195 Sinonasal Epithelial Responses to Long-Term Highly Effective CFTR Modulator Therapy

role in lung health.Mucociliary clearance (MCC) is a key process that clears airway surfaces, and airway epithelial cells produce a range of host defense molecules that work in concert with MCC, but in CF, dysfunction of the CFTR impairs MCC, producing airway surface dehydration, hyperconcentrated mucus, and cilia collapse.IL-1β is a predominant proinflammatory cytokine in CF that worsens mucus hyperconcentration by stimulating mucus secretion in the absence of fluid secretion, causing a vicious cycle of inflammation and mucus hyperconcentration.Recent studies have targeted IL-1 signaling in CF with anakinra, an IL-1 receptor antagonist, to control inflammation and mucus hypersecretion, but the spectrum of mechanisms through which IL-1β regulates innate host defense in normal airway epithelia is not fully elucidated.Understanding these mechanisms may provide further insights into the role of IL-1β in innate host lung defense and offer rationales for anti-inflammatory therapies, particularly in the context of highly efficient modulator therapy for CF.Methods: Well-differentiated normal human bronchial epithelial cells (hBECs) were exposed to IL-1β or vehicle.Quantitative polymerase chain reaction analysis, Western blot, and Ussing chamber assays were performed to assess the effects of IL-1β on CFTR expression and function.Fluid secretion and mucus concentration were measured by wet and dry weights.Cilia beating frequency (CBF) was measured by high-speed video microscopy.Apical nucleoside/nucleotide concentrations were measured by high-performance liquid chromatography.Bulk RNA-seq was performed on IL-1β or vehicle-exposed hBECs to characterize the transcriptional changes of genes related to MCC and antimicrobial properties.Results: Exposure of hBECs to IL-1β produced a significant increase in CFTR expression ( p < 0.01) and increased CFTR protein and function ( p < 0.001).MUC5B expression increased proportionately to CFTR expression in response to IL-1β administration.Fluid secretion increased significantly ( p < 0.001), leading to a modest decrease in mucus concentration ( p < 0.05) in apical mucus.CBF increased significantly in response to IL-1β ( p < 0.001), and apical nucleoside/nucleotide concentrations also increased after exposure to IL-1β ( p < 0.001), likely contributing to the increase in CBF.Bulk RNA-seq analyses revealed significant upregulation of genes related to anion transport (SLC26A4 and SLC26A9), cilia beating (TRPV4, ORAI1, and ADRB2), and antimicrobial activities (S100A8/A9, DEFB4A/B, LTF, PI3, CCL20, and DUOX2/DUOXA2) in response to IL-1β exposure.Conclusions: IL-1β enhances innate host defense through multiple mechanisms.Inhibiting IL-1 signaling could counteract its beneficial effects on airway epithelia, especially in CFTR-corrected people with CF.