The mucin bundles responsible for airway cleaning are retained in cystic fibrosis and by cholinergic stimulation
The beneficial effect of anti-cholinergic therapy for chronic obstructive pulmonary diseases like COPD is well-documented although cholinergic stimulation paradoxically inhibits liquid absorption, increases cilia beat frequency, and increases airway surface liquid transport.
Using pig tracheobronchial explants, we quantified basal mucus transport as well as after incubation with by the clinically used anti-muscarinic compound ipratropium bromide (Atrovent) and stimulation with acetylcholine.
As expected the surface liquid transport was increased by acetylcholine and carbachol. In contrast, the mucus bundles secreted from the submucosal glands normally transported on the cilia were stopped from moving by acetylcholine, an effect inhibited by ipratropium bromide. Interestingly, in pigs lacking a functional CFTR channel, the mucin bundles were almost immobile. As in wild-type pigs the cystic fibrosis (CF) surface liquid transport increased after carbachol stimulation. The stagnant CF mucin bundles were trapped on the tracheal surface attached to the surface goblet cells. Pseudomonas aeruginosa bacteria were moved by the mucus bundles in wild-type, but not CF pigs.
Acetylcholine thus uncouples airway surface liquid transport from transport of the surface mucin bundles as the bundles are dynamically inhibited by acetylcholine and the CFTR channel, explaining initiation of CF and COPD and opening novel therapeutic windows.
Conflict of interest: Dr. Ermund has nothing to disclose.
Conflict of interest: Dr. Meiss has nothing to disclose.
Conflict of interest: Dr. Dolan has nothing to disclose.
Conflict of interest: Dr. Bähr has nothing to disclose.
Conflict of interest: Dr. Klymiuk has nothing to disclose.
Conflict of interest: Dr. Hansson reports grants from NIH, ERC, Wallenberg, Lederhausen, CFF, during the conduct of the study.