Allergen and Ozone Exacerbate Serotonin-Induced Increases in Airway Smooth Muscle Contraction in a Model of Childhood Asthma

Abstract

Background: Serotonin (5-HT) modulates cholinergic neurotransmission and exacerbates airway smooth muscle (ASM) contraction in normal animal and nonasthmatic human tissue. Exposure to house dust mite allergen (HDMA) and ozone (O₃) leads to airway hyperreactivity and 5-HT-positive cells in the airway epithelium of infant rhesus monkeys. Research shows that concomitant exposure in allergic animals has an additive effect on airway hyperreactivity. Objectives: In this study, the hypothesis is that the exposure of allergic infant rhesus monkeys to HDMA, O₃ and in combination, acting through 5-HT receptors, enhances 5-HT modulation of postganglionic cholinergic ASM contraction. Methods: Twenty-four HDMA-sensitized infant monkeys were split into 4 groups at the age of 1 month, and were exposed to filtered air (FA), HDMA, O₃ or in combination (HDMA+O₃). At the age of 6 months, airway rings were harvested and postganglionic, and parasympathetic-mediated ASM contraction was evaluated using electrical-field stimulation (EFS). Results: 5-HT exacerbated the EFS response within all exposure groups, but had no effect in the FA group. 5-HT₂, 5-HT₃ and 5-HT₄ receptor agonists exacerbated the response. 5-HT concentration-response curves performed after incubation with specific receptor antagonists confirmed the involvement of 5-HT₂, 5-HT₃ and 5-HT₄ receptors. Conversely, a 5-HT₁ receptor agonist attenuated the tension across all groups during EFS, and in ASM contracted via exogenous acetylcholine. Conclusions: HDMA, O₃ and HDMA+O₃ exposure in a model of childhood allergic asthma enhances 5-HT exacerbation of EFS-induced ASM contraction through 5-HT₂, 5-HT₃ and 5-HT₄ receptors. A nonneurogenic inhibitory pathway exists, unaffected by exposure, mediated by 5-HT₁ receptors located on ASM.