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A Nutritional Approach to Managing Exercise-Induced Asthma

Mickleborough, Timothy D.

Exercise and Sport Sciences Reviews: July 2008 - Volume 36 - Issue 3 - p 135-144
doi: 10.1097/JES.0b013e31817be827

Exercise-induced asthma (EIA) is traditionally treated with the use of pharmacotherapy. However, there is now convincing evidence that a variety of dietary factors such as elevated omega-3 polyunsaturated fatty acids and antioxidant intake, and a sodium-restricted diet can reduce this condition. New therapies that are safe, effective, and likely to be used by individuals with EIA are needed.

This review examines the evidence as to whether dietary modification represents a potentially beneficial treatment intervention for asthmatic individuals with exercise-induced asthma.

Department of Kinesiology, Indiana University, Bloomington, IN, United States

Address for correspondence: Timothy D. Mickleborough, Ph.D., FACSM, Department of Kinesiology, Indiana University, 1025 E. 7th St, HPER 112, Bloomington, IN 47401 (E-mail:

Accepted for publication: February 17, 2008

Associate Editor: Susan R. Hopkins, M.D., Ph.D.

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Exercise-induced asthma (EIA) and exercise-induced bronchoconstriction are synonymous terms that describe a condition in which vigorous physical activity triggers acute airway obstruction after exercise in individuals with heightened airway reactivity. Exercise-induced asthma is typically defined as a greater than 10% reduction in postexercise forced expiratory volume (FEV1) compared with the preexercise value (1). Exercise-induced asthma is not an isolated disorder or specific disease, but rather part of the spectrum of asthmatic disease where exercise is one of many stimuli that may induce airflow limitation and may be the most prominent and troublesome feature of asthma. The response to exercise is considered a marker of asthma control and therefore is clinically relevant to asthma management. In addition, the response to exercise is useful to monitor treatment regimens and to identify tolerance to pharmacological medications.

The mechanisms responsible for EIA have been extensively investigated and likely involve multiple mechanistic pathways (1). It is generally accepted that exercise-induced hyperpnea plays an important role as an initiating stimulus through airway surface effects of water loss, which include mucosal cooling and dehydration (1). It has been suggested that transient dehydration causes an increase in airway surface liquid osmolarity which would activate proinflammatory mediators, such as histamine, neuropeptides, and the arachidonic acid (AA) metabolites leukotrienes (LT) and prostaglandins (PG) from resident airway cells, resulting in bronchial smooth muscle contraction and subsequent airway obstruction (1). Alternatively, it has been suggested that airway cooling primarily affects the bronchial vasculature, such that rapid rewarming of the airways after exercise may lead to vascular hyperemia and airway edema, which would contribute further to the airway narrowing (1). Although the precise pathophysiological mechanism involved in EIA remains unclear, it does seem that LT plays a role in mediating a portion of this airway narrowing because agents that act in two distant manners on the LT pathway - namely, LT receptor antagonists and 5-lipoxygenase inhibitors - are able to block a proportion of the bronchoconstrictor response. The inability of the LT agents to block more than 50% to 60% of the exercise-induced airway narrowing suggests that other mediators such as histamine and PG are also involved in the EIA response. Although EIA may be induced by changes in airway osmolarity and cooling and reactive hyperemia, it may also involve exercise-induced immunological changes in eicosanoid transcription signaling pathways, in particular the leukotriene transcription pathway (11).

There have been significant advances in asthma therapy during the last decade, but treatment is far from ideal. Clinical responses to current therapy, such as LT modifiers and corticosteroids, are heterogeneous, and even with optimal treatment, there is a substantial burden of unaddressed disease. Although daily medications such as LT modifiers provide only modest protection against symptoms, prolonged use of several medications can result in reduced effectiveness, or tachyphylaxis. For example, daily use of long-acting β2-agonists in the management of EIA in children has been questioned, and reversal of an asthma attack, such as EIA, may be ineffective in a large portion of asthmatic patients when short-acting β2-agonists are used daily. In addition, the use of inhaled corticosteroids, especially at higher doses, has been accompanied by concern about both systemic and local side effects. Although the treatment of EIA almost exclusively involves pharmacological intervention, there is now convincing evidence that dietary modification has the potential to reduce the severity of this condition, which may permit those who have EIA to potentially reach higher levels of performance with reduced reliance on pharmacotherapy. Thus, EIA may serve as a useful model for investigation of potential dietary interventions for reducing exercise-induced airway narrowing in asthmatic individuals.

Although the potential relationship between food tolerance and asthma has been investigated, and there are many studies that have examined the potential for dietary modification to reduce the severity of asthma, there have been comparatively few attempts to evaluate dietary change as a modifier of the EIA response. This article advances the hypothesis that diet can modify the severity of EIA. A number of dietary factors have been implicated in the pathogenesis of asthma and EIA, mainly because of their role in inflammatory reactions (19-21,29), activities of airway smooth muscle (7,12,19,21,29), and modulation of pulmonary microvascular volume and pressure (20). Therefore, the purpose of this review is to examine the evidence as to whether dietary modification represents a potentially beneficial adjunct or primary intervention for asthmatic individuals with EIA.

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Dietary Salt

It has been observed that asthma morbidity and mortality are greater in communities adopting a more Western lifestyle and in migrants as they move from rural underdeveloped areas to urban Westernized areas, and dietary sodium has been considered to be a dietary constituent, which has been implicated in this phenomenon. Dietary intake of salt (sodium chloride) is typically high, averaging 7 to 10 g·d−1 (2.8-4 g·d−1 of sodium) in Westernized areas, and this excess salt intake is associated with other diseases of smooth muscle constriction such as hypertension. The minimum recommended daily allowance for sodium in the United States is 500 mg·d−1, with an upper limit of less than 2400 mg of sodium per day considered optimal for health, a decision made mainly on the basis of the cardiovascular benefits to be derived by the population as a whole.

A number of epidemiological and cross-sectional studies have demonstrated a strong association between salt intake and asthma, such that a higher sodium chloride intake may potentiate asthma severity (15). These earlier epidemiological and cross-sectional studies led to a number of subsequent small interventional studies that have shown that a salt-restricted diet can improve pulmonary function and reduce symptoms and medication use and reduce airway hyperresponsiveness, compared with a high-salt diet, in individuals with asthma (15). Although these studies do support the concept of a relationship between sodium intake and asthma severity, a large randomized-controlled clinical trial is warranted to fully address whether dietary intake of sodium may increase the severity of disease in those with asthma. The clinical trial should include individuals with well-characterized asthma. The trial should also include data on baseline diet and be sufficiently powered to permit measurement of both physiological outcomes such as lung function and bronchial reactivity, as well as clinically important measures including daily symptoms scores and medication use.

Because most asthmatic individuals exhibit exercise-induced airway narrowing if challenged with the appropriate exercise intensity, a number of human studies have been conducted to assess the effect of dietary sodium manipulation on the severity of EIA (9,10,14,16,17,20). In most studies, subjects had mild-to-moderate persistent asthma and exhibited EIA as documented by a >10% decrease in postexercise FEV1 compared with preexercise values. Using a double-blind randomized crossover design, Mickleborough et al. (14,20) and Gotshall et al. (9) have shown that a 2-wk low-sodium diet (958-1446 mg·d−1) significantly improved postexercise pulmonary function, concomitant with a reduction in bronchodilator use (20), compared with a normal sodium diet (2414-3630 mg·d−1) and high-sodium diet (6730-8133 mg·d−1; Fig. 1). In addition to the observation that dietary salt manipulation can alter the degree of airway narrowing in individuals with EIA, three important observations have been made: first, arterial oxygen saturation during exercise was improved by reducing dietary salt and was exacerbated by increasing dietary salt in individuals with EIA (16); second, 1 wk is equally as effective as 2 wk of dietary salt restriction in improving postexercise pulmonary function in those with EIA (10); and third, both the sodium and chloride ion contribute to more severe EIA observed on a normal and high-salt diet (17).

Figure 1

Figure 1

Dietary salt may modulate EIA via multiple physiological mechanisms, which include a direct effect of the sodium and/or chloride ion (17) on airway smooth muscle contractility, the release of bronchoconstrictor mediators from airway cells either directly or through changes in airway osmolarity as a result of dietary salt modification (20), and the potential influence of dietary salt on vascular volume and microvascular pressure, resulting in mucosal edema and narrowing of the airway lumen (20) (Fig. 2).

Figure 2

Figure 2

Although the biological mechanisms that might explain the role of dietary salt intake in airway responsiveness remains uncertain, it may be due to intrinsic alterations of cellular ion transport. With increased sodium influx and an inhibited Na+/K+ ATPase, Na+-Ca2+ exchange could become the predominant mechanism for restoring intracellular sodium ([Na+]i) levels toward normal (30). This in turn could lead to a rise in free intracellular calcium ([Ca2+]i) and an increase in bronchial smooth muscle contraction (Fig. 2). In addition, it has been shown that a relative metabolic acidosis is present in salt-sensitive hypertensive subjects during dietary salt loading, resulting in a decrease in intracellular pH ([pHi]). This association between metabolic acidosis and hypertension may occur at the level of cells other than kidney cells, such as smooth muscle cells and mast cells, which are important in the pathogenesis of EIA (17) (Fig. 2).

In an attempt to delineate a possible mechanism by which dietary salt loading might exacerbate EIA, two studies (18,20) have been conducted. The first study used an animal model of EIA (18). It has been suggested that exercise-induced airway narrowing in individuals with asthma and hyperpnea-induced airway obstruction (HIAO) in guinea pigs are mediated by similar mechanisms. Therefore, Mickleborough and colleagues (18) used this animal model of EIA in an attempt to demarcate a possible mechanism by which dietary salt may exert an effect on airway hyperresponsiveness. The potential pathway of action of dietary salt was investigated by blocking LT production during HIAO in guinea pigs fed either a normal or high-salt diet for 2 wk. This study demonstrated that elevated dietary salt increased the HIAO response compared with a normal salt diet and that this effect may be mediated by changes in LT metabolism.

The second study conducted more recently by Mickleborough et al. (20) sought to examine more fully the effect of dietary salt manipulation on asthmatic patients who experience EIA. This study (20) demonstrated for the first time that dietary salt restriction lessens and dietary salt loading enhances airway inflammation in asthmatic patients after exercise and that modifying dietary salt intake alters postexercise diffusion capacity of the lung (DLCO) and pulmonary capillary blood volume (V C) in asthmatic subjects. Importantly, in this study, dietary salt loading increased and dietary salt restriction reduced the levels of induced sputum interleukin (IL)-8 concentration after exercise. Hyperosmolarity has been shown to stimulate IL-8 production in human bronchial epithelial cells in vitro. Because the human airway mucosa is a semipermeable membrane across which osmotic equilibration occurs, this may represent a potential pathway by which dietary salt loading increases airway osmolarity, and thereby, stimulate the release of bronchoconstrictive mediators (Fig. 2). The findings by Mickleborough et al. (20) suggest that salt-dependent changes in airway inflammation, vascular volume, and microvascular pressure might have substantial effects on airway function after exercise (Fig. 1).

In summary, there is now convincing evidence that the higher the salt intake, the greater the bronchoconstrictor response to exercise in asthmatic subjects. Although there are large variations in individual responses, a salt-restricted diet (approximately 1500 mg sodium per day) reduces the severity of EIA. There are no data as to the longer-term effect of a low-sodium diet on either the prevalence or severity of asthma or on EIA.

In the U.S. diet, 77% of sodium comes from processed and restaurant foods, 12% occurs naturally in foods, 6% is added at the table, and 5% is added during cooking. Many processed foods contain 1000 mg or more per serving, whereas typical restaurant meals contain 2300 to 4600 mg of sodium (1 to 2 teaspoons of salt). In light of these facts, a consensus has emerged that sodium levels in processed and restaurant foods should be reduced substantially. Practically, it may be difficult for an individual to restrict intake of salt. Typically, low-salt processed foods such as bread, peanut butter, and others have reduced palatability. However, dietary salt can be markedly reduced by avoiding processed foods and foods prepared in restaurants. Fresh meats cooked without salt, along with fresh fruits and vegetables, contain the least salt and retain palatability. Specific menu plans are available that give simple advice on dietary sodium restriction, with lists of foods particularly high or low in sodium to be avoided or preferred and menu plans, using the Dietary Approaches to Stop Hypertension (DASH) eating plan developed by the National Institutes of Health, to reduce dietary sodium intake to 1500 or 2400 mg·d−1. It has been shown that a dietary pattern that emphasizes fruits, vegetables, and low-fat dairy products and that is reduced in fats and sodium is more than twice as effective in lowering systolic blood pressure in adults as a diet that restricts sodium only. In addition, the DASH dietary pattern may hold promise in treating hypertension in all age groups and is currently being advocated by some as an approach that should be initiated in childhood to manage hypertension.

Electrolyte-replacement drinks, energy gels, and salt tablets, consumed during training and competition, are typically higher in sodium and may be contraindicated for those with EIA, although this has not been studied. It is important to emphasize that although a low-sodium diet can be considered as a therapeutic option for asthmatic individuals with EIA, it should be considered an adjunctive intervention to supplement optimal pharmacological management of asthma and not as an alternative.

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Antioxidant Supplementation

Epidemiological evidence demonstrating an inverse association of ascorbic acid and dietary fruit and vegetable intake with pulmonary function suggests that dietary antioxidants may modify the development of respiratory disease in susceptible individuals. This is confirmed by reports of an inverse association between specific antioxidant nutrients including vitamin C, vitamin E, β-carotene, selenium, manganese, zinc, copper, and asthma.

It has been established that asthmatic patients tend to have lower serum antioxidants, including vitamin C (ascorbic acid), and that low vitamin C intake can be correlated with asthma severity. These data suggest that asthmatic subjects may have an antioxidant deficiency and/or that they have increased oxidative stress that requires higher levels of reactive oxygen/nitrogen species (ROS/RNS) scavenging antioxidants.

In asthma, observational studies have shown encouraging evidence of a protective effect of vitamins C and E and selenium on disease prevalence and symptoms. In EIA, interventional studies using extended supplementation periods with antioxidants such as β-carotene, lycopene, and undenatured whey protein have been effective in improving pulmonary function (4,25,26). Neuman et al. (25) found a protective effect on postexercise pulmonary function (mean postexercise FEV1 drop of 5.15%) in EIA subjects with a daily dose of 64 mg β-carotene supplementation for 1 wk, whereas all subjects on the placebo diet demonstrated a mean reduction in postexercise FEV1 of 25.15%. In a subsequent study, the same authors (26) found that 1 wk of 30 mg of lycopene (LYC-O-MATO™) supplementation also improved postexercise pulmonary function. Subjects with EIA demonstrated a mean reduction in postexercise FEV1 of 26.5% on the placebo diet, whereas 7 d of LYC-O-MATO™ supplementation resulted in a significant improvement in postexercise FEV1, with an average decrease in postexercise FEV1 of 14.7%. More recently, Baumann et al. (4) found a reduction in the severity of EIA when subjects were supplemented with a cysteine donor whey protein for 8 wk. Eighteen EIA-positive subjects demonstrated a significant mean improvement in postexercise FEV1 from baseline (−22.6% ± 12.2%), 4 wk (−18.9% ± 12.9%), and 8 wk (−16.9% ± 11.6%), with concomitant reductions in forced expiratory flow at 25% to 75% FVC (FEF25% - 75%) on the undenatured whey protein diet. No changes in FEV1 or FEF25% - 75% were observed for any time points on the placebo diet. Murphy et al. (24) reported in abstract form that 500 mg·d−1 of ascorbic acid combined with α-tocopherol (300 mg·d−1) for 3 wk improved postexercise FEV1 compared with placebo. Recently, Tecklenburg et al. (29) have shown that 2 wk of 1500 mg·d−1 of ascorbic acid supplementation reduces the severity of EIA, intensity of symptoms, and markers of airway inflammation. The ascorbic acid diet significantly reduced the maximum fall in postexercise FEV1 (−6.4% ± 2.4%) compared with usual (−14.3% ± 1.6%) and placebo diet (−12.9% ± 2.4%; Fig. 3).

Figure 3

Figure 3

Conversely, Falk et al. (8) found that a daily dose of LYC-O-MATO™ did not affect pulmonary function after exercise in 19 adolescent athletes. The authors attributed their negative findings, which contrasts with previous research (4,24-26), to an exercise intensity that may not be sensitive enough to document EIA in an athletic population, a reduced environmental stress (testing took place in a warm, humid environment), and not accounting for other dietary factors (i.e., high dietary intake of natural antioxidants such as fruits and vegetables).

At present, only three interventional studies have investigated the efficacy of a single dose of ascorbic acid supplementation on the severity of EIA. Schachter and Schlesinger (28) studied 12 asthmatic patients with EIA and found a significant improvement in postexercise FEV1, with 500 mg of ascorbic acid taken 90 min before exercise, whereas the placebo treatment had no effect on postexercise pulmonary function. Cohen et al. (6) studied 20 asthmatic patients with EIA in which they were given either 2 g of ascorbic acid or placebo before an exercise challenge. Nine of the 20 subjects exhibited a protective effect on postexercise pulmonary function on the ascorbic acid diet. Five patients in the protected group continued with 500 mg·d−1 ascorbic acid for 2 wk and demonstrated continued protection. The studies by Schachter and Schlesinger (28) and Cohen et al. (6) were supported by evidence presented by Miric and Haxhiu (23), who demonstrated that pretreatment with ascorbic acid prevented a significant alteration in airway geometry induced by exercise in asthmatic subjects.

In pulmonary diseases such as asthma, oxidant stress induced mainly via inflammatory mechanisms inflicts tissue injury, sensitizes cells in the lung to proinflammatory mediators, and consequently aggravates the disease process. In asthmatic subjects, cytokines released from activated eosinophils and additional inflammatory cells can initiate ROS/RNS generation by pulmonary macrophages, interstitial cells, and leukocytes infiltrating lung tissue (27). Excess ROS/RNS may overwhelm antioxidant defense and consequently lead to bronchoconstrictor mediators responsible for EIA. The genes for these inflammatory mediators are regulated by redox-sensitive transcription factors nuclear factor (NF)-kappa(κ)B and activator protein-1 (27). NF-κB has also been shown to up-regulate the gene for inducible nitric oxide synthase (iNOS) resulting in increased FENO (a marker of airway inflammation) (27) and has been implicated in the up-regulation of proinflammatory cytokines and the release of proinflammatory eicosanoids, such as cysteinyl-LT and PG. Importantly, it has been demonstrated that ascorbic acid blocks tumor necrosis factor α (TNF-α)-mediated activation of NF-κB (5).

Preventing oxidative stress, with ascorbic acid supplementation, is unlikely to lead to complete resolution of airway obstruction after exercise but might be useful as an adjunct therapy in asthmatic patients. Additional research should be aimed at establishing what combination of antioxidants will be most effective in correcting airway dysfunction and to assess whether dietary manipulation with natural foods, high in antioxidants (i.e., fresh fruits and vegetables) is as effective as ascorbic acid supplementation in providing protection against EIA. It should be emphasized that although antioxidant supplementation is, in the main, effective in attenuating EIA, antioxidants can have pro-oxidant effects, especially when megadoses are used.

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Fish Oil Supplementation

During the past three decades, there has been significant interest in the therapeutic potential of fish oils for various inflammatory conditions such as rheumatoid arthritis, inflammatory bowel diseases, and asthma. Fish oil, rich in omega-3 (n-3) polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), compete with AA as substrates for the formation of inflammatory mediators, such as LT and PG. The EPA-derived metabolites have lower biological activity compared with the analogous AA derivatives (Fig. 4). In addition, n-3 PUFA seems to have additional antiphlogistic properties primarily through their effects on the neutrophil and macrophage component of the inflammatory response.

Figure 4

Figure 4

Eicosapentaenoic acid and DHA, derived from fish oil, can cause dual inhibition of cyclooxygenase-2 and 5-lipoxyeganse pathways for metabolism of AA. Eicosapentaenoic acid is a much less preferred substrate compared with AA for both pathways and generally by substrate competition inhibits release of AA-derived eicosanoids, thus reducing the generation of proinflammatory "tetraene" 4-series LT and 2-series prostanoids and production of cytokines from inflammatory cells (22) (Fig. 4). Eosinophils, mast cells, basophils, and alveolar macrophages can directly synthesize the 4-series cysteinyl (cyst) LT (C4 - E4), which can increase vascular permeability and contract smooth muscle cells, causing bronchoconstriction and vasoconstriction, and may directly increase eosinophilic airway inflammation. The EPA-derived "pentaene" 5-series cyst LT are equiactive with their tetraene counterparts in constricting nonvascular smooth muscle (22). Leukotriene B4 (LTB) is a potent chemoattractant and activator of neutrophils, without any significant effect on airway smooth muscle. However, LTB5, the 5,12,-dihydroxy derivative of EPA formed from LTA5, is a weak and partial antagonist compared with LTB4 in eliciting chemotactic and aggregating responses in polymorphonuclear leukocytes (PMNL). Consuming fish oil results in partial replacement of AA in inflammatory cell membranes by EPA and thus demonstrates a potentially beneficial anti-inflammatory effect of n-3 PUFA. Supplementing the diet with n-3 PUFA has been shown to reduce AA concentrations in neutrophils and neutrophil chemotaxis and reduce LT generation (13). These data are consistent with the proposed pathway by which dietary intake of n-3 PUFA modulates lung disease.

There has been increased emphasis on the beneficial effects for cardiovascular health of replacing lard and dairy fats rich in saturated fatty acids. This has led to increased consumption of vegetable oils rich in n-6 PUFA and a simultaneous decrease in consumption of oily fish and leafy vegetables, the major sources of n-3 PUFA. This dietary shift is characterized by a fall in consumption of saturated fats and an increase in n-6 PUFA. The anti-inflammatory properties of n-3 PUFA such as EPA and DHA and generally proinflammatory properties of dietary n-6 PUFA, such as linoleic acid, suggest that these dietary trends may have predisposed some individuals to inflammatory disorders, including asthma.

The hypothesis that the consumption of dietary fatty acids can influence the development and activity of an inflammatory disease such as asthma is attractive in view of the complex metabolic role that fatty acids play in cell metabolism and structure. The observational evidence on fish oil effects has been relatively consistent in demonstrating protection against asthma and/or allergy in relation to a high intake, and ecological and other cross-sectional data support the hypothesis that n-6 PUFA may increase and n-3 PUFA may decrease asthma risk. However, the clinical trial evidence is less conclusive than is the observational evidence.

Only a few studies have examined the specific effects of fish oil supplementation on EIA. Arm et al. (2) investigated the effects of 3.2 g EPA and 2.2 g DHA per day or placebo for 10 wk in asthmatic subjects. In the fish oil-supplemented group, total LTB production was inhibited by 50% in stimulated neutrophils, whereas no change was seen in the placebo group. Exercise challenges were completed in five subjects on placebo and six on fish oil, but no differences in airway pressure in response to exercise were detected.

Mickleborough and colleagues (21) have shown in 10 nonatopic elite athletes with EIA that 3 wk of fish oil supplementation (3.2 g EPA and 2.2 g DHA per day) reduced the fall in FEV1 at 15 min postexercise by almost 80% in conjunction with a greater than 20% reduction in bronchodilator use (Fig. 5). In addition, the increase in tissue phospholipid n-3 PUFA concentration was coincident with a significant suppression of the urinary and blood eicosanoids (LTE4, 9α, 11β-PGF2, and LTB4 respectively) and proinflammatory cytokines (TNF-α and IL-1β).

Figure 5

Figure 5

In a follow-up study, Mickleborough and colleagues (19) recently examined the effect of fish oil supplementation in 16 asthmatic patients who experienced EIA. The fish oil diet reduced the postexercise fall in FEV1 by approximately 64%. In addition, there was a significant improvement in asthma symptoms scores and a reduction in bronchodilator use (total number of doses/puffs) on the fish oil diet. In addition, sputum differential eosinophil, neutrophil, lymphocyte, and macrophage cell counts, and sputum supernatant concentrations of proinflammatory eicosanoids (LTC4-LTE4 and PGD2) and cytokines (TNF-α, IL-1β) were significantly reduced on the fish oil diet. In addition, the amount of LTB5, a weak and partial antagonist compared with LTB4 in eliciting chemotactic and aggregating responses, generated from activated PMNL was markedly increased after fish oil supplementation. These results strongly suggest that dietary supplementation with fish oil can suppress airway inflammation in asthmatic subjects with EIA.

In view of the clinical consequences, these findings point toward prophylactic and acute therapeutic effects of fish oil supplementation in inflammatory diseases such as asthma. It is possible that pharmacotherapy could be decreased in some patients with asthma and EIA in concert with increased fish-oil ingestion if both the drug and n-3 PUFA are exerting their therapeutic effects through the same molecular actions. Thus, the possibility exists for drug-diet interactions that confer greater anti-inflammatory benefits in the airway than either intervention alone or at least similar anti-inflammatory effects with less toxicity. In addition, further studies assessing the efficacy of fish oil supplementation on EIA should be directed at determining which of the active constituents of fish oil (EPA and/or DHA in various ratios) and daily intake of fish oil is most effective in suppressing EIA and airway inflammation and to evaluate the long-term tolerability of such a formulation.

Identifying the molecular mechanism(s) that underlies the many reports of the benefits of dietary n-3PUFA remains an important challenge for nutrition and medicine. Due to the fact that a new class of mediator families derived from fish oil, the EPA-and DHA-derived resolvins (RvE1 and RvD1) and the DHA-derived protectin (PD1), which act locally and possess potent anti-inflammatory novel bioactions, suggest exciting new therapeutic treatment strategies for asthma.

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The diuretic, respiratory, cardiovascular, and central stimulant effects of caffeine, a methylated xanthine alkaloid derivative (1,3,7-trimethlyxanthine), are widely known. The main sources of caffeine include coffee, tea, and caffeinated cola drinks. The International Olympic Committee (IOC) has recognized the performance-enhancing effects of caffeine, calling it an ergogenic substance and banning the drug from 1962 to 1972. Currently, the IOC lists caffeine as a restricted drug. Urinary levels up to a concentration of 12 mg·mL−1 are acceptable, representing casual use; however, levels above this are viewed as achieved through a deliberate attempt at doping by an athlete. Approximately 1000 mg of caffeine (approximately 8 cups of coffee) would be required to exceed the current IOC limit, but it is very important to note that individuals can metabolize caffeine at very different rates. Differences in metabolism, medications, and certain diseases may significantly alter the rate in which caffeine is cleared from the body. Generally, caffeine absorption is complete approximately within 1 h after ingestion, and the plasma concentration peaks after approximately 90 min. For doses lower than 10 mg·kg−1, the half-life of caffeine in the plasma is approximately 2.5 to 4.5 h in healthy adults.

Caffeine is related to theophylline, which has immunomodulatory, anti-inflammatory, and bronchoprotective effects that potentially contribute to its efficacy as a prophylactic antiasthma drug. Although it has traditionally been classified as a bronchodilator, the ability of theophylline to control chronic asthma is disproportionately greater than is explainable by its relatively small degree of bronchodilator activity. Caffeine inhibits phosphodiesterase, which stimulates cyclic adenosine monophosphate (cAMP) production, which in turn promotes relaxation of bronchial smooth muscle. In addition, caffeine can stimulate prostaglandin synthesis, which induces an increased cAMP.

A number of studies have explored the use of caffeine in asthma, and the conclusions from a Cochrane Review (3) suggest that in the six clinical trials evaluated, caffeine does seem to improve airway caliber modestly for up 4 h in individuals with asthma. To date, only two studies evaluating the effect of caffeine on pulmonary function in asthmatic individuals with EIA have been published (7,12). Kivity et al. (12) studied the effect of two doses of caffeine, 3.5 mg·kg−1 and 7mg·kg−1, on 10 asthmatic patients with EIA. Placebo or oral caffeine at 3.5 or 7 mg·kg−1 was administered 2 h before exercise. On the placebo postexercise, FEV1 dropped 25% compared with baseline, whereas the higher dose of caffeine reduced this decrease to 10%, which was statistically significant. The lower dose of caffeine did not demonstrate a statistical effect (with a 14% drop in FEV1). Although the only statistically significant findings were in doses of 7 mg·kg−1; the 3.5-mg·kg−1 dose also showed a trend toward EIA protection. It should be pointed out that the 7.5-mg·kg−1 dose of caffeine is equivalent to approximately 3 cups of coffee, which is an amount unlikely to be consumed by an individual before exercise. However, this amount of caffeine can be readily consumed before exercise if taken in pill form. Duffy and Phillips (7), using a randomized double-blind crossover placebo-controlled design, examined the efficacy of caffeine at 5 or 10 mg·kg−1 or placebo on postexercise pulmonary function in 11 asthmatic patients with EIA. Eucapnic hyperventilation of dry gas was used as a surrogate to exercise as a challenge to the airways. Caffeine or placebo was ingested 90 min before the dry gas challenge. Similar to the study of Kivity et al. (12), the higher dose of caffeine, which is equivalent to 5 cups of coffee, reduced the postexercise fall in FEV1 significantly from a decrease of 16.7% on placebo to 7.1%. The lower dose of caffeine did not have a significant impact on the postexercise FEV1 (−10.2%) compared with placebo (−16.7%). Therefore, in the 2 studies (7,12) conducted to date examining the efficacy of caffeine ingestion on EIA, postexercise pulmonary function was significantly improved to subclinical levels in EIA subjects. However, the dose of caffeine required to induce bronchodilation is high compared with usual dietary intakes.

Although it has been suggested that moderate amounts of caffeine (1 to 4 cups of coffee per day) cause only a mild diuresis, further research needs to be conducted to determine whether chronic, high-dose caffeine results in fluid-electrolyte imbalances. This effect should be considered by an athlete considering this approach to reducing EIA via the use of caffeine ingestion. In addition, the athlete should be cautioned that the high doses used in these studies are likely to cause urinary concentrations of caffeine in excess of the 12-mg·mL IOC limit and are likely to produce a positive test.

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The impact of a diet on exercise performance in asthmatic individuals has not been adequately assessed. Mickleborough et al. (21) observed no significant difference in exercise time to exhaustion (ETE) between a normal, placebo, and fish oil diet in elite athletes with EIA. There are various unanswered questions regarding this observation. First, it is generally accepted that ETE tests are not true measures of exercise performance because they do not mimic a competitive situation and are reported to have poor reliability. Having an athlete complete a fixed amount of work or a set distance covered in a certain time (i.e., time-trial type test) is much more reliable than ETE tests. Second, although most asthmatic individuals can complete exercise without bronchoconstriction occurring, it is possible that bronchoconstriction during exercise may be more common among individuals with more severe asthma than the subjects used in many of the studies discussed above. In addition, bronchoconstricting mediators, such as LT, PG, and histamine, may not have much of an effect during exercise because of prevailing bronchodilating mediators, such as nitric oxide and PGE2. Therefore, to accurately determine the influence of diet on exercise performance in asthmatic individuals, a laboratory time-trial type test should be used in conjunction with measuring pulmonary function during exercise.

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The purpose of this review was to examine the evidence as to whether dietary modification represents a potentially beneficial nonpharmacological intervention for asthmatic individuals with EIA. The interpretation of the evidence suggests that diet plays an important role in modifying the degree of exercise-induced airway narrowing in asthmatic individuals (Table). It is possible that any beneficial effect of diet on asthma and EIA is mediated through the combined effect of a variety of nutrients, rather than any single nutrient. The most effective method of exploiting this effect to individual and population benefit is almost certainly dietary manipulation to increase intake of natural foods, particularly fresh fruit and vegetables and oily fish, and to decrease salt consumption. A food-based approach that is accepted and tolerated is a preferable way to ensure long-term nutrient intake. From this, it follows that physicians should pay more attention to what their asthma/EIA patients eat and to incorporate dietary assessment and nutritional counseling in their everyday practice.



The dietary factors discussed in this review did not normalize postexercise pulmonary function in asthmatic individuals with EIA. However, on average, these dietary interventions did improve pulmonary function to below the clinical threshold of a 10% fall in postexercise FEV1 commonly used for diagnosis of EIA. This level of improvement is not unlike many pharmacological treatments, which also do not necessarily normalize pulmonary function in EIA, but do improve pulmonary function to subclinical levels. Thus, a salt-restricted diet and a diet high in fish oil and antioxidants could provide novel treatment approaches of airway hyperresponsiveness and pulmonary inflammation in asthmatic/EIA individuals. Consequently, the potential for enhancing the quality of life for those individuals with asthma/EIA by dietary modification is high.

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diet; airway; bronchoconstriction; eicosanoid; cytokine

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