| Autor: |
Cho, Do-Yeon, Zhang, Shaoyan, Skinner, Daniel F., Lim, Dong Jin, Banks, Catherine, Grayson, Jessica W., Tearney, Guillermo J., Rowe, Steven M., Woodworth, Bradford A. |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Int Forum Allergy Rhinol |
| Popis: |
INTRODUCTION: Abnormal chloride (Cl(−)) transport dehydrates airway surface liquid (ASL) in sinonasal epithelium leading to mucus stasis and chronic rhinosinusitis. As an experimental epithelium, rabbit tissue provides an excellent representation of human sinus disease, and the rabbit sinusitis model is established and well suited for therapeutic interventions in vivo. The objective of this study is to evaluate whether ivacaftor reverses the consequences of Pseudomonas aeruginosa-induced acquired CFTR dysfunction. METHODS: Rabbit nasal cavities were assessed for responsiveness to ivacaftor in vivo (nasal potential difference (NPD) assay). Rabbit nasal epithelial (RNE) cultures were incubated with an ultrafiltrate of P. aeruginosa (PAO1 strain) for 4 hours and tested for acquired CFTR dysfunction. Markers of mucociliary function, including airway surface liquid depth (ASL), periciliary liquid depth (PCL), ciliary beat frequency (CBF) and mucociliary transport (MCT) were measured by micro-optical coherence tomography (μOCT) following PAO1 and/or ivacaftor incubation. RESULTS: Ivacaftor resulted in a significant 21.8+/−2.1 mV mean NPD polarization that was significantly greater than low Cl(−) control (12.9+/−1.3; p = 0.01). PAO1 exposure induced a state of acquired CFTR dysfunction in rabbit nasal epithelium as measured by forskolin-stimulated short-circuit current (I(SC)) (control, 37.0+/−1.1 μA/cm(2) vs PAO1, 24.4+/−1.1 μA/cm(2); p < 0.001). RNE cultures exposed to PAO1 had inhibited mucociliary function, whereas co-incubation with ivacaftor restored mucociliary clearance as measured by μOCT. CONCLUSION: In RNE, ivacaftor robustly stimulates CFTR-mediated Cl- secretion and normalizes ASL and CBF in PAO1-induced acquired CFTR dysfunction Preclinical testing of CFTR potentiators as therapy for P. aeruginosa rabbit sinusitis is planned. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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