Journal article
Ionocyte CFTR Coordinates Chloride Absorption and Secretion to Balance Airway Fluid
American journal of respiratory and critical care medicine, Vol.211(10), pp.1935-1950
10/2025
DOI: 10.1164/rccm.202505-1242OC
PMCID: PMC12555048
PMID: 40815683
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) channel contributes to the precise control of airway surface liquid (ASL) 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.
To elucidate how CFTR in ionocytes mediates chloride absorption and secretion using conditional ionocyte-specific CFTR deletion or reactivation.
A novel transgenic ferret model (ROSA-TG::
-Cre
::
) was developed to specifically inactivate CFTR in ionocytes while simultaneously enabling fate mapping of ionocyte lineages. This model was utilized to investigate the mechanisms of ion and fluid transport by pulmonary ionocytes and their regeneration. A second transgenic ferret model (
-Cre
::
-cKI), which reactivates CFTR in CF ionocytes, was employed to further study therapeutically relevant cellular mechanisms of CFTR gene correction.
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.
Ionocyte-expressed CFTR is required for both chloride absorption and secretion, enabling salt and fluid transport in the large airways.
Details
- Title: Subtitle
- Ionocyte CFTR Coordinates Chloride Absorption and Secretion to Balance Airway Fluid
- Creators
- Feng Yuan - University of IowaJavahir Hajibabazade - University of IowaYaling Yi - University of IowaAdriane E Thompson - The University of Iowa Roy J and Lucille A Carver College of Medicine, Anatomy and Cell Biology, Iowa City, Iowa, United StatesLianwu Fu - University of Alabama at BirminghamYan Zhang - University of IowaZiyuan Wang - University of Southern CaliforniaYinghua Tang - University of IowaGrace N Gasser - University of IowaMeihua Hao - University of Alabama at BirminghamZiying Yan - University of IowaXingshen Sun - University of IowaJohn F Engelhardt - University of Iowa
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory and critical care medicine, Vol.211(10), pp.1935-1950
- DOI
- 10.1164/rccm.202505-1242OC
- PMID
- 40815683
- PMCID
- PMC12555048
- NLM abbreviation
- Am J Respir Crit Care Med
- ISSN
- 1535-4970
- eISSN
- 1535-4970
- Publisher
- AMER THORACIC SOC
- Grant note
- NIH: R01 HL165404, P30DK072482 NHLBI Federal: 75N92025C00007 Cystic Fibrosis Foundation: YAN23G0, YUAN24G0, ENGELH21XX0, 001478XX220, SUN22G0 Cystic Fibrosis Research Institute: 1267026
Supported by NIH grant R01 HL165404 and NHLBI Federal Contract 75N92025C00007 (J.F.E.) ; NIH grant P30DK072482 (DAVIS) ; Cystic Fibrosis Foundation grants YAN23G0 (Z.Y.) , YUAN24G0 (F.Y.) , ENGELH21XX0 (J.F.E.) , 001478XX220 (J.F.E.) , and SUN22G0 (X.S.) ; and the Cystic Fibrosis Research Institute grant 1267026 (F.Y.) .
- Language
- English
- Electronic publication date
- 08/15/2025
- Date published
- 10/2025
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984946844702771
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