- Email: [email protected]
Pharmacological regulation of the neuronal control of airway mucus secretion
249
Pharmacological regulation of the neuronal control of airway mucus secretion Duncan F Rogers The dominant neural control of human airway mucus secretion is cholinergic. There is no adrenergic control and sensory–efferent control is equivocal. Recent advances have identified several mechanisms that inhibit neurogenic mucus secretion. Muscarinic M3 receptor antagonists and tachykinin NK1 receptor antagonists inhibit neurogenic secretion. Muscarinic M2 receptors, nitric oxide and vasoactive intestinal peptide are inhibitory and regulate the magnitude of neurogenic secretion. The opening of large-conductance calcium-activated potassium channels is a common endogenous inhibitory mechanism and may represent the best therapeutic target. None of these inhibitory options are currently being targeted specifically for therapy of airway hypersecretion. Addresses Thoracic Medicine, National Heart & Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK; e-mail: [email protected] Current Opinion in Pharmacology 2002, 2:249–255 1471-4892/02/$ — see front matter © 2002 Elsevier Science Ltd. All rights reserved. Abbreviations large-conductance calcium-activated potassium channel BKCa COPD chronic obstructive pulmonary disease MUC mucin NANC non-adrenergic non-cholinergic NKA neurokinin A NO nitric oxide NOS NO synthase SP substance P VIP vasoactive intestinal peptide
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.
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, antienzymes, 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 efficiency is directly related to the elasticity and inversely proportional to the viscosity of the gel layer, and is dependent upon the depth of sol. Chronic increases in volume and viscosity of the mucus layer impair clearance and contribute to the pathophysiology of hypersecretory conditions of the airways, for example asthma and chronic bronchitis [2,3].
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 secretions from healthy individuals and patients with asthma or chronic bronchitis [9–11]. There is no information on which MUC gene products are released by neural stimulation; however, under basal conditions cat trachea produces a secretion with a higher ratio of a high-density, atypical mucin-like component to a lower density mucin component [12]. Vagal stimulation increases secretion of the typical, low-density mucin component. It is important to determine which mucins comprise basal and stimulated secretion in order to understand hypersecretory pathophysiology and attempt rational design of therapeutic drugs.
Innervation of airway secretory cells Adrenergic and cholinergic innervation
Airway mucus-secreting cells are innervated, neurotransmitter receptors are localised to secretory cells and neural stimulation increases secretion [13•]. Figure 1 shows innervation of airway goblet cells and localisation of muscarinic
250
Respiratory
Figure 1
(a)
(b)
(c)
L L
L Ep N
Ep G G
MG
Current Opinion in Pharmacology
Photomicrographs showing secretory cells, nerves and receptors in the airways. (a) Intraepithelial nerve fibre (N) lying between two goblet cells containing mucin granules (MG) in guinea-pig trachea. Arrow indicates intercellular junction. (b) Muscarinic receptors in ferret trachea. Darkfield illumination of tracheal section incubated with the muscarinic receptor
antagonist [3H]quinuclidinylbenzilate showing localisation of binding sites to submucosal glands (G) and, to a lesser extent, epithelium (Ep). (c) Tachykinin receptors in ferret trachea. Darkfield illumination of tracheal section incubated with [125I]-Bolton-Hunter–SP showing localisation of SP binding sites to epithelium (Ep) and glands (G). L, lumen.
and tachykinin receptors in the airways. Three neural pathways are currently recognised in the airways (Figure 2): sympathetic (adrenergic), parasympathetic (cholinergic) and a third system termed non-adrenergic non-cholinergic (NANC) [13•]. Cholinergic pathways are the dominant motor control of mucus secretion in the airways of all animal species studied, including humans [14]. In contrast, adrenergic control of secretion is apparent in experimental animals [13•] but cannot be demonstrated in human airways [15]. Adrenoceptors localise to airway secretory cells in a number of species, including humans, and respond to adrenoceptor agonists, although in human bronchi in vitro sympathomimetics induce small increases in secretion [16].
to the VIP/NOS/cholinergic nerves, in a number of species, inlcuding humans, C-fibres (afferents) containing SP, NKA and calcitonin gene-related peptide (CGRP) form a sensory neural system with a motor function (termed ‘sensory–efferent’ nerves) [13•]. These nerves are sensitive to capsaicin, the pungent principal of Capsicum peppers, and are also activated by other noxious stimuli such as cigarette smoke.
Non-adrenergic non-cholinergic innervation
The NANC neural system, which comprises excitatory and inhibitory components, is defined as responses that remain after adrenoceptor and cholinoceptor blockade [13•]. The neurotransmitters of the airway NANC neural system are low-molecular-weight peptides and gases. The peptides relevant to airway secretion are vasoactive intestinal peptide (VIP) and the sensory neuropeptides substance P (SP) and neurokinin A (NKA), the latter two collectively termed tachykinins. Nitric oxide (NO), produced by NO synthase (NOS), is a gaseous neurotransmitter. The distribution of the peptides and NO is complex and species-dependent. In human airways, some nerves contain both VIP and NOS and there is also colocalisation of VIP and NOS in cholinergic nerves [17]. In ferret trachea, few cholinergic nerves contain VIP or NOS, some neurones contain only VIP or only NOS, and there are many nerves that contain VIP, NOS and SP [18,19]. In contrast, in guinea-pig airways VIP and NOS are not associated with cholinergic nerves [17,20]. In addition
Pharmacological regulation of neuronal secretion Anticholinergics: muscarinic M3 receptor antagonists
Anticholinergic drugs are recommended in the management of both asthma and COPD [21–23]. 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 secretion in pig, cat and ferret tracheae [26,27]. In contrast, the M1 receptor is not involved with mucus output [26] but, together with the M3 receptor [27], may control water secretion. Tachykinin receptor antagonists
Three classes of tachykinin receptor are currently recognised: NK1, NK2 and NK3 [28]. The rank order of potency of endogenous agonist (SP, NKA and NKB) and synthetic ligands at these receptors has been studied in a variety of preparations, including human bronchi in vitro [29–31]. Studies using selective tachykinin receptor antagonists demonstrate that the NK1 receptor mediates neurogenic secretion in ferret trachea [32,33].
Neurogenic airway mucus secretion Rogers
251
Figure 2 Innervation of airway mucus-secreting cells. This simplified schematic shows the principal neuronal pathways that induce secretion. Cholinergic (parasympathetic) nerves constitute the dominant pathway (red), whereby acetylcholine (ACh) interacts with muscarinic M3 receptors to increase mucus output. Adrenergic (sympathetic) neural control of airway secretion (broken black lines and noradrenaline [NA]) is species-specific and has not been demonstrated in human airways. Blood-borne catecholamines like adrenaline (A) from the adrenal medulla interact with adrenoceptors (Ad) on the secretory cells to increase mucus output. Sensory nerve endings (blue) in the epithelium detect inhaled irritants and relay impulses via sensory (afferent) pathways to the central nervous system (CNS) to initiate reflex secretion (e.g. via cholinergic nerves). Axonal neurotransmission via collateral sensory–efferent pathways leads to release of sensory neuropeptides including SP and NKA, which interact with tachykinin NK1 receptors to increase secretion. The diagram does not illustrate how neuronal pathways that contain other neuropeptides (e.g. VIP), or NOS (which produces NO) interact with these main motor pathways to regulate the magnitude of secretion.
CNS
Airway epithelium
Nodose ganglion Vagus nerve
Inhaled irritants
Sensory terminal
Sensory nerve
Sensoryefferent nerve SP NKA Cholinergic nerve
NK1
ACh M3
Adrenergic nerve
Adrenal gland
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. Muscarinic M2 receptors
Muscarinic M2 receptors on cholinergic nerve terminals act as inhibitory autoreceptors that activate a negative-feedback loop whereby acetylcholine released from the nerves activates the M2 receptor to inhibit further acetylcholine release. In ferret trachea, the magnitude of secretion induced by cholinergic nerve stimulation is regulated by neuronal M2 receptors [26]. Pharmacological removal of the inhibitory influence of M2 receptors using methoctramine (an M2 receptor antagonist) increases the cholinergic secretory response up to fivefold. Opioids
Opioids depress nerve activity, including neural processes in the airways such as mucus secretion, by interacting with opioid receptors on the terminals of cholinergic and sensory afferent fibres [34]. Morphine inhibits tachykinin-induced mucus output in human bronchi in vitro [35]. In ferret and guinea-pig airways, activation of either µ (OP3) or δ (OP1) opioid receptors inhibits neurogenic mucus secretion [36,37]. Vasoactive intestinal peptide and related peptides
Exogenously administered VIP and related peptides have inconsistent effects on secretion that vary with preparation and species. For example, VIP and peptide histidine
NA A
Ad Mucus-secreting cell Current Opinion in Pharmacology
isoleucine (PHI) can either inhibit or stimulate secretion [31]. In contrast, both exogenous and endogenous VIP, and exogenous pituitary adenlyate cyclase activating peptide (PACAP), inhibit cholinergic and tachykininergic mucus output in ferret trachea via interaction with VPAC1 (previously known as VIP1) receptors [38•,39]. Inhibition by VIP of cholinergic mucus output is via prejunctional inhibition of acetylcholine release [38•]. Any small stimulatory effect of VIP on mucus output is masked by its marked inhibition of neurogenic mucus secretion. Nitric oxide
In ferret trachea, exogenous and endogenous NO inhibits both basal and neurogenic secretion, the latter apparently via inhibition of neurotransmission [40]. Potassium channels
Opening of cell membrane potassium channels induces K+ efflux, hyperpolarisation and ‘dampening’ of cell activity, including nerve activity. Activation of potassium channels that are sensitive to the intracellular concentration of ATP (KATP channels), for example using levcromakalim, inhibits neurogenic mucus output in guinea-pig and ferret tracheae [36,41]. However, inhibition by opioids and VIP of neurogenic mucus secretion is via activation of largeconductance calcium-activated potassium channels (BKCa) rather than KATP channels [36,38•]. VIP-mediated inhibition of cholinergic secretion involves inhibition of acetylcholine release from cholinergic nerves [39]. Thus, the endogenous potassium channel mediating inhibition of airway neurogenic secretion is the BKCa channel. An activator of this
252
Respiratory
Box 1
Table 1
Prejunctional inhibitory receptors in the airways.
Inhibitors of nerve activation.
Adenosine A2 receptor
Agent
Mechanism of action
α2-, β2-adrenoceptors
Capsazepine
Capsaicin VR1 receptor antagonist
CRF receptors
Frusemide
Cl– channel opener
Galanin receptors
Local anaesthetics
Na+ channel blockade
GABAB receptor
Ruthenium red
Capsaicin VR1 receptor antagonist
Sodium cromoglycate, nedocromil sodium
Possibly CI– channel openers
Cannabinoid CB2 receptor
Histamine H3 receptor NPY Y2 receptor *Opioid OP1, OP3 receptors P1, P2 purinoceptors Somatostatin receptors *VPAC1 receptor *Shown to mediate inhibition of neurogenic airway mucus secretion. CRF, corticotrophin-releasing factor; GABA, γ-aminobutyric acid; NPY, neuropeptide Y; OP1, δ opioid receptor; OP3, µ opioid receptor; VPAC, vasoactive intestinal and pituitary adenylate cyclase activating peptide.
channel, NS 1619, inhibits neurogenic secretion in ferret trachea [36].
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 submucosalgland hypertrophy [2,3]. Human bronchi containing hypertrophied glands exhibit increased secretion in vitro in response to acetylcholine and this is less effectively blocked by atropine than secretion in control tissue [43]. Cholinergic control of mucus secretion might be augmented in asthma because of dysfunctional airway muscarinic M2 receptors [14]. In addition, VIP-immunoreactive nerves are absent from the airways of patients with severe asthma [44]. Combined cholinergic hyperresponsiveness and reduced VIP inhibition could exaggerate mucus output when cholinergic nerves are triggered in asthmatic patients. In contrast, in patients with chronic bronchitis, the number and length of VIP-positive nerves is increased in submucosal glands [45]. This should enhance prejunctional inhibition of neurogenic secretion. Conversely, greater VIP release might enhance the postjunctional secretory effect of VIP, with the magnitude of neurogenic secretion being determined by the balance between prejunctional inhibition and postjunctional stimulation. Interestingly, VIP
inhibits mucus secretion from normal human airways in vitro but has little significant inhibitory effect on secretion in airways of patients with chronic bronchitis [46]. Sensory–efferent neural pathways may also be upregulated in asthma and COPD, although the evidence is equivocal [47•]. In asthma, SP-like immunoreactivity is raised in plasma, induced sputum and nasal lavage. The number of airway SP-containing nerve fibres may be increased in certain populations of asthmatics compared with control human airways. Tachykinin receptor mRNA is increased in asthmatic airways compared with control airways. In COPD, levels of SP are increased in induced sputum, although the distribution of tachykinin receptors is not different between smokers and controls [48].
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 (Figure 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 anticholinergic that dissociates very slowly from M1 and M3 receptors [49]. This attribute means that tiotropium bromide would inhibit water and mucus secretion by antagonising M1 and M3 receptors respectively, without removing the autoinhibitory effects of the M2 receptor. The clinical utility of tachykinin receptor antagonists in asthma or COPD is substantially unproven [47•,50]. This issue could be resolved, at least in part, by clinical studies of tachykinin NK1 receptor antagonists in airway hypersecretory conditions. Although selective receptor antagonists that target individual systems are useful, drugs that inhibit cholinergic and sensory–efferent airway nerve activity might be more beneficial if both cholinergic and sensory–efferent nerves
Neurogenic airway mucus secretion Rogers
253
Figure 3 Neuroregulation of airway mucus secretion. Pharmacological aproaches to reduce secretion are indicated in boxes. Shown in red, acetylcholine (ACh) released from cholinergic nerves induces secretion via muscarinic M3 receptors but inhibits ACh release, and thereby cholinergic secretion, via interaction with autoinhibitory M2 receptors. M3 receptor antagonists and M2 receptor agonists inhibit cholinergic secretion. Shown in blue, the tachykinins SP and NKA are released from sensory–efferent nerves and interact with tachykinin NK1 receptors to increase secretion. NK1 receptor antagonists block tachykinin-mediated mucus secretion. Shown in green, endogenous NO generated by NOS inhibits secretion by both neuroregulation and postjunctional inhibition of secretion. NO donors act similarly. Endogenous VIP (yellow) is released during nerve stimulation and induces a small increase in secretion via interaction with VPAC1 receptors on secretory cells. VIP also inhibits neurotransmitter release, and thereby neurogenic secretion, via interaction with prejunctional VPAC1 receptors. The inhibitory effect of VIP more than offsets any stimulatory effect on secretion. Interaction of opioids with prejunctional µ or δ opioid receptors (pink) inhibits secretion via neuroregulation. Opening of BKCa potassium channels (orange) appears to be the final common pathway of inhibition by VIP and opioid receptors. BKCa channel activators inhibit neurogenic secretion.
M2 agonist
Cholinergic nerve
ACh
NOS
M3 antagonist
Submucosal gland
VIP
BKCa channel activator
NO NO donor NOS
Sensory–efferent nerve
SP NKA NK1 antagonist
Muscarinic M3 receptor Muscarinic M2 receptor ACh Tachykin NK1 receptor
VIP VPAC1 receptor µ opioid receptor δ opioid receptor BKCa potassium channel SP and NKA Current Opinion in Pharmacology
contribute to hypersecretory pathophysiology. NO effectively inhibits both basal and neurogenic mucus secretion [40]; however, NO donors are not an attractive therapeutic option because the effects on airway homeostasis of inhibiting basal secretion are unknown, and may be deleterious. In addition, the principal site of action of NO is the vasculature and vasodilatation may produce unwanted side-effects. A better option would be BKCa channel activators because many neurally active inhibitors (opioids and VIP, for example) act ultimately through these endogenous channels. Evidence from animal studies supports this hypothesis; a BKCa channel activator effectively inhibits neurogenic secretion in ferret trachea [36,39].
the best therapeutic target available. Apart from muscarinic M1 and M3 receptor antagonists, none of the above inhibitory options are currently being targeted pharmacologically for management of airway hypersecretion. Clinical trials of selected compounds to investigate effects on mucus hypersecretion in asthma and COPD are warranted. An additional challenge in the design of such trials will be the selection of appropriate biomarkers of hypersecretion and of clinical end-points.
Conclusions
1.
Widdicombe JH, Widdicombe JG: Regulation of human airway surface liquid. Respir Physiol 1995, 99:3-12.
2.
Liu YC, Khawaja AM, Rogers DF: Pathophysiogy of airway mucus secretion in asthma. In Asthma: Basic Mechanisms and Clinical Management, edn. 3. Edited by Barnes PJ, Rodger IW, Thomson NC. London: Academic Press; 1998:205-227.
3.
Rogers DF: Mucus pathophysiology in COPD: differences to asthma, and pharmacotherapy. Monaldi Arch Chest Dis 2000, 55:324-332.
4.
Rogers DF: Airway goblet cells: responsive and adaptable frontline defenders. Eur Respir J 1994, 7:1690-1706.
5.
Finkbeiner WE: Physiology and pathology of tracheobronchial glands. Respir Physiol 1999, 118:77-83.
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 endogenous inhibitory mechanism for many inhibitors of neurogenic secretion and may be
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
254
Respiratory
6. •
Davies JR, Carlstedt I: Respiratory tract mucins. In Cilia and Mucus: from Development to Respiratory Defense. Edited by Salthe M. New York: Marcel Dekker, Inc.; 2001:167-178. Detailed account of respiratory mucins by two researchers at the forefront of mucin biology and biochemistry. Information on thirteen out of the fourteen currently described mucin genes and their products is given, including schematic diagrams of the domain structure of a number of the oligomeric mucus-forming mucins. See [7,8] for the two newly described mucins not discussed in the chapter. 7.
Williams SJ, Wreschner DH, Tran M, Eyre HJ, Sutherland GR, McGuckin MA: Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J Biol Chem 2001, 276:18327-18336.
8.
Yin BW, Lloyd KO: Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16. J Biol Chem 2001, 276:27371-27375.
9.
Thornton DJ, Davies JR, Kraayenbrink M, Richardson PS, Sheehan JK, Carlstedt I: Mucus glycoproteins from ‘normal’ human tracheobronchial secretion. Biochem J 1990, 265:179-186.
10. Thornton DJ, Carlstedt I, Howard M, Devine PL, Price MR, Sheehan JK: Respiratory mucins: identification of core proteins and glycoforms. Biochem J 1996, 316:967-975.
25. Mak JC, Barnes PJ: Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung. Am Rev Respir Dis 1990, 141:1559-1568. 26. Ramnarine SI, Haddad EB, Khawaja AM, Mak JC, Rogers DF: On muscarinic control of neurogenic mucus secretion in ferret trachea. J Physiol 1996, 494:577-586. 27.
Ishihara H, Shimura S, Satoh M, Masuda T, Nonaka H, Kase H, Sasaki T, Sasaki H, Takishima T, Tamura K: Muscarinic receptor subtypes in feline tracheal submucosal gland secretion. Am J Physiol 1992, 262:L223-L228.
28. Khawaja AM, Rogers DF: Tachykinins: receptor to effector. Int J Biochem Cell Biol 1996, 28:721-738. 29. Rogers DF, Aursudkij B, Barnes PJ: Effects of tachykinins on mucus secretion in human bronchi in vitro. Eur J Pharmacol 1989, 174:283-286. 30. Meini S, Mak JC, Rohde JA, Rogers DF: Tachykinin control of ferret airways: mucus secretion, bronchoconstriction and receptor mapping. Neuropeptides 1993, 24:81-89. 31. Ramnarine SI, Rogers DF: Non-adrenergic, non-cholinergic neural control of mucus secretion in the airways. Pulm Pharmacol 1994, 7:19-33.
11. Wickstrom C, Davies JR, Eriksen GV, Veerman EC, Carlstedt I: MUC5B is a major gel-forming, oligomeric mucin from human salivary gland, respiratory tract and endocervix: identification of glycoforms and C-terminal cleavage. Biochem J 1998, 334:685-693.
32. Ramnarine SI, Hirayama Y, Barnes PJ, Rogers DF: ‘Sensory–efferent’ neural control of mucus secretion: characterization using tachykinin receptor antagonists in ferret trachea in vitro. Br J Pharmacol 1994, 113:1183-1190.
12. Fung DC, Beacock DJ, Richardson PS: Vagal control of mucus glycoconjugate secretion into the feline trachea. J Physiol 1992, 453:435-447.
33. Khawaja AM, Liu Y, Rogers DF: Effect of non-peptide tachykinin NK1 receptor antagonists on non-adrenergic, non-cholinergic neurogenic mucus secretion in ferret trachea. Eur J Pharmacol 1999, 384:173-181.
13. Rogers DF: Motor control of airway goblet cells and glands. Respir • Physiol 2000, 125:129-144. Detailed review of current understanding of the neural control of airway mucus secretion, including neurally-acting inflammatory mediators, reflexes and metabolism of neurotransmitters. 14. Rogers DF: Muscarinic control of airway mucus secretion. In Muscarinic receptors in airways diseases. Edited by Zaagsma J, Meurs H, Roffel AF. Basel: Birkhäuser Verlag; 2001:175-201. 15. Baker B, Peatfield AC, Richardson PS: Nervous control of mucin secretion into human bronchi. J Physiol 1985, 365:297-305. 16. Phipps RJ, Williams IP, Richardson PS, Pell J, Pack RJ, Wright N: Sympathomimetic drugs stimulate the output of secretory glycoproteins from human bronchi in vitro. Clin Sci (Lond) 1982, 63:23-28. 17.
Fischer A, Canning BJ, Kummer W: Correlation of vasoactive intestinal peptide and nitric oxide synthase with choline acetyltransferase in the airway innervation. Ann NY Acad Sci 1996, 805:717-722.
18. Dey RD, Altemus JB, Rodd A, Mayer B, Said SI, Coburn RF: Neurochemical characterization of intrinsic neurons in ferret tracheal plexus. Am J Respir Cell Mol Biol 1996, 14:207-216. 19. Zhu W, Dey RD: Projections and pathways of VIP- and nNOScontaining airway neurons in ferret trachea. Am J Respir Cell Mol Biol 2001, 24:38-43. 20. Canning BJ, Fischer A: Localization of cholinergic nerves in lower airways of guinea pigs using antisera to choline acetyltransferase. Am J Physiol Lung Cell Mol Physiol 1997, 272:L731-L738. 21. British Thoracic Society: The British guidelines on asthma management. Thorax 1997, 52(Suppl 1):S1-S21. 22. British Thoracic Society: BTS guidelines for the management of chronic obstructive pulmonarty disease. Thorax 1997, 52(Suppl 5):S1-S28. 23. Culpitt SV, Rogers DF: Evaluation of current pharmacotherapy of chronic obstructive pulmonary disease. Expert Opin Pharmacother 2000, 1:1007-1020. 24. Lee AM, Jacoby DB, Fryer AD: Selective muscarinic receptor • antagonists for airway diseases. Curr Opin Pharmacol 2001, 1:223-229. Review of muscarinic receptor subtypes and of newly developed selective muscarinic receptor antagonists, for example tiotropium, including data from clinical trials in asthma and COPD.
34. Barnes PJ, Belvisi MG, Rogers DF: Modulation of neurogenic inflammation: novel approaches to inflammatory disease. Trends Pharmacol Sci 1990, 11:185-189. 35. Rogers DF, Barnes PJ: Opioid inhibition of neurally mediated mucus secretion in human bronchi. Lancet 1989, 1:930-932. 36. Ramnarine SI, Liu YC, Rogers DF: Neuroregulation of mucus secretion by opioid receptors and KATP and BKCa channels in ferret trachea in vitro. Br J Pharmacol 1998, 123:1631-1638. 37.
Kuo HP, Rohde JA, Barnes PJ, Rogers DF: Differential inhibitory effects of opioids on cigarette smoke, capsaicin and electricallyinduced goblet cell secretion in guinea-pig trachea. Br J Pharmacol 1992, 105:361-366.
38. Liu YC, Patel HJ, Khawaja AM, Belvisi MG, Rogers DF: • Neuroregulation by vasoactive intestinal peptide (VIP) of mucus secretion in ferret trachea: activation of BKCa channels and inhibition of neurotransmitter release. Br J Pharmacol 1999, 126:147-158. Pharmacological demonstration that activation of endogenous BKCa channels (by VIP) regulates the magnitude of neurogenic mucus output, and that inhibition of cholinergic-nerve-induced secretion is associated with inhibition of acetylcholine release. 39. Liu YC, Khawaja AM, Rogers DF: Effect of vasoactive intestinal peptide (VIP)-related peptides on cholinergic neurogenic and direct mucus secretion in ferret trachea in vitro. Br J Pharmacol 1999, 128:1353-1359. 40. Ramnarine SI, Khawaja AM, Barnes PJ, Rogers DF: Nitric oxide inhibition of basal and neurogenic mucus secretion in ferret trachea in vitro. Br J Pharmacol 1996, 118:998-1002. 41. Kuo HP, Rohde JA, Barnes PJ, Rogers DF: K+ channel activator inhibition of neurogenic goblet cell secretion in guinea pig trachea. Eur J Pharmacol 1992, 215:297-299. 42. Barnes PJ: Chronic obstructive pulmonary disease. N Engl J Med 2000, 343:269-280. 43. Sturgess J, Reid L: An organ culture study of the effect of drugs on the secretory activity of the human bronchial submucosal gland. Clin Sci 1972, 43:533-543. 44. Ollerenshaw S, Jarvis D, Woolcock A, Sullivan C, Scheibner T: Absence of immunoreactive vasoactive intestinal polypeptide in tissue from the lungs of patients with asthma. N Engl J Med 1989, 320:1244-1248.
Neurogenic airway mucus secretion Rogers
45. Lucchini RE, Facchini F, Turato G, Saetta M, Caramori G, Ciaccia A, Maestrelli P, Springall DR, Polak JM, Fabbri L, Mapp CE: Increased VIP-positive nerve fibers in the mucous glands of subjects with chronic bronchitis. Am J Respir Crit Care Med 1997, 156:1963-1968. 46. Coles SJ, Said SI, Reid LM: Inhibition by vasoactive intestinal peptide of glycoconjugate and lysozyme secretion by human airways in vitro. Am Rev Respir Dis 1981, 124:531-536. 47. Rogers DF: Tachykinin receptor antagonists for asthma and • COPD. Expert Opin Ther Patents 2001, 11:1097-1121. Critical evaluation of the possible involvement of sensory–efferent nerves and tachykinins in the pathophysiology of asthma and COPD, with discussion
255
of the relative potential contribution of tachykinin NK1, NK2 and NK3 receptors to different aspects of pathophysiology. Patent information and chemical structures of over 60 new tachykinin receptor antagonists is given. 48. Mapp CE, Miotto D, Braccioni F, Saetta M, Turato G, Maestrelli P, Krause JE, Karpitskiy V, Boyd N, Geppetti P, Fabbri LM: The distribution of neurokinin-1 and neurokinin-2 receptors in human central airways. Am J Respir Crit Care Med 2000, 161:207-215. 49. Barnes PJ: Tiotropium bromide. Expert Opin Invest Drugs 2001, 10:733-740. 50. Joos GF, Pauwels RA: Tachykinin receptor antagonists: potential in airways diseases. Curr Opin Pharmacol 2001, 1:235-241.
Pharmacological regulation of the neuronal control of airway mucus secretion Duncan F Rogers The dominant neural control of human airway mucus secretion is cholinergic. There is no adrenergic control and sensory–efferent control is equivocal. Recent advances have identified several mechanisms that inhibit neurogenic mucus secretion. Muscarinic M3 receptor antagonists and tachykinin NK1 receptor antagonists inhibit neurogenic secretion. Muscarinic M2 receptors, nitric oxide and vasoactive intestinal peptide are inhibitory and regulate the magnitude of neurogenic secretion. The opening of large-conductance calcium-activated potassium channels is a common endogenous inhibitory mechanism and may represent the best therapeutic target. None of these inhibitory options are currently being targeted specifically for therapy of airway hypersecretion. Addresses Thoracic Medicine, National Heart & Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK; e-mail: [email protected] Current Opinion in Pharmacology 2002, 2:249–255 1471-4892/02/$ — see front matter © 2002 Elsevier Science Ltd. All rights reserved. Abbreviations large-conductance calcium-activated potassium channel BKCa COPD chronic obstructive pulmonary disease MUC mucin NANC non-adrenergic non-cholinergic NKA neurokinin A NO nitric oxide NOS NO synthase SP substance P VIP vasoactive intestinal peptide
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.
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, antienzymes, 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 efficiency is directly related to the elasticity and inversely proportional to the viscosity of the gel layer, and is dependent upon the depth of sol. Chronic increases in volume and viscosity of the mucus layer impair clearance and contribute to the pathophysiology of hypersecretory conditions of the airways, for example asthma and chronic bronchitis [2,3].
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 secretions from healthy individuals and patients with asthma or chronic bronchitis [9–11]. There is no information on which MUC gene products are released by neural stimulation; however, under basal conditions cat trachea produces a secretion with a higher ratio of a high-density, atypical mucin-like component to a lower density mucin component [12]. Vagal stimulation increases secretion of the typical, low-density mucin component. It is important to determine which mucins comprise basal and stimulated secretion in order to understand hypersecretory pathophysiology and attempt rational design of therapeutic drugs.
Innervation of airway secretory cells Adrenergic and cholinergic innervation
Airway mucus-secreting cells are innervated, neurotransmitter receptors are localised to secretory cells and neural stimulation increases secretion [13•]. Figure 1 shows innervation of airway goblet cells and localisation of muscarinic
250
Respiratory
Figure 1
(a)
(b)
(c)
L L
L Ep N
Ep G G
MG
Current Opinion in Pharmacology
Photomicrographs showing secretory cells, nerves and receptors in the airways. (a) Intraepithelial nerve fibre (N) lying between two goblet cells containing mucin granules (MG) in guinea-pig trachea. Arrow indicates intercellular junction. (b) Muscarinic receptors in ferret trachea. Darkfield illumination of tracheal section incubated with the muscarinic receptor
antagonist [3H]quinuclidinylbenzilate showing localisation of binding sites to submucosal glands (G) and, to a lesser extent, epithelium (Ep). (c) Tachykinin receptors in ferret trachea. Darkfield illumination of tracheal section incubated with [125I]-Bolton-Hunter–SP showing localisation of SP binding sites to epithelium (Ep) and glands (G). L, lumen.
and tachykinin receptors in the airways. Three neural pathways are currently recognised in the airways (Figure 2): sympathetic (adrenergic), parasympathetic (cholinergic) and a third system termed non-adrenergic non-cholinergic (NANC) [13•]. Cholinergic pathways are the dominant motor control of mucus secretion in the airways of all animal species studied, including humans [14]. In contrast, adrenergic control of secretion is apparent in experimental animals [13•] but cannot be demonstrated in human airways [15]. Adrenoceptors localise to airway secretory cells in a number of species, including humans, and respond to adrenoceptor agonists, although in human bronchi in vitro sympathomimetics induce small increases in secretion [16].
to the VIP/NOS/cholinergic nerves, in a number of species, inlcuding humans, C-fibres (afferents) containing SP, NKA and calcitonin gene-related peptide (CGRP) form a sensory neural system with a motor function (termed ‘sensory–efferent’ nerves) [13•]. These nerves are sensitive to capsaicin, the pungent principal of Capsicum peppers, and are also activated by other noxious stimuli such as cigarette smoke.
Non-adrenergic non-cholinergic innervation
The NANC neural system, which comprises excitatory and inhibitory components, is defined as responses that remain after adrenoceptor and cholinoceptor blockade [13•]. The neurotransmitters of the airway NANC neural system are low-molecular-weight peptides and gases. The peptides relevant to airway secretion are vasoactive intestinal peptide (VIP) and the sensory neuropeptides substance P (SP) and neurokinin A (NKA), the latter two collectively termed tachykinins. Nitric oxide (NO), produced by NO synthase (NOS), is a gaseous neurotransmitter. The distribution of the peptides and NO is complex and species-dependent. In human airways, some nerves contain both VIP and NOS and there is also colocalisation of VIP and NOS in cholinergic nerves [17]. In ferret trachea, few cholinergic nerves contain VIP or NOS, some neurones contain only VIP or only NOS, and there are many nerves that contain VIP, NOS and SP [18,19]. In contrast, in guinea-pig airways VIP and NOS are not associated with cholinergic nerves [17,20]. In addition
Pharmacological regulation of neuronal secretion Anticholinergics: muscarinic M3 receptor antagonists
Anticholinergic drugs are recommended in the management of both asthma and COPD [21–23]. 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 secretion in pig, cat and ferret tracheae [26,27]. In contrast, the M1 receptor is not involved with mucus output [26] but, together with the M3 receptor [27], may control water secretion. Tachykinin receptor antagonists
Three classes of tachykinin receptor are currently recognised: NK1, NK2 and NK3 [28]. The rank order of potency of endogenous agonist (SP, NKA and NKB) and synthetic ligands at these receptors has been studied in a variety of preparations, including human bronchi in vitro [29–31]. Studies using selective tachykinin receptor antagonists demonstrate that the NK1 receptor mediates neurogenic secretion in ferret trachea [32,33].
Neurogenic airway mucus secretion Rogers
251
Figure 2 Innervation of airway mucus-secreting cells. This simplified schematic shows the principal neuronal pathways that induce secretion. Cholinergic (parasympathetic) nerves constitute the dominant pathway (red), whereby acetylcholine (ACh) interacts with muscarinic M3 receptors to increase mucus output. Adrenergic (sympathetic) neural control of airway secretion (broken black lines and noradrenaline [NA]) is species-specific and has not been demonstrated in human airways. Blood-borne catecholamines like adrenaline (A) from the adrenal medulla interact with adrenoceptors (Ad) on the secretory cells to increase mucus output. Sensory nerve endings (blue) in the epithelium detect inhaled irritants and relay impulses via sensory (afferent) pathways to the central nervous system (CNS) to initiate reflex secretion (e.g. via cholinergic nerves). Axonal neurotransmission via collateral sensory–efferent pathways leads to release of sensory neuropeptides including SP and NKA, which interact with tachykinin NK1 receptors to increase secretion. The diagram does not illustrate how neuronal pathways that contain other neuropeptides (e.g. VIP), or NOS (which produces NO) interact with these main motor pathways to regulate the magnitude of secretion.
CNS
Airway epithelium
Nodose ganglion Vagus nerve
Inhaled irritants
Sensory terminal
Sensory nerve
Sensoryefferent nerve SP NKA Cholinergic nerve
NK1
ACh M3
Adrenergic nerve
Adrenal gland
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. Muscarinic M2 receptors
Muscarinic M2 receptors on cholinergic nerve terminals act as inhibitory autoreceptors that activate a negative-feedback loop whereby acetylcholine released from the nerves activates the M2 receptor to inhibit further acetylcholine release. In ferret trachea, the magnitude of secretion induced by cholinergic nerve stimulation is regulated by neuronal M2 receptors [26]. Pharmacological removal of the inhibitory influence of M2 receptors using methoctramine (an M2 receptor antagonist) increases the cholinergic secretory response up to fivefold. Opioids
Opioids depress nerve activity, including neural processes in the airways such as mucus secretion, by interacting with opioid receptors on the terminals of cholinergic and sensory afferent fibres [34]. Morphine inhibits tachykinin-induced mucus output in human bronchi in vitro [35]. In ferret and guinea-pig airways, activation of either µ (OP3) or δ (OP1) opioid receptors inhibits neurogenic mucus secretion [36,37]. Vasoactive intestinal peptide and related peptides
Exogenously administered VIP and related peptides have inconsistent effects on secretion that vary with preparation and species. For example, VIP and peptide histidine
NA A
Ad Mucus-secreting cell Current Opinion in Pharmacology
isoleucine (PHI) can either inhibit or stimulate secretion [31]. In contrast, both exogenous and endogenous VIP, and exogenous pituitary adenlyate cyclase activating peptide (PACAP), inhibit cholinergic and tachykininergic mucus output in ferret trachea via interaction with VPAC1 (previously known as VIP1) receptors [38•,39]. Inhibition by VIP of cholinergic mucus output is via prejunctional inhibition of acetylcholine release [38•]. Any small stimulatory effect of VIP on mucus output is masked by its marked inhibition of neurogenic mucus secretion. Nitric oxide
In ferret trachea, exogenous and endogenous NO inhibits both basal and neurogenic secretion, the latter apparently via inhibition of neurotransmission [40]. Potassium channels
Opening of cell membrane potassium channels induces K+ efflux, hyperpolarisation and ‘dampening’ of cell activity, including nerve activity. Activation of potassium channels that are sensitive to the intracellular concentration of ATP (KATP channels), for example using levcromakalim, inhibits neurogenic mucus output in guinea-pig and ferret tracheae [36,41]. However, inhibition by opioids and VIP of neurogenic mucus secretion is via activation of largeconductance calcium-activated potassium channels (BKCa) rather than KATP channels [36,38•]. VIP-mediated inhibition of cholinergic secretion involves inhibition of acetylcholine release from cholinergic nerves [39]. Thus, the endogenous potassium channel mediating inhibition of airway neurogenic secretion is the BKCa channel. An activator of this
252
Respiratory
Box 1
Table 1
Prejunctional inhibitory receptors in the airways.
Inhibitors of nerve activation.
Adenosine A2 receptor
Agent
Mechanism of action
α2-, β2-adrenoceptors
Capsazepine
Capsaicin VR1 receptor antagonist
CRF receptors
Frusemide
Cl– channel opener
Galanin receptors
Local anaesthetics
Na+ channel blockade
GABAB receptor
Ruthenium red
Capsaicin VR1 receptor antagonist
Sodium cromoglycate, nedocromil sodium
Possibly CI– channel openers
Cannabinoid CB2 receptor
Histamine H3 receptor NPY Y2 receptor *Opioid OP1, OP3 receptors P1, P2 purinoceptors Somatostatin receptors *VPAC1 receptor *Shown to mediate inhibition of neurogenic airway mucus secretion. CRF, corticotrophin-releasing factor; GABA, γ-aminobutyric acid; NPY, neuropeptide Y; OP1, δ opioid receptor; OP3, µ opioid receptor; VPAC, vasoactive intestinal and pituitary adenylate cyclase activating peptide.
channel, NS 1619, inhibits neurogenic secretion in ferret trachea [36].
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 submucosalgland hypertrophy [2,3]. Human bronchi containing hypertrophied glands exhibit increased secretion in vitro in response to acetylcholine and this is less effectively blocked by atropine than secretion in control tissue [43]. Cholinergic control of mucus secretion might be augmented in asthma because of dysfunctional airway muscarinic M2 receptors [14]. In addition, VIP-immunoreactive nerves are absent from the airways of patients with severe asthma [44]. Combined cholinergic hyperresponsiveness and reduced VIP inhibition could exaggerate mucus output when cholinergic nerves are triggered in asthmatic patients. In contrast, in patients with chronic bronchitis, the number and length of VIP-positive nerves is increased in submucosal glands [45]. This should enhance prejunctional inhibition of neurogenic secretion. Conversely, greater VIP release might enhance the postjunctional secretory effect of VIP, with the magnitude of neurogenic secretion being determined by the balance between prejunctional inhibition and postjunctional stimulation. Interestingly, VIP
inhibits mucus secretion from normal human airways in vitro but has little significant inhibitory effect on secretion in airways of patients with chronic bronchitis [46]. Sensory–efferent neural pathways may also be upregulated in asthma and COPD, although the evidence is equivocal [47•]. In asthma, SP-like immunoreactivity is raised in plasma, induced sputum and nasal lavage. The number of airway SP-containing nerve fibres may be increased in certain populations of asthmatics compared with control human airways. Tachykinin receptor mRNA is increased in asthmatic airways compared with control airways. In COPD, levels of SP are increased in induced sputum, although the distribution of tachykinin receptors is not different between smokers and controls [48].
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 (Figure 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 anticholinergic that dissociates very slowly from M1 and M3 receptors [49]. This attribute means that tiotropium bromide would inhibit water and mucus secretion by antagonising M1 and M3 receptors respectively, without removing the autoinhibitory effects of the M2 receptor. The clinical utility of tachykinin receptor antagonists in asthma or COPD is substantially unproven [47•,50]. This issue could be resolved, at least in part, by clinical studies of tachykinin NK1 receptor antagonists in airway hypersecretory conditions. Although selective receptor antagonists that target individual systems are useful, drugs that inhibit cholinergic and sensory–efferent airway nerve activity might be more beneficial if both cholinergic and sensory–efferent nerves
Neurogenic airway mucus secretion Rogers
253
Figure 3 Neuroregulation of airway mucus secretion. Pharmacological aproaches to reduce secretion are indicated in boxes. Shown in red, acetylcholine (ACh) released from cholinergic nerves induces secretion via muscarinic M3 receptors but inhibits ACh release, and thereby cholinergic secretion, via interaction with autoinhibitory M2 receptors. M3 receptor antagonists and M2 receptor agonists inhibit cholinergic secretion. Shown in blue, the tachykinins SP and NKA are released from sensory–efferent nerves and interact with tachykinin NK1 receptors to increase secretion. NK1 receptor antagonists block tachykinin-mediated mucus secretion. Shown in green, endogenous NO generated by NOS inhibits secretion by both neuroregulation and postjunctional inhibition of secretion. NO donors act similarly. Endogenous VIP (yellow) is released during nerve stimulation and induces a small increase in secretion via interaction with VPAC1 receptors on secretory cells. VIP also inhibits neurotransmitter release, and thereby neurogenic secretion, via interaction with prejunctional VPAC1 receptors. The inhibitory effect of VIP more than offsets any stimulatory effect on secretion. Interaction of opioids with prejunctional µ or δ opioid receptors (pink) inhibits secretion via neuroregulation. Opening of BKCa potassium channels (orange) appears to be the final common pathway of inhibition by VIP and opioid receptors. BKCa channel activators inhibit neurogenic secretion.
M2 agonist
Cholinergic nerve
ACh
NOS
M3 antagonist
Submucosal gland
VIP
BKCa channel activator
NO NO donor NOS
Sensory–efferent nerve
SP NKA NK1 antagonist
Muscarinic M3 receptor Muscarinic M2 receptor ACh Tachykin NK1 receptor
VIP VPAC1 receptor µ opioid receptor δ opioid receptor BKCa potassium channel SP and NKA Current Opinion in Pharmacology
contribute to hypersecretory pathophysiology. NO effectively inhibits both basal and neurogenic mucus secretion [40]; however, NO donors are not an attractive therapeutic option because the effects on airway homeostasis of inhibiting basal secretion are unknown, and may be deleterious. In addition, the principal site of action of NO is the vasculature and vasodilatation may produce unwanted side-effects. A better option would be BKCa channel activators because many neurally active inhibitors (opioids and VIP, for example) act ultimately through these endogenous channels. Evidence from animal studies supports this hypothesis; a BKCa channel activator effectively inhibits neurogenic secretion in ferret trachea [36,39].
the best therapeutic target available. Apart from muscarinic M1 and M3 receptor antagonists, none of the above inhibitory options are currently being targeted pharmacologically for management of airway hypersecretion. Clinical trials of selected compounds to investigate effects on mucus hypersecretion in asthma and COPD are warranted. An additional challenge in the design of such trials will be the selection of appropriate biomarkers of hypersecretion and of clinical end-points.
Conclusions
1.
Widdicombe JH, Widdicombe JG: Regulation of human airway surface liquid. Respir Physiol 1995, 99:3-12.
2.
Liu YC, Khawaja AM, Rogers DF: Pathophysiogy of airway mucus secretion in asthma. In Asthma: Basic Mechanisms and Clinical Management, edn. 3. Edited by Barnes PJ, Rodger IW, Thomson NC. London: Academic Press; 1998:205-227.
3.
Rogers DF: Mucus pathophysiology in COPD: differences to asthma, and pharmacotherapy. Monaldi Arch Chest Dis 2000, 55:324-332.
4.
Rogers DF: Airway goblet cells: responsive and adaptable frontline defenders. Eur Respir J 1994, 7:1690-1706.
5.
Finkbeiner WE: Physiology and pathology of tracheobronchial glands. Respir Physiol 1999, 118:77-83.
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 endogenous inhibitory mechanism for many inhibitors of neurogenic secretion and may be
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
254
Respiratory
6. •
Davies JR, Carlstedt I: Respiratory tract mucins. In Cilia and Mucus: from Development to Respiratory Defense. Edited by Salthe M. New York: Marcel Dekker, Inc.; 2001:167-178. Detailed account of respiratory mucins by two researchers at the forefront of mucin biology and biochemistry. Information on thirteen out of the fourteen currently described mucin genes and their products is given, including schematic diagrams of the domain structure of a number of the oligomeric mucus-forming mucins. See [7,8] for the two newly described mucins not discussed in the chapter. 7.
Williams SJ, Wreschner DH, Tran M, Eyre HJ, Sutherland GR, McGuckin MA: Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J Biol Chem 2001, 276:18327-18336.
8.
Yin BW, Lloyd KO: Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16. J Biol Chem 2001, 276:27371-27375.
9.
Thornton DJ, Davies JR, Kraayenbrink M, Richardson PS, Sheehan JK, Carlstedt I: Mucus glycoproteins from ‘normal’ human tracheobronchial secretion. Biochem J 1990, 265:179-186.
10. Thornton DJ, Carlstedt I, Howard M, Devine PL, Price MR, Sheehan JK: Respiratory mucins: identification of core proteins and glycoforms. Biochem J 1996, 316:967-975.
25. Mak JC, Barnes PJ: Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung. Am Rev Respir Dis 1990, 141:1559-1568. 26. Ramnarine SI, Haddad EB, Khawaja AM, Mak JC, Rogers DF: On muscarinic control of neurogenic mucus secretion in ferret trachea. J Physiol 1996, 494:577-586. 27.
Ishihara H, Shimura S, Satoh M, Masuda T, Nonaka H, Kase H, Sasaki T, Sasaki H, Takishima T, Tamura K: Muscarinic receptor subtypes in feline tracheal submucosal gland secretion. Am J Physiol 1992, 262:L223-L228.
28. Khawaja AM, Rogers DF: Tachykinins: receptor to effector. Int J Biochem Cell Biol 1996, 28:721-738. 29. Rogers DF, Aursudkij B, Barnes PJ: Effects of tachykinins on mucus secretion in human bronchi in vitro. Eur J Pharmacol 1989, 174:283-286. 30. Meini S, Mak JC, Rohde JA, Rogers DF: Tachykinin control of ferret airways: mucus secretion, bronchoconstriction and receptor mapping. Neuropeptides 1993, 24:81-89. 31. Ramnarine SI, Rogers DF: Non-adrenergic, non-cholinergic neural control of mucus secretion in the airways. Pulm Pharmacol 1994, 7:19-33.
11. Wickstrom C, Davies JR, Eriksen GV, Veerman EC, Carlstedt I: MUC5B is a major gel-forming, oligomeric mucin from human salivary gland, respiratory tract and endocervix: identification of glycoforms and C-terminal cleavage. Biochem J 1998, 334:685-693.
32. Ramnarine SI, Hirayama Y, Barnes PJ, Rogers DF: ‘Sensory–efferent’ neural control of mucus secretion: characterization using tachykinin receptor antagonists in ferret trachea in vitro. Br J Pharmacol 1994, 113:1183-1190.
12. Fung DC, Beacock DJ, Richardson PS: Vagal control of mucus glycoconjugate secretion into the feline trachea. J Physiol 1992, 453:435-447.
33. Khawaja AM, Liu Y, Rogers DF: Effect of non-peptide tachykinin NK1 receptor antagonists on non-adrenergic, non-cholinergic neurogenic mucus secretion in ferret trachea. Eur J Pharmacol 1999, 384:173-181.
13. Rogers DF: Motor control of airway goblet cells and glands. Respir • Physiol 2000, 125:129-144. Detailed review of current understanding of the neural control of airway mucus secretion, including neurally-acting inflammatory mediators, reflexes and metabolism of neurotransmitters. 14. Rogers DF: Muscarinic control of airway mucus secretion. In Muscarinic receptors in airways diseases. Edited by Zaagsma J, Meurs H, Roffel AF. Basel: Birkhäuser Verlag; 2001:175-201. 15. Baker B, Peatfield AC, Richardson PS: Nervous control of mucin secretion into human bronchi. J Physiol 1985, 365:297-305. 16. Phipps RJ, Williams IP, Richardson PS, Pell J, Pack RJ, Wright N: Sympathomimetic drugs stimulate the output of secretory glycoproteins from human bronchi in vitro. Clin Sci (Lond) 1982, 63:23-28. 17.
Fischer A, Canning BJ, Kummer W: Correlation of vasoactive intestinal peptide and nitric oxide synthase with choline acetyltransferase in the airway innervation. Ann NY Acad Sci 1996, 805:717-722.
18. Dey RD, Altemus JB, Rodd A, Mayer B, Said SI, Coburn RF: Neurochemical characterization of intrinsic neurons in ferret tracheal plexus. Am J Respir Cell Mol Biol 1996, 14:207-216. 19. Zhu W, Dey RD: Projections and pathways of VIP- and nNOScontaining airway neurons in ferret trachea. Am J Respir Cell Mol Biol 2001, 24:38-43. 20. Canning BJ, Fischer A: Localization of cholinergic nerves in lower airways of guinea pigs using antisera to choline acetyltransferase. Am J Physiol Lung Cell Mol Physiol 1997, 272:L731-L738. 21. British Thoracic Society: The British guidelines on asthma management. Thorax 1997, 52(Suppl 1):S1-S21. 22. British Thoracic Society: BTS guidelines for the management of chronic obstructive pulmonarty disease. Thorax 1997, 52(Suppl 5):S1-S28. 23. Culpitt SV, Rogers DF: Evaluation of current pharmacotherapy of chronic obstructive pulmonary disease. Expert Opin Pharmacother 2000, 1:1007-1020. 24. Lee AM, Jacoby DB, Fryer AD: Selective muscarinic receptor • antagonists for airway diseases. Curr Opin Pharmacol 2001, 1:223-229. Review of muscarinic receptor subtypes and of newly developed selective muscarinic receptor antagonists, for example tiotropium, including data from clinical trials in asthma and COPD.
34. Barnes PJ, Belvisi MG, Rogers DF: Modulation of neurogenic inflammation: novel approaches to inflammatory disease. Trends Pharmacol Sci 1990, 11:185-189. 35. Rogers DF, Barnes PJ: Opioid inhibition of neurally mediated mucus secretion in human bronchi. Lancet 1989, 1:930-932. 36. Ramnarine SI, Liu YC, Rogers DF: Neuroregulation of mucus secretion by opioid receptors and KATP and BKCa channels in ferret trachea in vitro. Br J Pharmacol 1998, 123:1631-1638. 37.
Kuo HP, Rohde JA, Barnes PJ, Rogers DF: Differential inhibitory effects of opioids on cigarette smoke, capsaicin and electricallyinduced goblet cell secretion in guinea-pig trachea. Br J Pharmacol 1992, 105:361-366.
38. Liu YC, Patel HJ, Khawaja AM, Belvisi MG, Rogers DF: • Neuroregulation by vasoactive intestinal peptide (VIP) of mucus secretion in ferret trachea: activation of BKCa channels and inhibition of neurotransmitter release. Br J Pharmacol 1999, 126:147-158. Pharmacological demonstration that activation of endogenous BKCa channels (by VIP) regulates the magnitude of neurogenic mucus output, and that inhibition of cholinergic-nerve-induced secretion is associated with inhibition of acetylcholine release. 39. Liu YC, Khawaja AM, Rogers DF: Effect of vasoactive intestinal peptide (VIP)-related peptides on cholinergic neurogenic and direct mucus secretion in ferret trachea in vitro. Br J Pharmacol 1999, 128:1353-1359. 40. Ramnarine SI, Khawaja AM, Barnes PJ, Rogers DF: Nitric oxide inhibition of basal and neurogenic mucus secretion in ferret trachea in vitro. Br J Pharmacol 1996, 118:998-1002. 41. Kuo HP, Rohde JA, Barnes PJ, Rogers DF: K+ channel activator inhibition of neurogenic goblet cell secretion in guinea pig trachea. Eur J Pharmacol 1992, 215:297-299. 42. Barnes PJ: Chronic obstructive pulmonary disease. N Engl J Med 2000, 343:269-280. 43. Sturgess J, Reid L: An organ culture study of the effect of drugs on the secretory activity of the human bronchial submucosal gland. Clin Sci 1972, 43:533-543. 44. Ollerenshaw S, Jarvis D, Woolcock A, Sullivan C, Scheibner T: Absence of immunoreactive vasoactive intestinal polypeptide in tissue from the lungs of patients with asthma. N Engl J Med 1989, 320:1244-1248.
Neurogenic airway mucus secretion Rogers
45. Lucchini RE, Facchini F, Turato G, Saetta M, Caramori G, Ciaccia A, Maestrelli P, Springall DR, Polak JM, Fabbri L, Mapp CE: Increased VIP-positive nerve fibers in the mucous glands of subjects with chronic bronchitis. Am J Respir Crit Care Med 1997, 156:1963-1968. 46. Coles SJ, Said SI, Reid LM: Inhibition by vasoactive intestinal peptide of glycoconjugate and lysozyme secretion by human airways in vitro. Am Rev Respir Dis 1981, 124:531-536. 47. Rogers DF: Tachykinin receptor antagonists for asthma and • COPD. Expert Opin Ther Patents 2001, 11:1097-1121. Critical evaluation of the possible involvement of sensory–efferent nerves and tachykinins in the pathophysiology of asthma and COPD, with discussion
255
of the relative potential contribution of tachykinin NK1, NK2 and NK3 receptors to different aspects of pathophysiology. Patent information and chemical structures of over 60 new tachykinin receptor antagonists is given. 48. Mapp CE, Miotto D, Braccioni F, Saetta M, Turato G, Maestrelli P, Krause JE, Karpitskiy V, Boyd N, Geppetti P, Fabbri LM: The distribution of neurokinin-1 and neurokinin-2 receptors in human central airways. Am J Respir Crit Care Med 2000, 161:207-215. 49. Barnes PJ: Tiotropium bromide. Expert Opin Invest Drugs 2001, 10:733-740. 50. Joos GF, Pauwels RA: Tachykinin receptor antagonists: potential in airways diseases. Curr Opin Pharmacol 2001, 1:235-241.