Cholinergic tone contributes to airflow obstruction in
chronic obstructive pulmonary disease. Accordingly,
anticholinergics are effective
bronchodilators by blocking the
muscarinic M3 receptor on airway smooth muscle. Recent evidence indicates that
acetylcholine also contributes to airway
inflammation. However, which
muscarinic receptor subtype(s) regulates this process is unknown. In this study, the contribution of the M1, M2 and M3 receptor subtypes to cigarette
smoke-induced airway
inflammation was investigated by exposing
muscarinic receptor subtype deficient mice to cigarette
smoke for 4 days. In wild-type mice, cigarette
smoke induced an increase in macrophages, neutrophils and lymphocytes in bronchoalveolar lavage fluid. Neutrophilic
inflammation was higher in M1(-/-) and M2(-/-) mice compared to wild-type mice, but lower in M3(-/-) mice. Accordingly, the release of keratinocyte-derived
chemokine (KC),
monocyte chemotactic protein-1 and
interleukin-6 was higher in M1(-/-) and M2(-/-) mice, and reduced in M3(-/-) mice. Markers of remodelling were not increased after cigarette
smoke exposure. However, M3(-/-) mice had reduced expression of transforming growth factor-β1 and matrix
proteins. Cigarette
smoke-induced inflammatory cell recruitment and KC release were also prevented by the M3-receptor selective antagonist
1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) in wild-type mice. Collectively, our data indicate a pro-inflammatory role for the M3 receptor in cigarette
smoke-induced neutrophilia and
cytokine release, yet an anti-inflammatory role for M1 and M2 receptors.