Transepithelial ion transport is suppressed in hypoxic sinonasal epithelium§

Authors

  • Angela Blount MD,

    1. Department of Surgery, Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
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  • Shaoyan Zhang PhD,

    1. Department of Surgery, Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
    2. Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A
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  • Michael Chestnut BS,

    1. Department of Surgery, Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
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  • Brian Hixon BS,

    1. Department of Surgery, Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
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  • Daniel Skinner BS,

    1. Department of Surgery, Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
    2. Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A
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  • Eric J. Sorscher MD,

    1. Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A
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  • Bradford A. Woodworth MD

    Corresponding author
    1. Department of Surgery, Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
    2. Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A
    • BDB 563, 1530 3rd Ave S, Birmingham, AL 35294
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  • This research was funded by the American Rhinologic Society New Investigator Award (2009), Flight Attendant's Medical Research Institute Young Clinical Scientist Award (072218), and National Institutes of Health/National Heart, Lung, and Blood Institute (1K08HL107142-01) to Bradford Woodworth, MD; and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK072482-03) to Eric Sorscher, MD.

  • Bradford Woodworth, MD, is a consultant for Arthrocare ENT and Gyrus ENT. Eric Sorscher, MD, and Bradford Woodworth, MD, are inventors on a patent submitted regarding the possible activity of chloride secretagogues for therapy of sinus disease (Provisional Patent Application Under 35 U.S.C. ξ111(b) and 37 C.F.R ξ.53 (c) in the United States Patent and Trademark Office.

  • §

    The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Abstract

Objectives/Hypothesis:

Sinonasal respiratory epithelial mucociliary clearance is dependent on the transepithelial transport of ions such as Cl. The objectives of the present study were to investigate the role of oxygen restriction in 1) Cl transport across primary sinonasal epithelial monolayers, 2) expression of the apical Cl channels cystic fibrosis transmembrane conductance regulator (CFTR) and transmembrane protein 16A (TMEM16A), and 3) the pathogenesis of chronic rhinosinusitis.

Study Design:

In vitro investigation.

Methods:

Murine nasal septal epithelial (MNSE), wild type, and human sinonasal epithelial (HSNE) cultures were incubated under hypoxic conditions (1% O2, 5% CO2). Cultures were mounted in Ussing chambers for ion transport measurements. CFTR and TMEM16A expression were measured using quantitative reverse-transcription polymerase chain reaction (RT-PCR).

Results:

The change in short-circuit current (ΔISC in microamperes per square centimeter) attributable to CFTR (forskolin-stimulated) was significantly decreased due to a 12-hour hypoxia exposure in both MNSE (13.55 ± 0.46 vs. 19.23 ± 0.18) and HSNE (19.55 ± 0.56 vs. 25.49 ± 1.48 [control]; P < .05). TMEM16A (uridine triphosphate–stimulated transport) was inhibited by 48 hours of hypoxic exposure in MNSE (15.92 ± 2.87 vs. 51.44 ± 3.71 [control]; P < .05) and by 12 hours of hypoxic exposure in HSNE (16.75 ± 0.68 vs. 24.15 ± 1.35 [control]). Quantitative RT-PCR (reported as relative mRNA levels ± standard deviation) demonstrated significant reductions in both CFTR and TMEM16A mRNA expression in MNSE and HSNE owing to airway epithelial hypoxia.

Conclusions:

Sinonasal epithelial CFTR and TMEM16A-mediated Cl transport and mRNA expression were robustly decreased in an oxygen-restricted environment. These findings indicate that persistent hypoxia may lead to acquired defects in sinonasal Cl transport in a fashion likely to confer mucociliary dysfunction in chronic rhinosinusitis.

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