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

Kistemaker LEM, Bos IST, Hylkema MN, Hiemstra PS, Wess J, Meurs H, Kerstjens HAM & Gosens R.
Am J Respir Cell Mol Biol., 2014 Apr;50(4):690-8.



Rationale: Asthma is a chronic obstructive airway disease, characterized by inflammation and remodeling. Acetylcholine contributes to symptoms by inducing bronchoconstriction via the muscarinic M3 receptor. Recent evidence suggests that bronchoconstriction can regulate airway remodeling and therefore implies a role for the muscarinic M3 receptor.

Objectives: To study the contribution of the muscarinic M3 receptor to allergen-induced remodeling using muscarinic M3 receptor subtype deficient (M3R-/-) mice. Wild-type, M1R-/- and M2R-/- mice were used as controls. Methods C57Bl/6 mice were sensitized and challenged with ovalbumin (twice weekly, for 4 weeks). Control animals were challenged with saline.

Results: 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 of wild-type mice. These effects were absent or markedly lower in M3R-/- mice (30-100%), whereas M1R-/- and M2R-/- mice responded similar to wild-type mice. In addition, airway smooth muscle and pulmonary vascular smooth muscle mass were 35-40% lower in saline challenged M3R-/- mice compared to wild-type mice. Interestingly, allergen-induced airway inflammation, assessed as infiltrated eosinophils and Th2-cytokine expression, was similar or even enhanced in M3R-/- mice.

Conclusions: Our data indicate that acetylcholine contributes to allergen-induced remodeling and smooth muscle mass via the muscarinic M3 receptor, and not via M1 or M2 receptors. No stimulatory role for muscarinic M3 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.