title: Muscarinic receptor subtype-specific effects on cigarette smoke-induced inflammation in mice.
abstract: 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.
authors: University of Groningen, Groningen.
authors: Loes E M
authors: LE
authors: Kistemaker
authors: I S T
authors: IS
authors: Bos
authors: Machteld N
authors: MN
authors: Hylkema
authors: Martijn C
authors: MC
authors: Nawijn
authors: Pieter S
authors: PS
authors: Hiemstra
authors: Jürgen
authors: J
authors: Wess
authors: Herman
authors: H
authors: Meurs
authors: Huib A M
authors: HA
authors: Kerstjens
authors: Reinoud
authors: R
authors: Gosens
mesh_terms: D000109:Acetylcholine / Q000737:chemistry; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018680:Cholinergic Antagonists / Q000737:chemistry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*
chemical_list: D018680:Cholinergic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D000109:Acetylcholine