Lung afferent activity: Implications for respiratory sensation

Respiratory Physiology & Neurobiology 167 (2009) 2–8

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Lung afferent activity: Implications for respiratory sensation John Widdicombe ∗ University of London, 116 Pepys Road, London SW20 8NY, UK

a r t i c l e

i n f o

Article history: Accepted 23 September 2008 Keywords: Lung sensors Vagal reflexes Dyspnoea Cough Urge-to-cough Air hunger

a b s t r a c t Stimuli within the lung can cause the sensations of pain, ache, irritation and urge-to-cough. In general these are abolished or inhibited by vagal section or vagal anaesthesia, or local anaesthesia within the airways. They are present in patients with functional high cervical spinal cord transaction and after general neuromuscular paralysis. There are at least nine sensors in the bronchopulmonary system, studied almost entirely in animals. It is at present impossible to link any one sensor with any one pattern of sensation. It is reasonable to suppose that urge-to-cough arises from sensors what mediate cough, but there are at least five sensors involved in this reflex, and how they relate to unpleasant sensation is unknown. The problem is that sensation can almost only be studied in humans, and the vagal neural mechanisms almost only in other species. Vagal sensors can also ameliorate the sensation of air hunger, and this is probably due to the action of slowly adapting pulmonary stretch receptors (SARs). The same sensors may give rise to the awareness of lung volume and its changes. Many sensors in the lungs can be sensitized or desensitized by natural or imposed conditions, and this could underlie the sensitization and desensitization of dyspnoeic sensations that have been described. © 2008 Published by Elsevier B.V.

1. Introduction The logical approach to considering lung afferent activity in relation to respiratory sensation would be to list the known lung afferent sensors (Table 1) and to describe for each the sensations that follow their stimulation. But the surprise is that for none of the eight or so sensors is there any clear or even plausible evidence to support this approach; we do not know precisely what sensations if any are caused by any of sensors. The alternative approach, adopted here, is to identify respiratory sensations and then to discuss which bronchopulmonary sensors might probably or possibly mediate or contribute to them. Although there are many variant descriptions of respiratory sensation (Mahler et al., 1996; Lougheed et al., 2002; Gracely et al., 2007; Lansing et al., 2009), for the purposes of this paper they can be identified as pain/ache, irritation, tearing, tightness in the chest, urge-to-cough, air-hunger, sense of effort, unsatisfied inspiration, sense of lung volume and airflow (sense of breathing) and temperature sense, a shortlist of 10 sensations. These are the expressions (or their colloquial equivalents) that are usually put by the investigator into the mouth of the patient or subject. Most patients have never heard of the word dyspnoea, although breath-

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lessness is a valuable near equivalent; these two terms are usually thought to include air hunger, sense of effort and possibly tightness. Some of these sensations unmistakably come from the lungs and lower respiratory tract. These include pain or irritation on touching the respiratory tract; the pain or ache due to bronchopulmonary tumours; the pain or sensation of tearing when opening collapsed lung; the urge-to-cough and sense of irritation when an irritant gas is inhaled; and the sense of tightness during an attack of asthma or during a bronchial provocation test. With other sensations a bronchopulmonary origin is less obvious; these include awareness of thoracic volume and airflow, air hunger and sense of effort. Here the sensations could come from or be modified by information from the chest wall, diaphragm and abdominal wall. Some sensations, such as pleuritic pain or rubbing, have been claimed to be entirely extrapulmonary, but the conclusion may need to be reconsidered. Sensations from the larynx, although they are vagally mediated and may undoubtedly interact with those from the lower airways, are outside the scope of this paper. But if a respiratory sensation is thought to come from the lungs and airways, how is its afferent pathway to be established? If it is abolished or ameliorated by vagal section or vagal or bronchopulmonary local anaesthesia, the conclusion is convincing. But these procedures, when performed experimentally, are rare or absent nowadays (they were largely restricted to the 1970s and 1980s) given the rightful power of ethical committees. Electrical stimu-

J. Widdicombe / Respiratory Physiology & Neurobiology 167 (2009) 2–8 Table 1 Bronchopulmonary sensors that may mediate dyspnoeic and other sensations. Sensor

Pathway response

Respiratory reflex

Sensory response

SARs RARs A␦-nociceptors Cough receptors Pulmonary C-fibre Bronchial C-fibre NEBs Pleural

Vagi Vagi Vagi Vagi Vagi Vagi Vagi, symps Vagi, symps

Insp. inhibition Gasps, cough? Cough Cough Inhibit cough? Cough Unknown Unknown

Inhibit AH Unknown Unpleasant? UtC? Unpleasant?.UtC? Unpleasant? Unpleasant? UtC? Unknown Unpleasant?

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mechanisms in animals but cannot determine their related sensations. A final complication is that bronchopulmonary sensory pathways, both in the periphery and in the CNS, can be shown to exhibit plasticity, in particular sensitization (see below). The experiments in healthy humans and animals may not apply to those with respiratory diseases that may cause dyspnoea. This has been studied especially with cough-inducing sensors. A comparison with somatic sensation is obvious, as are the implications for respiratory sensation.

AH, air hunger; UtC, urge-to-cough; symps, sympathetic nerves; SARs, slowly adapting pulmonary stretch receptors; RARs, Rapidly adapting receptors. Unpleasant includes pain/ache, irritation, burning.

2. Pain, ache, irritation

lation of the vagus nerves is a recognised treatment for epilepsy (Banzett et al., 1999; Binks et al., 2001); it can cause pain and other unpleasant sensations localized to the chest, but respiratory and cardiovascular responses are weak or absent, so no information is provided to link the sensation with a particular afferent vagal pathway. In particular, although there is usually unpleasant sensation in the larynx, there is no cough. As part of treatment the pulmonary nerves are cut in lung transplant operations, which provide useful models for research on lung innervation. In the past some patients have had vagotomies or lung denervations as part of treatment, for example for pulmonary tumours, but these operations seem rare or absent nowadays. These procedures are easily carried out on nonhuman experimental mammals (hereafter called animals), but sensation can only be studied in these animals very imprecisely, perhaps by conditioned reflexes or general bodily responses, and this has seldom been done; studies on conditioned respiratory responses and ‘fear’ in rats shows promise (Nsegbe et al., 1997, 1999), but have yet to be developed to apply to dyspnoea. In patients who survive a functional high cervical spinal cord transsection, it is almost reasonable to assume that any remaining respiratory sensation comes from the lungs and airways and is conducted via the vagus nerves, but such patients are uncommon and are not often suitable for study; and at least in theory the sensation could have its origin in the CNS or structures such as the carotid body chemoreceptors. And then, if the sensation can be established as arising from the lungs and airways, what is/are its pathway/s? The afferent supply from the lungs is predominantly vagal in all species studied, but a sympathetic/spinal component has also been identified. Its role in respiratory sensation does not seem to have been analysed (see later). The vagal afferent innervation of the lungs and airways has been exhaustively explored for over 100 years, and many different peripheral sensors and afferent types of nerve have been identified (Table 1). Some are dealt with in detail in this Special Issue (Lee, 2009; Undem, 2009; Fisher, 2009; Kappagoda and Ravi, 2009). For example, touching the airway mucosa may activate at least six different types of nervous sensor, but we are not sure which types cause the sensation of pain or irritation; there are at least five types of airway sensor that are thought to be involved in cough, but no evidence as to which causes the sensation urge-to-cough. Table 1 lists the types of bronchopulmonary sensors identified histologically and by recording afferent action potentials in pulmonary nerves. The list may be incomplete. It is no exaggeration to say that the sensations caused by stimulation of individual sensor types have not been established for any of the sensors, although there may be a few pointers. Several afferent pathways may interact to cause various respiratory sensations. The problem is obvious: we can study respiratory sensations in humans but cannot do the experiments to analyse the sensors responsible for them; and we can analyse the neural

Over 50 years ago, Klassen et al. (1951) and Morton et al. (1951) showed that touching the tracheobronchial mucosa of unanaesthetized humans caused a painful burning sensation that was prevented by cutting the ipsilateral vagus nerve. The side of stimulation could be identified by the subject. Similarly the sensation of rawness due to tracheitis and the pain due to passing a tracheobronchial tube are abolished by local airway anaesthesia. Inflation of collapsed lung causes pain or a sensation of tearing (Burger and Macklem, 1968; Rodarte et al., 1997). A similar sensation of pain, often accompanied by shortness of breath and cough, is seen after prolonged exposure of healthy subjects to ozone (McDonnell et al., 1999). Inhalation of irritant aerosols, such as citric acid, ammonia, capsaicin and cigarette smoke, induces rawness and irritation in the lungs as well as the larynx (Milgren et al., 1992; Dicpinigaitis and Alva, 2005; Lee et al., 2007). Similar sensations can be obtained in patients with high cervical functional transaction of the spinal cord, but they are absent in patients after lung transplant. They are frequently accompanied by cough. The sensations must be derived from airway receptors, and the main question is which sensors are involved. Cough is now thought to be derived from at least four or five different types of airway sensor (Table 1), and there is considerable debate as to which are activated by various tussive stimuli, and how the cough responses to the different stimuli may vary (Mazzone, 2004; Kollarik et al., 2007; Canning et al., 2006; Kollarik and Undem, 2006). The main experimental problem seems to be that there are no or few ‘specific’ stimuli to the different types of sensor. Possible exceptions are that both PGF2␣ and bradykinin aerosols cause coughing and rawness in man, and in animals stimulate A␦and C-fibre sensors respectively (Coleridge and Coleridge, 1984). Pneumothorax is a powerful stimulus to dyspnoea in humans and stimulates RARs but not C-fibre sensors in animals. Pulmonary congestion is a powerful stimulant of pulmonary C-fibre sensors, but not a strong cause of dyspnoea in humans, except with the added stimulus of exercise. Phosgene causes pulmonary oedema before any unpleasant respiratory sensation (Henderson and Haggard, 1943), and is a strong activator of C-fibre sensors in animals (Coleridge and Coleridge, 1984). Small intravenous doses of capsaicin, widely used as an experimental cough stimulant, cause a raw sensation in the chest of humans, but no respiratory changes (Winning et al., 1988). By contrast, intravenous lobeline causes unpleasant sensations in the larynx but not in the lungs and, if the dose is increased, cough (Jain et al., 1972); the sensors for these responses are in the lungs (see also later). These are a few of many examples that show how difficult or impossible it is to correlate any particular dyspnoeic sensation with a particular bronchopulmonary sensor. The laryngeal sensation from intravenous injections of lobeline is presumably an example of referred pain. Another welldocumented example is the ipsilateral referral of pain to the cheek what sometimes accompanies lung diseases (Abraham et al., 2003).

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Whether non-referred pain and discomfort give rise to a unilateral sensation does not seem to have been determined, except in the early positive results of Klassen et al. (1951) and Morton et al. (1951). In summary, many but not all of the unpleasant sensations from the lungs (pain, ache and irritation) are associated with cough. As there are several sensors thought to be responsible for different types of cough, so there may be for unpleasant sensations. The degree of overlap is unknown. 3. Tightness The sensation of tightness in the chest is distinctive of asthma and induced bronchoconstriction. It can be caused by bronchoconstriction due to aerosols of histamine or methacholine (Moy et al., 1998; Binks et al., 2002; Laveneziana et al., 2006). It does not occur with laboured breathing due to hyperpnoea, increased respiratory loads or exercise. It is reported as ‘within the chest or lungs’ (Gandevia, 2007; Banzett, 2007). In asthma it is often the earliest symptom, ahead of wheezing (Simon et al., 1990; Moy et al., 2000). In one remarkable and early study on an asthmatic, bilateral vagal blockade with local anaesthesia abolished the symptom (Guz et al., 1970; Petit, 1970): ‘you’ve cured my asthma’, the patient pronounced (Widdicombe, 2005). Patients with functional high cervical cord transection can experience tightness, but not sense of effort, and the sensation of tightness can be induced by methacholine challenge. It is therefore difficult to conceive of any other neural source other than bronchopulmonary sensors and afferents, presumably vagal. However the identification of the sensors is more difficult. They are unlikely to be slowly adapting pulmonary stretch receptors (SARs), which cause bronchodilation and probably inhibit air hunger. As already described, other sensors that cause pain, irritation and cough must be different from those that produce tightness, because the qualities of the sensations are fundamentally different. One is searching for a sensor that responds primarily to airway smooth muscle contraction or the mediators, such as tachykinins, that cause or may be released during this process. Rapidly adapting receptors (RARs) are activated by airway smooth muscle contraction (Sant’Ambrogio and Widdicombe, 2001), and could be a candidate. Lee and colleagues have argued that bronchopulmonary C-fibre receptors may cause the sensation of tightness (Burki et al., 2006, 2008; Lee, 2009). They showed that intravenous injections of adenosine in humans usually caused tightness, abolished by local anaesthesia to the airways. This agent stimulates lung C-fibre sensors in rats (Ho et al., 2001). However there was no cough, and ventilation was increased, a response not typical of C-fibre stimulation in animals. Intuitively one feels that tightness has such a specific character that only one sensor type should be involved, and that it is still waiting to be established. An authoritative discussion of the problem is given by Lee (2009). 4. Urge-to-cough Recently the sensation ‘urge-to-cough’ has been studied, especially by Davenport and colleagues (Davenport et al., 2007; Vovk et al., 2007; Davenport, 2009). They showed that when subjects inhaled an aerosol of capcaicin, a well-established cough stimulant, they experienced an urge-to-cough before the cough itself. By the use of different capsaicin concentrations they showed that the urge-to-cough threshold was lower than the threshold for cough. Both the strength of the urge-to-cough sensation and the number and strength of coughs depended on the capsaicin concentration, and the urge-to-cough and number of coughs showed a linear

log/log relationship. Interestingly when the subjects concentrated on the sensation of cough, the threshold for urge-to-cough was lowered while that for cough was increased. Other evidence shows that mental concentration or distraction can increase cough threshold (Johnson et al., 2004; Smith et al., 2005). Similar results to those with capsaicin have been obtained with distilled water aerosols (fog), but with the interesting addition that with the urge-to cough occurring below cough threshold there is a small but clear stimulation of breathing (Lavorini et al., 2007). Whether this was a direct reflex response from the airways or a reaction to the sensation is not clear. When cough is induced in conscious humans by intravenous injections of lobeline, the cough is preceded by a sensation of irritation in the larynx and upper trachea, and smaller doses of lobeline cause the sensation but not cough (Dehghani et al., 2004). The sensation of irritation and the cough are both absent in patients who have had bilateral lung transplants, establishing their bronchopulmonary origin (Butler et al., 2001). The two studies did not ask the subjects about urgeto-cough, but the similarity with urge-to-cough in response to capsaicin is obvious. Are the two sensations the same or different? Do lobeline and capsaicin stimulate the same or different airway sensors? The probable central nervous mechanisms of urge-to-cough have been analysed in detail (Davenport, 2009), including fMRI scans in human brain (Mazzone et al., 2007). Children with congenital central hypoventilation syndrome (CCHS), who retain voluntary control of breathing but have lost chemical control, have a normal cough response to fog but no urge-to-cough (Lavorini et al., 2007), showing that the two phenomena can be isolated by a central nervous disorder. Patients with CCHS lack the sensation of air hunger with breath-holding and rebreathing (Shea et al., 1993). One cannot identify the vagal sensors that mediate urge-tocough, since too many sensors have been incriminated in the cough mechanism (Table 1) and various combinations of these sensors may interact in responding to different cough stimuli. Only capsaicin and fog have so far been used to quantitate urge-to-cough, although the effects of lobeline are qualitatively similar; it would be informative to see if similar responses were obtained with other stimuli. The latency of the expiration reflex pattern of cough, 15–30 ms from mucosa to expiratory muscles for the larynx of humans (Addington et al., 2003) and animals (Tomori and Stransky, 1973), is so fast that myelinated afferents would not have time to cause a preliminary urge-to-cough, but this does not rule out a role for them in slower and subsequent coughs.

5. Air hunger, sense of effort These sensations have been extensively studied and include the ‘need-to-breathe’ that occurs with breath-hold and eventually reaches a ‘breaking-point’, and the respiratory sensations during severe exercise or asphyxia. Air hunger and sense of effort have been identified as separate sensations with differences in their mechanisms (Lansing et al., 2009), but they can be considered together in relation to their possible vagal inputs. Most evidence points to sensory inputs from both the lungs and the respiratory muscles and joints (Gandevia, 2007). The hypothesis of Campbell and Howell (1963), that the sensation was due to ‘length/tension inappropriateness’ (a disparity between achieved and ‘commanded’ ventilation) in the respiratory muscles, has now largely been replaced by the view that sensory inputs from both the lungs and the respiratory muscle interact to create the sensation, perhaps modified by activity in collateral pathways in the brainstem (the ‘respiratory centre’) (Banzett, 2007; O’Donnell, 2007).

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Early studies showed that paralysis of the subject prevented the air hunger, suggesting that the vagal afferents played little role in the sensation (Campbell et al., 1969). However later work gave the opposite result, indicating that input from respiratory muscles and joints was not needed for the sensation of air hunger on breathholding and hypercapnia, and thus implicating other mechanisms (Banzett et al., 1990; Gandevia et al., 1993). The facts that breathholding time is considerably prolonged by bilateral vagal blockade, that the air hunger response to asphxyial gas mixtures is similarly reduced (Guz et al., 1970) and that airway local anaesthesia increases the breath-holding time (Winning et al., 1988) support the view that vagal afferent nerves can decrease the sensation of air hunger. This concept agrees with the fact that, at the breaking point of air hunger, the sensation can be relieved by increased ventilation with gas mixtures that do not improve the blood gas levels in normal humans (Hill and Flack, 1908) and in high cervical paraplegics (Manning et al., 1992; Block-Salisbury et al., 1998). It thus seems likely that the sense of air hunger is due mainly to chemoreceptor inputs and to brainstem circuits acting on the cerebral cortex, which can be inhibited by vagal afferents. The role of vagal afferents is uncertain and must be complex (Table 1). Lung inflation presumably stimulates receptors that can diminish the sense of air hunger, yet vagal blockade prolongs breath-holding time. Likely candidates for the first process are the SARs, since they inhibit medullary inspiratory activity and therefore in turn inspiratory drive and the sensation that goes with it. Consistent with this view is the observation that furosemide, which is known to stimulate SARs, inhibits the air hunger induced by hypercapnia in healthy humans with constrained ventilation (Moosavi et al., 2007). An interesting study by Nishino et al. (2008) showed that when air hunger was induced by breath-holding it was relieved by breathing, as expected, but increased by voluntary and citric acid-induced coughing; this suggested an interaction between dyspnoea-reducing and dyspnoea-enhancing mechanisms from the lungs. It is more difficult to identify the bronchopulmonary receptors that, when eliminated by vagal blockade, decrease air hunger; several of the types of sensor, e.g. RARs, cough and Cfibre sensors, are thought to be able to cause unpleasant respiratory sensation, and therefore might be incriminated. A convincing distinction between air hunger and the work of breathing has been made (Banzett, 2007). But in terms of the role and involvement of vagal pathways there does not seem convincing evidence of a difference, and the matter will not be pursued here.

6. Sense of breathing, temperature We are aware of the state of volume of our lungs over the vital capacity range, and of any rate of change of volume. Inflation of a single lobe of the lung can be identified laterally (Banzett et al., 1997). These sensations are still present after functional high cervical spinal cord transaction (Gandevia, 2007), and in that situation are presumably pulmonary and vagally mediated. However the same sensations are also present after bilateral vagal block by local anaesthesia (Guz et al., 1970). It therefore appears that the sensation of lung volume and its change can be derived from two sources. For that in the lungs, the SARs seem the most likely candidate. RARs by definition adapt rapidly and could not signal maintained volume changes. C-fibre sensors are not very volume sensitive (Coleridge and Coleridge, 1984) and, when activated for example by tissue damage or by mediators, do not give rise to a sense of volume change. There seem to be no studies of temperature sensors in the lungs, and no studies of the temperature coefficients of the known bronchopulmonary sensors. Inspired air is thought to attain body

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temperature by the time it reaches the smaller bronchi, but during the hyperpnoea of exercise the trachea and bronchi show considerably reduced temperatures (Gilbert et al., 1987). The laryngeal mucosa contains ‘cold sensors’ (see Widdicombe et al., 1988) although their respiratory reflex actions and inputs to affect sensation are not known. They also respond to airflow (which changes luminal temperature) but there is no indication that this variable reaches consciousness. It would be interesting to see if intubated patients had temperature sensation from their lower airways.

7. Vagal versus sympathetic pathways In animals, almost all reflexes from the lungs and lower airways are abolished by bilateral cervical vagotomy. This does not rule out a role for sympathetic afferents, but suggests that it is small, may be only modulatory, or may become important only if sensitized. There have been a number of studies that show that in bilaterally vagotomized animals weak respiratory reflex responses can be obtained by lung deflation, pulmonary microembolism, airway irritation and agents such as bradykinin, and that these responses are abolished by additional bilateral sympathectomy (Widdicombe, 1964; Kostreva et al., 1978; Saria et al., 1985; Soukhova et al., 2003). There have also been recordings from bronchopulmonary afferent sympathetic nerves (Cromer et al., 1933; Kostreva et al., 1975) that could mediate these reflexes. An important recent study in the guinea pig has explored sympathetic afferent pathways from the lungs and shown that they consist mainly of nonmyelinated fibres (Oh et al., 2006). They contain substance P and are activated by intrapulmonary capsaicin. Their main reflex action was airway dilatation, but respiratory responses were not measured. Much recent extensive research has concentrated on afferent nerves from airway neuroepithelial bodies (NEBs) (e.g. Brouns et al., 2003, 2006; Adriaensen et al., 2003, 2007; Yu et al., 2004). These have a complex histological structure with some afferent nerve terminals within the NEBs and close to the airway lumen, and others branching into the airway submucosa. Some afferent nerves pass up the vagi and others, unusual in that they contain much calcitonin gene-related peptide (CGRP), travel via the sympathetic nerves. No afferent nerve recordings have been established from the NEBs, although they may contribute to some of the recorded afferent activities the source of which has not been identified. These NEB sensors are thought to respond to airway hypoxia, although no reflex response to such a stimulus in the lungs has been established. Indeed pulmonary hypoxia may cause local vascular changes in the lungs, but seems to have no respiratory reflex actions; in humans a breath of a hypoxic gas mixture causes no sensation. Potentially NEBs could contribute to respiratory sensation, but there is no current evidence that they do so. A further group of sensors has been identified in the visceral pleura of animals, especially near the hilum and in interlobar pleura (e.g. Larsell, 1922; McLaughlin, 1933), and have recently been carefully studied histologically in rat and rabbit (Wedekind, 1997; Pintelon et al., 2007). The sensors give rise to myelinated afferent fibres, although their terminals may be nonmyelinated, and the fibres travel in sympathetic pathways. Their ultrastructure strongly suggests that they are sensory rather than motor. Although many textbooks say that the visceral pleura cannot give rise to sensation, based on reports from intrathoracic investigations and open-chest surgery, visceral pleural pathology can cause pain and dyspnoea, as can microembolism, where the pain is often described as ‘pleuritic’ (e.g. Mukherjee et al., 2000). There are also recent studies of afferents from the parietal pleura which, while not relevant to this paper, are relevant to the broader question of respiratory sensation (Jammes et al., 2005; Jammes and Delpierre, 2006).

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These sympathetic afferents from NEBs and pleural receptors could contribute to the nonvagal reflexes and the sympathetic nerve activity mentioned above. However there is no convincing reason to believe that they contribute to respiratory sensation, although any attempts to determine such a role do not seem to have been described which, as discussed above, is not very surprising.

8. Sensitization and desensitization There has been extensive recent research on the sensitization of bronchopulmonary sensors in relation to cough, and to cough itself (see Undem et al., 2002; Carr, 2004, 2007; Carr and Lee, 2006). This is one example of the ‘plasticity’ of the sensors—their ability to change their sensitivity in response to different environments. Changes related to sensitization of cough can be shown to apply to C-fibre sensors, A␦-nociceptors and RARs, and are reflected in intraneuronal inclusions such as neuropeptides, in membrane receptors and in transducers (Carr, 2007). These sensitizations can be produced by many stimuli that damage the airway epithelium, including agents such as acid aerosols, induced inflammation and immunomodulation (Riccio et al., 1996) and viral infections (Jacoby, 2004). The sensitization is non-specific, in the sense that it applies to many tussigenic stimuli, such as touch, acid, capsaicin, and inflammatory mediators and agents like histamine, bradykinin and prostaglandins. However some sensitizations have been related to particular sensory pathways. Two of many examples are the action of PGE2 on lung C-fibre sensors (Ho et al., 2001; Kwong and Lee, 2002), and of second-hand cigarette smoke on RARs and C-fibre sensors (Lee et al., 2007; Joad et al., 2007). With hyper-reactive airways it is common experience that large lung inflations and deflations in humans cause cough. The same stimuli activate RARS in animals (Widdicombe, 1954a,b). Here is not the place to detail the large literature on the subject of lung sensor sentsitization (see Undem et al., 2002; Carr, 2004, 2007; Carr and Lee, 2006), but to point out its relationship to sensitization of the dyspnoeic responses. Clearly if the threshold to a tussive stimulus such as capsaicin or citric acid is lowered, then so also will be the threshold of the urge-to-cough sensation. It seems certain that this will also apply to the sensation of pain and irritation, although this does not seem to have been often independently measured. To give two clear examples, after experimental chronic exposure to ozone, not only is the threshold to tussigenic stimuli reduced, but also the subjects complain of greater lung discomfort during the test and also of lung discomfort in the absence of the tussigenic test stimulus (Adams, 2003). Similarly, exposure to atmospheric pollution not only causes and sensitizes coughing but also causes irritation and shortness of breath even in the absence of coughing (Joad et al., 2007). Sensitization of the cough reflex also occurs at brainstem level in guinea pigs (Bonham et al., 2004, 2006; Joad et al., 2007), especially at the level of the nucleus of the tractus solitarius (NTS). The process involves enhancement of the action there of substance P acting on NK-1 receptors. Similarly ozone and allergen lead to enhanced activity of second-order neurones in the NTS (Joad et al., 2007). These are important studies in relation to the sensitization of the cough reflex. Their relevance to sensitization of dyspnoea depends on whether the neural pathways leading to dyspnoea travel through or bypass the second-order NTS neurones; conceptually the former seems more likely in which case a search for brainstem sensitization of dyspnoea would be valuable. Obviously this is difficult or impossible to study in humans. The cough reflex can be desensitized (from a normal baseline) in a number of ways (Widdicombe and Singh, 2006). Of relevance here are the inhibiting actions of cardiac and visceral afferent inputs on

cough (Hanacek et al., 2006); whether such inputs affect dyspnoeic sensation does not seem to have been established. Nasal stimuli can augment cough (Hanacek et al., 2006), and the same may be true for oral stimuli (Simon et al., 1991). Their interactions must be central. In summary, since many unpleasant and dyspnoeic lung sensations seem to be mediated by vagal afferents from the bronchi and lungs which also cause cough, it is not surprising that when the cough reflex is sensitized or desensitized so will be the respiratory sensations. However quantitative comparisons between the two reactions have seldom been made and we know little about the particular sensory pathways involved in the different conditions. 9. Conclusions There is convincing evidence that unpleasant sensations (including ‘dyspnoea’) can be derived from the lower airways and lungs, predominantly by vagal pathways. These sensations include pain/ache, irritation, tightness in the chest and urge-to-cough. The problem is to relate each sensory effect to the bronchopulmonary sensor(s) that give(s) rise to it. At least four or five sensors are involved in the production of reflex cough, and it seems likely that these sensor types are the basis of the different modalities of unpleasant respiratory sensation associated with irritant and damaging stimuli in the lungs. At present a more definitive role for each receptor type is difficult to establish. Sensors in the same bronchopulmonary regions can also decrease the sensation of air hunger and subserve awareness of lung volume and its changes. It seems likely that SARs mediate these non-dyspnoeic responses, but the argument is largely by elimination. Sensitization and desensitization may affect both reflexes such as cough and the sensations that go with them. References Abraham, P.J., Capobianco, D.J., Cheshire, W.P., 2003. Facial pain as the presenting symptom of lung carcinoma with normal chest radiograph. Headache 43, 499–504. Adams, W.C., 2003. Relation of pulmonary responses induced by 6.6-h exposures to 0. 08 ppm ozone and 2-h exposures to 0.30 ppm ozone via chamber and facemask inhalation. Inhal. Toxicol. 15, 1176–1182. Addington, W.R., Stephens, R.E., Widdicombe, J.G., Ockey, R.R., Anderson, J.W., Miller, S.P., 2003. Electrophysiological latency to the external obliques of the laryngeal cough expiration reflex in humans. Am. J. Phys. Med. Rehabil. 82, 370–373. Adriaensen, D., Broons, I., Van Genechten, J., Timmermans, J.P., 2003. Functional morphology of pulmonary neuroepithelial bodies: extremely complex airway receptors. Anat. Rec. 270A, 25–40. Adriaensen, D., Brouns, I., Pintelon, I., De Proost, I., Timmermans, J.P., 2007. Evidence for a role of neuroepithelial bodies as complex airway sensors: comparison with smooth muscle-associated airway receptors. J. Appl. Physiol. 102, 960–970. Banzett, R., 2007. The peripheral mechanisms of dyspnea. In: O’Donnell, D.E., Banzett, R.B., Carrieri-Kohlman, V., Casaburi, R., Davenport, P.W., Gandevia, S.C., Gelb, A.F., Mahler, A., Webb, K.A. (Eds.), Pathophysiology of Dyspnea in Chronic Obstructive Pulmonary Disease, 4. Proc. Am. Thorac. Soc., pp. 1456–2168. Banzett, R.B., Lansing, R.W., Brown, R., Topulos, G.P., Yager, D., Steele, S.M., Londono, B., Loring, S.H., Reid, M.B., Adams, L., et al., 1990. ‘Air-hunger’ from increased PCO2 persists after complete neuromuscular block in humans. Respir. Physiol. 81, 1–17. Banzett, R.B., Shea, S.A., Brown, R., Schwartzstein, R.M., Lansing, R., Guz, A., 1997. Perception of inflation of a single lung lobe in humans. Respir. Physiol. 107, 125–136. Banzett, R.B., Guz, A., Paydarfar, D., Shea, S.A., Schachter, S.C., Lansing, R.W., 1999. Cardiorespiratory variables and sensation during stimulation of the left vagus in patients with epilepsy. Epilepsy Res. 35, 1–11. Binks, A.P., Paydarfar, D., Schachter, S.C., Guz, A., Banzett, R.B., 2001. High strength stimulation of the vagus nerve in awake humans: a lack of cardiorespiratory effects. Respir. Physiol. 127, 125–133. Binks, A.P., Moosavi, S.H., Banzett, R.B., Schwartzstein, M., 2002. “Tightness” sensation of asthma does not arise from the work of breathing. Am. J. Respir. Crit. Care Med. 165, 78–82. Block-Salisbury, E., Sprengler, C.M., Brown, R., Banzett, R.B., 1998. Self-control and external control of mechanical ventilation give equal air hunger relief. Am. J. Respir. Crit. Care Med. 157, 415–420.

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