Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling

• Acetylcholine promotes airway inflammation and remodeling via M3 receptors.
• Airway nerves regulate airway hyper-responsiveness and inflammation.
• Bronchoconstriction might be an alternative driver of airway remodeling.
• Both neuronal and non-neuronal acetylcholine contribute to airway inflammation and remodeling.

Acetylcholine is the primary parasympathetic neurotransmitter in the airways, where it not only induces bronchoconstriction and mucus secretion, but also regulates airway inflammation and remodeling. In this review, we propose that these effects are all primarily mediated via the muscarinic M3 receptor. Acetylcholine promotes inflammation and remodeling via direct effects on airway cells, and via mechanical stress applied to the airways sequential to bronchoconstriction. The effects on inflammation and remodeling are regulated by both neuronal and non-neuronal acetylcholine. Taken together, we believe that the combined effects of anticholinergic therapy on M3-mediated bronchoconstriction, mucus secretion, inflammation, and remodeling may account for the positive outcome of treatment with these drugs for patients with chronic pulmonary obstructive disease (COPD) or asthma.