Durable Changes to Airway Mucus and Fluid Secretion Following Cholinergic Challenge

Abstract

Number of Tables: 1Conflict of interest statement: None declared. AbstractPurpose: Mucus abnormalities are central to the pathophysiology of several chronic airway diseases. Mucus secretion and clearance are regulated, in part, by cholinergic innervation.Prolonged cholinergic stimulation may contribute to mucus abnormalities in disease. Thus, we tested the hypothesis that prolonged cholinergic stimulation gives rise to lasting mucus abnormalities in airways. Methods:We delivered aerosolized bethanechol, a cholinergic agonist, to pig airways. Fortyeight hours later, we measured mucus secretion and mucociliary transport in tracheal segments ex vivo. Tracheal and bronchoalveolar lavage concentrations of the major secreted mucus glycoproteins, mucin5B (MUC5B) or mucin5AC (MUC5AC), were measured with ELISA and antibody labeling. Pig airway epithelia were cultured at the air-liquid interface and treated with bethanechol for forty-eight hours. Stimulated fluid secretion was measured with reflected microscopy and Ussing chambers were used to measure ion transport.Results: Airways from bethanechol-challenged pigs exhibited sheet-like mucus films, which were not associated with a greater abundance of MUC5AC or MUC5B. Epithelia treated with bethanechol had diminished fluid secretion and decreased Cltransport. However, mucus and fluid alterations were not associated with impaired mucociliary transport. Conclusions:These data suggest that cholinergic transmission induces sustained alterations in airway mucus properties. Such defects might compound and/or contribute to persistent mucus phenotypes found after the resolution of airway inflammation.