ArticleProceedings of the National Academy of Sciences of the United States of America2013
Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis airways.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers.
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Who cites it
112 citing papers in PubMed, 172 citations in OpenAlex.
- Effects of Tham Nasal Alkalinization on Airway Microbial Communities: A Pilot Study in Non-CF and CF Adults.The Annals of otology, rhinology, and laryngology · 2022Trial
- Is the SPLUNC1-Orai1 axis a critical determinant of lung health?Biochemical Society transactions · 2025Review
- Adenine base editing of CFTR using receptor targeted nanoparticles restores function to G542X cystic fibrosis airway epithelial cells.Cellular and molecular life sciences : CMLS · 2025Article
- Analysis of BeyfortusCurrent issues in molecular biology · 2024Review
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- Epithelial NaComprehensive Physiology · 2024Review
- ATP12A Proton Pump as an Emerging Therapeutic Target in Cystic Fibrosis and Other Respiratory Diseases.Biomolecules · 2023Review
- Expression of gain-of-function CFTR in cystic fibrosis airway cells restores epithelial function better than wild-type or codon-optimized CFTR.Molecular therapy. Methods & clinical development · 2023Article
- Infection, Allergy, and Inflammation: The Role ofMicroorganisms · 2023Review
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- Modeling of Respiratory Diseases Evolving with Fibrosis from Organoids Derived from Human Pluripotent Stem Cells.International journal of molecular sciences · 2023Review
- Putting bicarbonate on the spot: pharmacological insights for CFTR correction in the airway epithelium.Frontiers in pharmacology · 2023Article
- Airway surface hyperviscosity and defective mucociliary transport by IL-17/TNF-α are corrected by β-adrenergic stimulus.JCI insight · 2022Article
- Investigation of the Mechanism and Chemistry Underlying Staphylococcus aureusJournal of bacteriology · 2022Article
- Physiology and pathophysiology of human airway mucus.Physiological reviews · 2022Review
- Mucins and CFTR: Their Close Relationship.International journal of molecular sciences · 2022Review
- Charting a New Path: A Single-Cell Atlas of Porcine Cystic Fibrosis Airways at Birth.American journal of respiratory cell and molecular biology · 2022Article
- A Single-Cell Atlas of Large and Small Airways at Birth in a Porcine Model of Cystic Fibrosis.American journal of respiratory cell and molecular biology · 2022Article
- Inhibition of the sodium-dependent HCOeLife · 2022Article
- SPLUNC1 is a negative regulator of the Orai1 CaPhysiological reports · 2022Article
52 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
The ability to maintain proper airway surface liquid (ASL) volume homeostasis is vital for mucus hydration and clearance, which are essential aspects of the mammalian lung's innate defense system. In cystic fibrosis (CF), one of the most common life-threatening genetic disorders, ASL dehydration leads to mucus accumulation and chronic infection. In normal airways, the secreted protein short palate lung and nasal epithelial clone 1 (SPLUNC1) effectively inhibits epithelial Na(+) channel (ENaC)-dependent Na(+) absorption and preserves ASL volume. In CF airways, it has been hypothesized that increased ENaC-dependent Na(+) absorption contributes to ASL depletion, and hence increased disease. However, this theory is controversial, and the mechanism for abnormal ENaC regulation in CF airways has remained elusive. Here, we show that SPLUNC1 is a pH-sensitive regulator of ENaC and is unable to inhibit ENaC in the acidic CF airway environment. Alkalinization of CF airway cultures prevented CF ASL hyperabsorption, and this effect was abolished when SPLUNC1 was stably knocked down. Accordingly, we resolved the crystal structure of SPLUNC1 to 2.8 Å. Notably, this structure revealed two pH-sensitive salt bridges that, when removed, rendered SPLUNC1 pH-insensitive and able to regulate ASL volume in acidic ASL. Thus, we conclude that ENaC hyperactivity is secondary to reduced CF ASL pH. Together, these data provide molecular insights into the mucosal dehydration associated with a range of pulmonary diseases, including CF, and suggest that future therapy be directed toward alkalinizing the pH of CF airways.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.