Bronchial asthma is widely believed to be a disease involving reversible bronchospasm in inflamed airways. The disease is closely correlated with atopy and, at least in some cases, is thought to involved immunological stimulation of airway mast cells, i.e. the allergic reaction. Nerve stimulation in the airways can results in several of the signs and symptoms of asthma including bronchoconstriction, mucus secretion and inflammation. Afferent (sensory) nerves can be stimulated by a variety of environmental irritants, by cold dry air, and by exercise. Thus, rather than an immunological basis of asthma, a perversion in the neuronal control of airway function has been considered a viable hypothesis to explain the symptoms, and perhaps even cause, or certain types of this disease. This proposal is based on the concept that the neuronal and immunological theories of asthma may be integrate by the fact that mast cells and nerves functionality interact in the airways. The long term objective of this proposal is to critically define, in a mechanistic level, the functional communication between mast cells and nerves in the human airways. The major hypothesi addressed in this proposal is that antigenic stimulation of mast cells leads to a substantive and long-lasting increase in the excitability of sensory fibers in the airway wall and in the parasympathetic efferent innervation of the airways. Moreover, it is hypothesized that antigen challenge results in a phenotypical change in the sensory neuropeptide innervation of the airways. Immunohistochemical techniques together with intracellular and extracellular electrophysiological studies will be carried out to address specific hypothesis related to the mechanism of mast cell-nerve interactions. These hypotheses will be addressed in an animal model and, in some cases, human bronchial neuronal preparations. Using these techniques the anatomy and electrophysiology and function of the airway innervation will be investigated before and after immunologically stimulation of the intrinsic mast cells with specific antigen challenge. The results from this 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 asthma, and ultimately suggest new therapeutic strategies for treatment of this complex disease.
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