J Korean Med Sci.  2020 Aug;35(32):e272. 10.3346/jkms.2020.35.e272.

Effects of Ammonium Chloride on Ozone-induced Airway Inflammation: the Role of Slc26a4 in the Lungs of Mice

Affiliations
  • 1Division of Allergy and Respiratory Diseases, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
  • 2Department of Environmental Health Sciences, Soonchunhyang University, Asan, Korea
  • 3Soonchunhyang Medical Research Institute, Soonchunhyang University College of Medicine, Cheonan, Korea

Abstract

Background
Exposure to ozone (O3) induces neutrophilic inflammation and goblet cell hyperplasia in humans and experimental animals. Because the solute carrier family 26-member 4 (Slc26a4; pendrin) gene induces mucin production and intraluminal acidification in the airways, it was hypothesized to be a key molecule in O3-induced airway injury. Thus, we evaluated the role of Slc26a4 and the protective effects of ammonium chloride (NH4Cl) in O3 -induced airway injury in mice.
Methods
Six-week-old female BALB/c mice were exposed to filtered air or O3 for 21 days (2 ppm for 3 hr/day). NH4Cl (0, 0.1, 1, and 10 mM) was administered intratracheally into the airways. Airway resistance was measured using a flexiVent system, and bronchoalveolar lavage fluid (BALF) cells were differentially counted. Slc26a4 and Muc5ac proteins and mRNA were measured via western blotting, real-time polymerase chain reaction, and immunostaining. Tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-17, IL-1β, and caspase-1 were analyzed via western blotting.
Results
The levels Slc26a4 protein and mRNA significantly increased in lung tissues from Day 7 to Day 21 of O3exposure, with concomitant increases in lung resistance, numbers of goblet cells in lung tissues, and inflammatory cells and thiocyanate (SCN ) levels in BALF in a time-dependent manner. Treatment with NH4Cl significantly reduced these changes to levels similar to those of sham-treated mice, with a concomitant reduction of Slc26a4 proteins in lung lysates and SCN − levels in BALF. Slc26a4 protein was co-expressed with muc5ac protein in the bronchial epithelium, as indicated by immunofluorescence staining. NH4 Cl treatment also significantly attenuated the O3 -induced increases in IFN-γ, TNF-α, IL-17, IL-1β, and p20-activated caspase-1.
Conclusion
Slc26a4 may be involved in O3 -induced inflammatory and epithelial changes in the airways via activation of the inflammasome and the induction of IL-17 and IFN-γ. NH4 Cl shows a potential as a therapeutic agent for controlling O3 -induced airway inflammation and epithelial damage by modulating Slc26a4 expression.

Keyword

Slc26a4; AHR; Ozone; Neutrophilic Inflammation; Muc5ac; NH4Cl
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