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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1677-1688
Number of pages12
JournalEuropean Respiratory Journal
Volume42
Issue number6
DOIs
Publication statusPublished - Dec-2013

Keywords

  • OBSTRUCTIVE PULMONARY-DISEASE
  • NONNEURONAL CHOLINERGIC SYSTEM
  • BRONCHIAL EPITHELIAL-CELLS
  • AIRWAY SMOOTH-MUSCLE
  • PHARMACOLOGICAL-PROPERTIES
  • ACETYLCHOLINE-RECEPTOR
  • CHEMOTACTIC ACTIVITY
  • TIOTROPIUM BROMIDE
  • MURINE AIRWAYS
  • IN-VITRO

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