Contribution of pulmonary ionocytes and neuroendocrine cells to ion transport-mediated airway surface liquid maintenance

PROJECT SUMMARY/ABSTRACT Regulation of ion transport across the epithelium is vital to the health and function of the airways. Active and passive ion and water movement is responsible for maintaining a periciliary fluid layer through which cilia can move mucus and protect the airways against particles, irritants, and pathogens. While there is clear evidence of disease caused by specific ion channel mutations (CFTR) as well acquired ion channel dysfunction during/contributing to disease severity (COPD, asthma), the contribution of individual cell types of the pulmonary epithelium to ion transport maintenance is poorly understood. Our experimental evidence demonstrates that alterations in the frequencies of pulmonary ionocytes and neuroendocrine cells in airway epithelial cultures result in dramatic differences in ion transport properties. Altogether, these cell types, along with tuft-like cells, comprise about 0.8% of the total cell numbers in the human tracheal epithelium. Pulmonary ionocytes are a newly identified cell type in the airways with extremely high expression of many ion channels with vital functions in the respiratory tract. The dramatic impact of ionocytes and pulmonary neuroendocrine cells on the ion transport properties of human airway cultures despite their rare frequencies led to our hypothesis that these cell types are highly involved in the regulation and maintenance of ion transport balance across the entire epithelium and are able to impact ion transport functions in other cell types through intercellular communication. By utilizing novel murine models and applying innovative techniques to primary murine and human airway epithelial cells, the research outlined in this proposal will define the contribution of these rare cell types to the overall ion transport functions of the airway epithelium and will also define the role of CFTR in these cells. We will thereby fully characterize the significance of pulmonary ionocytes and neuroendocrine cells to ion transport-mediated airway surface liquid regulation and identify potential cell and ion channel targets for therapeutic treatment of common airway diseases.