Late Breaking Abstract - IL-33 enhances contractions and mast cell mediator release in isolated human bronchi

<bold>Background:</bold> interleukin (IL)-33, thymic stromal lymphopoetin (TSLP) and IL-25 are key initiators of airway inflammation in asthma. We have previously shown that a combination of the three enhances antigen-induced contractions of isolated human bronchi by increasing the release of mast cell mediators. <bold>Objective:</bold> to investigate which one of IL-33, TSLP or IL-25 enhances responses to antigen or hyperosmolar stimulation of human small bronchi and human lung mast cells (HLMCs). <bold>Methods:</bold> intact segments of human bronchi (inner ⌀ 0.5-2 mm) and HLMCs were isolated from human lung tissue, and exposed to IL-33, TSLP or IL-25 (100 ng/mL). Antigen-induced (0.5 and 5 μg/mL anti-IgE) and hyperosmolar-induced (850 mOsm mannitol) contractile responses of bronchial segments were studied using myographs. HLMCs degranulation in response to antigen (0.2 or 2 μg/mL of anti-IgE) or hyperosmolar activation (0.7 M mannitol) was studied using flow cytometry. Release of mast cell mediators was monitored by liquid chromatography coupled to tandem mass spectrometry and fluorescent spectrometry. <bold>Results:</bold> anti-IgE and mannitol both evoked contractions of bronchial segments. Exposure to IL-33 enhanced the contractions by 62% and 78% respectively, while also doubling antigen-induced release of prostaglandin (PG)D₂, PGF_2α, PGE₂ and histamine from the bronchial segments. HLMCs activated by anti-IgE or mannitol increased their degranulation and release of major prostanoids and cysteinyl leukotrienes, which was enhanced by exposure to IL-33. <bold>Conclusion:</bold> IL-33 amplifies bronchoconstriction of human small bronchi to antigen- and hyperosmolar stimulation by increasing HLMC degranulation and release of lipid mediators.