Muscarinic receptors on airway mesenchymal cells: Novel findings for an ancient target

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Abstract

Since ancient times, anticholinergics have been used as a bronchodilator therapy for obstructive lung diseases. Targets of these drugs are G-protein-coupled muscarinic M1, M2 and M3 receptors in the airways, which have long been recognized to regulate vagally-induced airway smooth muscle contraction and mucus secretion. However, recent studies have revealed that acetylcholine also exerts pro-inflammatory, pro-proliferative and pro-fibrotic actions in the airways, which may involve muscarinic receptor stimulation on mesenchymal, epithelial and inflammatory cells. Moreover, acetylcholine in the airways may not only be derived from vagal nerves, but also from non-neuronal cells, including epithelial and inflammatory cells. Airway smooth muscle cells seem to play a major role in the effects of acetylcholine on airway function. It has become apparent that these cells are multipotent cells that may reversibly adopt (hyper)contractile, proliferative and synthetic phenotypes, which are all under control of muscarinic receptors and differentially involved in bronchoconstriction, airway remodeling and inflammation. Cholinergic contractile tone is increased by airway inflammation associated with asthma and COPD, resulting from exaggerated acetylcholine release as well as increased expression of contraction related proteins in airway smooth muscle. Moreover, muscarinic receptor stimulation promotes proliferation of airway smooth muscle cells as well as fibroblasts, and regulates cytokine, chemokine and extracellular matrix production by these cells, which may contribute to airway smooth muscle growth, airway fibrosis and inflammation. In line, animal models of chronic allergic asthma and COPD have recently demonstrated that tiotropium may potently inhibit airway inflammation and remodeling. These observations indicate that muscarinic receptors have a much larger role in the pathophysiology of obstructive airway diseases than previously thought, which may have important therapeutic implications.

Introduction

The use of anticholinergics as therapeutics in obstructive airways diseases dates back several thousands of years. Thus, in various ancient cultures inhalation of smoke or fumes from medicinal plants of the nightshade (Solanaceae) family, such as thorn apple (Datura stramonium) and henbane (Hyoscyamus niger), was advocated (reviewed in Refs. [1], [2]). These plants contain the anticholinergic alkaloids atropine, hyoscyamine and scopolamine that may have relieved the airway symptoms. Shortly after its introduction to the United Kingdom from India in the early 19th century, inhalation of stramonium from combustible powders or cigarettes was adopted as a first-line treatment of asthma in the Western world. In the mid-19th century this was heavily endorsed by the English physician Henry Hyde Salter, who considered asthma as a nervous disease causing spasm of the airway smooth muscle that could be relieved by smoking of stramonium to suppress nervous irritation [3]. Already in the second half of the 19th century, it was also recognized that the anticholinergic therapy was of benefit for patients with tobacco-related chronic bronchitis and emphysema [4], [5]. Smoking of anti-asthma cigarettes containing herbal anticholinergics has been advocated well into the 20th century, when inhalation therapies of atropine and its more safe synthetic quaternary ammonium derivatives ipratropium, oxitropium and tiotropium became gradually available. Quite remarkably, herbal cigarettes are still available online without prescription and, as the seeds of Datura [6], have been used to induce hallucinations by ingestion [1].

According to the current guidelines for the treatment of asthma [7] and chronic obstructive pulmonary disease (COPD) [8], anticholinergics are presently primarily prescribed as bronchodilators. In COPD, short-acting ipratropium and oxitropium as well as long-acting tiotropium are used, all being at least as effective as their β2-adrenergic counterparts, presumably because cholinergic contractile tone is the major reversible component of airways obstruction in these patients [9]. In the treatment of asthma only the short-acting anticholinergics ipratropium and oxitropium are used, which are generally less effective than short-acting β2-agonists due to the variety of contractile mediators involved in this disease, but which – in association with β2-agonists - may well be of benefit in acute asthma [10], [11], [12].

Although during the last 150 years anticholinergics have primarily been used to target bronchoconstriction as well as mucus secretion, recent studies during the past decennium have indicated that these drugs may have hitherto unrecognized non-bronchodilatory effects in COPD, including improved disease control and reduced exacerbation rates, improved quality of life, as well as reduced decline in lung function in subgroups of patients [13], [14], [15], [16], [17]. Moreover, recent findings in airway cells and animal models indicate that, in addition to their well-known role in airway constriction and mucus secretion, muscarinic receptors are importantly involved in the regulation of other pathophysiological processes in the airways, including airway inflammation and remodeling (reviewed in Refs. [17], [18], [19]). Moreover, acetylcholine in the airways may not only be derived from parasympathetic nerves, but also from non-neuronal cells, including epithelial and inflammatory cells, which may support its novel mechanisms of action in the airways [17], [18], [19], [20].

Mesenchymal cells, including airway smooth muscle cells and fibroblasts, seem to play a major role in the effects of acetylcholine on airway function. Apart from their classical key role in airway constriction, it has become apparent that airway smooth muscle cells are multipotent cells that may reversibly adopt (hyper)contractile, proliferative and synthetic phenotypes, which are all under control of muscarinic receptors and differentially involved in bronchoconstriction, airway remodeling and inflammation [18], [19], [21]. Increased airway smooth muscle contractility and proliferation as well as inflammatory and fibrotic responses by these cells may importantly contribute to airway hyperresponsiveness and lung function decline, that determine disease severity both in asthma and in COPD [18], [21], [22], [23], [24], [25]. In addition, fibroblasts are crucially involved in airway remodeling, by enhanced proliferation and production of extracellular matrix proteins, which have recently been shown to be under important control of muscarinic receptors [26], [27].

In this review, we will discuss some recent findings on potential novel mechanisms underlying muscarinic receptor-mediated airway obstruction, hyperresponsiveness, inflammation and remodeling in asthma and COPD, with particular focus on the role of mesenchymal cells in these processes. Moreover, these findings will be placed into therapeutic perspective.

Section snippets

Parasympathetic pathway

The cholinergic parasympathetic system in the lung is the dominant neural bronchoconstrictor pathway in humans [28]. The role of vagal nerve activation in bronchoconstriction and its potential implication for obstructive lung diseases such as asthma were already described more than a century ago by the Dutch Nobel prize laureate Einthoven [29]. It is currently known that release of the neurotransmitter acetylcholine from efferent vagal parasympathetic nerves in the airways causes airway smooth

Muscarinic receptor signaling in airway smooth muscle

Muscarinic receptors on airway smooth muscle are a mixture of Gi-coupled M2 receptors and Gq-coupled M3 receptors (Table 1). Although M2 receptors are the predominant subtype in this tissue, particularly in the large airways, pharmacological studies have indicated that under normal conditions contraction in both central and peripheral airways is primarily mediated by the M3 receptor [59], [60], [61]. This has been confirmed by in vivo studies using subtype-selective knock-out mice,

Airway inflammation

With the discovery of a non-neuronal cholinergic system in circulating inflammatory cells, as outlined above, the hypothesis was originally proposed by Wessler et al. [166] that such a non-neuronal cholinergic system might contribute to inflammatory airways diseases, including asthma. It is now evident that inflammatory cells express components of a non-neuronal cholinergic system and that anticholinergic therapy modulates inflammatory responses in the airways (see Ref. [19] for a recent

Conclusions and future perspectives

Recent studies have indicated that muscarinic receptors have a much larger role in airway physiology than previously thought. Thus, in addition to airway smooth muscle contraction and mucus secretion, acetylcholine has shown to exert pro-inflammatory, pro-proliferative and pro-fibrotic actions in the airways, involving muscarinic receptor stimulation on mesenchymal, epithelial and inflammatory cells. Moreover, acetylcholine in the airways is not only a neurotransmitter released by vagal nerves,

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