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Mechanisms of acute cough
Pulmonary Pharmacology & Therapeutics 17 (2004) 389–391 www.elsevier.com/locate/ypupt
Summary
Mechanisms of acute cough Clive Pagea,*, Sandra M. Reynoldsa, Auralyn J. Mackenziea, Pierangelo Geppettib a
Division of Pharmaceutical Sciences, Sackler Institute of Pulmonary Pharmacology, Guy’s Campus, King’s College London, London SE1 1UL, UK b Clinical Pharmacology Unit, Department of Critical Care Medicine, University of Florence, Italy Received 8 September 2004; accepted 14 September 2004
Abstract The physiology of cough has become one of the primary focuses of recent research into the cough reflex. Peripherally, interest in differentiating subtypes of airway afferent fibres to determine their contributions to the cough reflex has led to the discovery of an RAR-fibre subtype that responds exclusively to tussive stimuli in the anaesthetized guinea pig and has been hypothesized to initiate the normal defensive cough reflex. Further investigations have begun to more fully differentiate these and other afferent fibre types pharmacologically. Centrally, investigations into the involvement of respiratory networks and gating mechanisms in the cough reflex have contributed to our understanding of the control of cough. Pathological changes in the cough reflex resulting from disease are also beginning to be elucidated. Further research in this area should lead to a more complete understanding of cough and a more rational approach to its treatment. q 2004 Elsevier Ltd. All rights reserved. Keywords: Acute cough; Cough reflex; Receptors; Afferent nerves
Cough is a basic protective reflex designed to keep inhaled irritants out of the respiratory tract. However, the processes involved in eliciting cough are far more complex than the physiological manifestation would suggest. Cough can be elicited by mechanical stimuli as well as a variety of chemical stimuli. The cough reflex can also be ‘sensitized’, leading to phenotypic changes both peripherally and centrally. The articles in this section focus primarily on elucidating the physiological mechanisms involved in the normal cough reflex at the peripheral and central levels and how pathological changes can affect these mechanisms.
1. Membrane receptors and ion channels related to cough The cough reflex is initiated by stimulation of vagal sensory nerves. The mechanism of action of how tussive stimuli activate membrane receptors and channels on such sensory nerves involved in cough has received scant attention probably due to the difficulty of studying * Corresponding author. E-mail address: [email protected] (C. Page). 1094-5539/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2004.09.028
the different afferent nerve types independent of each other. Undem and colleagues have made significant advances in our understanding of membrane receptors and ion channels involved in the initiation of the cough reflex [1]. Depolarization of the terminal membrane (generator potential) initiates action potential discharge and, if the generator potential is of sufficient amplitude, regenerative action potential discharge is evoked. The sensory nerves involved in the cough reflex are capable of inducing generator potentials. There are two main groups of receptors associated with generator potentials in cough: (1) ligandgated ion channels (ionotropic) and (2) G-protein coupled receptors (metabotropic). Activators of ligand-gated ion channels include agonists of TRPV1 and other TRP channels, acid sensing ion channels (ASIC) channels, 5-HT3, P2X and nicotinic receptors. Activation of the transient receptor potential vanilloid 1 (TRPV1) channel which is stimulated by capsaicin, is a well-known mechanism that generates the cough response in humans. TRPM8, activated by menthol, which has been shown to be an effective antitussive agent in healthy human subjects in a cough-evoked model [2], has been also proposed to function as a transducer of cold stimuli in the somatosensory nervous system [3]. An apparent
390
C. Page et al. / Pulmonary Pharmacology & Therapeutics 17 (2004) 389–391
contradictory finding is that TRPV8 colocalizes in TRPV1 expressing neurones. ANKTM1, which is activated by mustard oil and possibly by cannabinoids and TRPV4, an osmoceptor also activated by a phorbol ester derivative may also play a role in the cough response. There have been great advances in our knowledge about TRP channels, but further investigation is needed to establish their exact role in the cough response. When citric acid is applied to a receptive field of guinea pig afferent nerve fibres of low threshold mechanosensitive RARs, they respond immediately. Their pH threshold for activation of RARs is 6.7, but RARs are only activated by rapid changes in pH, and the mechanism by which acid excites RARs is rapidly inactivating. This is consistent to what is known about activation of ASICs and in particular ASIC3, which is expressed by nodose neurones. The cough fibre response to acid resembles the response mediated by ASIC3, in that it rapidly inactivates after activation and it also has low threshold for acid-induced activation. C-fibres also respond to acid, but the selective TRPV1 antagonist iodo-resiniferatoxin does not seem to abolish the response to acid. Thus, these ASIC type channels may prove to be a good drug target. Activation of 5-HT receptors, especially by 5-HT-3 receptor agonists, robustly activates sensory C-fibres but such activation has no effect on cough fibres or RARs. Thus, 5-HT, that only appears to activate nodose derived C-fibres, could prove a useful pharmacological tool to distinguish between nociceptive afferents. ATP has also been shown to activate pulmonary C-fibres in dogs, a response that was inhibited by P2X receptor-selective antagonists. ATP, however, seems only to activate nodose derived C-fibres and has no effect on jugular derived C-fires or rapidly adapting low threshold mechanoreceptors. Afferent nerve terminals can also be depolarized by activation of G-protein coupled receptors (GPCRs). Among the GPCRs that activate afferent nerve terminals much attention has been directed to the bradykinin B2, the histamine H1, the prostanoid, adenosine, opiate and tachykinin receptors. The signalling events leading to GPCR-mediated membrane depolarization is more complicated than that of ligand-gated ion channel receptors. It is thought that GPCR-mediated membrane depolarization occurs through classical second messenger systems such as activation of phospholipase C, which in turn leads to membrane depolarization and ionic events, including the Ca influx mediated by TRPV1. However, the signal transduction between GPCR and eventual generator potential remains elusive. Undem and colleagues speculate that the opening of calcium-activated chloride channels may contribute to GPCR-mediated membrane depolarization of afferent airway nerves. Certain lipoxygenase products (e.g. 12-HPETE and 15-HPETE) activate TRPV1 channels, whilst TRPV1 antagonists inhibit bradykinin-induced responses in airway C-fibres. Bradykinin-induced responses are also inhibited
by lipoxygenase inhibitors suggesting that certain tussive stimuli work indirectly through the release of lipoxygenase products. The ability of bradykinin or prostaglandins to activate/sensitize bronchial C-fibres may be also independent of TRPV1 [4]. Irrespective of the mechanism activation of certain GPCRs may result in sensitization of the cough to other nerve activators.
2. Sensory pathways mediating cough in guinea pigs There has been much debate in the past as to which afferent nerves are responsible for the cough reflex. In recent years, our understanding of afferent sensory nerves has greatly improved and has lead to further subdivisions. Mechanical airway afferent nerves are the rapidly adapting (RARs) or the slowly adapting (SARs) receptors, which have been classified on their adaptation during sustained lung inflations, and their cell bodies are located mainly in the nodose ganglia. Airway nociceptive afferent nerves (C-fibres) are defined by their responsiveness to irritant chemicals like capsaicin, and have their cell bodies in the jugular and nodose ganglia. RARs are believed to be the likely primary sensory nerve subtype that initiate coughing in human and animal studies. Further investigation has lead us to question this, for instance stimuli like histamine and methacholine which are known stimulators of RARs do not initiate coughing. In addition, although RARs are tonically active during the respiratory cycle, cough is only elicited by very selective stimulants. Recent studies from Canning et al. [1] have described a vagal afferent nerve subtype that innervates the guinea pig that appears essential for cough in this animal. This new fibres belong to a subtype of low threshold mechanoreceptors derived exclusively from the nodose ganglia. They are differentiated from RARs due to their conduction velocity and their location in the airways. They are activated in anaesthetized guinea pigs by mechanical probing of the mucosa, distilled water and citric acid, which are all known stimulants of cough. Conversely this new ‘cough receptor’ fibre is not activated by bradykinin, capsaicin, ATP, hypertonic saline or airway smooth muscle constriction or stretch. The alpha-3 expressing isozyme of NaC/KCATPase, expressed solely by the cough receptor, appears to be essential to the normal sensory function of this cough receptor nerve terminal. Capsaicin and bradykinin, known stimulators of airway C-fibres, can evoke cough in conscious animals and humans. However, in anaesthetized guinea pigs capsaicin and bradykinin failed to evoke cough [1].
3. Central pathways of cough Much information has been obtained on the mechanisms underlying the induction of cough at the peripheral level. However, fewer studies have been carried out to investigate
C. Page et al. / Pulmonary Pharmacology & Therapeutics 17 (2004) 389–391
the central control of cough, as they pose a much greater challenge. Shannon and co-workers have been working with an impressive cough model which records neurone activity using microelectrode arrays in neuromuscular-blocked ventilated cats. They have determined that the neuronal networks regulating normal breathing are also involved in generating cough. These neuronal networks are located mostly in the ventrolateral medulla, although other subnetworks in the nucleus tractus solitarii (nTS), midline raphe nuclei, pons and cerebellum have also been found to fire in response to normal breathing and tussive stimuli. Analysis of the interactions among cough responsive neurones has led to a proposed mechanism for how cough is regulated centrally. While the central pathways of the cough reflex are being progressively elucidated, the next step is to determine their pharmacology. At the moment, the precise site of action of many centrally acting antitussive drugs, including, for instance, diphenhydramine, glaucine, and caramiphen is unknown [5]. Bolser presented some novel theories on how cough could be regulated by a ‘gating mechanism’ that controls the whole cough network’s input on the expiratory pathways and how the pharmacology of these ‘gates’ may be important to the phenotype of the cough reflex. One observation of particular interest that contributed to these ideas was that some neurones quiescent during normal breathing were found to be recruited during cough. Other neurones have been found to increase or decrease their firing rate in response to cough. These neurones may form part of this gating mechanism, although it is still equally likely that regular respiratory neurones may perform this function. Further research in this area will hopefully clarify the organization of cough regulation and lead to the identification of potential sites of action for antitussive drugs. While knowledge about the central pathways of cough reflex is increasing, the clinical relevance of this novel acquisition is uncertain. Nishino has studied a patient group with the neurodegenerative disease multiple system atrophy (MSA) who have a pathologically reduced response to
391
protussive stimuli. While, they speculate that the pathological changes occurring in the CNS are affecting the cough reflex, it has not yet been determined at what site the disease interrupts the cough response. Further research with patients having pulmonary diseases associated with cough urgently need to be undertaken.
4. Conclusions This session provided us with much needed knowledge on regulation of the cough reflex, especially the finding of a cough receptor fibre that is responsible for initiating defensive cough. This cough receptor is probably subject to modulation by other afferent nerves, which may well be responsible for the manifestation of a heightened sensitivity of these fibres leading to abnormal cough. Possible drug target may come from targeting receptors on such sensory nerves receptors in the periphery, although the important question remains unanswered, as to whether a peripherally acting is better than a centrally acting antitussive drug for treating cough.
References [1] Canning BJ, Mazzone SB, Meeker SN, Mori N, Reynolds SM, Undem BJ. Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 2004;557: 543–558. [2] Morice AH, Marshall AE, Higgins KS, Grattan TJ. Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax 1994;49:1024–1026. [3] McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002;416:52–58. [4] Kollarik M, Dinh QT, Fischer A, Undem BJ. Capsaicin-sensitive and -insensitive vagal bronchopulmonary C-fibres in the mouse. J Physiol 2003;551:869–879. [5] Reynolds SM, Mackenzie AJ, Spina D, Page CP. The Pharmacology of Cough. Trends Pharmacol Sci 2004; (In Press).
Summary
Mechanisms of acute cough Clive Pagea,*, Sandra M. Reynoldsa, Auralyn J. Mackenziea, Pierangelo Geppettib a
Division of Pharmaceutical Sciences, Sackler Institute of Pulmonary Pharmacology, Guy’s Campus, King’s College London, London SE1 1UL, UK b Clinical Pharmacology Unit, Department of Critical Care Medicine, University of Florence, Italy Received 8 September 2004; accepted 14 September 2004
Abstract The physiology of cough has become one of the primary focuses of recent research into the cough reflex. Peripherally, interest in differentiating subtypes of airway afferent fibres to determine their contributions to the cough reflex has led to the discovery of an RAR-fibre subtype that responds exclusively to tussive stimuli in the anaesthetized guinea pig and has been hypothesized to initiate the normal defensive cough reflex. Further investigations have begun to more fully differentiate these and other afferent fibre types pharmacologically. Centrally, investigations into the involvement of respiratory networks and gating mechanisms in the cough reflex have contributed to our understanding of the control of cough. Pathological changes in the cough reflex resulting from disease are also beginning to be elucidated. Further research in this area should lead to a more complete understanding of cough and a more rational approach to its treatment. q 2004 Elsevier Ltd. All rights reserved. Keywords: Acute cough; Cough reflex; Receptors; Afferent nerves
Cough is a basic protective reflex designed to keep inhaled irritants out of the respiratory tract. However, the processes involved in eliciting cough are far more complex than the physiological manifestation would suggest. Cough can be elicited by mechanical stimuli as well as a variety of chemical stimuli. The cough reflex can also be ‘sensitized’, leading to phenotypic changes both peripherally and centrally. The articles in this section focus primarily on elucidating the physiological mechanisms involved in the normal cough reflex at the peripheral and central levels and how pathological changes can affect these mechanisms.
1. Membrane receptors and ion channels related to cough The cough reflex is initiated by stimulation of vagal sensory nerves. The mechanism of action of how tussive stimuli activate membrane receptors and channels on such sensory nerves involved in cough has received scant attention probably due to the difficulty of studying * Corresponding author. E-mail address: [email protected] (C. Page). 1094-5539/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2004.09.028
the different afferent nerve types independent of each other. Undem and colleagues have made significant advances in our understanding of membrane receptors and ion channels involved in the initiation of the cough reflex [1]. Depolarization of the terminal membrane (generator potential) initiates action potential discharge and, if the generator potential is of sufficient amplitude, regenerative action potential discharge is evoked. The sensory nerves involved in the cough reflex are capable of inducing generator potentials. There are two main groups of receptors associated with generator potentials in cough: (1) ligandgated ion channels (ionotropic) and (2) G-protein coupled receptors (metabotropic). Activators of ligand-gated ion channels include agonists of TRPV1 and other TRP channels, acid sensing ion channels (ASIC) channels, 5-HT3, P2X and nicotinic receptors. Activation of the transient receptor potential vanilloid 1 (TRPV1) channel which is stimulated by capsaicin, is a well-known mechanism that generates the cough response in humans. TRPM8, activated by menthol, which has been shown to be an effective antitussive agent in healthy human subjects in a cough-evoked model [2], has been also proposed to function as a transducer of cold stimuli in the somatosensory nervous system [3]. An apparent
390
C. Page et al. / Pulmonary Pharmacology & Therapeutics 17 (2004) 389–391
contradictory finding is that TRPV8 colocalizes in TRPV1 expressing neurones. ANKTM1, which is activated by mustard oil and possibly by cannabinoids and TRPV4, an osmoceptor also activated by a phorbol ester derivative may also play a role in the cough response. There have been great advances in our knowledge about TRP channels, but further investigation is needed to establish their exact role in the cough response. When citric acid is applied to a receptive field of guinea pig afferent nerve fibres of low threshold mechanosensitive RARs, they respond immediately. Their pH threshold for activation of RARs is 6.7, but RARs are only activated by rapid changes in pH, and the mechanism by which acid excites RARs is rapidly inactivating. This is consistent to what is known about activation of ASICs and in particular ASIC3, which is expressed by nodose neurones. The cough fibre response to acid resembles the response mediated by ASIC3, in that it rapidly inactivates after activation and it also has low threshold for acid-induced activation. C-fibres also respond to acid, but the selective TRPV1 antagonist iodo-resiniferatoxin does not seem to abolish the response to acid. Thus, these ASIC type channels may prove to be a good drug target. Activation of 5-HT receptors, especially by 5-HT-3 receptor agonists, robustly activates sensory C-fibres but such activation has no effect on cough fibres or RARs. Thus, 5-HT, that only appears to activate nodose derived C-fibres, could prove a useful pharmacological tool to distinguish between nociceptive afferents. ATP has also been shown to activate pulmonary C-fibres in dogs, a response that was inhibited by P2X receptor-selective antagonists. ATP, however, seems only to activate nodose derived C-fibres and has no effect on jugular derived C-fires or rapidly adapting low threshold mechanoreceptors. Afferent nerve terminals can also be depolarized by activation of G-protein coupled receptors (GPCRs). Among the GPCRs that activate afferent nerve terminals much attention has been directed to the bradykinin B2, the histamine H1, the prostanoid, adenosine, opiate and tachykinin receptors. The signalling events leading to GPCR-mediated membrane depolarization is more complicated than that of ligand-gated ion channel receptors. It is thought that GPCR-mediated membrane depolarization occurs through classical second messenger systems such as activation of phospholipase C, which in turn leads to membrane depolarization and ionic events, including the Ca influx mediated by TRPV1. However, the signal transduction between GPCR and eventual generator potential remains elusive. Undem and colleagues speculate that the opening of calcium-activated chloride channels may contribute to GPCR-mediated membrane depolarization of afferent airway nerves. Certain lipoxygenase products (e.g. 12-HPETE and 15-HPETE) activate TRPV1 channels, whilst TRPV1 antagonists inhibit bradykinin-induced responses in airway C-fibres. Bradykinin-induced responses are also inhibited
by lipoxygenase inhibitors suggesting that certain tussive stimuli work indirectly through the release of lipoxygenase products. The ability of bradykinin or prostaglandins to activate/sensitize bronchial C-fibres may be also independent of TRPV1 [4]. Irrespective of the mechanism activation of certain GPCRs may result in sensitization of the cough to other nerve activators.
2. Sensory pathways mediating cough in guinea pigs There has been much debate in the past as to which afferent nerves are responsible for the cough reflex. In recent years, our understanding of afferent sensory nerves has greatly improved and has lead to further subdivisions. Mechanical airway afferent nerves are the rapidly adapting (RARs) or the slowly adapting (SARs) receptors, which have been classified on their adaptation during sustained lung inflations, and their cell bodies are located mainly in the nodose ganglia. Airway nociceptive afferent nerves (C-fibres) are defined by their responsiveness to irritant chemicals like capsaicin, and have their cell bodies in the jugular and nodose ganglia. RARs are believed to be the likely primary sensory nerve subtype that initiate coughing in human and animal studies. Further investigation has lead us to question this, for instance stimuli like histamine and methacholine which are known stimulators of RARs do not initiate coughing. In addition, although RARs are tonically active during the respiratory cycle, cough is only elicited by very selective stimulants. Recent studies from Canning et al. [1] have described a vagal afferent nerve subtype that innervates the guinea pig that appears essential for cough in this animal. This new fibres belong to a subtype of low threshold mechanoreceptors derived exclusively from the nodose ganglia. They are differentiated from RARs due to their conduction velocity and their location in the airways. They are activated in anaesthetized guinea pigs by mechanical probing of the mucosa, distilled water and citric acid, which are all known stimulants of cough. Conversely this new ‘cough receptor’ fibre is not activated by bradykinin, capsaicin, ATP, hypertonic saline or airway smooth muscle constriction or stretch. The alpha-3 expressing isozyme of NaC/KCATPase, expressed solely by the cough receptor, appears to be essential to the normal sensory function of this cough receptor nerve terminal. Capsaicin and bradykinin, known stimulators of airway C-fibres, can evoke cough in conscious animals and humans. However, in anaesthetized guinea pigs capsaicin and bradykinin failed to evoke cough [1].
3. Central pathways of cough Much information has been obtained on the mechanisms underlying the induction of cough at the peripheral level. However, fewer studies have been carried out to investigate
C. Page et al. / Pulmonary Pharmacology & Therapeutics 17 (2004) 389–391
the central control of cough, as they pose a much greater challenge. Shannon and co-workers have been working with an impressive cough model which records neurone activity using microelectrode arrays in neuromuscular-blocked ventilated cats. They have determined that the neuronal networks regulating normal breathing are also involved in generating cough. These neuronal networks are located mostly in the ventrolateral medulla, although other subnetworks in the nucleus tractus solitarii (nTS), midline raphe nuclei, pons and cerebellum have also been found to fire in response to normal breathing and tussive stimuli. Analysis of the interactions among cough responsive neurones has led to a proposed mechanism for how cough is regulated centrally. While the central pathways of the cough reflex are being progressively elucidated, the next step is to determine their pharmacology. At the moment, the precise site of action of many centrally acting antitussive drugs, including, for instance, diphenhydramine, glaucine, and caramiphen is unknown [5]. Bolser presented some novel theories on how cough could be regulated by a ‘gating mechanism’ that controls the whole cough network’s input on the expiratory pathways and how the pharmacology of these ‘gates’ may be important to the phenotype of the cough reflex. One observation of particular interest that contributed to these ideas was that some neurones quiescent during normal breathing were found to be recruited during cough. Other neurones have been found to increase or decrease their firing rate in response to cough. These neurones may form part of this gating mechanism, although it is still equally likely that regular respiratory neurones may perform this function. Further research in this area will hopefully clarify the organization of cough regulation and lead to the identification of potential sites of action for antitussive drugs. While knowledge about the central pathways of cough reflex is increasing, the clinical relevance of this novel acquisition is uncertain. Nishino has studied a patient group with the neurodegenerative disease multiple system atrophy (MSA) who have a pathologically reduced response to
391
protussive stimuli. While, they speculate that the pathological changes occurring in the CNS are affecting the cough reflex, it has not yet been determined at what site the disease interrupts the cough response. Further research with patients having pulmonary diseases associated with cough urgently need to be undertaken.
4. Conclusions This session provided us with much needed knowledge on regulation of the cough reflex, especially the finding of a cough receptor fibre that is responsible for initiating defensive cough. This cough receptor is probably subject to modulation by other afferent nerves, which may well be responsible for the manifestation of a heightened sensitivity of these fibres leading to abnormal cough. Possible drug target may come from targeting receptors on such sensory nerves receptors in the periphery, although the important question remains unanswered, as to whether a peripherally acting is better than a centrally acting antitussive drug for treating cough.
References [1] Canning BJ, Mazzone SB, Meeker SN, Mori N, Reynolds SM, Undem BJ. Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 2004;557: 543–558. [2] Morice AH, Marshall AE, Higgins KS, Grattan TJ. Effect of inhaled menthol on citric acid induced cough in normal subjects. Thorax 1994;49:1024–1026. [3] McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002;416:52–58. [4] Kollarik M, Dinh QT, Fischer A, Undem BJ. Capsaicin-sensitive and -insensitive vagal bronchopulmonary C-fibres in the mouse. J Physiol 2003;551:869–879. [5] Reynolds SM, Mackenzie AJ, Spina D, Page CP. The Pharmacology of Cough. Trends Pharmacol Sci 2004; (In Press).