Peripheral sensory nerves stimulation lead to bronchoconstriction-augment in passive sensitized human precision-cut lung slices and is histamine 1 receptor dependent

Stimulation of afferent C-fibers axons with capsaicin causes a release of neuropeptides. These sensory neuropeptides can act on a number of effector cells in the respiratory tract such as mast cells and smooth muscle cells, which lead to bronchoconstriction. Increasing evidences point to mast cell-nerve as a functional unit as well as a key component of pathophysiological responses. However, the exact mechanisms by which mast cells and afferent nerves interact in the process of bronchoconstriction during allergic asthma are unknown. Here we propose a suitable ex vivo model using passively sensitized human precision-cut lung slices to investigate key molecules involved in mast cell-nerve crosstalk. Human PCLS were generated using resection material from lung tumor patients. In order to mimic an allergic situation, human precision cut lung slices (PCLS) were passively sensitized with plasma from HDM-allergic of healthy donors and subsequently incubated +/- the histamine 1 receptor antagonist Ceterizine®. Bronchoconstriction was provoked with the allergen house dust mite (HDM) or with the TRPV1 receptor agonist capsaicin. Bronchoconstriction was measured by videomicroscopy. The reduction of the airway area [% of initial airway area] was analysed. In addition mast cell tryptase and IgE immune-staining was performed in order to visualize mast cell degranulation. Immunostaining of sensory nerve fibers and mast cells showed the anatomical proximity in the airways of three human donors. Capsaicin-treated passive sensitized PCLS showed mast cell degranulation using primary antibodies against mast cell tryptase, mast cell bound IgE and the neuropeptide substance P. Capsaicininduced bronchoconstriction showed reduction of the airway area of 40 %. Capsaicininduced bronchoconstriction was totally inhibited by 10 µM of the histamine 1 receptor antagonist. Here we demonstrated a functional interaction of sensory nerves and mast cell mediators in human lung tissue leading to a significant increase in bronchoconstriction from passive sensitized human PCLS in response to the C-fiber agonist capsaicin. Thereby our ex vivo model reveals the importance of neuroimmunologic features involved in respiratory diseases such as allergic asthma