Over the past decade, concerns have been raised about the effects of heavy exercise on airway health because higher than expected rates of asthmalike symptoms and airway hyperresponsiveness, which is defined as an increase in the ease and degree of bronchoconstriction in response to external stimuli, occur in elite athletes of different sports, such as swimmers or skiers (4,18,19,21,24). Increased ventilation during exercise is believed to potentiate environmental exposures to dry and cold air in skiers (24), irritants in swimmers (18), and allergens in summer sports participants (19). Most studies, however, regarded elite athletes developing respiratory symptoms after heavy exercise, whereas little is known on airway responsiveness in relation to training or acute exercise in nonasthmatic, nonelite athletes, who represent a much larger population than top athletes.
The level of physical activity has never been considered as possibly important in modulating airway responsiveness. Deep inspirations are known to play a central role in opposing airway narrowing in healthy subjects (30). We hypothesized that endurance training may evoke adaptations in the airway by repeated lung inflation-induced stretches of airway smooth muscle associated with exercise. Therefore, we first tested whether airways responsiveness at rest differed between nonasthmatic, nonelite athletes and sedentary, nonasthmatic controls. We then examined the effects of acute exercise on airway responsiveness in a subgroup of the same athletes after a marathon race.
Airway hyperresponsiveness in athletes might be associated with airway inflammation. The association between these two factors is controversial, however. In elite swimmers, a significant relationship was found between airway hyperresponsiveness and increased sputum eosinophils (18). On the other hand, no relationship between airway responsiveness and inflammation could be found in cross-country skiers (21). We previously reported that nonelite runners showed marked airway neutrophilia and increased concentration of exhaled nitric oxide (NO) after a marathon race compared with baseline (5), suggesting that exhaled NO, which is believed to reflect airway inflammation, may correlate with airway inflammation in athletes. NO, however, also acts as a bronchodilator (23,34) and might be involved in the modulation of bronchial tone and, consequently, airway responsiveness after exercise (9). We therefore assessed whether changes in NO could be associated with the response to methacholine in the absence of deep inspirations.
We studied 20 nonelite long-distance runners and 20 healthy sedentary subjects of comparable age (Table 1). Control subjects were considered sedentary if they exercised less than 2 h·wk−1. None of the athletes was a current or exsmoker, whereas two sedentary subjects were light smokers (1.25 and 2.5 packs-per-year history). One athlete reporting a history of allergic rhinitis was under no treatment and asymptomatic at the time of the study. No subject reported any symptom compatible with asthma, nor received any treatment for upper or lower respiratory or inflammatory problems. Subjects were excluded from the study if they reported an upper respiratory infection in the preceding 4 wk. Coffee or tea were not allowed in the morning before a test. The protocol was approved by the ethics committee of the University of Palermo, and each subject gave written informed consent.
Medical history was obtained from each subject, followed by physical examination, routine spriometry, and conventional methacholine bronchoprovocation test as previously described (5,28). Briefly, baseline spirometry was obtained by a computerized water-sealed spirometer (Biomedin; Padua, Italy), according to American Thoracic Society (ATS) criteria (3). Then, sterile diluent [phosphate-buffered saline (PBS) solution] and increasing concentrations of methacholine (0.025, 0.075, 0.25, 0.75, 2.5, 7.5, and 25 mg·mL−1) were delivered through an ampul-dosimeter (Mefar Elettromedicali; Bovezzo, Italy) activated by inspiratory efforts. Diluent and methacholine were inhaled during five slow breaths, from forced residual capacity (FRC) to TLC. Spirometry was obtained 3 min after inhaling diluent or each methacholine concentration, and the best FEV1 among three consecutively acceptable spirometric maneuvers was recorded at each step. The test was stopped when FEV1 dropped by 20% from the postdiluent value, or after a methacholine concentration of 25 mg·mL−1 had been delivered. For a subject to enter the subsequent phase of the study, the standard methacholine challenge had to be negative (i.e., FEV1 decreased by less than 20% after methacholine 25 mg·mL−1). During the screening phase, no runner was excluded as a result of this criterion.
Single-dose methacholine tests in the absence of deep inspirations.
To evaluate airway responsiveness in the absence of deep inspirations, we performed single-dose methacholine bronchoprovocation as previously described (30,31). Our experience indicates that this procedure is sensitive and well suited to study airway reactivity in healthy subjects (30), and different responses to single doses of methacholine exist even among healthy subjects (30,32). The concentration of methacholine causing at least 20% reduction in FEV1 was determined in each subject by a series of single-dose (20, 40, and 75 mg·mL−1) methacholine bronchoprovocation carried out in the absence of deep breaths. If the first concentration was ineffective, the challenge was repeated with the higher concentration, until the expected level of reduction in FEV1 was attained or the highest concentration was delivered. The single-dose bronchoprovocation was repeated on the same day (at least 2 h after the previous single-dose challenge) if the reduction in FEV1 from baseline induced by the previous single-dose challenge was less than 5%, or on the following day if FEV1 had dropped by more than 5%.
The detailed protocol for the single-dose methacholine provocation is depicted in Figure 1. At baseline, three acceptable combined partial–maximal spirometric maneuvers were obtained (see below). Subjects were then instructed to breathe quietly and to avoid deep inspiratory maneuvers (to total lung capacity) for 20 min. Thereafter, subjects inhaled the single methacholine dose during five tidal breaths and, 3 min later, a single combined partial–maximal spirometry was repeated.
Because the deep inspiratory maneuver of conventional spirometry can attenuate the response to methacholine (30), we modified spirometry by incorporating a partial forced expiratory maneuver (from end tidal inspiration to residual volume) immediately before the maximal forced expiratory maneuver (Fig. 2). Using this combination of a partial and a maximal expiratory maneuver, the inspiratory vital capacity (IVC) (i.e., the volume from the end of the forced partial expiratory maneuver to the end of the maximal inspiration) was recorded. The difference between the postmethacholine IVC and the best IVC from the three acceptable measurements was expressed as percent change from baseline. Because TLC remains unchanged (22), methacholine-induced changes in IVC reflect changes in residual volume. Because IVC depends on the residual volume attained by a partial expiratory maneuver, it offers the advantage of not being affected by a preceding deep inspiration.
To assess the effect of prolonged exercise on airway responsiveness, six runners were also studied by the same protocol approximately 1 h after finishing the Palermo International Marathon (December 8, 2001). Table 2 reports the weather and air quality data recorded during the race. Subjects were tested by methacholine at 75 mg·mL−1, both at rest (between 10 and 14 d prerace) and after the race. Spirometry (PDS Koko, Lousville, CO) and blood samples (see below) were obtained in each athlete within 15 min after completion of the race. The athletes were then transported to the hospital for the single-dose methacholine challenge, which was performed at 1 h after completing the marathon. At 4–6 wk after the marathon race, the same methacholine challenge was repeated under resting conditions.
For the six athletes running the marathon race, blood samples were obtained from the subject’s antecubital vein at rest, 10–14 d prerace, and within 15 min after completing the marathon to measure plasma cortisol and catecholamine levels. Baseline plasma levels of catecholamine were also measured in six sedentary controls. For plasma cortisol, blood was drawn into sterile tubes containing EDTA (Vacutainer, Becton Dickinson, San Jose, CA), and cortisol levels assessed by radioimmunoassay (Immunotech, SA, Marseille, France) according to manufacturer instructions (sensitivity 0.36 mg·dL−1). For catecholamine, blood samples were drawn into ice-cold glass tubes containing glutathione and EDTA, and spun at 2000 × g for 20 min, at 4°C. Plasma was separated and stored at −80°C. Plasma catecholamine assay was performed by a commercial kit (ESA, Chelmsford, MA).
Exhaled NO measurements.
Before single-dose methacholine bronchoprovocation tests, exhaled NO concentration was measured by chemiluminescence (Sievers Instruments, Boulder, CO). Exhaled NO was measured in triplicate at a constant expiratory flow of 50 mL·s−1 against a respiratory resistance of 20 cm of H2O, and the mean value was recorded for analysis (2).
Data are reported as means ± SD. Unpaired t-tests were used to compare the runner and sedentary groups with respect to age, baseline lung function, concentration of methacholine required to induce the targeted reductions in lung function in the absence of deep inspirations, and changes in IVC and FEV1 from baseline in the absence of deep inspirations. Paired t-test was employed to compare baseline levels of cortisol, catecholamine, and NO with those obtained immediately after the marathon race. ANOVA for repeated measures with Fisher’s correction was used to assess differences in lung function variables at different time points in the athletes who ran the marathon. Relationships between variables were analyzed by simple linear regression. Multiple regression was used to assess whether lung volumes and training status influenced postmethacholine IVC. In all analyses, P values less than 0.05 were considered statistically significant.
Baseline differences between athletes and sedentary controls.
The two study groups were similar for age and gender distribution (Table 1). In athletes, mean training volume was 68 km·wk−1 (range 40–100), and racing experience was 11 ± 8 yr (mean ± SD). Lung volumes were higher in nonelite runners compared with sedentary controls, as expected (7,10,17). FEV1/FVC was the same in both groups, and by means of FEV1 no subject had evidence of bronchial obstruction at baseline. FRC was significantly higher in runners compared with controls (P = 0.005), whereas residual volume was not different (P = 0.31).
By conventional methacholine challenge, no subject reached a measurable PC20. FEV1 at the highest methacholine concentration of 25 mg·mL−1 decreased on average by 3.3 ± 4.9% in athletes and by 7.2 ± 6.1% in sedentary controls (P = 0.01).
Effect of endurance training on deep inspiration-devoid bronchoprovocation.
After single-dose methacholine challenge at rest, IVC decreased by 10.5 ± 8.1% in nonelite runners and by 24.3 ± 16.1% in sedentary controls (P = 0.002). In absolute values, the mean difference in IVC (baseline vs postmethacholine) was 0.55 ± 0.46 L in runners and 1.06 ± 0.74 L in the control group (P = 0.01).
All athletes received the highest single dose of methacholine (concentration: 75 mg·mL−1) without reaching the safety cutoff of 20% reduction in FEV1. In contrast, all but two sedentary subjects reached this cutoff; five subjects reacted at a methacholine concentration of 20 mg·mL−1, five subjects at 40 mg·mL−1, and ten at 75 mg·mL−1 (group mean methacholine concentration: 52.5 ± 24 mg·mL−1, P = 0.0002 vs runners). The percent reduction in FEV1 at the highest dose of methacholine was 12.3 ± 9.4% in runners and 33.9 ± 14.9% in sedentary controls (P < 0.0001).
To account for the variability in the dose of methacholine used in the two groups, we calculated the ratio of the IVC reduction after single-dose methacholine challenge and the concentration of methacholine used. This ratio, which is termed reactivity index (Fig. 3), was fivefold lower in nonelite athletes (0.14 ± 0.11) compared with sedentary controls (0.71 ± 0.63, P < 0.0005). The reactivity index in runners did not correlate with the amount of weekly training (r = 0.10, P = 0.67) or the years of running experience (r = 0.26, P = 0.27).
Finally, we evaluated whether the difference in airway responsiveness between the two groups might be accounted for by different baseline lung volumes. By simple regression analysis, TLC did not correlate with percent reduction in IVC in runners (r = 0.30, P = 0.28) or in controls (r = 0.08, P = 0.82); similar findings were obtained for FRC (runners: r = 0.25, P = 0.38; controls: r = 0.36, P = 0.23). Analysis of TLC or FRC as percent of predicted yielded similar results. Multiple regression analysis, with TLC (or FRC) and the study subject group (runners or controls) as independent variables, and the percent reduction in IVC as dependent variable, showed a significant effect of the subject group (P = 0.03 for both analyses) but not of TLC (P = 0.83) or FRC (P = 0.53).
Effect of acute exercise on deep inspiration-devoid bronchoprovocation.
None of the six athletes who ran the marathon reported cough, wheeze, chest tightness, or excess airway mucus production after the race. Mean race time was 220 ± 46 min. Spirometric measurements obtained in marathon runners by 15 min postrace (Table 3) did not include IVC measurements (field measurements). ANOVA indicated significant changes in FEV1, FVC, and FEF25–75. Compared with resting values, FEV1 and FVC decreased immediately after the race by 6.3 ± 2.8 and 2.8 ± 1.5%, respectively (mean ± SD, P = 0.02 and P = 0.01 by post hoc analysis), but FEV1/FVC was unchanged. Also, the reduction in FEF25–75 was 10.8 ± 10.7%. The largest reduction in FEV1 observed was 9.6% in one subject only, with the reduction in FVC being 4.4%. Individual data are shown in Table 4. Two subjects showed modest, but significant, decreases in FEF25–75, suggesting that bronchospasm was operative in those two runners (26). Because of this apparent postexercise bronchospasm, these two runners may have been in a refractory period that protected them from spasm during the 1-h postmarathon challenge. At 60 min after the completion of the marathon race (i.e., before the postrace methacholine challenge), spirometric values had returned to resting values. Spirometry was again similar to resting values when the same subjects were retested at rest 4–6 wk postrace.
The reduction in IVC from baseline was lower at 60 min postrace (−6.3 ± 4.4%) than at rest (−10.0 ± 6.7%), although the difference was not significant (ANOVA: P = 0.53. Methacholine-induced changes in FEV1 showed a statistically significant difference (P = 0.01), because FEV1 decreased by 5.5 ± 1.4% after the race, as opposed to −12 ± 3.3 and −11.5 ± 6.9% for challenges 10–14 d prerace and 4–6 wk postrace, respectively.
Plasma epinephrine and norepinephrine levels were 177 ± 30 and 313 ± 40 pg·mL−1, respectively, in runners at rest, and almost doubled after the marathon (epinephrine: 323 ± 33 pg·mL−1, norepinephrine: 506 ± 37 pg·mL−1, P < 0.01 vs baseline for both). Resting catecholamine levels in sedentary controls were similar to those of the athletes (epinephrine: 172 ± 37 pg·mL−1, P = 0.89; norepinephrine: 260 ± 30 pg·mL−1, P = 0.34).
Exhaled NO in runners was higher after the marathon than at rest (14.9 ± 1.2 vs 5.3 ± 0.6 ppb; P = 0.002), confirming our previous data (4). Similarly, plasma cortisol significantly increased after the marathon compared with the resting state (28 ± 1.8 vs 15.1 ± 3.3 μg·dL−1, P = 0.03). Changes in exhaled NO, plasma cortisol, or catecholamine concentrations, however, did not correlate with the differences in methacholine-induced IVC and FEV1 reductions.
Baseline differences between athletes and sedentary controls.
This study tested the hypothesis that endurance training and exercise may contribute to modulate airway responsiveness in nonasthmatic, nonelite athletes. At rest, airway responsiveness to single-dose methacholine challenge in the absence of deep inspirations was greatly attenuated in nonelite runners compared with sedentary subjects; after a competitive marathon, the “airway hyporesponsiveness” state of the athletes became more pronounced. Under the conditions of this study and with the assumption that our subjects are representative of nonelite athletes, airway responsiveness, therefore, appeared to be lower in nonasthmatic, nonelite runners than in sedentary individuals.
This is the first study employing the single-dose methacholine challenge test in the absence of deep inspiration in athletes. When deep inspirations are avoided, healthy subjects respond to single-dose methacholine bronchoprovocation with measurable reductions in lung function (30). This bronchoprovocation test is safe and reliable, and has been applied in young (30) and old (28) healthy subjects, and in patients with asthma or chronic obstructive pulmonary disease (COPD) (31,33).
An inhaled spasmogen such as methacholine is expected to have an impact on both lung volume and expiratory flow parameters. Although relationships between flow and volume exist, these two elements may also be somewhat independent of each other. This study was not designed to evaluate partial flow parameters, but rather concentrated on lung volume changes. Further studies are needed to assess whether partial flow measurements will provide additional information.
Conventional methacholine challenge versus no deep inspiration methacholine challenge.
Both runners and sedentary controls were clinically classified as normoreactive to methacholine, but the conventional methacholine challenge caused smaller reduction in lung function in athletes than in controls. Given that the outcome of the conventional provocation protocol depends, among other factors, on the protective and dilatory effects of deep inspiration, our approach to eliminate the deep breath effect using the single-dose challenges appears appropriate. Indeed, our data clearly show that the hyporesponsiveness of athletes is at least partly caused by factors unrelated to deep inspiration. Because of the multiple pathophysiologic mechanisms involved in exaggerated airway narrowing, the results of various bronchoprovocation challenges can differ from each other (1,26), and can provide different and complementary information regarding the pathways that lead to bronchoconstriction. In this scenario, the methacholine bronchoprovocation test explores only one aspect of the airway responsiveness; therefore, the results of the current study describe a physiologic phenomenon of the respiratory system that needs to be confirmed by employing different bronchoconstrictor agents.
Effect of endurance training on the airway response to methacholine.
Our runners not only experienced a minimal fall (−10.5%) in IVC after single-dose methacholine bronchoprovocation in the absence of deep inspirations, but also received higher doses of methacholine than sedentary controls. The reactivity index (see Fig. 3), calculated to take both these factors into account, was fivefold lower in runners compared with controls. Differences in airway responsiveness could be caused by higher lung volumes in runners than in controls, but baseline TLC and FRC did not correlate with single-dose methacholine-induced bronchoconstriction. Higher lung volumes could also result in greater inflation pressures during deep inspirations in athletes; however, maximal inspiratory strength did not differ between marathon runners and sedentary controls (11). Our results argue against low airway responsiveness of runners being causally related to high baseline lung volumes.
We favor the interpretation that endurance exercise may affect airway smooth muscle through hyperventilation and changes in breathing pattern. Increased ventilation during exercise depends more on increased tidal volume than on respiratory frequency (28), and the former was shown to reduce the response to methacholine in acute studies on anesthetized, mechanically ventilated dogs (29). Moreover, exercise caused a reduction in airway resistance in healthy subjects (14), which was also induced by voluntary hyperventilation. A direct effect of ventilation during exercise on airway responsiveness, therefore, is a reasonable hypothesis.
Increasing amplitude and duration of length oscillations applied to relaxed airway smooth muscle decrease its force generation (35). In vitro, a 3% increase in smooth muscle length reduced force generation by 50%, a result similar to the effect of isoproterenol (15). This can be explained by bridge dynamic disruption (13) and plastic reorganization of the cytoskeleton (16), both decreasing airway smooth muscle contractility. After a deep inspiration, airway smooth muscle length can increase by 12% from baseline (13). We, therefore, speculate that, in nonasthmatic subjects, habitual endurance exercise may induce permanent changes within the airway smooth muscle that result in decreased contractility.
Effect of acute exercise on airway response to methacholine.
We also tested whether airway responsiveness in our athletes may be influenced by habitual training volume or running experience, but found no significant correlation. It is likely that, given the multiple determinants of airway reactivity, this issue can be addressed only in studies on very large samples of athletes. We theorized that prolonged high intensity exercise may increase the mechanical strain on airway smooth muscle, thus magnifying the airway hyporesponsiveness recorded in athletes at rest. As expected (26,27), spirometric parameters decreased shortly after the marathon: bronchospasm (26), or early closure of small airways and increased residual volume following acute accumulation of extravascular lung water (27). When postmarathon methacholine bronchoprovocation data were obtained, however, lung function had returned to the resting values, and FEV1, but not IVC, decreased less compared with the challenge performed at rest. The discrepancy between the behavior of these two variables may be explained by the dilatory effect exerted by the single deep inspiratory maneuver involved in the FEV1, but not in the IVC, measurement. This effect appeared enhanced by the marathon race. The absence of exercise-induced bronchoconstriction in four of the six runners rules out the possibility of low responsiveness of the airways against spasmogens being attributed to the refractory period that follows bronchospasm in these four runners (8,12).
We measured exhaled NO, plasma catecholamine level, and cortisol to assess whether they may correlate to postrace changes in airway function or responsiveness. As for the rationale of the NO measurement, transgenic mice overexpressing NO synthase-2 in bronchial epithelial cells showed decreased responsiveness to methacholine associated with doubled exhaled NO concentration (20). Despite the significant postrace elevations in these three variables, they did not correlate with the changes in airway responsiveness. This was somehow expected, because field studies do not allow recruitment of large samples.
Limitations of the current study.
Among other possible limitations of our study, we did not assess whether our subjects were atopic by prick tests. No clinical evidence or positive history of atopy was noted in our subjects. In addition, the Mediterranean climate makes our data not applicable to athletes chronically exposed to extreme environmental conditions during exercise. Also, the possibility exists that our athletes have maintained healthier diets and lifestyles (i.e., avoiding passive smoking exposure or excessive alcohol consumption) that, in turn, could play a protective role on airway reactivity.
In conclusion, habitual endurance training and exercise appear to attenuate airway responsiveness against a direct spasmogen inhaled in the absence of deep inspirations in nonasthmatic, nonelite runners. At present, we do not know the amount of training necessary for such airway hyporesponsiveness to develop, or whether this phenomenon is restricted to runners or occurs in other endurance athletes. The hypothesis that a subgroup of subjects has an inherited predisposition at the airway level favoring endurance activities cannot be excluded; however, our observations suggest that a sedentary lifestyle may have an impact on airway function and favor development of airways hyperresponsiveness and asthma in predisposed individuals. These concepts merit further exploration in nonelite and elite athletes, and in subjects with bronchial asthma.
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Keywords:©2005The American College of Sports Medicine
ATHLETES; ENDURANCE TRAINING; BRONCHIAL REACTIVITY; METHACHOLINE; LUNG INFLATION; MARATHON RACE