Many of the symptoms of allergic diseases result from inappropriate activation of sensory nerves. In the case of allergic airway disorders, such activation may manifest as coughing, sneezing, and a host of other symptoms. While the close anatomic association between mast cells and peripheral nerves may explain why allergic inflammation is particularly adept at perturbing airway neurophysiology, relatively little is known about the effect of antigenic activation of mast cells on control in the respiratory system. The goal of this proposal is to understand the consequences of immunological activation of airway mast cells on sensory nerves within the respiratory tract, and focuses on the hypothesis that allergen challenge in mast cells leads to mast cell-dependent modulation of sensory nociceptive C-fibers.
The specific aims are to characterize the effects of acute allergen challenge on activity and excitability of mouse vagal sensory bronchopulmonary C-fibers, and to address the hypothesis that allergen-induced changes in the electrophysiological properties of vagal sensory bronchopulmonary C-fibers are dependent on activation of tissue mast cells. To address these aims, a mouse model will be used. The trachea, bronchi, and lungs with the vagus nerve and vagal sensory ganglia will obtained from mice actively sensitized to ovalbumin (OVA), and extracellular recording of action potentials from afferent nerves in the lungs and airway wall will be performed. A C-fiber will be obtained, and its response to OVA with respect to activation and changes in excitability will be evaluated. To assess the role of mast cells in the effect of allergen on electrophysiological properties of airway C-fibers, experiments will be repeated in tissue isolated from OVA-sensitized mast cell-deficient sash -/- mice. Finally, an attempt will be made to rescue the electrophysiological effects of allergen on airway C-fibers by reconstituting sash-/- mice with bone marrow-derived mast cells, sensitizing them to OVA, and evaluating the effect of allergen challenge on C-fiber electrophysiology. This study will yield information on the mechanisms by which allergic inflammation alters neurophysiology in the airways that will be helpful in understanding the pathophysiology of allergic airway disease, and may lead to novel therapeutic strategies aimed at limiting the symptoms of those afflicted.
