The Non-neuronal cholinergic system: an emerging drug target in the airways

The non-neuronal cholinergic system is widely expressed in human airways. Choline acetyltransferase (ChAT) and/or acetylcholine are demonstrated in more or less all epithelial surface cells (goblet cells, ciliated cells, basal cells), submucosal glands and airway smooth muscle fibres. Acetylcholine is also demonstrated in the effector cells of the immune system (lymphocytes, macrophages, mast cells). Epithelial, endothelial and immune cells express nicotinic and muscarinic receptors. Thus the cytomolecule acetylcholine can contribute to the regulation of basic cell functions via auto-/paracrine mechanisms (proliferation, differentiation, ciliary activity, secretion of water, ions and mucus, organization of the cytoskeleton, cell-cell contact). Acetylcholine also modulates immune functions (release of cytokines; proliferation, activation and inhibition of immune cells). Preliminary experimental evidence suggests that mucosal inflammation may be associated with raised acetylcholine levels, impairing cell and organ homeostasis. It should be considered that anti-muscarinic drugs which are applied for the treatment of chronic airway diseases antagonize the effect of both neuronal and non-neuronal acetylcholine. Non-neuronal acetylcholine, however, is still active, possibly directly within the cell cytosol and also via nicotinic receptors localized on various non-neuronal cells. It is an essential task to clarify the pathophysiological role of the non-neuronal cholinergic system in more detail to develop new drugs which can target the synthesis, release, inactivation and cellular activity of non-neuronal acetylcholine.