Muscarinic M₃ Receptors Contribute to Allergen-Induced Airway Remodeling in Mice

Abstract

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. The objective of this work was to study the contribution of the muscarinic M3 receptor to allergen-induced remodeling using muscarinic M3 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 of WT mice. These effects were absent or markedly lower in M3R(-/-) 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(-/-) 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 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.

Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling

“…Although growth factor-induced proliferation was dependent on the M 3 receptor, matrix protein deposition was dependent on the muscarinic M 2 receptor in vitro. However, in vivo, knock out of the M 2 receptor did not affect allergen-induced remodeling [29], which might be explained by M 2 receptor dysfunction after allergen challenge [15,38].…”

“…Interestingly, in M 3 R -/-mice, a marked inhibition of airway remodeling was observed, without inhibition of the allergic inflammatory response [29]. Generally, airway structural changes after allergen challenge are attributed to eosinophilic inflammation [39], and tiotropium has previously been shown to inhibit eosinophilic inflammation in animal models of asthma [5,7].…”

“…The hypothesis that bronchoconstriction might be the driver of allergen-induced airway remodeling suggests that neuronal acetylcholine also has an important role in allergic asthma [29]. Increasing evidence supports this notion.…”

“…Recently, the effects of acetylcholine on airway remodeling in response to allergen exposure were also demonstrated to be mediated via the M 3 receptor [29]. From animal models of asthma, it was already known that acetylcholine has a role in allergen-induced airway inflammation and remodeling.…”

Protective Effects of Antimuscarinics on the Bladder Remodeling After Bladder Outlet Obstruction

“…As only one dosage for each drug was used and the maximal effect was not known, we still could not conclude whether M2 receptor played a role in the remodeling of BOO. In the airway, allergen-induced changes were demonstrated to be via the muscarinic M3 receptor, and not via M1 or M2 receptors [24]. In bladder remodeling, however, further research is needed to determine the actual effect of each subtype.…”