Involvement of small airways, those of <2 mm in internal diameter, is present in all stages of
asthma and contributes substantially to its pathophysiologic expression. Therefore, small airways are a potential target to achieve optimal
asthma control. Airway tone, which is increased in
asthma, is mainly controlled by the vagus nerve that releases
acetylcholine (ACh) and activates
muscarinic ACh receptors (mAChRs) post-synaptically on airway smooth muscle (ASM). In small airways, M3 mAChRs are expressed, but there is no vagal innervation. Non-neuronal ACh released from the epithelial cells that may express
choline acetyltransferase in response to inflammatory stimuli, as well as from other structural cells in the airways, including fibroblasts and mast cells, can activate mAChRs. By antagonizing M3 mAChR, the contraction of the ASM is prevented and, potentially, local
inflammation can be reduced and the progression of remodeling may be averted. In fact, ACh also contributes to
inflammation and remodeling of the airways and regulates the growth of ASM. Several experimental studies have demonstrated the potential benefit derived from the use of mAChR antagonists, mainly long-acting mAChR antagonists (LAMAs), on small airways in
asthma. However, there are several confounding factors that may cause a wrong estimation of the relationship between LAMAs and small airways in
asthma. Further studies are needed to differentiate broncholytic and anti-inflammatory effects of LAMAs and to better understand the interaction between LAMAs and
corticosteroids, also in the context of a triple
therapy that includes a β2 -AR agonist, at different levels of the bronchial tree.