Elsevier

Life Sciences

Volume 91, Issues 21–22, 27 November 2012, Pages 1126-1133
Life Sciences

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Regulation of airway inflammation and remodeling by muscarinic receptors: Perspectives on anticholinergic therapy in asthma and COPD

https://doi.org/10.1016/j.lfs.2012.02.021Get rights and content

Abstract

Acetylcholine is the primary parasympathetic neurotransmitter in the airways and an autocrine/paracrine secreted hormone from non-neuronal origins including inflammatory cells and airway structural cells. In addition to the well-known functions of acetylcholine in regulating bronchoconstriction and mucus secretion, it is increasingly evident that acetylcholine regulates inflammatory cell chemotaxis and activation, and also participates in signaling events leading to chronic airway wall remodeling that is associated with chronic obstructive airway diseases including asthma and COPD. As muscarinic receptors appear responsible for most of the pro-inflammatory and remodeling effects of acetylcholine, these findings have significant implications for anticholinergic therapy in asthma and COPD, which is selective for muscarinic receptors. Here, the regulatory role of acetylcholine in inflammation and remodeling in asthma and COPD will be discussed including the perspectives that these findings offer for anticholinergic therapy in these diseases.

Introduction

Acetylcholine is the primary parasympathetic neurotransmitter in the airways and a paracrine/autocrine hormone released from non-neuronal origins. The role of acetylcholine in the regulation of bronchomotor tone and mucus secretion from airway submucosal glands is well established (Belmonte, 2005). More recent findings suggest that acetylcholine, acting on muscarinic receptors, regulates additional functions in the airways, including inflammation and remodeling in obstructive airway diseases such as asthma and COPD (Gosens et al., 2006, Racke and Matthiesen, 2004, Racke et al., 2006). Based on these findings, we have previously questioned the traditional view on the role of acetylcholine, and suggested new possibilities for therapeutic targeting of muscarinic receptors in asthma and COPD (Gosens et al., 2006). In this review, we will discuss the role of muscarinic receptors in obstructive airway disease further and update the discussion in view of these recent research papers and trials. In view of the selectivity of currently used anticholinergics for muscarinic receptors, we will not elaborate on the role of nicotinic receptors in this review. Nicotinic receptors are, however, expressed in the airways and mediate anti-inflammatory effects of acetylcholine. For excellent reviews on the anti-inflammatory role of nicotinic receptors, we would like to refer to recently published reviews and to other reviews in this special issue (Cui and Li, 2010, Rosas-Ballina and Tracey, 2009, Wessler and Kirkpatrick, 2008).

Section snippets

Biosynthesis, metabolism and mode of action of acetylcholine

Acetylcholine is synthesized from choline and acetyl-CoA mainly by the enzyme choline acetyltransferase (ChAT) (Wessler and Kirkpatrick, 2008). Airway neurons and non-neuronal cells such as airway epithelial cells express ChAT and release acetylcholine (Proskocil et al., 2004). Further, macrophages, mast cells, lymphocytes, granulocytes, fibroblasts and smooth muscle cells all have been suggested to express ChAT (Wessler and Kirkpatrick, 2008), although the release of acetylcholine from these

Airway inflammation

Asthma and COPD are both characterized by chronic airway inflammation, albeit that the patterns of inflammation are markedly different. Different subtypes of T cells are involved in asthma and COPD: in asthma there is an increase in TH2 (CD4+) cells, whereas in COPD CD8+ T cells predominate. Furthermore, the inflammation that occurs in asthma can be described as eosinophilic, whereas that occurring in COPD is mainly neutrophilic. However, when disease severity increases these differences become

Airway remodeling

Airway inflammation in chronic airway diseases such as asthma and COPD is often associated with cellular and structural alterations in the airways, referred to as airway remodeling (Jeffery, 2001). Airway remodeling is considered a major component of irreversible airflow limitation in these diseases (An et al., 2007), is progressive, and correlates with disease severity (Hogg et al., 2004, James et al., 2009). Airway remodeling in asthma and COPD is characterized by mucus gland hypertrophy,

Clinical implications

The above mentioned in vitro and in vivo studies indicate significant pro-inflammatory and remodeling effects for acetylcholine via muscarinic receptors, suggesting that anticholinergics may have anti-inflammatory and anti-remodeling properties in asthma and COPD patients. This hypothesis still needs to be proven in clinical studies, however. In the UPLIFT study, COPD patients treated with tiotropium during a 4 year period showed an improved quality of life and lung function, and a reduction in

Conflict of interest statement

RG and HM have acquired research funding from Boehringer Ingelheim. LK and TA have no conflict of interest to declare.

Acknowledgments

The authors would like to thank the Netherlands Asthma Foundation (grant 3.2.08.014) and the Groningen Center for Drug Research for financial support.

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