Muscarinic receptor signaling in the pathophysiology of asthma and COPD

Abstract

Anticholinergics are widely used for the treatment of COPD, and to a lesser extent for asthma. Primarily used as bronchodilators, they reverse the action of vagally derived acetylcholine on airway smooth muscle contraction. Recent novel studies suggest that the effects of anticholinergics likely extend far beyond inducing bronchodilation, as the novel anticholinergic drug tiotropium bromide can effectively inhibit accelerated decline of lung function in COPD patients. Vagal tone is increased in airway inflammation associated with asthma and COPD; this results from exaggerated acetylcholine release and enhanced expression of downstream signaling components in airway smooth muscle. Vagally derived acetylcholine also regulates mucus production in the airways. A number of recent research papers also indicate that acetylcholine, acting through muscarinic receptors, may in part regulate pathological changes associated with airway remodeling. Muscarinic receptor signalling regulates airway smooth muscle thickening and differentiation, both in vitro and in vivo. Furthermore, acetylcholine and its synthesizing enzyme, choline acetyl transferase (ChAT), are ubiquitously expressed throughout the airways. Most notably epithelial cells and inflammatory cells generate acetylcholine, and express functional muscarinic receptors. Interestingly, recent work indicates the expression and function of muscarinic receptors on neutrophils is increased in COPD. Considering the potential broad role for endogenous acetylcholine in airway biology, this review summarizes established and novel aspects of muscarinic receptor signaling in relation to the pathophysiology and treatment of asthma and COPD.

Adrenergic Agonist and Antagonist Action in Airways of Patients with Bronchial Asthma

“…These results are in full coherence with the results of the author Mue Mue et al [25]. In addition to the bronchodilator effect, author Gosens et al suggest that anticholinergic substances, especially those of extended action like tiotropium bromide, might also reduce the constriction of lung functions [26].…”

Effects of Inhaled Tiotropium on Left Ventricular Diastolic Function in Chronic Obstructive Pulmonary Disease Patients after Pulmonary Resection

“…21) Recent reports have suggested that tiotropium bromide has anti-inflammatory activity via the muscarinic M3 receptor. 22) In this study, WBC counts and CRP levels were relatively lower after than before treatment, but there were no significant differences because their values were within normal ranges even before treatment. These results suggest that tiotropium inhibits systemic inflammatory reactions, which might lead to beneficial effects on LV diastolic dysfunction.…”

Two Guanylylcyclases Regulate the Muscarinic Activation of Airway Smooth Muscle

“…Moreover, this muscarinic activation seems to be involved in the remodelling and functional changes of ASM described in asthma and COPD as described in references [1][2][3][4][5][6]73]. We discussed the existence of two cGMP signals, at 20-s and 60-s in [36], which are products of two distinctive guanylyl cyclases, the NO-sensitive soluble guanylyl cyclases (NO-sGC) and Natriuretic Peptide Receptor Guanylyl Cyclase-B (NPR-GC-B).…”

“…Statistically significant difference between the Control with respect to mastoparan as indicated with asterisk (*p<0.05). Thus, a dysfunction of these M2/M3AChR signal transducing cascades has been implied in the pathophysiological mechanisms of bronchial asthma as mentioned in references [1,3,4] and Chronic Obstructive Pulmonary Disease (COPD) in [3]. In this sense, we attempted to evaluate these novel signal transducing cascades involving guanylyl cyclase activities above discussed, in an experimental asthma model in rats as described in reference [70].…”

“…Acetylcholine (Ach) is the predominant parasympathetic neurotransmitter, acting as an autocrine or paracrine hormone in the airways and its role in the regulation of bronchomotor tone and mucus secretion from airway submucosal glands in the respiratory tract is well established as described in [2]. More recent findings suggest that acetylcholine regulates additional functions in the respiratory tract, may promoting airway inflammation and remodelling, including airway smooth muscle thickening in inflammatory lung diseases as reported in references [3][4][5]. Another source of ACh is the non-neuronal cells and tissues, particularly inflammatory cells and the airway epithelium as described in references [6][7][8].…”