Muscarinic M₃ receptors contribute to allergen-induced airway remodeling in mice

Loes E. M. Kistemaker*, Sophie T. Bos, Willemieke M. Mudde, Machteld N. Hylkema, Pieter S. Hiemstra, Juergen Wess, Herman Meurs, Huib A. M. Kerstjens, Reinoud Gosens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

48 Citations (Scopus)

Abstract

Asthma is a chronic obstructive airway disease, characterized by inflammation and remodeling. Acetylcholine contributes to symptoms by inducing bronchoconstriction via the muscarinic M-3 receptor. Recent evidence suggests that bronchoconstriction can regulate airway remodeling, and therefore implies a role for the muscarinic M-3 receptor. The objective of this work was to study the contribution of the muscarinic M-3 receptor to allergen-induced remodeling using muscarinic M-3 receptor subtype-deficient (M3R-/-) mice. Wild-type (WT), M1R-/-, and M2R-/- mice were used as controls. C57Bl/ 6 mice were sensitized and challenged with ovalbumin (twice weekly for 4 wk). Control animals were challenged with saline. Allergen exposure induced goblet cell metaplasia, airway smooth muscle thickening (1.7-fold), pulmonary vascular smooth muscle remodeling (1.5-fold), and deposition of collagen I (1.7-fold) and fibronectin (1.6-fold) in the airway wall ofWT mice. These effects were absent or markedly lower inM(3)R(-/-) mice (30-100%), whereas M1R-/- and M2R-/- mice responded similarly to WT mice. In addition, airway smooth muscle and pulmonary vascular smooth muscle mass were 35-40% lower in saline-challenged M3R-/- 2 mice compared with WT mice. Interestingly, allergen-induced airway inflammation, assessed as infiltrated eosinophils and T helper type 2 cytokine expression, was similar or even enhanced in M3R-/- mice. Our data indicate that acetylcholine contributes to allergen-induced remodeling and smooth muscle mass via the muscarinic M-3 receptor, and not via M-1 or M-2 receptors. No stimulatory role for muscarinic M-3 receptors in allergic inflammation was observed, suggesting that the role of acetylcholine in remodeling is independent of the allergic inflammatory response, and may involve bronchoconstriction.

Original languageEnglish
Pages (from-to)690-698
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume50
Issue number4
DOIs
Publication statusPublished - Apr-2014

Keywords

  • airway pharmacology
  • anticholinergics
  • asthma
  • nonneuronal acetylcholine
  • NONNEURONAL CHOLINERGIC SYSTEM
  • HUMAN LUNG FIBROBLAST
  • SMOOTH-MUSCLE
  • TIOTROPIUM BROMIDE
  • ACETYLCHOLINE-RECEPTOR
  • MEDIATE STIMULATION
  • UNCONTROLLED ASTHMA
  • GROWTH-FACTOR
  • INFLAMMATION
  • BRONCHOCONSTRICTION

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