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 involve immunological stimulation of airway mast cells, i.e. the allergic reaction. Nerve stimulation in the airways can result in several of the signs and symptoms of asthma including bronchoconstriction, mucus secretion and inflammation. Thus, a perversion in the neuronal control of airway function has also been considered as viable hypothesis to explain the symptoms, and perhaps even cause, of this complex disease. This proposal is based on the concept that these two theories may be integrated by the fact that mast cells and nerves functionally interact in the airways. The long term objective of this proposal is to critically define, at a mechanistic level, the functional communication between mast cells and nerves in the human airways. The major hypothesis addressed in this proposal is that antigenic stimulation of mast cells leads to a substantive and long-lasting increase in the excitability of parasympathetic efferent and C-fiber afferent neurons in the guinea pig and human bronchi. To address this hypothesis the airway parasympathetic and C-fiber innervation will be studied at the cellular level, using intracellular microelectrophysiological techniques. This allows for the direct evaluation of the synaptic transmission in bronchial parasympathetic ganglions, and characteristics of the membrane properties of C-fibers neurons in the nodose ganglion. Additionally the function of the airway innervation of the airway will be studied by quantifying neurotransmitter release from airway nerves, and by studying the neurogenic effects on smooth muscle tone, and plasma extravasation in the airways. With these models, the 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 physiology 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 disease.
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