We defined the contribution of histamine and leukotrienes to allergen-induced airway obstruction in asthmatics; 12 subjects with allergic asthma underwent identical allergen bronchoprovocations on four occasions. At a control session, all subjects displayed early (EAR) and late asthmatic (LAR) reactions. The mean (+/- SE) drop in FEV1 during EAR (0-2 h) and LAR (2-12 h) was 29 +/- 2% and 28 +/- 4%, respectively. Thereafter, the influence of 1 wk randomized pretreatment with the leukotriene receptor antagonist zafirlukast (Accolate) (80 mg twice daily), the antihistamine loratadine (10 mg twice daily), and the combination of both antagonists was assessed. Expressed as AUC FEV1 in percent of the control reaction, zafirlukast reduced the response during EAR and LAR by 62 +/- 11% and 55 +/- 12%, respectively (p < 0.05 versus control). Loratadine inhibited EAR and LAR by 25 +/- 14% and 40 +/- 16%, respectively (p < 0.05 versus control). Zafirlukast was significantly more effective than loratadine during EAR but not during LAR. The combination of zafirlukast and loratadine reduced the AUC FEV1 during EAR and LAR further, by 75 +/- 8% and 74 +/- 14%, respectively (p < 0.05 versus control). The combination was significantly (p < 0.05) more effective than either drug alone during the LAR. The findings indicate that leukotrienes and histamine together mediate the major part of both the EAR and the LAR following exposure of asthmatics to allergen. Combination of leukotriene antagonism and antihistamines may represent a new strategy for treatment of airway obstruction in asthma.

These results indicate that mast cell activation is a feature not only of the early but also the late asthmatic response. Finally, increased LTE4 supports the contribution of the leukotrienes to airway obstruction during both phases of the asthmatic response to allergen.

Exercise-induced bronchoconstriction (EIB) is thought to occur in 70-80% of asthmatics, most commonly amongst those with moderate-to-severe airway hyperresponsiveness [1]. It is characterized by transient airflow obstruction resulting in a Š15% decrease in forced expiratory volume in one second (FEV1) following 5-8 min of exercise. The fall in FEV1 reaches a maximum approximately 10 min after exercise and gradually normalizes over the next hour [2]. The precise pathophysiology of EIB remains unclear, although it is widely accepted that during exercise the upper airways are unable to adequately warm and humidify the increased volumes of inspired air. This results in airway cooling and increased airway fluid osmolality in the lower airways [3,4]. One hypothesis suggests that hyperosmolar triggering of mast cells and possibly other inflammatory cells results in the release of bronchoconstricting mediators, e.g. cysteinyl-leukotrienes (cys-LTs), histamine and prostaglandin (PG)D 2 [5].Previous indications for the participation of mast cell mediators in the pathogenesis of EIB are based on pharmacological data. For example, disodium cromoglycate (DSCG), a drug which stabilizes mast cell membranes, is effective in blunting exercise-induced asthma [6,7]. Pretreatment with a number of H 1 receptor antagonists has been shown to attenuate EIB [8][9][10]; however, the degree of protection afforded by this class of drugs has been modest. More recently, studies employing leukotriene receptor antagonists [11,12] and biosynthesis inhibitors [13] have implicated leukotrienes in the airway bronchoconstrictor response to exercise.The direct approach of measuring mast cell mediator release in response to exercise challenge has yielded ambiguous results. Some studies have reported an elevation in plasma and whole blood histamine concentrations following EIB [14,15], while other studies have failed to verify those findings [16,17]. Apart from the methodological problems encountered when sampling plasma histamine [18] and its short half-life in the circulation, approximately 1 min [19], it has been suggested that elevations in plasma histamine mainly reflect the basophilia which normally accompanies exercise [20]. Increases in the levels of tryptase and PGD 2 , both specific mast cell markers, have been detected in nasal lavage following nasal provocation with cold dry air [21], but not after exercise [22,23].The purpose of this study was to provide evidence to establish mast cell activation as a feature of EIB. To this end, a combination of mast cell markers, 9α,11β-PGF 2 Sullivan, A. Roquet, B. Dahlén, F. Larsen, A. Eklund, M. Kumlin, P.M. O'Byrne, S-E. Dahlén. ©ERS Journals 1998. ABSTRACT: Controversy remains about the causative mediators in the bronchoconstrictive response to exercise in asthma. This study examined whether mast cell activation is a feature of exercise-induced bronchoconstriction by measuring urinary metabolites of mast cell mediators. Evidence for mast cell activation during exercise-induced bronchoconstriction....

Repeated low-dose allergen exposure induces an allergic airway inflammation in asthmatic subjects. The inflammation is associated with an altered AM phenotype pattern, consistent with an influx of monocytes and a hypothetical increased accessory cell function in the airways, possibly contributing to the development and sustenance of airway inflammation in asthma.