CELLULAR REGULATION OF RESPIRATORY CILIA

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Impairment of mucociliary clearance can be either acutely induced by inhaled irritant or antigen, or found in chronic diseases such as cystic fibrosis, asthma and bronchitis. Chronic impairment affects some 17 million people in the United States and acute episodes many times more. Effective regulation of mucociliary transport is required to maintain airway patency. Prevention of diseases in the airways from inhaled insults is dependent on the integrity of the neural, inter- and intra- cellular regulatory mechanisms for ciliary beat frequency, CBF, and axial metachronal wave velocity, MWV/a; the two parameters responsible for the effectiveness of mucus transport. This project proposes to investigate how adrenergic, cholinergic, and purinergic agonists interact with the luminal and basolateral aspects of the cell to delineate potential intra- and inter-cellular pathways that independently regulate CBF and MWV/a. There are at least four major receptor-initiated pathways that regulate the stimulation of CBF. Two of these can be activated on the basolateral membrane; an adenylate cyclase - cAMP dependent and a phospholipase C - inositol phosphate (IP3) dependent pathway. Two can be activated from the airway lumen (presumably on the cilia); a guanylate cyclase - cGMP dependent and a phospholipase C - inositol phosphate (IP3) dependent pathway. Each of these pathways is coupled to a calcium activated potassium channel whose patency is a necessary precondition for stimulation of CBF. Only one of these pathways, the basolateral adenylate cyclase-cAMP dependent pathway causes an increase in intracellular cAMP and concomitant decrease in MWV/a. Two in vitro assays, namely CBF and MWV/a, will be derived from a newly developed double beam laser light scattering system. By delineating the control mechanisms for these functions, it will be possible in the longer terms to establish the independent and collective roles of CBF and MWV/a on mucociliary transport. This will first be studied in vitro and confirmed in vivo as technology available. Delineating the inter- and intra-cellular pathways regulating ciliary function is fundamental to understanding of the response of the mucociliary system to inhaled irritants and endogenous inflammatory mediators and is a prerequisite to determine functional abnormalities caused by toxins or disease. Whether pharmaceutic or molecular approaches are developed for prophylactic or therapeutic intervention depends on the cellular and molecular basis of the abnormality in which this project will provide such direction and the basis for future studies.