Cough and Airway Disease: The Role of Ion Channels

Sara J. Bonvini and Maria G. Belvisi

Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College, Exhibition Road, London SW7 2AZ, UK,

Correspondence: Professor Maria G Belvisi, Tel: +44 (0)207 594 7828, Fax: +44 (0)207 594 3100,

E-mail: m.belvisi@imperial.ac.uk

Sources of support: Medical Research Council (MRC) project grant MR/K020293/1

Abstract

Cough is the most common reason for patients to visit a primary care physician, yet it remains an unmet medical need. It can be idiopathic in nature but can also be a troublesome symptom across chronic lung diseases such as asthma, COPD and idiopathic pulmonary fibrosis (IPF). Chronic cough affects up to 12% of the population and yet there are no safe and effective therapies. The cough reflex is regulated by vagal, sensory afferent nerves which innervate the airway. The Transient Receptor Potential (TRP) family of ion channels are expressed on sensory nerve terminals, and when activated can evoke cough. This review focuses on the role of 4 TRP channels; TRP Vannilloid 1 (TRPV1), TRP Ankyrin 1 (TRPA1), TRP Vannilloid 4 (TRPV4) and TRP Melastatin 8 (TRPM8) and the purinergic P2X3 receptor and their possible role in chronic cough. We conclude that these ion channels, given their expression profile and their role in the activation of sensory afferents and the cough reflex, may represent excellent therapeutic targets for the treatment of respiratory symptoms in chronic lung disease.

Keywords: Transient receptor potential (TRP), ion channels, sensory nerves, vagus, cough

Introduction

Cough is the most common reason for a visit to the doctor in the UK [1]. Acute cough (under 8 weeks duration) is ordinarily a result of a viral or bacterial upper respiratory tract infection [3] and is often resolved following clearance of the infection [3]. Chronic cough however can last for over 8 weeks and is either a result of a number of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) [2,4,5] or is idiopathic in origin, where sufferers can be triggered by normally innocuous stimuli leading to uncontrolled bouts of coughing [6]. This can severely impact the quality of life for sufferers [7]. In the UK over $156 million was spent on cough medications in the year ending March 2013 [8], despite the fact, cough medications have been shown to be ineffective [9]. The reference antitussive codeine has been shown to be not to be effective compared to placebo [10] and has some dangerous side effects such as respiratory depression and sedation [11]. With chronic cough affecting up to 12% of the general population [12] there is an urgent need for new, safe and effective therapies.

Airway Sensory Nerves

Cough is initiated following activation of airway sensory nerves. Airway sensory nerves are tailored to detect changes in the physical and chemical environment [13], and if required elicit protective reflex events such as cough. Although cough is often described as a reflex it can also be a voluntary event which is not initiated by sensory afferent nerve stimulation. Cough can often be preceded by a sensation of airway irritation often likened to itching and referred to as an “urge-to-cough”. There is some debate about whether this is always reflex in nature and dependent upon sensory nerve activation or whether cognitive processes are involved with some level of volitional control [14, 15]. However, for the purposes of this review the text will focus on cough as a reflex event

Sensory nerve terminals are widely distributed throughout the airway, and terminals are generally near the epithelium or innervating structures (e.g. neuroepithelial bodies, mucosal glands and airway smooth muscle (ASM)) although terminals are not limited to these [16]. Receptors present on certain airway sensory nerves housed within the vagus nerve detect potentially dangerous stimuli and if the activation reaches a certain threshold then an action potential is produced which is carried up the vagus nerve and synapses in distinct regions of the medulla where the reflex is processed. A signal is then sent through cholinergic parasympathetic efferents to cause reflex bronchoconstriction [17] or via motor nerves to the larynx, respiratory muscles and diaphragm to cause cough [18](and reviewed in [19]). These reflexes are normally protective, however in disease airway reflexes can become aberrant, leading to an increase in symptoms such as cough, but also dyspnea, wheeze, bronchoconstriction and mucus hypersecretion [20] which can lower the quality of life of sufferers [21]. Vagal afferent nerves originate from the nodose and jugular ganglia, which have different embryological origins and house different populations of nerve fibres which differ in their chemical and mechanical responsiveness [22]. In the guinea pig nodose afferent neurons project to the nucleus of the solitary tract (nTS), and jugular neurons have their central terminations in the paratrigeminal nucleus (Pa5). Nodose neurons express more of the 160 KD neurofilament proteins and the alpha3 subunit of Na(+)/K(+) ATPase and significantly more jugular neurons expressed the neuropeptides substance P (SP) and, especially, calcitonin gene-related peptide (CGRP). Indeed, terminal fibers in the Pa5 compared to the nTS were characterized by their significantly greater expression of CGRP [23].

The main fibre types responsible for cough are C fibres, which are slower conducting, unmyelinated and chemosensitive and Aδ fibres, which are myelinated, fast conducting and more mechanosensitive. Axons projecting from the cell bodies of the vagus reach the airways via multiple nerve branches including the superior laryngeal nerve and recurrent laryngeal nerve which carry fibres to the trachea and bronchi [24, 25]. Much of the investigation behind sensory reflexes has been carried out in animals and translational studies are yet to be undertaken in human tissue. However a recent study utilising immunohistochemistry in whole mount biopsies of human airway innervation has indicated that the morphology of human lungs is similar to that of guinea pigs [26].

Ion Channels on Airway Sensory Nerves

The Transient Receptor Potential (TRP) family are a large family of ion channel proteins some of which are expressed on airway sensory nerve terminals. They are so named from their original discovery in Drosophilla which showed a transient response to bright light [27]. In mammals, TRP channels act as cellular sensors [28] as they respond to a variety of stimuli present in the cellular environment including temperature changes, chemicals, stretch, osmolarity, pH and oxidation [29]. They are defined by their structural homology rather than by ligand or ion activity and show a preference for Ca2+ [30]. There are around 30 mammalian TRP families known to date in six subfamilies based on amino acid sequence: TRPV (vanniloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), TRPP (polycistin) and TRPC (caninocal) [28]. TRP channels have the same basic structure with an intracellular N and C terminus, varying numbers of ankyrin repeats with 6 transmembrane domains. The cation pore is present between domain 5 and 6 [31]. As TRP channels conduct cations, when they are activated they can depolarise cells [30]. If the stimulus reaches a critical threshold, this produces an action potential and sensory nerve activation which can initiate a wide range of cellular responses [32]. In addition, the increase in terminal calcium may allow for local vesicle release of neuropeptides, independent of action potential formation, to induce neurogenic inflammation although there is not much evidence for this in human airways [33]. Furthermore, it should also be made clear that the central terminals of afferents are also likely to express the ion channel of interest and this represents an alternative site for possible modulation of synaptic transmission.

P2X3 receptors are members of the purinergic P2X family of ion channels, of which there are 7 members, which function as homo or heterotrimers formed of proteins subunits encoded by genes for P2X1-P2X7 [34,35]. P2X receptors show preference for ATP over breakdown products such as Adenosine Monophosphate (AMP) [36]. Alongside ATP, the ATP derivative αβ-Methylene ATP (αβ-MeATP) is a potent agonist. αβ-MeATP is a more stable ligand selective for P2X1 and P2X3 containing receptors. For activation to occur, three molecules of ATP are bound to extracellular portions of open P2X channels [37]. P2X3 receptors are rapidly desensitised, the channel opens milliseconds following activation, and deactivates within tens of milliseconds [38]. P2X3 receptors are widely expressed on small to medium diameter sensory nerves and when activated can lead to depolarisation of airway sensory nerves and cough [39-41].

A number of ion channels are expressed associated with the pathophysiology and symptomatology of a number of respiratory diseases including asthma, COPD and IPF [42-44]. Further, a number of ion channels have been shown to be expressed and activate airway sensory nerves to cause cough in both health and disease [45]. Therefore further investigation into the mechanism of action of ion channels in airway diseases may lead to the development of novel therapeutics.

In this review we have highlighted 4 TRP channels; TRPV1, TRPA1, TRPV4 and TRPM8 alongside the purinergic receptor P2X3 and outlined their physiological role in the airways and also in chronic airway diseases such as asthma, COPD and IPF where the cough is known to be a major symptom.

TRPV1 in the airways

TRPV1 is a Ca2+ permeable non- selective ion channel. It acts a noxious heat sensor when it is activated by temperatures over 42oC and is also activated by a wide range of exogenous and endogenous ligands including capsaicin, low pH, resinoferotoxin and endogenous mediators such as anandamide and HPETE [29, 42, 46-48] ]. TRPV1 can also be indirectly activated through G Protein coupled receptors, where agonists bind to the GPCR and initiate downstream signalling which leads to the activation of TRPV1. These agonists include bradykinin, PGE2 and Protein Activated Receptor 2 (PAR2) agonists [49, 50].

In the airways TRPV1 has been shown to be expressed in both nodose and jugular ganglia neurons [51]. TRPV1 is also highly expressed in other nociceptive neurons in dorsal root and trigeminal ganglia [42, 52] and in a range of non-neuronal cells [53]. TRPV1 activation by capsaicin has been well documented to cause cough in both animals and man [54-56] and activation of the receptor by a variety of ligands including capsaicin, resinoferotoxin and PGE2 can cause activation of the vagus nerve in guinea pig,mouse and human tissue. [50, 54-56]. TRPV1 is well known to activate C fibres but has also been shown to activate the more mechanically sensitive Aδ fibres as demonstrated in single fibre afferent recordings in a guinea-pig vivo model. However, A–mechanoceptor activation by capsaicin may also be secondary to bronchospasm and therefore an indirect effect cannot be ruled out [39, 57]. PGE2, citric acid, bradykinin and low pH have also all been shown to cause cough partially through TRPV1 [50,58].

TRPA1 in the airways

TRPA1 is the only member of the Ankyrin family of TRP channels and was first discovered in cultured human lung fibroblasts [59] but is now known to be widely expressed in sensory nociceptive neurons in the vagal, jugular and nodose ganglia [51, 60]. However, unlike TRPV1, TRPA1 only seems to activate C-fibres and interestingly single cell PCR experiments identified that although they are often co-expressed in neurons within the jugular and nodose ganglia they are also found separately [57, 61, 62]. It is a polymodal ion channel shown to be a sensor of noxious cold [60, 63]. TRPA1 channels are activated by a range of natural products such as allyl isothiocyanate, allicin and cannabinol, found in mustard oil, garlic and cannabis [64-68] and by environmental irritants (eg, acrolein, present in air pollution and CS) [62, 69, 70]. TRPA1 is also the molecular target for reactive and electrophilic by-products of oxidative stress including reactive oxygen species (ROS), nitrative (RNS) and carbonilyc (RCS) stress. Interestingly, this also includes electrophiles such as hypochlorite and hydrogen peroxide [71-73]. Recently, LPS was also identified as a TRPA1 activator and exerts fast, membrane delimited, excitatory actions via TRPA1 which develop independently of TLR4 activation [74]. Interestingly, recent data has also demonstrated an interaction between diesel exhaust particles (DEP) and the activation of airway C-fibre afferents. Polycyclic aromatic hydrocarbons (PAHs), major constituents of DEP, were implicated in this process via activation of the aryl hydrocarbon receptor (AhR) and subsequent mitochondrial ROS production, which is known to activate TRPA1 on nociceptive C-fibres [62, 72]. TRPA1 can also be indirectly activated by the inflammatory mediators PGE2 and bradykinin [50] and also through activation of PAR2 [75]. In the airways TRPA1 is highly expressed in neuronal tissue including nasal trigeminals, vagal airway neurons and spinal DRGs [51, 61], and is predominantly expressed on C fibres [62]. Activation of TRPA1 causes activation of vagal bronchopulmonary C fibres [51, ,62], and causes cough in both animals and man [76]. Unlike TRPV1, TRPA1 has only been shown to activate C fibres and not the more mechanically sensitive Aδ fibres [57, 62].

TRPV4 in the airways

TRPV4 is a Ca2+ permeable ion channel with 6 ankyrin repeats within the cytosolic N terminus and is activated by moderate temperature (>24oC) [77,78]. TRPV4 was originally characterised as an osmosensor, as TRPV4-/- mice showed systemic osmotic abnormalities [79]. There are a large number of both exogenous and endogenous stimuli of TRPV4 including the small molecule activator GSK1016790a , the synthetic phorbol ester 4α-phorbol 12,13-didecanoate (4αPDD), hypoosmolar solution and arachidonic acid derivatives such as 5’6’ epoxyeicosatrienoic acid (EET) [39, 80-82]. Similarly to both TRPV1 and TRPA1, activation of TRPV4 is linked to the GPCR PAR2. PAR2 activation stimulates TRPV4 channels directly, through receptor operated gating of TRPV4 [83, 84]

DRG neurons have been shown to express TRPV4 [85] and TRPV4 mRNA has been detected in pulmonary sensory neurons [86]. However a recent paper showed TRPV4 to only be expressed on 1 out of 32 nodose and 0 out of 32 jugular ganglia neurons, suggesting that TRPV4 is exerting its effects on accessory cells and acting on sensory neurons via an indirect mechanism [39].

TRPV4 activation has been associated with the release of ATP in a number of systems including the bladder and airway [39, 87, 88]. In the case of airway sensory nerves, TRPV4 agonists were shown to cause Ca2+ flux in guinea pig nodose ganglia, depolarisation of guinea pig, mouse and human vagal nerves, firing of Aδ fibres (not C-fibres) and cough in conscious guinea pigs [39]. This was shown to be through the release of ATP and subsequent activation of P2X3 on neurons to cause the functional TRPV4 responses [39].

TRPM8 in the airways

TRPM8 is the 8th member of the melastatin family of ion channels and is activated by cool temperatures (15-28oC) [89]. It is a ligand gated ion channel which functions as a homotetramer [90] expressed in a subpopulation of primary afferent neurons within the DRG and TG ganglia which on the whole do not express TRPV1 and TRPA1 [60, 91, 92]. Single cell PCR has indicated that TRPM8 is expressed in 60% nasal trigeminal neurons and retrogradely labelled jugular neurons following the administration of a tracer dye to the airways [51, 93-95]. TRPM8 is activated by the cooling compounds menthol, icilin and eucalyptol [92, 96].

TRPM8 is thought to be responsible for cough and bronchoconstriction caused by the inhalation of cold air [92, 95], however menthol, which is thought to exert its actions through the TRPM8 channel, has been shown to have a more protective effect. Menthol can inhibit citric acid induced cough in man [97] and causes a short lasting decrease in capsaicin cough in normal subjects [98]. It has been used as an over the counter medication for a number of years for its antitussive properties [99], and is often added to cigarettes to inhibit irritancy [90].The ability of menthol to activate vagal sensory nerves is difficult to reconcile with its anti-tussive activity. However, investigators have suggested that menthol supresses cough by a reflex transduced through TRPM8-dependent activation of nasal trigeminal afferent neurons although the authors state that non TRPM8-dependent mechanisms cannot be ruled out [100]. However, more conclusive evidence awaits the use of selective TRPM8 receptor blockers.

P2X3 in the airways

ATP is a ubiquitous signalling molecule which can activate the ionotropic P2X receptors and the metabotropic P2Y receptors [101]. ATP has been shown to activate airway sensory nerves where receptors containing P2X3 subunits have been shown to play a crucial role [102-104]. P2X3 forms homotrimeric P2X3 receptors (consisting of 3 P2X3 subunits) or heterotrimeric P2X2/P2X3 receptors (consisting of 2 P2X3 subunits and 1 P2X2 subunit [105]. However, in physiological studies of airway afferents P2X3 homomeric channel activation seems to be insufficient to sustain action potential firing withthe P2X2/3 heteromeric channels needed for this.

Although it can be found on epithelial cells and enteric neurons, P2X3 is almost exclusively expressed on sensory neurons [106]. P2X3 is predominantly expressed in the airways on small to medium diameter C or Aδ fibres from the nodose or jugular ganglia [107]. Activation of P2X3 on airway sensory nerves by the ATP derivative αβ-methylene ATP (αβ-MeATP) has been shown to cause depolarisation of human and guinea pig vagus nerves [39]. ATP has also been shown to activate sensory fibres from the nodose and jugular ganglia, which was blocked by the selective P2X3 antagonist A-317492 [107]. In humans, ATP was shown to cause cough and bronchoconstriction in asthmatic subjects, smokers and patients with COPD [40,41].

Cough in Disease and a role for ion channels

Both cough and airway sensory nerve responses have been shown to be altered in cough challenge studies with different tussive agents across disease conditions. A recent study has highlighted that in COPD, both cough and airway sensory nerve responses are altered and that the profile of responses differs when comparing to healthy controls, chronic cough patients and asthmatics suggesting that there are specific neurophenotypes in airway disease [56]. Investigation into the changes that occur in cough in airway disease, may help to highlight what mechanisms are important in neuronal dysfunction and the generation of debilitating symptoms and highlight novel therapeutic targets.

Asthma

Asthma is one of the most common aetiologies of chronic cough, being the cause of 24-29% of cases [6, 108, 109]. Cough is a defining symptom of asthma and as such is key in the diagnosis and management of the disease [110]. There is also a subtype of asthma known as cough variant asthma (CVA) where cough is the defining symptom of the disease [111]. Cough as a symptom is more common in patients with severe disease [112] and can predict poor prognosis [113]. In some patients cough is the symptom which carries an overriding concern, and has the most impact on the quality of life of patients, with patients willing to have higher levels of symptoms such as wheeze in exchange for a decreased cough response [114]. The cough rate of asthmatics is significantly higher than in healthy volunteers [56, 115, 116].

There are a number of reasons that could be behind the enhanced cough reflex seen in asthmatics. There is an increased level of PGE2 and bradykinin [117] present in the asthmatic airway, both of which have been shown to activate TRPA1 and TRPV1 [50] and cause cough [58, 117, 118, ]. Furthermore, in a study of individuals with asthma from six chest clinics in five French cities the data showed that there were significant associations between TRPV1 SNPs and cough symptoms [119]. Further, increased ATP levels, released during inflammation have been shown in the BAL of mice exposed to allergen challenge compared to saline control [120], and asthmatic patients show symptoms such as bronchoconstriction, cough and dyspnea following aerosolised ATP exposure [40].

COPD

Cough with or without sputum is one of the primary symptoms of COPD alongside breathlessness [121]. Patients with mild to moderate airflow obstruction report cough and sputum production more frequently than those with severe disease [122]. Cough is experienced by 70% of COPD patients, and occurs on a daily basis in 40% of patients [123]. Objective cough rates of COPD patients are higher than healthy controls, with current smokers having the highest daily cough rates [121]. Similarly to asthmatic patients, cough has been shown to adversely affect quality of life of sufferers, with a recent study highlighting that cough in the previous seven days is an important determinant of health related quality of life in patients with stable COPD [124]. Responses to capsaicin have also been shown to be enhanced following cigarette smoke exposure in the guinea pig, and capsaicin cough sensitivity is increased, shown by a lower capsaicin logC5 in patients with COPD [56], indicating a role for TRPV1. Further using donor human tissue, depolarisation induced by capsaicin was enhanced in the vagus nerve tissue of smokers compared to that of non- smokers [56].

Compounds within cigarette smoke such as acrolein and crotonaldehyde have been shown to cause cough through activation of TRPA1 [67, 69, 70, 76], suggesting that this channel could play a role in cough induced by cigarette smoke which is a key disease driver of COPD . TRPA1 is also a key neural sensor of oxidative stress, which is known to be increased in COPD [72]. The substantial increase in inflammatory mediators in COPD may also be a factor in the enhanced cough response. There is an increase in the more indirect tussive stimuli such as tachykinins in the airways [125] and similarly to asthma, there is increased ATP levels in COPD patients [126, 127] and increased cough, dyspnea and throat irritation in patients with COPD following aerosol administration of ATP [41]. The increased neutrophil infiltration into the lungs of patients with COPD leads to a higher levels of proteases in the lung, including neutrophil elastase. This is a major protease released during inflammation, has a high circulating concentration and a long half-life of 6-8hours [128] and has been shown to activate TRPA1 and TRPV4 [84]. Furthermore, the excess mucus found in COPD airways could also cause chronic cough through mechanical stimulation [129].

IPF

The most common presenting symptoms of IPF are dyspnoea and cough [130], where cough prevalence has been reported to be as high as 80% in IPF patents [131, 132]. The frequency of cough in IPF patients is also high, 24 hour objective cough monitoring has shown that cough counts are at a similar level to chronic coughers, and higher than patients with asthma and COPD [133, 134]. Cough was shown to be more prevalent in never smokers and patients with more advanced disease [131], and was shown to be an independent predictor of disease progression and could predict a shorter transplant free survival time [131]. The reasons behind the enhanced cough reflex seen in IPF are currently unknown. It has been hypothesised that mechanical distortion of the lungs may affect nerve fibres [134], as there is an increased cough reflex sensitivity to mechanical stimulation of the chest wall in patients with IPF [135]. The increase in subclinical inflammation seen in IPF may also activate nerves [131]. Further, both neurotrophins and ATP have been shown to be increased in the bronchioalveolar lavage fluid (BALF) of patients with IPF compared to normal subjects [132-136] which could suggest another mechanism of the heightened cough reflex. The role of ion channels in cough in IPF is yet to be determined. Increased cough counts to capsaicin in IPF patients compared to normal controls would suggest a potential role for TRPV1 [132], and increased ATP levels in the BAL may suggest that P2X3 may be involved, and perhaps the TRPV4/ATP/P2X3 axis [136]. Further testing using ion channel inhibitors in cough patients and also further pre-clinical work using models of IPF may help to uncover a more distinct role for ion channels the cough response in IPF.

Idiopathic Chronic Cough When chronic cough is not found to have any underlying disease cause it is known to be unexplained or idiopathic [137]. Initial diagnosis involves systematic evaluation to uncover a suspected underlying cause [138], and when no underlying cause is found and the cough response remains unresponsive to treatment then a diagnosis of idiopathic or refractory chronic cough is given. This can account for up to 42% of patients presenting to speciality cough clinics [139]. Often clinical examination, chest radiography and spirometry present as normal [140]. Chronic cough, interestingly, is twice as common in women as in men [141].

One theory for the enhanced cough is that patients with chronic cough suffer from abnormal neuronal pathways controlling the cough reflex [138]. This is supported by the fact that the cough response to capsaicin was doubled in patients with chronic cough compared to healthy controls [142] and also that most patients with chronic cough report sensations of airway irritation in the throat (75%) or chest (15%) associated with an irresistible urge to cough [143]. The fact that the cough response to the TRPV1 agonist capsaicin was doubled would suggest that TRPV1 could play a role in idiopathic chronic cough. A recent clinical study investigated the role of a TRPV1 antagonist SB-705498 on both capsaicin induced cough and objective cough frequency. Cough reflex sensitivity to capsaicin was slightly reduced, proving some target engagement, however unfortunately 24 hour cough counts, patient reported cough severity, urge to cough and cough specific quality of life were not improved compared to placebo [144]. This would suggest that perhaps TRPV1 is not responsible for the excess coughing seen in idiopathic chronic cough or that this compound was not sufficiently efficacious and so not an optimal tool compound for proof of concept studies. Perhaps the most convincing role of an ion channel in cough associated with respiratory disease has come with the recent clinical studies involving the P2X3 antagonist AF-219. AF-219 significantly inhibited daytime objective cough frequency by 75% in patients with refractory chronic cough [145]. There was a reported side effect of loss of taste, which caused some patients to drop out of the trial, however with later studies with lower concentrations of AF-219, the taste effect was substantially reduced while retaining an inhibitory effect against cough [146]. This is the first antagonist that targets the afferent arm of the reflex which has shown good efficacy in chronic coughers and indicates that ATP and P2X3 could play a major role in the cough reflex. However, it should be noted that AF-219 inhibits both the homomeric P2X3 receptor and the P2X2/3 heteromeric channels and it is still not clear whether the efficacy of this compound is due to antagonist activity at the homomeric or heteromeric channels. However, there are possible reasons to question whether antagonism at P2X3 is responsible for the efficacy of AF-219. The homomeric P2X3 receptor desensitizes rapidly, and in physiological studies of airway afferents the P2X3 homomeric channel activation is insufficient to sustain action potential firing and P2X2/3 heteromeric channels are needed for this. This question will remain unanswered until more selective compounds are trialled.

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Conclusions

In this review we have highlighted the role of several ion channels in the activation of sensory nerves and the cough reflex across chronic lung diseases. We have also speculated on which of these channels may be appropriate targets. However, we will only have conclusive evidence as to the role of various ion channels in the control of cough across disease pathologies with the advent of clinically ready, safe and efficacious compounds for use in interventional studies. With the discovery of anti-tussive activity of AF-219 in chronic idiopathic cough patients a new era has dawned with ion channel drug discovery programmes being initiated by several Pharma companies aimed at finding new therapeutics to target chronic cough. This will be welcome news to the many patients who are afflicted with this debilitating condition.

FIGURE LEGEND

Figure 1: Effect of ion channels in cough in airway disease

A number of endogenous ligands for various ion channels are increased in airway diseases where chronic cough is a major symptom such as COPD, asthma, IPF and idiopathic chronic cough. All diseases have shown an increase in ATP in the airways, which can activate the ion channel P2X3. There is also an increase in proteases and inflammatory mediators such as PGE2 in certain diseases which can activate the ion channels TRPV4 and TRPA1 and TRPV1. Oxidative stress is also a factor in some airway diseases which can activate TRPA1. When these ion channels are activated on airway sensory nerves, this causes an influx of calcium which leads to depolarisation, which can trigger an action potential which leads to airway reflexes such as cough.

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