Chloride secretagogues for acquired CFTR dysfunction in chronic rhinosinusitis

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DESCRIPTION (provided by applicant): Ineffective mucociliary clearance (MCC) is a common pathophysiologic process that underlies airway inflammation and infection. Decreased transepithelial Cl- transport secondary to an acquired Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) deficiency may contribute to respiratory epithelial dysfunction by abrogating MCC and increasing mucus viscosity. The central hypothesis of the current proposal is that persistent mucosal inflammation and infection in chronic rhinosinusitis (CRS) results from acquired (partial) CFTR deficiency, creating a localized environment that impairs MCC. This hypothesis will be tested with three Specific Aims. Specific Aim 1 will investigate CFTR deficiency in a well-characterized in vitro culture model of sinonasal epithelium. Our Preliminary Data indicate that lipopolysaccharide not only promotes inflammation, but leads to CFTR repression in sinonasal epithelium. CFTR transcription, maturational processing (protein biochemistry), and channel potentiation (patch clamp analysis) will be used to determine the mechanism underlying this observation. Specific Aim 2 will test the hypothesis that Cl- secretagogues can offset acquired defects in CFTR-mediated ion transport. Compounds of this class, including VX-770, UCCF-152, and bioflavonoids have received considerable recent attention in both the scientific and lay press for their emerging role in cystic fibrosis (CF) therapeutics. We will investigate whether Cl- secretagogues 1) overcome acquired CFTR defects and 2) stimulate MCC (measured by ciliary beat frequency). Specific Aim 3 will determine the extent of acquired CFTR deficiency in human CRS ex vivo and in vivo. Transepithelial ion transport will be quantified in sinus mucosal explants in the Ussing chamber and in vivo, using a well established nasal potential difference assay. The proposal will therefore develop an innovative approach to better understand the pathogenic mechanisms of CRS, a disease understudied in the past, and develop an entirely novel treatment strategy for sinus and nasal airway disease predicated on activation of fluid and electrolyte secretion with leading edge Cl- secretagogues. PUBLIC HEALTH RELEVANCE: Chronic rhinosinusitis (CRS) affects nearly 16% of the US population each year, has an enormous economic impact resulting in billions of dollars in healthcare expenditures, and causes significant decrements in patient quality of life in terms of nasal airway specific morbidity, as well as general health and vitality. Because treatment options for CRS are usually limited to antimicrobials and anti-inflammatories, the research presented in this proposal provides a means to understand the pathogenic mechanism underlying CRS, and a new therapeutic strategy for restoring and/or increasing CFTR activity in sinus and nasal epithelium.