Control of airway surface liquid (ASL) volume is vital for pulmonary defense against inhaledpathogens/toxicants. Deficits in ASL volume produce airways obstruction and airways infection, reflectingthe absence of periciliary liquid (PCL) volume and adhesion of dehydrated mucus to airway surfaces. Muchis known about the ion transport processes that control transepithelial ion fluxes, but there are little or nodata describing how these processes are coordinately regulated to adjust the mass of salt and, hence, wateron airway surfaces in the ranges required for health. Studies of patients with genetic lung diseases, e.g.,cystic fibrosis, have suggested that regulation of both the CFTR and ENaC channels are vital for thisprocess. More recently, a number of clues have suggested a role for nucleotides (NTs) and nucleosides(NSs) in ASL in regulating the balance between Na+ absorption and Cl- secretion to generate ASL volumehomeostasis. Indeed, we hypothesize that 1) ASL [NT+NS]s are so critical for ASL volume regulation that intheir absence, airway epithelia revert to a purely Na+-absorbing state and deplete all ASL from airwaysurfaces; and 2) the volume of ASL is proportional to the rate of ATP release (JATP) onto airway surfaces.To test these hypotheses and generate a comprehensive description of ASL volume homeostasis, wepropose three Specific Aims: 1) Aim 1 - measure JATP and extracellular NT+NS metabolism to develop amathematical model that will integrate ASL NT+NS concentrations with a biophysical model of ion transportto describe the regulation of ASL volume homeostasis; 2) Aim 2 - test in human bronchial epithelial (HBE)cultures the requirement for NTs and NSs in the acute regulation of ASL volume homeostasis and themechanisms that mediate these regulatory processes; and 3) Aim 3 - test the requirement for NT+NS incontrolling ASL volume in mutant mouse models in vivo. Relevance to Public Health: Accurate quantitativeknowledge of the factors that control ASL homeostasis, i.e., the 'hydration' of airway surfaces, will aid inelucidation of the pathogenesis of major human airways diseases, e.g., COPD, CF, and asthma, and willprovide insights into novel therapeutic mechanisms to hydrate airway surfaces and hence, restore normalhost defense.
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