Glutathione and bicarbonate nanoparticles improve mucociliary transport in cystic fibrosis epithelia

Author:

Cho Do Yeon123ORCID,Rivers Nicholas J.1ORCID,Lim Dong‐Jin1,Zhang Shaoyan1,Skinner Daniel1,Yang Lydia1,Menon Adithya J.1,Kelly Olivia Jo1,Jones Martin P.1,Bicknell Brenton T.1,Grayson Jessica W.1ORCID,Harris Elex2,Rowe Steven M.124,Woodworth Bradford A.12ORCID

Affiliation:

1. Department of Otolaryngology‐Head and 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 Veterans Affairs Birmingham Alabama USA

4. Departments of Medicine Pediatrics, Cell Developmental and Integrative Biology University of Alabama at Birmingham Birmingham Alabama USA

Abstract

AbstractIntroductionCystic fibrosis (CF) airway disease is characterized by thick mucus and impaired mucociliary transport (MCT). Loss of functional cystic fibrosis transmembrane receptor (CFTR) leads to acidification and oxidation of airway surface mucus. Replacing bicarbonate (HCO3) topically fails due to rapid reabsorption and neutralization, while the scavenging antioxidant, glutathione sulfhydryl (GSH), is also rapidly degraded. The objective of this study is to investigate GSH/NaHCO3 nanoparticles as novel strategy for CF airway disease.MethodsGSH/NaHCO3 poly (lactic‐co‐glycolic acid) nanoparticles were tested on primary CF (F508del/F508del) epithelial cultures to evaluate dose‐release curves, surface pH, toxicity, and MCT indices using micro‐optical coherence tomography. In vivo tests were performed in three rabbits to assess safety and toxicity. After 1 week of daily injections, histopathology, computed tomography (CT), and blood chemistries were performed and compared to three controls. Fluorescent nanoparticles were injected into a rabbit with maxillary sinusitis and explants visualized with confocal microscopy.ResultsSustained release of GSH and HCO3 with no cellular toxicity was observed over 2 weeks. Apical surface pH gradually increased from 6.54 ± 0.13 (baseline) to 7.07 ± 0.10 (24 h) (p < 0.001) and 6.87 ± 0.05 at 14 days (p < 0.001). MCT, ciliary beat frequency, and periciliary liquid were significantly increased. When injected into the maxillary sinuses of rabbits, there were no changes to histology, CT, or blood chemistries. Nanoparticles penetrated rabbit sinusitis mucus on confocal microscopy.ConclusionFindings suggest that GSH/NaHCO3 nanoparticles are a promising treatment option for viscous mucus in CF and other respiratory diseases of mucus obstruction such as chronic rhinosinusitis.

Funder

National Center for Complementary and Integrative Health

National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

Wiley

Subject

Otorhinolaryngology,Immunology and Allergy

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