Ionocyte CFTR Coordinates Chloride Absorption and Secretion to Balance Airway Fluid

作者：Feng Yuan, Javahir Hajibabazade, Yaling Yi, Adriane E. Thompson, Lianwu Fu, Yan Zhang, Ziyuan Wang, Yinghua Tang, Grace N. Gasser, Meihua Hao, Ziying Yan, Xingshen Sun, John F. Engelhardt · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2025 · DOI：10.1164/rccm.202505-1242oc · 被引用次数：6 · 研究领域：Neonatal Respiratory Health Research、Neuroscience of respiration and sleep、Ion Transport and Channel Regulation

Abstract Rationale 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. Objectives To elucidate how CFTR in ionocytes mediates chloride absorption and secretion using conditional ionocyte-specific CFTR deletion or reactivation. Methods A novel transgenic ferret model (ROSA-TG::FOXI1-CreERT2::CFTR 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 (FOXI1-CreERT2::CFTR-cKI), which reactivates CFTR in CF ionocytes, was used to further study therapeutically relevant cellular mechanisms of CFTR gene correction. Measurements and Main Results I...