The long term goal is to understand the role of mucociliary clearance in the maintenance of bronchial hygiene and how this may be compromised by drugs, disease and inhaled pollutants. We hope to learn how to prevent diseases of the airways, alleviate the symptoms, arrest the pathology, and eventually reverse compromised physiological function. Inhaled pollutants both cause and aggravate diseases of the airways of the lungs. The retention of mucus in the airways due to pulmonary insult is a major factor leading to increased morbidity and mortality. The major mechanism responsible for the transport of mucus from the lungs is the beating of cilia. The neurogenic pathways, mediators and mechanisms whereby pollutants effect their response on ciliary beat frequency is not well understood. We postulate that pollutants stimulate C-fibers which initiate a neural reflex that is mediated via the vagus that has both cholinergic and peptidergic components. In addition, mediator release from mast cells may play an important role. Agents or mediators may exert their effect predominantly on the luminal or basolateral side of the epithelium. Two specific assays for ciliary beat frequency (CBF) using laser light scattering will be used in concert to test our hypotheses. One assay will measure CBF in the trachea of the intact dog and the other will measure CBF on tracheal tissue samples, derived from these same dogs, mounted in a two sided chamber in which either the luminal or basolateral side of the epithelium can be independently irrigated with the test agent(s). Capsaicin, a demonstrated stimulant of C-fibers, will be used as a surrogate pollutant. Having established the dose-response of CBF to capsaicin, that component not mediated via the vagus that is due to mediator release from mast cells will be determined by stabilizing the mast cells with cromolyn sodium. The vagal component will be investigated by a vagal cold block and the cholinergic component of the vagal reflex determined by administration of atropine. The response of the two putative peptidergic components of the vagal reflex, substance P (SP) and vasointestinal peptide (VIP), will then be evaluated.
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