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. Methacholineprovocations assess AHR in asthma patients mainly by direct stimulationofsmooth muscle cells. Using in vivo mouse models, mast cells have been implicated in AHR,but the mechanism behind has remained unknown.METHODS: Cpa3Cre/+ mice, which lack mast cells, were used to assess the role of mast cells inhouse dust mite (HDM)-induced experimental asthma. Effects of methacholine in presence or absence of ketanserin were assessed on lung function, andin lung mast cells in vitro. Airway inflammation, mast cell accumulation and activation, smooth muscle proliferation,HDM-induced bronchoconstriction were evaluated.RESULTS: Repeated intranasal HDM sensitization induced allergic airway inflammation associated with accumulation and activation of lung mast cells. Lack of mast cells, absence of activating Fc-receptors, or antagonizingserotonin (5-HT)2A receptors abolishedHDM-induced trachea contractions.HDM-sensitized mice lacking mast cells had diminished lung-associated 5-HT levels, reduced AHR and methacholine-induced airway contraction, while blocking 5-HT2A receptors in wild types eliminated AHR, implying that mast cells contribute to AHR by releasing 5-HT. Primary mouse and human lung mast cells express muscarinic M3 receptors. Mouse lung mast cells store 5-HT intracellularly, and methacholine induces release of 5-HT from lung-derived mouse mast cells and Ca2+ flux in human LAD-2 mast cells.CONCLUSIONS: Methacholineactivates mast cells to release 5-HT, which by acting on 5-HT2A receptors enhances bronchoconstriction and AHR. Thus, M3-directed asthma treatments like tiotropium may also act by targeting mast cells.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Lungmedicin och allergi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Respiratory Medicine and Allergy (hsv//eng)

Nyckelord

Airway hyperresponsiveness

Asthma

House dust mite

Mast cells

Mouse model

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