  		Figure 2. Correlation between the concentration of NO derivatives in induced sputum and airway vascular permeability index in asthmatic patients.

 


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  		Figure 3. Correlation between airway vascular permeability index and the severity of EIB in asthmatic patients. Left: percentage of maximal fall in FEV1. Right: AUC0–30.

 


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  		Figure 4. Correlation between airway vascular permeability index and magnitude of eosinophilic inflammation in asthmatic patients. Left: percentage of eosinophils in induced sputum. Right: ECP in induced sputum. N.S. = not significant.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, higher levels of airway vascular permeability index were found in EIB-positive asthmatics than in EIB-negative asthmatics and normal control subjects. Moreover, there was a significant correlation between airway vascular permeability index and NO levels in induced sputum, the production of which was markedly increased in asthmatics. The role of excessively produced NO, if any, in the pathogenesis of bronchial asthma is under active investigation, and NO is known to be one of the important markers of airway inflammation. In fact, we previously found that NO levels in induced sputum were correlated with the magnitude of airway inflammation.6 However, the role of endogenous NO in EIB has been little studied in humans, and the pathogenetic mechanisms of EIB, potentially involving mucosal, neurogenic, smooth-muscle, and vascular tissues continue to be discussed. Elucidation of induced NO as an important participant, and identification of the target tissue involved, would be important contributions that could lead to an increased understanding of asthma and clinical interventions for the prevention and treatment of EIB. In our earlier study,4 we found that endogenous NO contributes to the prolonged airway narrowing phase rather than to the maximal airway narrowing evoked by exercise, and suggested another possible explanation for the roles of endogenous NO in EIB, except as a marker of airway inflammation. That is, NO is a potent vasodilator in the bronchial circulation and may mediate the hyperemia seen in asthmatic airways.9 Thus, NO may increase the exudation of plasma by increasing blood flow to leaky postcapillary venules, thus increasing airway edema.10 These findings suggest that endogenous NO is likely to play an important role in modulating bronchial microcirculation. Therefore, it seems likely that excessive production of NO contributes to the increase in airway vascular permeability in asthmatics.

The importance of the vascular phenomena in exercise-induced airway narrowing has previously been suggested.2 The bronchial circulation arises from the aorta and supplies the trachea, extrapulmonary, and intrapulmonary airways. In asthmatics, the bronchial capillary bed is hypertrophied and hyperplastic. Because of its location and ability to alter its size in the asthmatic state, the bronchial circulation could exert an important influence on airway geometry: vascular engorgement, capillary leakage, and edema formation could induce airway narrowing. Many of the inflammatory mediators thought to cause constriction of bronchial smooth muscle can also cause dilatation and leakage of the mucosal and submucosal capillary beds and induce airway wall thickness. A previous study11 suggested that small increases in wall thickness induced by airway inflammation could produce striking changes in airway responsiveness to various stimuli such as exercise, even when there was a trivial increase in resting airway muscle tone. Thus, mucosal edema may have a profound effect on airway function and can explain the heightened reactivity characteristic of bronchial asthma. Rapid expansion of the blood volume in the peribronchial vascular plexi, capillary leakage, and airway mucosal edema formation induced by endogenous NO may contribute to the airway narrowing after exercise. In the present study, we found that there was a significant correlation between airway vascular permeability index and the severity of EIB. These findings suggest that increased vascular permeability resulting from NO-mediated vascular phenomena induced airway wall edema and followed exercise-induced airway narrowing. ß2-Agonists like albuterol may thus not only prevent EIB by their action on bronchial smooth muscle but also by tightening of the endothelium (prevention of endothelial cell contraction) and in their capacity to increase the rate of water transport to the airway surface, leading to removal of airway edema fluid.12

A previous study13 suggested that hypertonic saline solution aerosols we used in this study increased vascular permeability in a dose-dependent fashion. Moreover, hyperosmolarity, which is believed to mimic the stimulus responsible for EIB, is known to cause vasodilation and plasma leakage mediated by endogenous NO.14 A more recent study15 determined that NO plays an intimate role in the development of airway obstruction that follows hyperpnea, which also mimics the stimulus of EIB. These findings suggested that NO is a crucial mediator in the response of mucosal microcirculation to the hypertonic and thermal stimulus. In asthmatic patients, the presence of inflammatory cells and their cytokines makes the concept of microvascular leakage very tenable. Indeed, sensory neuropeptides also induced microvascular leakage, leading to airway wall edema and extravasation of plasma into the airway lumen.16 The receptor antagonists of sensory neuropeptides thus improved the area under the curve of the percentage fall in FEV1 and recovery time after exercise without attenuating the maximal airway narrowing evoked by exercise.17 In the present study, we found that magnitude of airway vascular permeability stimulated by hypertonic saline solution, but not that of eosinophilic inflammation, is a sensitive marker of the severity of EIB. Asthmatic airway inflammation therefore may be a heterogeneous process of which sputum eosinophilia is only one part, and it may be that sputum eosinophilia and airway vascular permeability reflect different components of the inflammatory process.

In summary, our findings suggest that increased airway vascular permeability via excessive production of NO correlates with the severity of EIB in asthmatics, and that assessment of albumin flux in airway lining fluid stimulated by hypertonic saline solution is a good predictor of the severity of EIB.


   Footnotes
 
Abbreviations: AUC0–30 = area under the curve of the percentage fall in FEV1 plotted against time for 30 min; ECP = eosinophil cationic protein; EIB = exercise-induced bronchoconstriction; NO = nitric oxide

Supported by grant-in-aid for Scientific Research (13670611) from the Ministry of Education, Science and Culture, Japan.

Received for publication July 27, 2001. Accepted for publication January 15, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Anderson, SD (1984) Is there a unifying hypothesis for exercise-induced asthma?. J Allergy Clin Immunol 73,660-665[CrossRef][ISI][Medline]
  2. McFadden, ER (1990) Hypothesis: exercise-induced asthma as a vascular phenomenon. Lancet 335,880-882[CrossRef][ISI][Medline]
  3. Barnes, PJ, Belvisi, MG (1993) Nitric oxide and lung disease. Thorax 48,1034-1043[ISI][Medline]
  4. Kanazawa, H, Hirata, K, Yoshikawa, J (2000) Role of endogenous nitric oxide in exercise-induced airway narrowing in patients with bronchial asthma. J Allergy Clin Immunol 106,1081-1087[CrossRef][ISI][Medline]
  5. . American Thoracic Society (1987) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 136,225-244[ISI][Medline]
  6. Kanazawa, H, Shoji, S, Yamada, M, et al (1997) Increased levels of nitric oxide derivatives in induced sputum in patients with asthma. J Allergy Clin Immunol 99,624-629[CrossRef][ISI][Medline]
  7. Eggleston, PA, Guerrant, JL (1976) A standard method of evaluating exercise-induced asthma. J Allergy Clin Immunol 58,414-425[CrossRef][ISI][Medline]
  8. Makker, HK, Lau, LC, Thomson, HW, et al (1993) The protective effect of inhaled leukotriene D4 receptor antagonist ICI204219 against exercise-induced asthma. Am Rev Respir Dis 147,1413-1418[ISI][Medline]
  9. Barnes, PJ (1995) Nitric oxide and airway disease. Ann Med 27,91-97
  10. Miura, M, Ichinose, M, Kageyama, N, et al (1996) Endogenous nitric oxide modifies antigen-induced microvascular leakage in sensitized guinea pig airways. J Allergy Clin Immunol 98,144-151[CrossRef][ISI][Medline]
  11. Laitinen, LA, Laitinen, A, Widdicombe, J (1987) Effects of inflammatory and other mediators on airway vascular beds. Am Rev Respir Dis 135,567-570[ISI][Medline]
  12. Nadel, JA, Widdicombe, JH, Peatfield, AC (1985) Regulation of airway secretions, ion transport, and water movement. Handbook of physiology: the respiratory system I ,419-445 American Physiological Society Bethesda, MD.
  13. Umeno, E, McDonald, DM, Nadel, JA (1990) Hypertonic saline increases vascular permeability in the rat trachea by producing neurogenic inflammation. J Clin Invest 85,1905-1908[Medline]
  14. Smith, TL, Prazma, J, Coleman, CC, et al (1993) Control of the mucosal microcirculation in the upper respiratory tract. Otolaryngol Head Neck Surg 109,646-652[ISI][Medline]
  15. Kotaru, C, Coreno, A, Skowronski, M, et al (2001) Exhaled nitric oxide and thermally induced asthma. Am J Respir Crit Care Med 163,383-388[Abstract/Free Full Text]
  16. Barnes, PJ (1986) Asthma as an axon reflex. Lancet 1,242-245[CrossRef][ISI][Medline]
  17. Ichinose, M, Miura, M, Yamauchi, H, et al (1996) A neurokinin 1-receptor antagonist improves exercise-induced airway narrowing in asthmatic patients. Am J Respir Crit Care Med 153,936-941[Abstract]



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