Inhaled muscarinic antagonists for COPD—does an anti-inflammatory mechanism really play a role?
Introduction
Chronic obstructive pulmonary disease is currently ranked as the fifth leading cause of death in the world. The disease is characterised by airflow limitation that is usually progressive and associated with inflammation within the lung induced most commonly by tobacco smoke. The chronic airflow limitation is suggested to result from the inflammatory response leading to remodelling and narrowing of airways. Cough and sputum are early signs of the disease that often develop before airflow limitation is evident (www.goldcopd.org). Many patients experience worsening of symptoms (exacerbations) owing to a decline in lung function, often presented as dyspnoea that appears to be secondary to a viral/bacterial infection and the associated inflammatory response [1, 2]. Exacerbations are correlated with reductions in quality of life, pulmonary function and survival [3]. Acetylcholine is the major neurotransmitter of parasympathetic nerve fibres that innervate smooth muscle and glands via an action on two classes of receptors—muscarinic and nicotinic. Activation of the latter has been associated with anti-inflammatory effects whilst activation of muscarinic receptors is associated with bronchoconstriction and mucous secretion via actions at M3 and M1 muscarinic receptors, respectively [4]. Thus non-selective inhaled muscarinic antagonists (such as ipratropium and tiotropium) inhibit bronchoconstriction and improve lung function [5]. Recent evidence also suggests that muscarinic receptor activation has pro-inflammatory effects in a wide variety of cells implicated in inflammation and remodelling [6•]. In addition it is now appreciated that acetylcholine can also be synthesised and released from non-neuronal cells and thus can exert local muscarinic control of cellular function in the absence of vagal innervation [4, 7]. In neutrophils isolated from patients with COPD, tiotropium inhibits the pro-inflammatory effects of acetylcholine [8•]. This evidence suggests that clinically, inhaled muscarinic antagonists such as tiotropium might be capable of exerting anti-inflammatory effects as well as bronchodilator effects in COPD.
Section snippets
Can muscarinic antagonists exert anti-inflammatory effects in the lung?
Tiotropium has been shown to inhibit acetylcholine-induced release of leukotriene B4 (LTB4) from human isolated lung alveolar macrophages and A549 cells [9], IL-8 from normal human bronchial epithelium [10], collagen synthesis from human lung fibroblasts [11] and mitogenesis of human airway smooth muscle cells [12]. Similar conclusions have also been derived from studies of cells isolated from patients with COPD [8•]. In this study, acetylcholine induced the release of the chemotactic factor LTB
Can effects on lung hyperinflation and pulmonary vasculature explain the clinical benefits of inhaled tiotropium?
Hyperinflation is often defined as an elevation of functional residual capacity (end expiratory lung volume) above normal at the end of expiration and is present in the vast majority of patients with COPD [24]. In normal lung the expiratory airflow is sufficient for complete exhalation before inspiration. Dynamic hyperinflation occurs when patients commence inhalation before full exhalation has been achieved, and thus functional residual capacity increases [25]. The net effect of continued
Potential influence of tiotropium on virus-induced exacerbations of COPD
Viral infection is increasingly being recognised as an important factor in inducing exacerbations in COPD [1, 37•]. Two recent publications have documented that tiotropium has the potential to inhibit viral effects in the lung. In the first study, inhalation of tiotropium was shown to inhibit capsaicin-induced cough in patients who had a viral-induced upper respiratory tract infection—URI [38], but not in patients without an URI. The second publication [39•], demonstrated that tiotropium
Conclusions
At present, there is no convincing clinical evidence to support work in isolated cells or animal models of lung inflammation, which have demonstrated anti-inflammatory effects of muscarinic antagonists such as tiotropium. Currently the beneficial affects of muscarinic antagonists in COPD can be explained by inhibition of vagal nerve induced smooth muscle constriction in bronchi and possibly in the pulmonary vasculature. Clinical benefit as measured by improvements in lung function,
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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