Hypoxia‐induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis
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Published:2023-12-11
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ISSN:2042-6976
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Container-title:International Forum of Allergy & Rhinology
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language:en
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Short-container-title:Int Forum Allergy Rhinol
Author:
Cho Do‐Yeon123ORCID,
Zhang Shaoyan12,
Norwood T. Graham1,
Skinner Daniel12,
Hollis Tonja A.1,
Ehrhardt Marie L.1,
Yang Lydia C.1,
Lim Dong‐Jin12,
Grayson Jessica W.1ORCID,
Lazrak Ahmed24,
Matalon Sadis24,
Rowe Steven M.25,
Woodworth Bradford A.12ORCID
Affiliation:
1. Department of Otolaryngology–Head & Neck Surgery University of Alabama at Birmingham Birmingham Alabama USA
2. Gregory Fleming James Cystic Fibrosis Research Center University of Alabama at Birmingham Birmingham Alabama USA
3. Division of Otolaryngology Department of Surgery Veteran Affairs Medical Center Birmingham Alabama USA
4. Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham Alabama USA
5. Departments of Medicine Pediatrics, Cell Developmental and Integrative Biology University of Alabama at Birmingham Birmingham Alabama USA
Abstract
AbstractIntroductionHypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo.MethodsCystic fibrosis bronchoepithelial cells expressing wild‐type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24 h. Time‐dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole‐cell and cell‐attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro‐optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF‐1α, pH, sinus potential difference (SPD), and MCT were determined.ResultsUssing chamber (p < 0.05), whole‐cell (p < 0.001), and single channel patch‐clamp (p < 0.0001) showed significant inhibition of Cl− currents in hypoxic cells. Cytoplasmic free radicals showed time‐dependent elevation peaking at 4 h (p < 0.0001). Airway surface liquid (p < 0.0001), periciliary liquid (p < 0.001), and MCT (p < 0.01) were diminished. Co‐incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (p < 0.0001), increased HIF1α mRNA (p < 0.05), reduced pH (p < 0.01), and decreased MCT (p < 0.001). SPD measurements demonstrated markedly diminished transepithelial Cl− transport (p < 0.0001).ConclusionHypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Environmental Health Sciences
National Center for Complementary and Integrative Health
Cystic Fibrosis Foundation
National Institute of Allergy and Infectious Diseases
National Heart, Lung, and Blood Institute
Subject
Otorhinolaryngology,Immunology and Allergy