Muscarinic receptor subtype-specific effects on cigarette smoke-induced inflammation in mice

Loes E. M. Kistemaker*, I. S. T. Bos, Machteld N. Hylkema, Martijn C. Nawijn, Pieter S. Hiemstra, Juergen Wess, Herman Meurs, Huib A. M. Kerstjens, Reinoud Gosens

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

34 Citaten (Scopus)


Cholinergic tone contributes to airflow obstruction in chronic obstructive pulmonary disease. Accordingly, anticholinergics are effective bronchodilators by blocking the muscarinic M-3 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 M-1, M-2 and M-3 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 M-1(-/-) and M-2(-/-) mice compared to wild-type mice, but lower in M-3(-/-) mice. Accordingly, the release of keratinocyte-derived chemokine (KC), monocyte chemotactic protein-1 and interleukin-6 was higher in M-1(-/-) and M-2(-/-) mice, and reduced in M-3(-/-) mice. Markers of remodelling were not increased after cigarette smoke exposure. However, M-3(-/-) mice had reduced expression of transforming growth factor-beta 1 and matrix proteins. Cigarette smoke-induced inflammatory cell recruitment and KC release were also prevented by the M-3-receptor selective antagonist 1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) in wild-type mice.

Collectively, our data indicate a pro-inflammatory role for the M-3 receptor in cigarette smoke-induced neutrophilia and cytokine release, yet an anti-inflammatory role for M-1 and M-2 receptors.

Originele taal-2English
Pagina's (van-tot)1677-1688
Aantal pagina's12
TijdschriftEuropean Respiratory Journal
Nummer van het tijdschrift6
StatusPublished - dec-2013

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