English: Putative effects of guaifenesin on mucus in chronic or acute hypersecretory respiratory conditions. a The airway is composed of a mucus gel layer covering the epithelium, which includes ciliated cells, Clara cells, goblet cells and submucosal glands. The mucociliary complex can be subdivided into two layers – an upper mucus gel layer containing MUC5AC and MUC5B mucins, and a lower layer of periciliary fluid containing cell surface-tethered mucins. Mucociliary clearance (MCC) is effected by the rhythmic sweeping motion of cilia. Prolonged exposure to irritants such as cigarette smoke or allergens can lead to overproduction and hypersecretion of mucus. Guaifenesin has been postulated to promote mucociliary clearance via a number of mechanisms. (1) Indirect activation/stimulation of gastrointestinal vagal afferent nerves triggers reflex parasympathetic glandular secretion from submucosal glands and goblet cells (green stars), increasing hydration of mucus layer for more effective mucociliary clearance. Guaifenesin also affects secretion from goblet and Clara cells (red stars), resulting in (2) decreased mucin production and secretion (green circles, goblet cells; blue squares, Clara cells), and (3) reduced viscoelasticity of mucus, which increases the ability of ciliary movement to remove mucus. Together these changes serve to enhance MCC and mucus clearance. b–d Guaifenesin has direct effects on MCC-related processes in airway epithelial cells. In cultured human differentiated tracheobronchial epithelial cells, 24-h treatment with guaifenesin (2 or 20 μg/mL) significantly suppressed mucin production and mucin secretion (b), while 6-h treatment with guaifenesin (2–200 μg/mL) significantly enhanced mucociliary transport rates (c). At 1 h and 6 h after guaifenesin treatment (0–200 μg/mL), significant dose-dependent decreases were observed in mucus viscosity and elasticity at typical ciliary beat frequency (1 rad/s) (d), as measured by G*1 (vector sum of viscosity and elasticity at 1 rad/s). Panels b-d adapted from Seagrave et al., 2011 [13]