New insights into pathogenesis of exercise-induced bronchoconstriction.

PURPOSE OF REVIEW: Exercise-induced bronchoconstriction (EIB) refers to acute airflow obstruction that is triggered by a period of physical exertion. Here we review recent findings about the epidemiology of EIB, immunopathology leading to EIB, and the latest understanding of the pathogenesis of EIB. RECENT FINDINGS: Longitudinal studies demonstrated that airway hyper-responsiveness to exercise or cold air at an early age are among the strongest predictors of persistent asthma. Patients that are susceptible to EIB have epithelial disruption and increased levels of inflammatory eicosanoids such as cysteinyl leukotrienes (CysLT)s. The leukocytes implicated in production of eicosanoids in the airways include both a unique mast cell population as well as eosinophils. A secreted phospholipase A(2) (sPLA(2)) enzyme that serves as a regulator of CysLT formation is present in increased quantities in asthma. Transglutaminase 2 (TGM2) is expressed at increased levels in asthma and serves as a regulator of secreted phospholipase A(2) group X (sPLA(2)-X). Further, sPLA(2)-X acts on target cells such as eosinophils to initiate cellular eicosanoid synthesis. SUMMARY: Recent studies have advanced our understanding of EIB as a syndrome that is caused by the increased production of inflammatory eicosanoids. The airway epithelium may be an important regulator of the production of inflammatory eicosanoids by leukocytes.

The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo.

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo-controlled, randomized, double-blind, two-period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise-induced asthma. The patients received placebo or roflumilast (500 microg/day) for 28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1, 14, and 28. FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1, 3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF-alpha level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise-induced asthma. This result was accompanied by a significant reduction of TNF-alpha levels ex vivo. Treatment with roflumilast was safe and well tolerated.

Role of neutral endopeptidase in exercise-induced bronchoconstriction in asthmatic subjects.

The membrane-bound metalloproteinase, neutral endopeptidase (NEP), is a degrading enzyme of both bronchoconstrictor and bronchodilator peptides within the airways. To examine the role of NEP in exercise-induced bronchoconstriction (EIB) in asthmatic subjects, we used inhaled thiorphan, a NEP inhibitor, as pretreatment to a 6-min standardized exercise challenge. Thirteen clinically stable asthmatic subjects participated in this double-blind, placebo-controlled, crossover study that was performed on 2 days separated by 48 h. Thiorphan was administered by two inhalations of 0.5 ml containing 1.25 mg/ml. Subsequently, exercise was performed on a bicycle ergometer at 40-50% of predicted maximal voluntary ventilation while inhaling dry air (20 degrees C, relative humidity 6%). The airway response to exercise was measured by forced expiratory volume in 1 s (FEV1) every 3 min, up to 30 min postexercise challenge, and was expressed both as the maximal percent fall in FEV1 from baseline and as the area under the time-response curve (AUC) (0-30 min). The acute effects of both pretreatments on baseline FEV1 were not different (P > 0.2), neither was there any difference in maximal percent fall in FEV1 between thiorphan and placebo (P > 0.7). However, compared with placebo, thiorphan reduced the AUC by, on average, 26% [AUC (0-30 min, +/-SE): 213.6 +/- 47.7 (thiorphan) and 288.6 +/- 46.0%fall.h (placebo); P = 0.047]. These data indicate that NEP inhibition by thiorphan reduces EIB during the recovery period. This suggests that bronchodilator NEP substrates, such as vasoactive intestinal polypeptide or atrial natriuretic peptide, modulate EIB in patients with asthma.

Increased blood [TAME]-esterase activity during exercise-induced asthma.

Twelve non-atopic asthmatic children who were reported to be suffering from exercise-induced asthma (E-IA), and eight non-asthmatic children, were studied in an attempt to discern possible associations between N-alpha-tosyl-L-arginine methyl ester [TAME]-esterase activity and E-IA, and the late asthmatic responses. Lung function tests and clinical examinations were performed at rest, and immediately and four hours after cycling for 6 min. Concomitant blood investigations revealed a consistent elevation in the asthmatics of [TAME]-esterase activity and peripheral blood eosinophil levels, immediately following exercise. Our findings suggest that E-IA is associated with a certain threshold of [TAME]-esterase activity as measured by a simple and a rapid colorimetric method.

Serum dopamine beta-hydroxylase and free fatty acids in exercise-induced asthma.

Serum dopamine beta-hydroxylase activity, which is thought to reflect noradrenaline secretion, and free fatty acid level were measured in twenty atopic asthmatic children, of whom ten had exercise-induced asthma (EIA), after exercise on the treadmill. There was a significant decrease in the level of serum dopamine beta-hydroxylase activity in the asthmatics who developed EIA and this closely accompanied the onset of airflow obstruction. There was no change in the free fatty acid levels. In contrast, the asthmatics, who did not have EIA showed a significant rise in the levels of dopamine beta-hydroxylase activity and free fatty acids after the same exercise task. Our results suggest that the atopic children studied, who developed EIA, may have had an impaired noradrenaline response to exercise. It is further suggested that this impaired noradrenaline secretion may facilitate mediator release and contribute to the airflow obstruction in EIA.

Changes in angiotensin-converting enzyme activity and angiotensin I level in asthmatic and healthy children after submaximal physical work.

The changes in angiotensin-converting enzyme activity and serum angiotensin I levels have been studied in 16 controls subjected to submaximal physical work. Baseline (Pre-exercise) angiotensin I levels were identical in both groups. Physical exercise caused an elevation that was more marked in the asthmatic group than in the control group. The activity of serum angiotensin-converting enzyme differed in the two groups even before physical exercise, the asthmatic children having exhibited an activity level significantly lower than that of the healthy controls. after submaximal work, the enzyme activity increased in healthy subjects but decreased in asthmatic children.