GUAIFENESIN MODIFIES AIRWAY MUCUS, REDUCES MUCUS-CELL SURFACE INTERACTIONS, AND INCREASES MUCOCILIARY TRANSPORT IN AN ORGANOTYPIC IN VITRO MODEL OF MUCUS HYPERSECRETION

Abstract

SESSION TITLE: Phenotyping and Management of COPD SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: Airway mucus hypersecretion is a hallmark of chronic bronchitis (CB) and is strongly associated with cough discomfort, reduced pulmonary function, recurring respiratory infections, and the development of obstructive lung disease. Guaifenesin (GGE) is currently the only FDA-approved oral expectorant and the most common active ingredient in prescription and over-the-counter medicines for treatment of acute respiratory congestion and stable CB. Studies in patients with CB demonstrate that GGE reduces airway secretion viscoelasticity and mucus adhesion, inhibits cough reflex sensitivity, and increases mucociliary clearance (MCC). However, despite its broad use, the mechanism of action for GGE remains unclear. Here, we investigate whether GGE acts directly on the respiratory epithelium to modify epithelial cell secretions, reduce mucus/mucosa interactions, and enhance mucociliary transport (MCT) using an organotypic in vitro model of mucus hypersecretion. METHODS: Primary human bronchial epithelial cells (hBECs) were collected from healthy (HC), heavy smoker (HS; 48.3±18.9 pack year), and COPD (51.3±10.3 pack year) donor lungs (N=3 per group), and differentiated at an air-liquid interface to a mucociliary phenotype. At culture day 35, 20µg/ml GGE was supplemented to the basolateral medium and cultures were maintained in the presence of drug for an additional 15 days. Apical secretions were allowed to accumulate for the duration of the 15-day treatment. Following treatment, mucus concentration, mucus/mucosa interaction strength, in vitro MCT, ciliary beat frequency (CBF), and mucin protein expression were compared. RESULTS: Apical secretions collected from HS and COPD cultures had a higher mucus concentration (12.3±3.0 and 11.1±2.2 % solids, respectively) than HC cultures (7.6±1.1). Moreover, increased mucus concentration was associated with greater mucus/mucosa interaction strength and lower baseline MCT as compared to HC. In all donor groups, 15-day GGE treatment reduced mucus concentration (? % solids: 2.2±1.2 HC, 1.9±0.6 HS, and 2.4±1.8 COPD) and mucus/mucosa interaction strength (? mN/cm: 1.8±0.4 HC, 3.6±1.9 HS, and 1.6±0.4 COPD). GGE-mediated reductions in mucus concentration and mucus/mucosa interaction strength translated to increased in vitro MCT (? µm/sec: 35.1±21.9 HC, 19.6±30.1 HS, and 4.7±0.8 COPD). GGE treatment did not significantly alter MUC5AC or MUC5B secreted protein levels, or CBF. CONCLUSIONS: Our findings indicate that GGE significantly reduces airway mucus concentration, reduces mucus-cell surface interaction strength, and increases MCT in vitro through direct interactions with airways epithelial cells in all donor groups (HC, HS, and COPD). CLINICAL IMPLICATIONS: These data suggest that GGE may act directly at the level of the respiratory epithelium to modify airway mucus and improve MCC in conditions characterized by mucus hypersecretions. DISCLOSURES: Global Medical Lead Respiratory relationship with Reckitt Benckiser Please note: $1001 - $5000 Added 04/10/2020 by Graça Maria Alves da Cunha Coutinho, source=Web Response, value=Salary No relevant relationships by Brian Button, source=Web Response Receive research support relationship with Reckitt Benckiser Please note: >$100000 Added 04/09/2020 by Phillip Clapp, source=Web Response, value=Grant/Research Support No relevant relationships by Miriam Figueira, source=Web Response no disclosure on file for Ly Nguyen; Employee relationship with Rekitt Benckiser Please note: >$100000 Added 06/11/2020 by Karin Nicholson, source=Web Response, value=Salary No relevant relationships by Timother Shea, source=Web Response No relevant relationships by Holly Thacker, source=Web Response