Mechanisms of asthma and allergic inflammation
Airway immunopathology of asthma with exercise-induced bronchoconstriction

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Background

Exercise-induced bronchoconstriction (EIB) is a common cause of symptoms in a subgroup of asthmatic subjects. The pathobiology that makes this group of asthmatic subjects susceptible to bronchoconstriction after a brief period of exercise remains poorly understood.

Objective

We sought to determine whether there are differences in lower airway inflammation and production of cytokines and eicosanoids between asthmatic subjects with and without EIB.

Methods

Two distinct groups of asthmatic subjects based on a priori definitions were identified, one with moderate-to-severe EIB and the other without significant bronchoconstriction after exercise challenge. Both groups met the definition of asthma on the basis of bronchodilator response, bronchial hyperresponsiveness, or both. A comparative immunopathology study was conducted by using induced sputum to identify differences in lower airway inflammation and production of cytokines and eicosanoids.

Results

The groups had similar baseline lung function and bronchodilator response and did not have any asthma exacerbations within the prior year. The concentration of columnar epithelial cells was markedly higher in the group with EIB (1.4 × 105 vs 2.9 × 104 cells/mL, P = .01). The concentration of eosinophils was higher in the group with EIB (3.6 × 104 vs 4.9 × 103 cells/mL P = .04). Cysteinyl leukotrienes (CysLTs; 727.7 vs 151.9 pg/mL, P = .01) and the ratio of CysLTs to prostaglandin E2 (1.85 vs 1.04, P = .002) in the airways were higher in the group with EIB.

Conclusion

Injury to the airway epithelium, overexpression of CysLTs, relative underproduction of prostaglandin E2, and greater airway eosinophilia are distinctive immunopathologic features of asthma with EIB.

Section snippets

Subjects

The University of Washington Institutional Review Board approved the study protocol, and written informed consent was obtained from all participants. Subjects 18 to 59 years of age were recruited who had a physician's diagnosis of asthma for 1 year or longer and used only an inhaled β2-agonist for asthma treatment. In accordance with a priori definitions, asthmatic subjects with EIB (EIB+ group) were identified with a 30% or greater decrease in FEV1 after exercise challenge, and asthmatic

Subject characteristics

The characteristics of each of the groups are listed in Table I. The diagnosis of asthma was confirmed in the EIB group by a 12% or greater bronchodilator response in 4 participants and by a methacholine PC20 of 8 mg/mL or less (mean, 2.8 mg/mL; range, 0.25-8 mg/mL) in 6 participants. There were no differences in baseline lung function or response to the administration of a bronchodilator between the 2 groups. None of the patients in either group reported an asthma-related emergency department

Discussion

Asthma is a phenotypically diverse syndrome that is defined in part by the presence of increased BHR.1 The degree and type of BHR is variable among patients with asthma. The severity of direct BHR is related to baseline lung function,24 possibly indicating structural remodeling of the lung. In contrast, indirect BHR is measured by the response to stimuli, such as exercise, hypertonic aerosols, and AMP, and is thought to act indirectly through the release of inflammatory mediators into the

Acknowledgments

We greatly appreciate the technical assistance of Linda Deller, Patricia McDowell, Peter Meyer, John Smith, and Jon Rudzinski. We thank Dr Lianne Sheppard for her guidance on the biostatistics.

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    Supported by a National Institutes of Health grant HL04231 (TSH) and an American Lung Association Clinical Research Grant (TSH).

    Disclosure of potential conflict of interest: Dr Hallstrand has given lectures (2001-2004) in sessions at regional and national meetings, which were funded in part by Merck & Co, Inc, and received research support from a Merck & Co Medical School grant awarded to the University of Washington in 2000. Mr Moody does not have a financial relationship with a commercial entity that has an interest in the subject of this article. Dr Aitken does not have a financial relationship with a commercial entity that has an interesting the subject of this article. Dr Henderson has given lectures (2001-2004) in sessions at regional, national, and international meetings, which were funded in part by Merck & Co, Inc, and received research support from a Merck & Co Medical School grant awarded to the University of Washington in 2002.

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