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Published ahead of print on August 6, 2003, doi:10.1164/rccm.200303-373OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 1181-1189, (2003)
© 2003 American Thoracic Society

Fish Oil Supplementation Reduces Severity of Exercise-induced Bronchoconstriction in Elite Athletes

Timothy D. Mickleborough, Rachael L. Murray, Alina A. Ionescu and Martin R. Lindley

Department of Kinesiology, Indiana University, Bloomington, Indiana; School of Sport Science, Physical Education, and Recreation, University of Wales Institute, Cardiff; and Section of Respiratory Medicine, University of Wales College of Medicine, University Hospital of Wales and Llandough Hospital, NHS Trust, Penarth, United Kingdom

Correspondence and requests for reprints should be addressed to Timothy D. Mickleborough, Ph.D., Department of Kinesiology, Indiana University, 1025 East 7th Street, HPER 112, Bloomington, IN 47401. E-mail: tmickleb{at}indiana.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In elite athletes, exercise-induced bronchoconstriction (EIB) may respond to dietary modification, thereby reducing the need for pharmacologic treatment. Ten elite athletes with EIB and 10 elite athletes without EIB (control subjects) participated in a randomized, double-blind crossover study. Subjects entered the study on their normal diet, and then received either fish oil capsules containing 3.2 g eicosapentaenoic acid and 2.2 g docohexaenoic acid (n-3 polyunsaturated fatty acid [PUFA] diet; n = 5) or placebo capsules containing olive oil (placebo diet; n = 5) taken daily for 3 weeks. Diet had no effect on preexercise pulmonary function in either group or on postexercise pulmonary function in control subjects. However, in subjects with EIB, the n-3 PUFA diet improved postexercise pulmonary function compared with the normal and placebo diets. FEV1 decreased by 3 ± 2% on n-3 PUFA diet, 14.5 ± 5% on placebo diet, and 17.3 ± 6% on normal diet at 15 minutes postexercise. Leukotriene (LT)E4, 9{alpha}, 11ß-prostaglandin F2, LTB4, tumor necrosis factor–{alpha}, and interleukin-1ß, all significantly decreased on the n-3 PUFA diet compared with normal and placebo diets and after the exercise challenge. These data suggest that dietary fish oil supplementation has a markedly protective effect in suppressing EIB in elite athletes, and this may be attributed to their antiinflammatory properties.

Key Words: exercise-induced asthma • diet • omega-3 polyunsaturated fatty acids • cytokines • eicosanoids

Exercise-induced bronchoconstriction (EIB) is a condition characterized by transient airway narrowing during (1) or after (2, 3) exercise, resulting in decrements in postexercise pulmonary function. A high prevalence of EIB and asthma-like symptoms, such as wheezing, chest tightness, abnormal breathlessness, cough, and/or sputum production have been reported in the elite athlete population (4–10). Collectively, these data suggest that EIB is more prevalent in elite athletes compared with non-elite athletes and the general population. This relatively high incidence of EIB in elite athletes may be due to exercise hyperventilation, prolonged exposure to allergens and bronchial irritants, and excessive inhalation of cold, dry air (7, 11).

The mechanisms responsible for bronchial hyperreactivity after exercise in patients with asthma have been extensively investigated (12, 13). However, EIB in elite athletes is less understood and likely involves multiple mechanisms. It has been suggested that transient dehydration of the airways activates the release of inflammatory mediators, such as histamine, neuropeptides, and arachidonic acid (AA) metabolites (leukotrienes [LTs] and prostaglandins [PGs]), from airway cells (2, 13, 14), resulting in bronchial smooth muscle contraction. On the other hand, it has been suggested that rapid rewarming of the airways after exercise leads to vascular hyperemia and airway edema (12), which would further contribute to the bronchoconstriction. The possibility also exists that repetitive high-intensity exercise itself may contribute to the development of EIB by the release of inflammatory cytokines (15). Recent evidence of airway remodeling in cross-country skiers (16–18), and the fact that EIB in athletes does not respond well to pharmacologic prophylaxis (17), suggests a pathology different from that found in asthma.

Treatment of EIB almost exclusively involves the use of pharmacologic medications. However, there is accumulating evidence that dietary modification can modify the severity of exercise-induced asthma and EIB (19–24). Eicosapentaenoic acid (EPA) and docosahexaenoic acid are omega-3 (n-3) polyunsaturated fatty acids (PUFA) derived from fish oil that competitively inhibit n-6 PUFA AA metabolism and thus reduce the generation of inflammatory 4-series LT and 2-series PG mediators (25) and the production of cytokines from inflammatory cells (26). Consuming fish oil results in partial replacement of AA in inflammatory cell membranes by EPA (25, 26). This response alone is a potentially beneficial antiinflammatory effect of n-3 PUFA. It has been demonstrated that supplementing the diet with n-3 PUFA has reduced AA concentrations in neutrophils and neutrophil chemotaxis, reduced LT generation (25, 27), and reduced airway late response to allergen exposure (28). These data are consistent with the proposed pathway by which dietary intake of n-3 PUFA modulates lung disease. However, clinical data on the effect of fish oil supplementation in asthma have been equivocal. Although no clinical improvement in asthmatic symptoms has been observed in some interventional studies (29–32), other studies have demonstrated an improvement in asthmatic status after n-3 PUFA supplementation (28, 33–37). To date only one study has evaluated the effect of fish oil supplementation on the airway response to exercise in patients with asthma (29). The study demonstrated no significant change after 10 weeks of fish oil supplementation in the maximal postexercise fall in airway conductance compared with presupplementation values.

Because inflammatory mediators have been implicated in the development of EIB in elite athletes (16–18, 38), it seems reasonable to suggest that manipulating dietary n-3 PUFA consumption will influence the severity of EIB. Therefore, the aim of this study was to investigate the effects of high dietary n-3 PUFA ingestion on pulmonary function and proinflammatory mediator and cytokine production in nonasthmatic elite athletes with EIB. We hypothesized that a diet high in n-3 PUFA will improve pulmonary function and reduce several proinflammatory markers in athletes with EIB. Some of the results from preliminary analysis of data from this study have been previously reported in the form of an abstract (39).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Ten subjects with clinically diagnosed EIB and 10 subjects with no history, signs, or symptoms of EIB (control subjects) were recruited from a population of university students and sporting teams throughout Cardiff, UK, who were either ranked at the collegiate or national level in their particular sport (n = 10, triathletes; n = 5, cross-country running; n = 5, track running). Flyers were posted, and visits to sporting teams were made to identify potential subjects with EIB. All subjects with EIB had a history of shortness of breath and intermittent wheezing after exercise, relieved by inhaled bronchodilator therapy (n = 6, salbutamol and n = 4, terbutaline), but were otherwise free of atopic asthma, as diagnosed by their physician. Subjects were not selected if they had a doctor diagnosis of asthma and a history of respiratory complications. All subjects with EIB reported by questionnaire having worse asthmalike symptoms after exercise and increased bronchodilator usage in the winter compared with the summer months. An initial test was conducted to screen all subjects for the presence of EIB, as indicated by a drop of greater than 10% in postexercise FEV1 compared with preexercise values (7, 40). Control subjects were determined to be free of EIB using the same criteria. Each subject completed a health questionnaire and gave written informed consent to participate before enrolment in the study, approved by the University of Wales Institute, Cardiff Research Ethics Committee. Table 1 indicates that the two groups were well matched according to age, physical characteristics, and fitness level.


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  		TABLE 1. Subject characteristics

 
Study Design and Protocol
The study was conduced as a randomized, double-blind crossover trial over 7 consecutive weeks during the months of November and December. All subjects entered the study on their normal (normal) diet (Phase 1), after which they were randomly assigned to either receive 18 capsules of Max-EPA (Seven Seas Ltd., Hull, UK), which consisted of 3.2 g EPA and 2.2 g of docosahexaenoic acid (n = 5, n-3 PUFA diet) or placebo (n = 5, placebo) capsules (Seven Seas Ltd.) containing olive oil for 3 weeks (Phase 2). Thereafter, they followed a 2-week washout period (normal diet) and then switched to the alternative diet for the remaining 3 weeks (Phase 3). Dietary cards were recorded throughout the study period. In addition, all subjects with EIB were asked to record bronchodilator use during the last 2 weeks on the normal diet and during the last 2 weeks of each dietary treatment period.

At the beginning of the study (Phase 1; normal diet) and at the end of each treatment period (Phases 2 and 3) all subjects reported to the laboratory and had venous blood drawn before exercise for neutrophil fatty acid analysis and for the determination of LTB4 and cytokine production (tumor necrosis factor–{alpha} [TNF-{alpha}] and interleukin [IL]-1ß). Additional blood was collected at 15 and 60 minutes postexercise for the determination of LTB4, TNF-{alpha}, and IL-1ß concentration. A single urine sample was collected before exercise and at 15, 60, and 120 minutes postexercise for the determination of urinary LTE4 and 9{alpha}, 11ß-prostaglandin(PG)F2 concentration. Pulmonary function was assessed preexercise and at 1, 5, 10, 15, 30, 45, and 60 minutes postexercise. At the end of the 2-week washout period, all subjects reported to the laboratory to have additional venous blood drawn to verify that neutrophil fatty acid composition, LT, PG, and cytokine concentrations had returned to baseline levels established at the beginning of the study on the normal diet. (See online supplement for additional details on the study design.)

Exercise Challenge Test
All subjects were instructed to avoid both coffee and strenuous physical exertion during the 24 hours before the exercise challenge, and subjects with EIB were instructed to withhold their pulmonary medications for the appropriate time. At an initial screening test conducted on the normal diet and at the end of each treatment period, each subject was required to run on a motorized treadmill (Woodway ELG 2, Rhein, Germany), which was elevated 1% per minute, until volitional exhaustion (40). Each subject wore a nose-clip during the exercise bout to promote mouth breathing, as nasal breathing decreases the water loss from the airways (41). In addition, each subject inspired compressed dry air (relative humidity < 10%) at room temperature (22°C) collected in a 150-L Douglas bag (Cranlea and Co., Birmingham, UK) attached to the inspiratory port of a two-way breathing valve connected to a mouthpiece (42, 43). During the exercise test, heart rate was continuously monitored by ECG (Pulmolab EX670; Morgan Medical Ltd., Gillingham, Kent, UK), and breath-by-breath analysis of expired gases was accomplished by indirect open circuit calorimetry (Pulmolab EX670; Morgan Medical Ltd.) (see online supplement for further details on the exercise challenge test).

Pulmonary Function Tests
Pulmonary function tests were conduced on all subjects using a Superspiro computerized spirometer (Micro Medical Ltd., Rochester, Kent, UK). Subjects were required to perform three acceptable FVC maneuvers according to the American Thoracic Standardization of Spirometry (44) (see online supplement for further details).

Urinary LTE4 and 9{alpha}, 11ß-PGF2 Quantification
Urinary LTE4 was measured by a modified HPLC–radioimmunoassay originally described by Tagari and coworkers (45) and used clinically to determine changes in urinary LTE4 levels in subjects with EIB after exercise challenge (46). Cross-reactivity of the LTE4 antibody against an array of related compounds was: LTE4, 100%; LTE5, 78.14%; LTC4 and LTD4, 18.12%; LTB4, 6-trans-LTB4, 20-OH-LTB4, PGD2, and thomboxane(TX)B2, less than 0.01%, etc. Urinary 9{alpha}, 11ß-PGF2 analysis was performed by enzyme immunoassay. Cross-reactivity of the 9{alpha}, 11ß-PGF2 antibody against an array of related compounds was: 9{alpha}, 11ß-PGF2, 100%; PGF2, 0.24%; PGE2 and TXB2, 0.21%; PGD2, 0.01%; and less than 0.01% for LTB4, PGA1, PGA2, etc (see online supplement for additional details on the method used to perform these measurements).

Ex vivo Whole Blood LTB4 Analysis
To stimulate ex vivo LTB4 formation, whole blood was incubated with 50 µM calcium ionophore A23187 (free acid, molecular weight: 523.6) in dimethyl sulfoxide at 37°C for 30 minutes. The plasma LTB4 concentration was determined using a competition-based enzyme immunoassay, as described by Pradelles and coworkers (47), with minor modifications. Cross-reactivity of the LTB4 antibody against an array of related compounds was: LTB4, 100%; 6-trans-LTB4, 25.0%; LTB5, 14.58%; 5(S), 12(S)-DiHETE, 6%; LTD4, 0.96%; 20-hydroxy-LTB4, 0.50%; LTE4, 0.30%; and 0.20% for LTC4, etc (see online supplement for additional details on the method used to perform these measurements).

Inflammatory Cytokine Analysis
Circulating immunoreactive TNF-{alpha}, IL-1ß, and their soluble receptors were determined by ELISA (R&D Systems, Europe Ltd., Abingdon, Oxford, UK). The ELISA used for the determination of IL-1ß is specific for the measurement of natural and recombinant human IL-1ß (100%). This ELISA does not cross-react with human IL-1{alpha}, IL-1RA, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, or TNF-{alpha}. Likewise, the ELISA used for the determination of TNF-{alpha} is specific for the measurement of natural and recombinant human TNF-{alpha}. This ELISA does not cross-react with human IL-1ß, IL-1{alpha}, IL-2–13, TNF-ß, etc (see online supplement for additional details on the method used to perform these measurements).

Neutrophil Phospholipid Fatty Acid Analysis
Neutrophils were purified from 10 ml of anticoagulated venous blood to more than 95% by means of dextran sedimentation (Pharmacia, Milton Keynes, Bucks, UK) and centrifugation on a cushion of Lymphoprep (Nyegaard, Birmingham, UK) (48) and stored under argon at -70°C before extraction of phospholipids using the method developed by Bligh and Dyer (49). Fatty acid composition was analyzed by gas chromatography (50) (see online supplement for additional details on the method used to perform these measurements).

Statistical Analysis
Data were analyzed using the SPSS version 11 statistical software (SPSS Inc., Chicago, IL). The data were assessed for normality using the Kolmogorov–Smirnov test, and Levene's test was used to test for homogeneity of variance between groups. A two-way repeated measures analysis of variance was used to analyze the data, with both treatment and time as "within-subject" effects, whereas a two-way analysis of variance was used to analyze "between-subject" effects. Mauchly's test was conducted to determine whether sphericity was violated. If sphericity was violated, the repeated measures analysis of variance was corrected using the Greenhouse–Geiser correction factor. Pairwise comparisons, with a Bonferroni adjustment (used to maintain an overall type-I error rate of 5%), were used to isolate differences in group means: dividing {alpha} by the number of pairwise comparisons to be made. The percentage change in urinary LTE4 excretion, LTB4, and TNF-{alpha} and in IL-1ß production was calculated using the following formula: (postchallenge value - prechallenge value) x 100/(prechallenge value)

Correlations between urinary LTE4 excretion after exercise and pulmonary function were calculated using the Pearson product moment correlation. On all diets, the percentage change in urinary LTE4 excretion was correlated with the maximal decrease in postexercise FEV1. Data are expressed as mean ± SD.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects
All subjects with EIB and control subjects who entered the trial completed it. There were no significant differences (p > 0.017) in bronchodilator use (total number of doses/puffs) between the normal diet (58 ± 16 puffs) and placebo diet (55 ± 17 puffs). However, bronchodilator use significantly declined (p < 0.05) to 39 ± 13 puffs during the last 2 weeks on the n-3 PUFA diet. A 2 x 2 analysis of variance used to test for the presence of carry-over effects indicated that none was present (p > 0.05) for all measures of lung function and inflammatory markers. This was further supported by inflammatory mediator and cytokine levels measured at the end of the 2-week washout period returning to baseline values established at the beginning of the study (normal diet).

Pulmonary Function
Pre- and postexercise pulmonary function values for subjects with EIB and control subjects are shown in Table 2 and Table E1 of online supplement, respectively. No significant difference (p > 0.017) was observed in preexercise (baseline) pulmonary function among diets in either group. The differential effect of the percentage change in FEV1 pre- to postexercise in control subjects and subjects with EIB is shown in Figure 1 . No significant differences (p > 0.017) in the percentage change in FEV1 pre- to postexercise were observed for the control subjects on any diet. Subjects with EIB demonstrated a significant (p < 0.017) percent change in FEV1 pre- to postexercise on the normal and placebo diets. However, on the n-3 PUFA diet, the subjects with EIB (Figure 1) demonstrated no significant difference (p > 0.017) in the percentage change in FEV1 pre- to postexercise. FEV1 decreased by 3 ± 2% on n-3 PUFA diet, 14.5 ± 5% on placebo diet, and 17.3 ± 6% on normal diet at 15 minutes postexercise. Similar patterns were observed for FVC.


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  		TABLE 2. Preexercise (baseline) pulmonary function for subjects with exercise-induced bronchoconstriction and control subjects

 


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  		Figure 1. The percent change in FEV1 from pre- to postexercise in subjects with exercise-induced bronchoconstriction (EIB) and control subjects across the three diets. Reductions in FEV1 in excess of 10% represent abnormal pulmonary function. Letters (a,b) refer to comparisons by diet within respective time period. Different letters designate significant difference (p < 0.017). Closed circles, subjects with EIB with normal diet; open circles, subjects with EIB with placebo diet; closed inverted triangles, subjects with EIB with omega-3 (n-3) polyunsaturated fatty acids (PUFA) diet; open inverted triangles, control subjects with normal diet; closed squares, control subjects with placebo diet; open squares, control subjects with n-3 PUFA diet.

 
Inflammatory Markers
Mean (SD) urinary LTE4 and 9{alpha}, 11ß-PGF2 levels and plasma levels of LTB4, TNF-{alpha}, and IL-1ß for subjects with EIB are shown in Figures 2–5 and 6 , respectively. No significant changes (p > 0.013) in inflammatory markers as result of exercise or any treatment were observed in the control subjects. Whereas no significant difference (p > 0.05) was observed between pre-placebo supplementation and post-placebo supplementation at preexercise in LTE4, 9{alpha}, 11ß-PGF2, LTB4, TNF- {alpha}, and IL-1ß values, postexercise values increased significantly (p < 0.017) compared with preexercise values on the placebo diet and normal diet in subjects with EIB. However, on the n-3 PUFA diet, urinary LTE4 excretion (Figure 2) was significantly reduced (p < 0.017) postsupplementation at preexercise and 15 minutes postexercise by 19.4 pg/mg creatinine and 13.1 pg/mg creatinine, respectively, compared with the mean presupplementation LTE4 concentration (56.9 ± 13.3 pg/mg creatinine). Mean urinary excretion of 9{alpha}, 11ß-PGF2 (Figure 3) on the n-3 PUFA diet decreased significantly (p < 0.017 postsupplementation at preexercise by 16.8 ng/mg mmol creatinine-1 and by 13.9 ng/mg mmol creatinine-1 at 15 minutes postexercise compared with the presupplementation level 53.2 + 12.4 ng/mg mmol creatinine-1). The n-3 PUFA supplementation resulted in a significant reduction of 17.7 ± 6.7%, 22.6 ± 6.3% (p < 0.017), and 22.5 ± 6.7% (p < 0.001), respectively, in preexercise values (p < 0.017) for LTB4, IL-1ß, and TNF-{alpha} production (Figures 4, 5, and 6, respectively) and a significant reduction (p < 0.05) in IL-1ß of 15.1 + 4.7% at 15 minutes postexercise compared with pre–n-3 PUFA supplementation values. In addition, n-3 PUFA postsupplementation LTE4, LTB4, TNF-{alpha}, and IL-1ß levels were significantly reduced (p < 0.017) compared with the normal and placebo diet at all respective time points.



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  		Figure 2. Mean urinary leukotriene E4 excretion (pg/mg mmol·creatinine-1). *Indicates significant difference (p < 0.013) compared with respective presupplementation value within diet. Letters (a,b) designate significant difference (p < 0.017) compared with respective time point between diet.

 


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  		Figure 5. Mean plasma levels of interleukin-1ß (pg/ml). *Indicates significant difference (p < 0.013) compared with respective presupplementation value within diet. Letters (a,b) designate significant difference (p < 0.017) compared with respective time point between diet.

 


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  		Figure 6. Mean plasma levels of tumor necrosis factor–{alpha} (pg/ml). *Indicates significant difference (p < 0.013) compared with respective presupplementation value within diet. Letters (a,b) designate significant difference (p < 0.017) compared with respective time point between diet.

 


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  		Figure 3. Mean urinary 9{alpha}, 11ß-PGF2 excretion (ng/mg creatinine). *Indicates significant difference (p < 0.013) compared with respective presupplementation value within diet. Letters (a,b) designate significant difference (p < 0.017) compared with respective time point between diet.

 


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  		Figure 4. Mean plasma levels of leukotriene B4 (ng/ml). *Indicates significant difference (p < 0.013) compared with respective presupplementation value within diet. Letters (a,b) designate significant difference (p < 0.017) compared with respective time point between diet.

 
There was no significant correlation between the maximal fall in FEV1 and postexercise change in urinary LTE4 excretion on the normal and placebo diets in subjects with EIB (Pearson correlation coefficient: r = -0.357, p = 0.676, and r = -0.394, p = 0.613, respectively) or between the inhibitory effect of the n-3 PUFA diet on urinary LTE4 excretion and the protective effect on the maximal fall in FEV1 (Pearson's correlation coefficient: r = -0. 228) in subjects with EIB.

Neutrophil Phospholipid Fatty Acid Content
The fatty acid content of the neutrophil phospholipid was assessed in subjects with EIB (Table 3) and control subjects (see Table E2 in the online supplement) and expressed as a percentage of total fatty acid content. No significant differences (p > 0.025) were observed in subjects with EIB and control subjects in neutrophil membrane content for linoleic acid, AA, EPA, and docosahexaenoic acid comparing pre- and post-placebo supplementation values. However, after the n-3 PUFA supplementation period, EPA content significantly increased (p < 0.025) to 3.79 ± 2.1%, whereas AA and linoleic acid contents significantly decreased (p < 0.001) to 11.9 ± 4.2% and 5.9 ± 2.7%, respectively, of total neutrophil fatty acid content in subjects with EIB (Table 3). In the control group (Table E2 in the online supplement), EPA content significantly increased (p < 0.025) to 4.10 ± 1.8%, whereas AA and linoleic acid contents were significantly reduced (p < 0.025) to 11.6 ± 3.4 and 5.4 ± 2.3%, respectively, of total neutrophil fatty acid content after n-3 PUFA supplementation. No significant changes (p > 0.025) were observed in docosahexaenoic acid content after n-3 PUFA consumption in either the EIB or the control group.


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  		TABLE 3. Fatty acid composition of neutrophil extracts expressed as a percentage of total fatty acid content before and after the 3-WEEK dietary supplementation period in subjects with exercise-induced bronchoconstriction

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study has demonstrated for the first time that 3 weeks of dietary n-3 PUFA supplementation markedly reduces the severity of EIB in elite athletes. The airway response to exercise was used to assess changes in nonspecific bronchial responsiveness during dietary supplementation with n-3 PUFA. The n-3 PUFA diet significantly improved postexercise pulmonary function to below the diagnostic limit of a 10% postexercise fall in FEV1 in conjunction with a significant decrease in bronchodilators drug use. In addition, the increase in tissue phospholipid n-3 PUFA concentration in subjects with EIB was coincident with a significant suppression of the proinflammatory eicosanoids LTE4, PGD2 metabolite 9{alpha}, 11ß-PGF2 and LTB4 and proinflammatory cytokines TNF-{alpha} and IL-1ß.

Verification of diet compliance was accomplished by neutrophil phospholipid fatty acid analysis. Dietary enhancement with 3.2 g of EPA for 3 weeks produced a considerable increase in EPA content of neutrophil phospholipid in both subjects with EIB and control subjects, thus confirming dietary compliance with n-3 PUFA supplementation. The dose of EPA selected for this study has previously been shown to have antiinflammatory potential, as shown by its effect on leukocyte function (25, 29). The potential antiinflammatory effect of n-3 PUFA stems from its active ingredient, EPA, which is a competitive substrate with AA for the generation of inflammatory mediators. The derivatives of AA (an n-6 PUFA) are LTB4, a potent neutrophil chemoattractant and proinflammatory mediator, and the cysteinyl series of LT (LTC4, LTD4, and LTE4), which produce potent smooth muscle contraction and bronchoconstriction (38). AA is the progenitor of LTB4 via the 5-lipoxygenase enzymatic pathway. EPA, the n-3 homolog of AA, can inhibit AA metabolism competitively via these enzymatic pathways and, thus, can suppress production of the n-6 eicosanoid mediators. Thus, increasing dietary n-3 fats can shift the balance of the eicosanoids produced to a less inflammatory mixture by reducing the production of proinflammatory LT.

This study supports data from earlier reports that urinary concentrations of LTE4 increase after exercise in adults with mild asthma (51) and in children with asthma but not in children without asthma (52). Postexercise increases in urinary LTE4 (51, 52) and reduced postexercise bronchoconstriction with cys-LT1 receptor antagonist treatment, thereby blocking the action of cysteinyl-LT on their receptors in human airways (38, 53), provide compelling evidence for cysteinyl-LT involvement in EIB. In addition, the n-3 PUFA diet markedly blunted urinary LTE4 excretion postexercise in subjects with EIB, which is in agreement with von Scacky and coworkers (54) who observed a 35% reduction in urinary LTE4 after dietary supplementation of n-3 PUFA in healthy volunteers. The results of this study have shown that incorporation of n-3 PUFA into neutrophil phospholipid was accompanied by a reduction in LTB4 release in subjects with EIB after exercise. This corroborates other studies that have shown that increased EPA content in neutrophil membrane phospholipids attenuates the neutrophil chemotactic activity and the generation of LT B products in patients with asthma (27–29, 32), inhibits the 5-lipoxygenase pathway of neutrophils and moncycytes, and attenuates the LTB4-mediated functions of neutrophils in vitro (25). LTB4 has been implicated in the pathogenesis of exercise-induced asthma. Arm and colleagues (55) observed increased synthesis of LTB4 by neutrophils stimulated in vitro by unopsonozed zymosan and calcium ionophore isolated from patients with asthma after exercise, whereas Sugoro and colleagues (56) observed an improvement in pulmonary function and a decrease in urinary concentration of LTB4 after exercise after treatment with a LT antagonist in subjects with exercise-induced asthma.

Although the present study has shown a diminution of the AA "4-series" tetraene sulfidopeptide LT, the EPA-derived "5 series" pentaene sulfidopeptide LT LTC5, LTD5, and LTE5 are biologically identical to their tetraene counterparts in causing bronchoconstriction (57). It has been suggested that changing to production of pentaene rather than tetraene sulfidopeptides with dietary manipulation may not result in a major difference in biological response (airway reactivity) if there is no reduction in total sulfidopeptide LT production. (31). However, although this study did not measure the pentaene sulfidopeptides, we have clearly shown that the bronchoconstrictor response to exercise and the tetraene sulfidopeptide LTs are markedly reduced on the n-3 PUFA diet. This suggests that the tetraene LTs are important in elite athletes with EIB and that the EPA-derived pentaene LTs may have diminished biological capacity, the reason for which is unknown but may be related to dosage and duration of the n-3 PUFA diet.

Significant increases after exercise in the PGD2 urinary metabolite 9{alpha}, 11ß-PGF2 were observed in the elite athletes with EIB, which confirms previous findings of increased urinary 9{alpha}, 11ß-PGF2 concentrations after exercise in patients with asthma (58, 59). Although 9{alpha}, 11ß-PGF2, the initial metabolite of PGD2, is a marker of mast cell activation and a potent bronchoconstrictor, eosinophils can also generate PGD2, albeit in small amounts (59, 60). It has been shown that degranulation of mast cells occurs on exposure to a hyperosmotic stimuli in vitro (61), and it has been suggested that hyperosmolarity of the airway-lining fluid occurs during hyperpnea with cold dry air (62). The n-3 PUFA diet in this study suppressed urinary 9{alpha}, 11ß-PGF2 generation after exercise, suggesting that mast cell activation is an important determinant of EIB in elite athletes.

Dietary enrichment with n-3 PUFA in this study resulted in significant attenuation in the production of proinflammatory cytokines TNF-{alpha} and IL-1ß in subjects with EIB. It has been shown that dietary supplementation with n-3 PUFA results in decreased monocyte synthesis of TNF-{alpha} and IL-1ß in healthy subjects (26, 63). However, Hodge and coworkers (30) while demonstrating reductions in TNF-{alpha} production after fish oil supplementation observed no effect on the clinical severity of asthma. These cytokines have proinflammatory activity that can stimulate the synthesis of collagenases (64) and increase the expression of adhesion molecules necessary for leukocyte extravasation (65), and both cytokines have been implicated in the pathogenesis of asthma (30, 66). TNF-{alpha} increases the responsiveness of human bronchial tissue in vitro (67) and increases airway responsiveness in vivo in healthy, normal subjects (68). Our findings that plasma levels of TNF-{alpha} are increased in elite athletes with EIB are in agreement with the findings of Sue-Chu and coworkers (16). These authors reported a greater macroscopic inflammatory index in the proximal airways of skiers than in healthy, nonathletic subjects, which was even greater in skiers with hyperresponsive airways and in those with ski-induced asthma. Such changes were accompanied by increased lymphocyte cell count in bronchoalveolar lavage samples in elite cross-country skiers with EIB. TNF-{alpha} was above the detectable threshold in 40% of skiers and was not detected in the healthy control subjects.

To our knowledge this is the first study to assess the effect of n-3 PUFA supplementation on pulmonary function and inflammatory mediator production in elite athletes with EIB. However, Arm and coworkers (29) attempted to determine the effect of fish oil supplementation on pulmonary function after exercise in patients with asthma. After 10 weeks of daily supplementation with 3.2 g EPA and 2.2 g docosahexaenoic acid, subjects underwent a histamine challenge, exercise challenge, and blood neutrophil studies. Although there was a significant increase in n-3 PUFA neutrophil content and a 50% inhibition of total LTB synthesis (LTB4 and LTB5), there was no detectable change in the clinical outcome (e.g., histamine response, exercise response, specific conductance of the airway, or symptoms scores). The divergent findings between this study and that of Arm and coworkers (29) are difficult to reconcile, especially because their study had a longer duration supplementation period with an identical fish oil dosage as the current study. However, although it has been suggested that all individuals who exhibit EIB by demonstrating reductions in postexercise pulmonary function are asthmatic to some degree (69), recent evidence of airway remodeling in cross-country skiers with EIB (16, 18, 70), and the fact it has been shown that inhaled corticosteroids appear to have no effect on airway inflammatory markers or obstructive symptoms in athletes with EIB (17), indicates a different pathphysiology in EIB compared with common asthma. Evidence of this concept comes from the study of Sue-Chu and coworkers (70) who reported a higher frequency of lymphoid aggregates in endobronchial biopsies from a population of young, elite cross-country ski athletes, with asthma-like symptoms, compared with healthy, young control subjects. An increase in the number of neutrophils has been observed in the sputum of elite swimmers after training (11), and an increased neutrophil concentration in bronchoalveolar lavage fluid has been observed in a canine model of hyperpnea with cold dry air (71, 72), providing further evidence that the inflammatory processes in athletes with EIB may be different from that in individuals with common asthma, although these conclusions are highly speculative. No measures of inflammatory cells and mediators in the airway lumen via sputum induction were made in this study. However, future work should be directed toward assessing clinically useful markers of airway inflammation such as eosinophils, neutrophils, and soluble cell makers to gain a greater insight into the heterogeneity of EIB in elite athletes (73).

It has been proposed that the increased bronchial hyperresponsiveness documented in elite athletes may be due to repetitive airway trauma of the epithelium with consequent remodeling (2) and due to exposure to cold/dry air at high ventilation rates, which renders these athletes susceptible to severe thermal and osmotic stimuli (16, 72, 74). Karjalainen and coworkers (18) reported an increase in the expression of extracellular matrix protein, tenascin, in the proximal airways of cross-country skiers with EIB, which may reflect ongoing healing and repair and airway remodeling after tissue injury due to repeated exposure of the airways to inadequately conditioned air. Furthermore, Davies and colleagues (71) have recently observed in a canine model of hyperventilation histologic changes commonly associated with airway dysfunction in patients with asthma, suggesting that repeated exercise in cold weather can cause airway remodelling and morphologic changes similar to those seen in asthma. However, in contrast to asthma, the airway damage caused by the repeated hyperpnea challenge with cold, dry air was reversible with rest.

In conclusion, this study has shown that supplementing the diet with n-3 PUFA represents a potentially beneficial treatment for elite athletes with EIB. Dietary modification of EIB with marine oils or highly enriched sources of n-3 PUFA has the potential of optimizing the additive effects of drug–diet combinations in elite athletes with EIB. The use of pharmacologic treatment could be decreased in athletes with EIB, in concert with increased fish oil ingestion if both the drug and fish oil are exerting their therapeutic effects through the same molecular actions, e.g., LTE4 and LTB4 production. This might also apply to new drugs or to new treatment modalities that aim to suppress cytokine concentrations. Thus, the possibility exists for drug–diet interactions that confer greater antiinflammatory benefits than either agent alone or similar antiinflammatory effects with less toxicity. The differences between reports on the effect of fish oil supplementation in allergic asthma and exercise-induced bronchial hyperreactivity are probably methodologic. The small number of studies and the different methods used for the assessment of bronchial hyperreactivity call for further trials before the benefits of fish oil supplementation can be assessed (75). In addition, due to the fact the present study's findings are in contrast with those of Arm and coworkers (29), further reproduction of these findings is warranted.


   FOOTNOTES
 
This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: T.D.M. has no declared conflict of interest; R.L.M. has no declared conflict of interest; A.A.I. has no declared conflict of interest; M.R.L. has no declared conflict of interest.

Received in original form March 13, 2003; accepted in final form July 26, 2003


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 DISCUSSION
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