Ionocyte CFTR Coordinates Chloride Absorption and Secretion to Balance Airway Fluid

<b>Rationale:</b> The CFTR (cystic fibrosis transmembrane conductance regulator) channel contributes to the precise control of airway surface liquid volume by regulating fluid absorption and secretion, both of which are disrupted in cystic fibrosis (CF). CFTR is highly expressed in pulmonary ionocytes, yet conflicting evidence has emerged regarding how pulmonary ionocytes regulate ion and fluid transport. Different groups have shown that pulmonary ionocytes mediate chloride and fluid absorption, but whether ionocytes and/or secretory cells mediate chloride secretion remains unclear. This question has important therapeutic implications. Thus, there is a need to improve our understanding of cell type-specific CFTR functions on which to rationally design therapeutic approaches for CF. <b>Objectives:</b> To elucidate how CFTR in ionocytes mediates chloride absorption and secretion using conditional ionocyte-specific CFTR deletion or reactivation. <b>Methods:</b> A novel transgenic ferret model (ROSA-TG::<i>FOXI1</i>-Cre^ERT2::<i>CFTR</i>^L/L) was developed to specifically inactivate CFTR in ionocytes while simultaneously enabling fate mapping of ionocyte lineages. This model was used to investigate the mechanisms of ion and fluid transport by pulmonary ionocytes and their regeneration. A second transgenic ferret model (<i>FOXI1</i>-Cre^ERT2::<i>CFTR-</i>cKI), which reactivates CFTR in CF ionocytes, was used to further study therapeutically relevant cellular mechanisms of CFTR gene correction. <b>Measurements and Main Results:</b> Ionocyte-specific CFTR facilitates both chloride absorption and secretion, supporting the dual role of ionocytes in airway fluid homeostasis. Deletion of CFTR within ionocytes led to rapid renewal of CFTR-competent ionocytes from lineage-negative progenitors. <b>Conclusions:</b> Ionocyte-expressed CFTR is required for both chloride absorption and secretion, enabling salt and fluid transport in the large airways.