RT Journal Article
SR Electronic
T1 Muscarinic receptor subtype-specific effects on cigarette smoke-induced inflammation in mice
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1677
OP 1688
DO 10.1183/09031936.00112412
VO 42
IS 6
A1 Loes E.M. Kistemaker
A1 I.S.T. Bos
A1 Machteld N. Hylkema
A1 Martijn C. Nawijn
A1 Pieter S. Hiemstra
A1 Jürgen Wess
A1 Herman Meurs
A1 Huib A.M. Kerstjens
A1 Reinoud Gosens
YR 2013
UL http://erj.ersjournals.com/content/42/6/1677.abstract
AB 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. Inhibition of the muscarinic M3 receptor prevents inflammation in response to cigarette smoke exposure in mice http://ow.ly/p7UdG