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 erj01124-2012
DO 10.1183/09031936.00112412
A1 Loes E.M. Kistemaker
A1 I.S.T. Bos
A1 M.N. Hylkema
A1 M.C. Nawijn
A1 P.S. Hiemstra
A1 J. Wess
A1 H. Meurs
A1 H.A.M. Kerstjens
A1 R. Gosens
YR 2013
UL http://erj.ersjournals.com/content/early/2013/02/07/09031936.00112412.abstract
AB Cholinergic tone contributes to airflow obstruction in COPD. 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) regulate(s) this process is unknown.In this study, the contribution of the muscarinic 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 four 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 KC, MCP-1 and IL-6 was higher in M1−/− and M2−/− mice and reduced in M3−/− mice. Markers of remodeling were not increased after cigarette smoke exposure. However, M3−/− mice had reduced expression of TGF-β1 and matrix proteins. Cigarette smoke-induced inflammatory cell recruitment and KC release were also prevented by the M3–receptor selective antagonist 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.