ReviewPharmacological regulation of the neuronal control of airway mucus secretion
Introduction
Airway mucus secretion is a primary defence mechanism against inhaled ‘insult’ and is under both humoral and neuronal control. Under normal circumstances, secretion is regulated to produce a mucus layer with a depth and physicochemical composition optimal for protection of the mucosal surface [1]. In contrast, in respiratory diseases associated with mucus hypersecretion—for example asthma and chronic obstructive pulmonary disease (COPD)—regulation of secretion becomes aberrant and produces a mucus layer that instead of contributing to airway homeostasis now contributes to pathophysiology 2., 3.. One factor contributing to the mucus hypersecretion of asthma and COPD could be upregulation of neuronal signalling to secretory structures in the airways. Inhibition of airway nerve activity may, therefore, be a therapeutic option to reduce airway mucus hypersecretion. This article discusses advances over the past three years in our understanding of the pharmacological regulation of airway neuronal secretion, emphasising inhibitory therapeutic options: antagonists at postjunctional receptors on secretory cells or drugs that act prejunctionally to inhibit nerve activity. A brief description of respiratory tract mucus and the innervation of airway secretory cells is given first. Although most information is from experimental animals, human data will be emphasised where available.
Section snippets
Respiratory tract mucus
A film of viscoelastic liquid, often termed mucus, protects the mucosal surface of the airways [1]. The liquid is a dilute aqueous solution of electrolytes, enzymes, anti-enzymes, antioxidants, antibacterials, lipids, mediators and high-molecular-weight mucous glycoproteins (termed mucins). The liquid forms an upper gel layer that traps inhaled particles and a lower sol layer in which cilia beat to remove mucus and particles from the lung, a process termed mucociliary clearance. Clearance
Respiratory tract mucins
The viscoelastic properties of airway mucus are attributed mainly to mucins. Mucins are synthesised in, and secreted by, epithelial goblet cells [4] and submucosal glands [5] and comprise a peptide backbone, termed apomucin, with highly glycosylated regions [6•]. Apomucins are encoded by specific mucin (MUC) genes. Fourteen human MUC genes are currently recognised, namely MUC1–4, MUC5AC, MUC5B, MUC6–9, MUC11–13 and MUC16 6•., 7., 8.. MUC5AC and MUC5B gene products are the major mucins in airway
Adrenergic and cholinergic innervation
Airway mucus-secreting cells are innervated, neurotransmitter receptors are localised to secretory cells and neural stimulation increases secretion [13•]. Fig. 1 shows innervation of airway goblet cells and localisation of muscarinic and tachykinin receptors in the airways. Three neural pathways are currently recognised in the airways (Fig. 2): sympathetic (adrenergic), parasympathetic (cholinergic) and a third system termed non-adrenergic non-cholinergic (NANC) [13•]. Cholinergic pathways are
Anticholinergics: muscarinic M3 receptor antagonists
Anticholinergic drugs are recommended in the management of both asthma and COPD 21., 22., 23.. Although categorised as bronchodilators, part of their beneficial effect may be inhibition of cholinergic secretion [13•]. Five muscarinic receptor types have been cloned, of which four are currently recognised pharmacologically (designated M1–M4) [24•]. Muscarinic M1 and M3 receptors localise to submucosal glands in human and ferret airways 25., 26.. The M3 receptor mediates cholinergic mucus
Neuroregulation
The magnitude of neurally induced (neurogenic) responses can be regulated via activation of endogenous prejunctional inhibitory receptors and ion channels (Box 1, Table 1). A number of these mechanisms inhibit neurogenic airway secretion and are discussed below.
Neuronal contribution to hypersecretion in asthma and COPD
Autonomic abnormalities may contribute to the mucus hypersecretion of chronic bronchitis and asthma. Chronic bronchitis is characterised by cough and chronic sputum production and is the hypersecretory component of COPD, a progressive debilitating respiratory condition linked to cigarette smoking [42]. Cough and sputum production is also a feature of asthma, particularly during an attack [2]. Both conditions are associated with increased airway mucus, goblet-cell hyperplasia and
Therapeutic possibilities: inhibition of neuronal airway secretion
The potential involvement of these different neural systems in the pathophysiology of airway hypersecretion suggests that inhibiting these mechanisms is a therapeutic option, in particular for asthma and COPD (Fig. 3). Antagonists at neurotransmitter receptors on the secretory cells are clearly an option. Non-selective anticholinergics such as ipratropium bromide are already used therapeutically in asthma and COPD and have beneficial effects on sputum production. Tiotropium bromide is a new
Conclusions
The dominant neural control of mucus secretion in human airways is cholinergic. Adrenergic control is restricted to the activity of blood-borne catecholamines and sensory–efferent neural control is equivocal. Antagonists at muscarinic M1 and M3 receptors inhibit water and mucus secretion and tachykinin NK1 receptor antagonists act similarly. Muscarinic M2 receptors, NO and VIP are predominantly inhibitory and regulate the magnitude of neurogenic secretion. Opening of BKCa channels is a common
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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