(410) Hypoxia-induced CFTR dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis

Background: Hypoxia due to sinus obstruction is considered a major pathogenic mechanism leading to the development of sinusitis. We previously identified that hypoxia induces an acquired CFTR dysfunction in sinonasal epithelial cells in vitro with corresponding reductions in mucociliary function. CF patients on modulator therapy with obstructed sinuses have persistent hypoxia that abrogates the impact of CFTR correction. The objective of the current study is to define the electrophysiologic characteristics of induced hypoxia in vitro and within a rabbit model in vivo.

Methods: Cystic fibrosis bronchoepithelial cells expressing wild-type CFTR (CFBE41o^- wild-type) were exposed to 1% or atmospheric O₂ for 24 hours. CFTR currents were recorded in the whole-cell mode of the patch-clamp technique. A rabbit model of hypoxic maxillary sinusitis was created by blocking the ostiomeatal complex for 14 days. We harvested tissue for relative mRNA expression of hypoxia-inducible factor-1 alpha (HIF-1α), an indirect marker hypoxia, and pH recordings of the airway surface liquid. Rabbits underwent sinus potential difference (SPD) assay to determine forskolin-stimulated change in transepithelial Cl^- transport across the epithelium.

Results: Whole-cell patch-clamp showed near complete inhibition of Cl^- currents of CFBE41o^- wild-type cells after 24-hour hypoxia incubation (n=6; 80 mV holding potential; 198.8+/-106.8 vs. 931.1+/-250.4 pA). Rabbit sinus mucosa after experimentally induced sinusitis exhibited significantly increased Hif1α mRNA in sinusitis rabbits (n=5; 616.1+/-83.5 vs. 382.5+/-50.0, p< 0.05) and the mucosal surface showed significantly reduced pH (n≥13, 7.12+/-0.05 vs. 7.34+/-0.05; p< 0.01). SPD measurements demonstrated markedly diminished transepithelial Cl^- transport (-4.2 ± 1.0 vs. -19.5+/-1.3 mV; p< 0.0001)

Conclusions: Hypoxia induces severe CFTR dysfunction according to patch clamp technique in vitro and SPD in vivo. Improved oxygenation is critical to reducing the impact on persistent mucociliary dysfunction and may explain persistance of chronic sinusitis in select individuals on CFTR modulator therapy.

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