Mast cell?derived serotonin enhances methacholine?induced airway hyperresponsiveness in house dust mite?induced experimental asthma

Background Airway hyperresponsiveness (AHR) is a feature of asthma in which airways are hyperreactive to stimuli causing extensive airway narrowing. Methacholine provocations assess AHR patients mainly by direct stimulation smooth muscle cells. Using vivo mouse models, mast cells have been implicated AHR, but the mechanism behind has remained unknown. Methods Cpa3Cre/+mice, lack cells, were used role house dust mite (HDM)-induced experimental asthma. Effects methacholine presence or absence ketanserin assessed on lung function and vitro. inflammation, cell accumulation activation, proliferation, HDM-induced bronchoconstriction evaluated. Results Repeated intranasal HDM sensitization induced allergic inflammation associated with activation Lack activating Fc-receptors, antagonizing serotonin (5-HT)2A receptors abolished trachea contractions. HDM-sensitized mice lacking had diminished lung-associated 5-HT levels, reduced methacholine-induced contraction, while blocking 5-HT2A wild types eliminated implying that contribute releasing 5-HT. Primary human express muscarinic M3 receptors. Mouse store intracellularly, induces release from lung-derived Ca2+ flux LAD-2 Conclusions activates 5-HT, acting enhances AHR. Thus, M3-directed treatments like tiotropium may also act targeting