and specific aims): A key factor in the normal function of the respiratory tract is the regulation of mucociliary transport by the airway epithelium. A number of factors appear to influence this process, and the regulation of these factors is complex. Prostaglandins (PGs) have characteristics that suggest they could be important mediators controlling physiological parameters that affect mucociliary clearance (MCC), including ion transport, ciliary beat frequency (CBF) and perhaps even mucin release by goblet cells. Airway surface liquid (ASL) is a 15-30 um thick layer of low viscosity fluid that covers the mucosal surface of the epithelium lining the conducting airways. This fluid layer represents the medium in which ciliary beating occurs, propelling the overlaying layer of thicker, more viscous mucus and entrapped debris out of the lung. The efficiency of this process is highly dependent upon the thickness of the ASL, and this in turn is influenced by the rate of salt and water transport across the airway epithelium. Changes in the electrolyte composition of the ASL may also affect other aspects of mucociliary action. These include not only physical properties of the overlying mucous layer but also the CBF. The composition of the ASL may be critical for the antimicrobial activity of molecules such as defensins, which are secreted by cells of the airway epithelium and serve as a first line of defense against bacterial infection of the respiratory tract. The overall hypothesis tested in this application is that PGs play a central role in regulating those properties of ASL that are crucial for efficient MCC. The goal is to define and quantitate the contribution of PGs to regulation of MCC and to determine the underlying mechanism by which PGs contribute to this process. The focus will be on the prostaglandin PGE2 and its actions mediated through four cell surface receptors.
The specific aims are: 1) Generation of mouse lines deficient in each of the PGE2 receptors; 2) Examination of PG production, receptor expression and signal transduction in normal and inflamed mouse airways; 3) Characterization of the role of PGE2 in regulation of ion transport, CBF, and mucus secretion in mouse airway epithelium; and 4) Examination of the role of PGE2 in airway disease in mouse.
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