Inflammatory basis of exercise-induced bronchoconstriction

Abstract

Rationale: Exercise-induced bronchoconstriction (EIB) is a highly prevalent condition with unclear pathogenesis. Two competing theories of the pathogenesis of EIB differ regarding the inflammatory basis of this condition.

Objectives: Our goals were to establish whether epithelial cell and mast cell activation with release of inflammatory mediators occurs during EIB and how histamine and cysteinyl leukotriene antagonists alter the airway events occurring during EIB.

Methods: Induced sputum was used to measure mast cell mediators and eicosanoids at baseline and 30 minutes after exercise challenge in 25 individuals with asthma with EIB. In a randomized, double-blind crossover study, the cysteinyl leukotriene antagonist montelukast and antihistamine loratadine or two matched placebos were administered for two doses before exercise challenge.

Main results: The percentage of columnar epithelial cells in induced sputum at baseline was associated with the severity of EIB. After exercise challenge, histamine, tryptase, and cysteinyl leukotrienes significantly increased and prostaglandin E(2) and thromboxane B(2) significantly decreased in the airways, and there was an increase in columnar epithelial cells in the airways. The concentration of columnar epithelial cells was associated with the levels of histamine and cysteinyl leukotrienes in the airways. Treatment with montelukast and loratadine inhibited the release of cysteinyl leukotrienes and histamine into the airways, but did not inhibit the release of columnar epithelial cells into the airways.

Conclusions: These data indicate that epithelial cells, mast cell mediators, and eicosanoids are released into the airways during EIB, supporting an inflammatory basis for EIB.

Figures

Figure 1.

Relationship between the percentage of columnar epithelial cells in induced sputum at baseline and the severity of exercise-induced bronchoconstriction (EIB) as measured by the maximum fall in FEV1 over the first 15 minutes after exercise challenge.

Figure 2.

Effects of exercise challenge on the concentrations of columnar epithelial cells (a), lymphocytes (b), and macrophages (c) in persons with asthma and EIB. Comparisons were made between baseline and 30 minutes after exercise separated by an average of 9.9 days (range, 4–18 days). The box plots show the median (line), interquartile range (box), and the 10th and 90th percentiles (whiskers).

Figure 3.

Effects of exercise challenge on the levels of mast cell mediators (a and b) and eicosanoids (c–f) in induced sputum of individuals with asthma with EIB. Comparisons were made between baseline and 30 minutes after exercise challenge on separate days an average of 9.9 days apart (range, 4–18 days). The figures show the individual data points and the geometric mean value. The levels of histamine, tryptase, and CysLTs significantly increased, and PGE2 and TXB2 significantly decreased.

Figure 4.

Relationships between the concentrations of CysLTs (upper panel) and histamine (lower panel) and the concentration of epithelial cells in induced sputum after exercise challenge in individuals with asthma with EIB.

Figure 5.

FEV1 (mean ± SEM) before and after exercise challenge after two doses of montelukast and loratadine or two matched placebos 36 and 12 hours before exercise challenge in a randomized, double-blind crossover study. Treatment with montelukast and loratadine significantly reduced the severity of EIB (p < 0.001).

Figure 6.

Symptoms of dyspnea (mean ± SEM) according to the Borg scale (0–10) during the final 6 minutes of exercise at greater than 85% of maximum heart rate and over the 15 minutes after exercise challenge in persons with asthma and EIB. After exercise challenge there was a significant reduction in symptoms of dyspnea at all time points during treatment with montelukast and loratadine (p

Figure 7.

Effects of treatment with montelukast and loratadine on the levels of mast cell mediators (a and b) and eicosanoids (c–f) in induced sputum 30 minutes after exercise challenge in individuals with asthma with EIB. Comparisons were made between treatment with montelukast and loratadine as compared with administration of two matched placebos an average of 6.8 days apart (range, 4–14 days). The figures show the individual data points and the geometric mean value. The levels of histamine and CysLTs significantly decreased.