Both the irritating as well as the potentially debilitating symptoms of allergic airway disease are due in large part to perturbation in neuronal activity. Thus sneezing, nonproductive coughing, increased mucus secretion, reversible bronchospasm, and inordinate sensations of dyspnea are a consequence of abnormal afferent (sensory) input to the central nervous system, alterations in signal processing within the CNS, and/or alterations in the function of parasympathetic nerves. There has been much knowledge gained in the past two decades regarding the immunological and biochemical basis of the inflammation that accompanies allergic airway disease. Relatively little remains known, however, about how this inflammation modulates airway sensory and autonomic innervation such that the symptoms of disease occur. The long range goal of this proposal is to develop a better understanding of the mechanism and mediators involved in allergen- induced neuromodulation of the airways. We have previously made progress in investigating the influence of mast cell activation and allergic inflammation on airway sensory mechanosensors. There is little known about the influence of allergen challenge on the biology of nociceptive C-fibers in the airways. This is a gap in our knowledge that studies in Aim 1 begins to fill. In this Aim we will characterize the effect of antigen challenge on specific subtypes of bronchopulmonary C-fibers in the mouse. We will address the hypothesis that antigen stimulation leads to overt activation of one subtype of C-fiber and causes an increase in excitability of all C-fiber types. We will address the hypothesis that mast cell activation is a necessary condition underlying the allergen-induced C-fiber modulation.
In Aim 2 we address our novel hypothesis that mast cell release mediators capable of stimulated mas-related-gene (Mrg) receptors on sensory nerves resulting in an increase in C-fiber excitability. In the third and final Aim we specifically address the hypothesis that proteases within mast cell granules can modulate C-fiber activity via activation of protease activated receptors (PARs) located within the neuronal membranes. The results from our multidisciplinary approach should be of intrinsic value in providing new knowledge regarding the cellular neurophysiology of the airways. The results may also shed new light on the complex pathophysiology of allergic airway diseases, i.e., asthma, and ultimately suggest new therapeutic strategies for treatment of these complex disorders.
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