Leukotriene Bronchoconstriction Induced by Allergen and Exercise

P. M. O'BYRNE

Asthma Research Group and Department of Medicine, McMaster University, Hamilton, Ontario, Canada

	INTRODUCTION

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Airway hyperresponsiveness to a wide variety of bronchoconstrictor agonists is a characteristic finding in patients with current, symptomatic asthma. The agonists include inhaled pharmacological agonists, such as histamine (1) acting on airway H₁ receptors, the cholinergic agonist methacholine (2) acting on airway M₃ receptors, the cysteinyl-leukotrienes (3) acting on airway Cys-LT₁ receptors, and the stimulatory prostaglandins (PG)D₂ (4) and PGF_2a (5) likely acting on airway TP receptors. These agonists are considered to be direct stimuli causing bronchoconstriction in individuals with asthma, because their action is directly on specific airway receptors.

Airway hyperresponsiveness is also present to a number of physical stimuli such as exercise (6), isocapnic hyperventilation of cold, dry air (7), and hypo- and hypertonic aerosols (8). The bronchoconstriction that develops after exposure to the physical stimuli is indirect, because it occurs through the release of constrictor mediators from cells within the airways, which subsequently act on their specific receptors to mediate bronchoconstriction.

Another important indirect stimulus for bronchoconstriction in many individuals with asthma is environmental allergens. The responses after inhaled allergens are often quite different from those after the other indirect stimuli, in that the acute bronchoconstrictor responses are often followed by the development of late-phase bronchoconstrictor responses (9), airway inflammation (10), and an increase in airway hyperresponsiveness (11). The focus of this article is to evaluate the evidence that the cysteinyl-leukotrienes (LT) C₄, D₄, and E₄ are released in asthmatic airways and are the main cause of bronchoconstriction after exposure to exercise and environmental allergens, and of the changes in airway hyperresponsiveness after the inhalation of allergen.

	EXERCISE-INDUCED BRONCHOCONSTRICTION

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The term "exercise-induced asthma" has often been used to describe the bronchoconstriction that occurs after exercise; however, this is a misnomer, as exercise, unlike allergen inhalation (12) or occupational sensitizers (13), is not known to cause asthma, but rather causes bronchoconstriction in patients with asthma. Thus, the term exercise-induced bronchoconstriction is to be preferred.

Exercise-induced bronchoconstriction occurs in 70-80% of patients with current symptomatic asthma, and is more likely to occur in patients with moderate to severely increased airway responsiveness. Indeed, for any given exercise challenge, the magnitude of the resulting bronchoconstriction is correlated with the degree of airway hyperresponsiveness (14). This means that in many patients with mild, episodic asthma, who, in general, have mildly increased airway responsiveness, even strenuous exercise does not cause bronchoconstriction.

Exercise-induced bronchoconstriction occasionally occurs during exercise itself. Much more commonly, bronchodilation occurs during exercise, and this lasts for 1-3 min after exercise (15). This is followed by the onset of bronchoconstriction, beginning by 3 min, which generally peaks by 10-15 min and has resolved by 60 min (Figure 1). Exercise-induced bronchoconstriction is likely caused by the efforts of the airways to condition to body temperature and to fully humidify the increased volumes of air inhaled during exercise (16).

View larger version (11K): [in this window] [in a new window]   Figure 1.   Exercise-induced bronchoconstriction as measured by the percent fall in FEV1 after exercise. The peak bronchoconstriction occurs 15-30 min after exercise and the FEV1 usually has recovered by 1 h.

	EXERCISE REFRACTORINESS

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In 1966 McNeill and colleagues (17) identified that, in many asthmatic patients with exercise-induced bronchoconstriction, the episode of bronchoconstriction is followed by a period during which exercise causes less bronchoconstriction, and that with repeated bouts of exercise the bronchoconstriction can be abolished. Subsequently, Edmunds and coworkers (18) labeled this effect as exercise refractoriness and noted that the refractory period after exercise generally lasts less than 4 h. Several mechanisms have been proposed to explain exercise refractoriness. These have included depletion of preformed mediators from mast cells; prolonged protection afforded by increases in catecholamines released during the first exercise challenge; and release of inhibitory mediators during exercise bronchoconstriction, which partially protects the airways against repeated episodes of bronchoconstriction.

	CYSTEINYL-LEUKOTRIENES AND EXERCISE- INDUCED BRONCHOCONSTRICTION

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The cysteinyl-leukotrienes are, overall, the most important mediators causing exercise-induced bronchoconstriction in individuals with asthma. This was not immediately obvious from the initial studies, which attempted to measure mediator release in the airways after exercise by measuring the excretion of urinary LTE₄ (19). However, a subsequent study of children with asthma did demonstrate an increase in urinary LTE₄ after exercise-induced bronchoconstriction (20). The most compelling evidence of an important role for the cysteinyl-leukotrienes comes from a number of studies that have demonstrated marked attenuation of exercise-induced bronchoconstriction after pretreatment with a variety of different Cys-LT₁ receptor antagonists, thereby blocking the action of the cysteinyl-leukotrienes on their receptors in human airways. Receptor antagonists such as MK-571 (21), zafirlukast [Accolate, either given orally (22) or by inhalation (23)], montelukast (Singulair) (24), or cinalukast (25) inhibit the maximal bronchoconstrictor response after exercise by between 50 and 80%, greatly shortening the time to recovery of normal lung function, and thereby markedly reducing the time-response curve. Indeed, in 30-50% of subjects with asthma studied, these receptor antagonists completely inhibit the response. The long-lasting receptor antagonist cinalukast reduced the area under the time-response curve after exercise by > 80% in subjects with asthma, and this effect lasted more than 8 h after dosing (25) (Figure 2). An even longer duration of protection was achieved with montelukast (24). There is heterogeneity among subjects, in that in some subjects interruption of the leukotriene cascade results in a complete inhibition of the bronchospastic response to exercise whereas in others this intervention has no effect. This indicates that the pathways leading to bronchoconstriction after exercise vary among individuals with asthma, and that in some, mediators other than the leukotrienes may be more important bronchoconstrictor agonists.

View larger version (29K): [in this window] [in a new window]   Figure 2.   The effects of treatment with three different doses of cinalukast on exercise-induced bronchoconstriction as measured by the area under the time- response curve. On the first day of treatment the protective effect at each dose was maintained for at least 8 h. After 1 wk of treatment, the protective effect for the lowest (10 mg) dose was lost, but persisted for the two higher doses. [Reproduced with permission from Reference 25.]

	INHIBITORY PROSTAGLANDINS AND EXERCISE- INDUCED REFRACTORINESS

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Inhibitory prostaglandins are important in causing tachyphylaxis to the bronchoconstrictor effects of histamine in subjects with asthma. This has been demonstrated by Manning and colleagues (26), who demonstrated histamine tachyphylaxis to repeated challenges with inhaled histamine, which lasted at least 6 h. This effect was abolished by pretreatment with the cycloxygenase inhibitor indomethacin (26), implicating the release of inhibitory prostaglandins in causing this response. In addition, pretreatment with exogenous oral PGE₁ reduces airway hyperresponsiveness to inhaled histamine and methacholine (27). Histamine tachyphylaxis is mediated by stimulation of histamine H₂ receptors, as pretreatment with the H₂ receptor antagonist cimetidine prevented histamine tachyphylaxis in subjects with asthma (28). The cell(s) of origin of this prostanoid is not yet known, but it likely originates from a structural cell in the airway epithelium (29) or airway smooth muscle (30).

As a result of these studies, we postulated that histamine released after exercise (31) causes bronchoconstriction in subjects with asthma, but also results in exercise refractoriness through inhibitory prostaglandin released by stimulation of histamine H₂ receptors. This was supported by studies that demonstrated that pretreatment with indomethacin prevented the development of exercise refractoriness (32, 33), implicating the release of an inhibitory prostaglandin in mediating this response. However, several subsequent studies suggested that this hypothesis is incorrect. This is because exercise-induced bronchoconstriction is markedly attenuated, and indeed in some subjects abolished, by pretreatment with Cys-LT₁ receptor antagonist (21, 22, 25). This indicates that the cysteinyl-leukotrienes, rather than histamine, are the main mediator responsible for exercise-induced bronchoconstriction. Also, pretreatment with the H₂ receptor antagonists cimetidine or ranitidine, which effectively prevent histamine tachyphylaxis, did not prevent exercise refractoriness (34). Therefore, histamine-induced inhibitory prostaglandin release did not appear to be the cause of exercise refractoriness.

To explain these diverse findings, we speculated that stimulation of the Cys-LT₁ receptor by the cysteinyl-leukotrienes after exercise may result in inhibitory prostaglandin release and the development of exercise refractoriness. This hypothesis was supported by studies that demonstrated that tachyphylaxis to inhaled LTD₄ occurs in subjects with asthma, that cross-tachyphylaxis exists between exercise and inhaled LTD₄, and that this cross-tachyphylaxis was prevented by pretreatment with the cycloxygenase inhibitor flurbiprofen (35). Also, inhaled PGE₂ markedly attenuates exercise broncoconstriction (36) (Figure 3). Therefore, it appears that cysteinyl-leukotrienes are released in response to exercise. This results in bronchoconstriction, but also in the release of inhibitory prostaglandins, such as PGE₂, which partially attenuates further exercise-induced bronchoconstriction.

View larger version (12K): [in this window] [in a new window]   Figure 3.   The fall in FEV1 after exercise over time after treatment with inhaled placebo (open circles) or PGE2 (closed circles). PGE2 significantly attenuated the magnitude of exercise bronchoconstriction and shortened the recovery time. [Reproduced with permission from Reference 36.]

	ALLERGEN-INDUCED AIRWAY RESPONSES.

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The inhalation of environmental allergens is overall the most important cause of asthma. Inhalation of allergens by sensitized subjects results in bronchoconstriction, which develops within 10 min of the inhalation, reaches a maximum within 30 min, and generally resolves within 1-3 h, the early asthmatic response (EAR) (9). In some subjects who develop an early asthmatic response, the bronchoconstriction persists and either does not return to baseline values or recurs after 3-4 h and reaches a maximum over the next few hours, the late asthmatic response (LAR) (9), and may last 24 h or more.

Allergen inhalation can also result in a transient increase in airway hyperresponsiveness that has been described to occur as early as 3 h after allergen inhalation (37) and that can persist for days or weeks after allergen inhalation (11). In general, however, allergen-induced airway hyperresponsiveness lasts 2-4 d (11). Allergen-induced airway hyperresponsiveness is most marked in subjects who develop late responses (11), although small and transient changes also occur in individuals with isolated early responses.

Allergen-induced late responses and airway hyperresponsiveness are associated with airway inflammation (10), with numbers of activated airway eosinophils and metachromatic cells being increased at 7-8 h and eosinophils further increased 24 h after allergen inhalation (38). The appearance of metachromatic cells and activated eosinophils in the airways likely explains the development of late responses.

	CYSTEINYL-LEUKOTRIENES AND ALLERGEN RESPONSES

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The bronchoconstriction that occurs during the early and late responses is in large part caused by allergen-induced release of cysteinyl-leukotrienes. This was initially suggested by Brocklehurst (39), who demonstrated the production of slow-reacting substance of anaphylaxis (SRS-A) after sensitized lung fragments were challenged by specific allergens. SRS-A is now known to consist of the cysteinyl-leukotrienes (40).

Several investigators have demonstrated increases in urinary LTE₄ after allergen-induced bronchoconstriction (41, 42). The increases in urinary LTE₄ were significantly correlated, in one study, with the magnitude of the bronchoconstriction (41). The best evidence, however, of a central role for the cysteinyl-leukotrienes in causing allergen-induced bronchoconstriction is suggested by the observations that a number of different LTD₄ receptor antagonists and leukotriene synthesis inhibitors have been demonstrated to markedly attenuate bronchoconstrictor responses after allergen inhalation (43) (Figure 4). These studies have indicated that LTD₄ antagonists and leukotriene synthesis inhibitors attenuate allergen-induced early responses by up to 80% (43, 44), and also attenuate the late response by up to 50% (44), suggesting that, as inhaled leukotriene D₄ does not itself cause the development of late responses (47), newly generated cysteinyl-leukotrienes, possibly from inflammatory cells, such as eosinophils recruited into the airways during the late asthmatic response (10, 38), are partially responsible for the bronchoconstriction during this response. The component of allergen-induced early and late responses not influenced by antileukotrienes is caused by histamine release (48).

View larger version (16K): [in this window] [in a new window]   Figure 4.   Mean (± SEM) percent change in FEV1 from baseline during the early and late asthmatic response to allergen inhalation after BAYx1005 (middle curve, closed circles) and placebo (bottom curve, open circles) pretreatment and after treatment with inhaled diluent (top curve). [Reproduced with permission from Reference 44.]

While consistent results from several studies have established a role for Cys-LTs in the pathogenesis of the EAR and LAR, a role for Cys-LTs in the development of allergen-induced airway hyperresonsiveness (AHR) is less certain. Taylor and colleagues (43) observed a significant attenuation of AHR 6 h after allergen inhalation following pretreatment with the Cys-LT receptor antagonist ICI-204,219, but other investigators (45, 46) were unable to confirm this finding 24 and 30 h after allergen inhalation following treatment with the 5-LO-activating protein (FLAP) antagonists MK-886 and MK-0591, respectively. One study (49) has demonstrated significant attenuation of allergen-induced airway hyperresponsiveness in subjects with asthma 24 h after allergen inhalation (Figure 5). This difference is likely caused by the fact that previously reported studies were insufficiently powered to demonstrate such an effect on allergen-induced airway hyperresponsiveness (50).

View larger version (18K): [in this window] [in a new window]   Figure 5.   Ratio of methacholine airway responsiveness, expressed as PC20 before and after 1 wk of treatment with pranlukast or placebo treatment, measured the day before inhaled allergen (left columns) or 24 h after inhaled allergen (right columns). Pranlukast significantly reduced the development of allergen-induced methacholine airway hyperresponsiveness (*p < 0.05). [Reproduced with permission from Reference 49.]

Allergen-induced airway inflammation may also be due in part to the release of cysteinyl-leukotrienes. Inhaled LTE₄ has been shown to cause eosinophil infiltration into airway biopsies from subjects with asthma, an effect not seen with inhaled methacholine (51). Also, one study has shown that pretreatment with the Cys-LT₁ receptor antagonist has been shown to attenuate allergen-induced influx into the airways after segmental allergen challenge (52). These studies suggest that the cysteinyl-leukotrienes, released as a result of allergen inhalation, may play a role in causing allergen-induced airway inflammation. However, cysteinyl-leukotrienes may not act directly to recruit eosinophils after allergen inhalation. While LTD₄ does not cause eosinophil chemotaxis in vitro, one group of investigators has shown that inhaled LTD₄ caused increases in eosinophils in induced sputum from subjects with asthma (53); however, they also demonstrated a similar effect with inhaled methacholine, suggesting that the sputum eosinophilia was a nonspecific effect in their studies. In one study, we have compared and contrasted the effects of inhaled allergen and inhaled LTD₄ in causing sputum eosinophilia in a group of subjects with allergic asthma, known to develop allergen-induced late responses. This study has demonstrated that in contrast to inhaled allergen, LTD₄ did not increase sputum eosinophil numbers. This suggests that while LTD₄ may be necessary for allergen-induced airway eosinophilia, it is not sufficient and must be involved as a cofactor with other mediators.

	CONCLUSIONS

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The release of cysteinyl-leukotrienes is the most important cause of bronchoconstriction after inhaled environmental allergens in subjects with atopic asthma and of exercise-induced bronchoconstriction. In addition, the cysteinyl-leukotrienes are also important in causing allergen-induced late responses and possibly eosinophil influx into the airways. The cysteinyl-leukotrienes also appear to initiate the release of inhibitory prostaglandins, which attenuate subsequent bronchoconstrictor responses to themselves, which is responsible for the development of exercise refractoriness with repeated exercise challenges.

	Footnotes

Correspondence and requests for reprints should be addressed to P. M. O'Byrne, M.D., Department of Medicine, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5 Canada. E-mail: obyrnep{at}fhs.mcmaster.ca.

	References

TOP INTRODUCTION EXERCISE-INDUCED... EXERCISE REFRACTORINESS CYSTEINYL-LEUKOTRIENES AND... INHIBITORY PROSTAGLANDINS AND... ALLERGEN-INDUCED AIRWAY... CYSTEINYL-LEUKOTRIENES AND... CONCLUSIONS REFERENCES

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