ReviewAcetylcholine: a novel regulator of airway smooth muscle remodelling?
Introduction
Airway remodelling is a pathological feature observed both in asthma and in chronic obstructive pulmonary disease (COPD). The nature of this airway remodelling is different, however, as is the palette of inflammatory cells that are involved in the pathophysiology of these diseases. Comparative studies have demonstrated a prominent role for CD8+ lymphocytes, neutrophils and macrophages in COPD; asthma on the other hand is best characterised by eosinophilic inflammation and CD4+ lymphocytes (Jeffery, 2000, Jeffery, 2001). Nevertheless, all of the mentioned inflammatory cells are potential sources of growth factors, proteases, cytokines and chemokines that generate structural changes in the airways (Hirst, 2000, Hirst, 2003). In COPD, these structural changes include destruction of the lung parenchyma (leading to emphysema), fibrosis, epithelial metaplasia, mucus gland hypertrophy and increases in vascular and airway smooth muscle mass (Jeffery, 2001). As for COPD, asthma is characterised by mucus gland hypertrophy, subepithelial fibrosis and increases in airway smooth muscle mass. However, in asthma, the epithelium is fragile, the basement membrane is thickened and there is no emphysema. In addition, the increased airway smooth muscle mass in asthma may be more pronounced in the larger airways, whereas in COPD this smooth muscle thickening occurs more prominently in the small airways (Barnes et al., 1998, Jeffery, 2000, Jeffery, 2001).
Despite of differences in the pattern of airway smooth muscle thickening, the observation that airway smooth muscle mass is increased in both inflammatory diseases is interesting in view of its putative role in airway hyperreactivity and chronic airways obstruction. In addition, recent findings have shown that airway smooth muscle is not only involved in contraction, but is also capable of dynamically interacting with its environment, especially in inflammatory conditions. Thus, airway smooth muscle cells can proliferate, migrate, secrete substances such as chemokines, cytokines, extracellular matrix proteins and growth factors and, importantly, adapt to these functions by changing its phenotype from contractile to proliferative/synthetic or even hypercontractile (Halayko and Amrani, 2003, Halayko and Solway, 2001, Hirst, 2000, Hirst, 2003; Panettieri, 2003). As such, airway smooth muscle is now considered to play an active role in the regulation of airway remodelling in inflammatory airway diseases. The functions mentioned above are induced by growth factors and inflammatory mediators from the local environment and support the inflammatory response. Interestingly, a vast number of the acute inflammatory mediators (e.g. bradykinin, leukotrienes, histamine) exert their effect through G protein-coupled receptors (GPCRs) present in the airway smooth muscle cell membrane (Billington and Penn, 2003). Since contractile neurotransmitters, including acetylcholine, also activate GPCRs present in airway smooth muscle, their regulatory role in the airways is likely to exceed contraction. Nevertheless, the potential role of increased cholinergic activity in airway remodelling in asthma and COPD has thus far received little attention.
Section snippets
Acetylcholine release in airway inflammation
The primary source of acetylcholine in the airways is the vagal nerve. The release of acetylcholine from the vagal nerve is regulated by a variety of prejunctional receptors, including autoinhibitory muscarinic M2 receptors (Aas and Maclagan, 1990). In animal models of allergic airway inflammation and asthma, muscarinic M2 autoreceptor dysfunction has been found to contribute to exaggerated acetylcholine release from the vagal nerve both in vivo and ex vivo (Fryer and Wills-Karp, 1991, Larsen
Cholinergic signalling in airway smooth muscle
In order to better understand the established and potential effects of acetylcholine on airway smooth muscle, insight in the signal transduction that underlies muscarinic receptor activation is essential. Airway smooth muscle expresses both Gi-coupled muscarinic M2 and Gq-coupled muscarinic M3 receptors, the former being the predominant population, comprising ∼80% of the total muscarinic receptor population (Roffel et al., 1988, Roffel et al., 2001). Gq-coupled muscarinic M1 receptors are not
Phenotype, contractility and contractile protein expression
Accommodating the elements that comprise the contractile machinery, has for a long time been considered the prominent function of airway smooth muscle. This does not imply incapability to self-regulation, however, considering recent findings focusing on plasticity in airway smooth muscle function under pathophysiological conditions (Halayko and Amrani, 2003, Halayko and Stephens, 1994, Halayko and Solway, 2001, Hirst et al., 2000a, Hirst et al., 2000b). Airway smooth muscle may be induced to
Concluding remarks
Muscarinic receptor antagonists such as ipratropium bromide and tiotropium bromide are often used for the treatment of COPD and represent an important co-treatment in severe asthmatics (Barnes et al., 1995). They are used as bronchodilators and are generally not considered to have beneficial effects on airway remodelling. Nevertheless, there is evidence that prolonged treatment with these anticholinergics may improve lung function in patients with COPD (Rennard et al., 1996, Tashkin and Kesten,
Acknowledgements
Sophie Bos, Dedmer Schaafsma, Sue McKay, Manne Krop, Annet Tonkes and Maartje Hiemstra are all greatly acknowledged for their contributions to some of the studies described in this paper. We wish to thank the Netherlands Asthma Foundation for financial support (NAF grant 99.53).
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