Repeated allergen exposure and airway responses. Modulation of eicosanoid production

Abstract

Early airway responses (immediate airflow obstruction and airway plasma exudation), late airway response and bronchial hyperresponsiveness to non-sensitizing agents are important features of allergic asthma. Mediators released from mast cells including histamine, cysteinyl leukotrienes and thromboxane A2 contribute to the early airway responses induced by allergen challenge, whereas the airway inflammation is considered to be central to the late airway response and bronchial hyperresponsiveness. Repeated inhaled exposures to low doses of allergen may have important significance, because this type of exposure may be common in our everyday life. The aim of the present study was to investigate (1) the consequences of repeated allergen exposures in the airways of guinea pigs and rats sensitised with an occupational allergen (trimellitic anhydride), (2) the roles of cysteinyl leukotrienes and thromboxane A2 in early airway response in guinea pigs, and (3) the modification of production of cysteinyl leukotrienes and thromboxane A2 after repeated allergen exposure. Intradermal injection of trimellitic anhydride induces IgE and IgG anti-TMA antibodies in rats. Repeated allergen exposure induce bronchial hyperresponsiveness to acetylcholine accompanied by epithelial damage, goblet cells hyperplasia, and airway narrowing in sensitised rats. Eosinophil infiltration is reduced during repeated allergen exposures in sensitised rats. Previous repeated allergen exposures attenuate immediate airflow obstruction and airway plasma exudation induced by a subsequent high dose allergen challenge in H-1 receptor blocked guinea pigs, and this inhibition is not allergen-specific, suggesting a common pathway such as mediator production. A stable thromboxane A2 mimetic (U-46619) and a prostaglandin F-like compound (8-epi-PGF2a) increase lung resistance and airway plasma exudation in naïve guinea pigs. A leukotriene receptor antagonist (ICI 198,615) and a cyclooxygenase inhibitor (indomethacin) attenuate the immediate airflow obstruction and airway plasma exudation induced by a high dose allergen challenge in sensitised guinea pigs, suggesting that cysteinyl leukotrienes and thromboxane A2 are involved in the allergen induced immediate airflow obstruction and airway plasma exudation. The production of cysteinyl leukotrienes and thromboxane B2 in BAL in the immediate airway response to a high dose allergen challenge is strongly inhibited by previous repeated allergen exposure. Incubation of isolated airway tissues from sensitised guinea pigs with arachidonic acid and calcium ionophore (A23187) causes production of cysteinyl leukotrienes and thromboxane A2, with evidence of enhanced activities of these pathways by repeated allergen exposure. We conclude that repeated allergen exposures induce bronchial hyperresponsiveness and airway inflammation. The inhibition of immediate airflow obstruction and plasma exudation induced by a high dose allergen challenge after repeated allergen exposures is due to the reduction of cysteinyl leukotrienes and thromboxane A2 production. The mechanism of reduction of cysteinyl leukotrienes and thromboxane A2 production is neither allergen specific nor due to downregulated activity of 5-lipoxygenase and cyclooxygenase pathways, but rather imply intracellular mechanisms localised between direct allergen-Ig interaction and mediator-producing enzymes in cysteinyl leukotrienes and thromboxane A2 producing cells.