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The stimuli for coughing in normal individuals include airway mucus and the small
quantities of material inhaled in the normal course of eating, drinking and breathing.
Abnormal stimulation of coughing is caused by excessive airway mucus and other
secretions, excessive quantities of foreign material, noxious irritants such as smoke,
airway inflammation and airway compression.
Compression and collapse of the airways is a common cause of coughing in dogs and
is important in tracheal collapse, pulmonary neoplasia and left-sided cardiac failure
with left atrial enlargement. In such situations a combination of airway collapse and
airway inflammation may also exist.
HE COUGH MECHANISM AND THE FUNCTION OF THE COUGH
REFLEX
Coughing is an airway reflex mediated by airway receptors that react to
either pressure or chemical stimuli. In several cardiopulmonary diseases,
such as left atrial enlargement, tracheal collapse and primary neoplasms,
coughing is primarily associated with mechanical compression of the
airway. In other conditions a combination of inflammatory mediators
stimulating irritant receptors, and airway exudates stimulating
mechanoreceptors, results in coughing.
Large numbers of cough receptors are located in the larynx, at the thoracic
inlet and tracheal bifurcation. The numbers of receptors decrease further
down the respiratory tract and there are no receptors present in the
peripheral airways or alveoli.
The cough reflex therefore functions mainly in the larger airways, although
material from the lower airways and alveoli can move to the level of the
larger airways where coughing will help to remove it.
The function of coughing is to assist the removal of material from the
airways. This material may have been inhaled or produced in the airways.
Coughing also prevents additional inhalation of material, or movement of
inhaled material into the peripheral airways.
With respiratory diseases, airway defence mechanisms result in increased
production of mucus from goblet cells and mucous glands in the airway.
Respiratory diseases will also result in inflammatory exudates entering the
respiratory tract. This material can accumulate in the lower airways and
alveoli.
Alveolar and lower airway material is usually removed through
phagocytosis by alveolar macrophages, but because of the presence of the
surface tension reducing agent surfactant in the alveoli, this material can
also move cranially by a capillary action.
Once material comes in contact with ciliated epithelium, it is transported by
ciliary beating towards the trachea where there is the highest density of
cough receptors.
Coughing then propels the material into the oropharynx where it is
swallowed.
Considering these factors it can be appreciated that coughing is an extremely
important protective mechanism for the respiratory system.
However, coughing caused by mechanical compression of the airways has
no protective function, may cause airway epithelial damage and should be
controlled, particularly if it is causing exhaustion.
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Causes of Cough
The possible causes of cough are numerous. Infection is the leading cause in both
smokers and nonsmokers. Bronchitis, sinusitis, and the common cold are often
characterized by productive or nonproductive coughing.
The second most common cause of cough is tobacco smoke, a known irritant to the
respiratory mucosa. Among cigarette smokers, cough may vary from a nagging
side effect with periodic nocturnal episodes to a chronic bronchitis ( ie, chronic
productive cough for at least 3 months a year for at least 2 consecutive years ) with
significant disruption of daily activities.
In nonsmokers,allergic rhinitis and sinusitis with postnasal drip are the next most
common causes of cough.Asthma is another common cause,and its diagnosis can
require subtle distinctions.Patients may present with a nonproductive (often
nocturnal ) cough, sleep disturbance, chest tightness or wheezing, and
dyspnea.Asthma may be exacerbated by gastroesophageal reflux.
Cough may be caused by irritation from occupational, environmental, or physical
agents.Pulmonary conditions ( eg, chronic obstructive pulmonary disease )or
cardiac conditions ( eg, congestive heart failure ) may cause coughing.Several
intrathoracic conditions that cause structural changes, including tumors and
adenopathy, may produce cough either by exerting extrinsic pressure on the
trachea, bronchi, or lung parenchyma or by interfering with function of a recurrent
laryngeal nerve.
Certain medications can cause acute cough as a side effect.The angiotensin
converting enzyme ( ACE ) inhibitors cause a dry, hacking cough in more than
15% of patients taking these medications, possibly by stimulating C fibers in the
airways and activating the cough reflex arc.After discontinuation of the causative
drug, the cough usually resolves within 1 to 14 days.Beta blockers can cause cough
as a result of drug induced bronchospasm.Inhaled medications, such as beta
agonists, cromolyn sodium (Intal ) , corticosteroids, and anesthetics,have also been
found to sometimes cause a dry, hacking cough, apparently by local irritation.
Granulomatous diseases(eg, Sarcoidosis, Wegener’s granulomatosis),congenital
syndromes (eg,Cystic fibrosis, Immotile cilia syndrome),and many other
conditions can also cause cough. In rare patients, irritation of the auditory canal by
a hair or impacted cerumen may stimulate the ninth cranial nerve ( which inervates
the tympanic membrane) and lead to a debilitating cough. Psychogenic cough may
occur with or without an organic basis. Psychogenic cough typically increases
during stress or with parental or medical attention and subsides with sleep.
Mechanism of Cough
The cough reflex arc is complex . Controlled by its nerve center in the medulla, the
reflex arc is served by afferent fibers of the vagus, trigeminal, glossopharyngeal,
and phrenic nerves.Stimuli to tissue innervated by these nerves may precipitate the
cough response.
Cough receptors are located in the bronchi, diaphragm, external auditory canal,
larynx, nose, paranasal sinuses , pericardium, pharynx, pleura, stomach, trachea
and tympanic membrane. The efferent pathway of this arc stems from the
medullary center through the vagus, phrenic, and spinal motor nerves, which
innervate the intrinsic and accessory muscles of respiration.
The act of coughing involves synchronous participation of a number of muscles
during the inspiratory and expiratory phases. During inspiration, the glottis opens,
bronchioles enlarge, and lungs expand with the help of the diaphragm and the
thoracic and abdominal muscles. Thus, the lungs are stretched and ready for recoil.
The glottis closes at the height of inspiration, and the chest contracts with
inspiration, thereby increasing the intrathoracic pressure to well over 100 mm Hg.
Consequently, when the glottis gives way and opens, the rate of air flow is as high
as 600 L/min,or up to 500 miles/hr. Even though the common cold and most
infectious causes of tracheobronchiti are short-lived , cough may linger for 1 to 3
weeks because of simple epithelial damage or overt bronchial hyperactivity .
Frequent, paroxysmal coughing is particularly distressing to patients and others in
their environment and disrupts work and sleep.
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Abstract
The cough reflex represents a primary defensive mechanism for airway protection in a
variety of mammalian species. However, excessive and inappropriate coughing can
emerge as a primary presenting symptom of many airway diseases. Cough disorders are
characterized by a reduction in the threshold for reflex initiation and, as a consequence,
the occurrence of cough in response to stimuli that are normally innocuous in nature.
The current therapeutic strategies for the treatment of cough disorders are only
moderately effective. This undoubtedly relates in part to limitations in our understanding
of the neural components comprising the cough reflex pathway. The aim of this review is
to provide an overview of current concepts relating to the sensory innervation to the
mammalian airways, focusing particularly on the sensory receptors that regulate cough.
In addition, the review will highlight particular areas and issues relating to cough
neurobiology that are creating controversy in the field.
Introduction
The basic nature of the respiratory system (i.e., inspiration of air from the surrounding
environment for gas exchange), as well as the shared nature of the initial anatomical
structures for the passage of food and air, places the airways and lungs under the
constant threat of exposure to a variety of harmful airborne particles, organisms and
other substances as well as aspirated gastric contents or accidental inhalation of
foodstuffs. It is therefore not surprising that a variety of defensive mechanisms have
evolved along with the normal function of the respiratory system to help protect against
such threats. Airway protection relies upon specialized epithelial barriers and immune
responses as well as a variety of highly co-ordinated neural reflex responses that help to
limit the degree of potential harm and ultimately remove or expel the harmful substance
from the airways.
Perhaps the most widely recognized neural response involved in airway protection is
coughing. Coughing is generally characterized by a reflex-evoked modification of
breathing pattern in response to airway irritation [1]. Reflex cough occurs when subsets
of airway afferent (sensory) nerves are activated by inhaled, aspirated or locally
produced substances. These afferent nerves provide modifying inputs to the brainstem
neural elements controlling respiration, and consequently help generate the cough
respiratory pattern [1-3]. Although widely studied for many years, there has been much
debate surrounding the identity of the airway afferent nerve subtype that precipitates
reflex coughing (see below). In addition, cough can also be initiated voluntarily. Little is
known about the cortical pathways responsible for voluntary coughing, although they
likely share similarities with those pathways responsible for voluntary breath holding and
other conscious modifications of respiration. This review will focus on the current
understanding of the anatomical and physiological arrangement of the sensory
components responsible for reflex coughing. In addition the review will highlight how
modifications of the sensory pathways from the airways could lead to inappropriate
coughing in disease.
Classification of afferent nerve fiber types innervating the airways
and lungs
Before describing which afferent nerve fibers are involved in reflex coughing, it seems
appropriate to first provide a brief overview of the various afferent nerve subtypes that
have been described in the mammalian airways. For the purposes of this review, much
of the classification of airway afferents will relate to information gained from studies
employing guinea pigs, the most widely utilized species with respect to airway
innervation and cough. Whether studies in guinea pigs (or indeed any other
experimental animal) can be directly translated to humans is a subject for additional
debate. The discussion will also be restricted to only those afferent fibers that innervate
the airways caudal to (and including) the larynx.
Airway sensory nerves do not form a homogeneous population. However, to date, there
is no single classification scheme that adequately and unambiguously subcategorizes the
various afferent nerve subtypes that have been described in the airways. Although a
functional classification is commonly employed (describing the physiological
responsiveness of airway afferents), subtypes can be alternatively delineated based on
their origin, location in the airways, neurochemistry, electrophysiological properties or by
the reflexes that are evoked secondary to afferent activation [4]. This lack of a universal
classification scheme, coupled with attempts to classify an afferent subtype using only
one phenotypic trait, often leads to some confusion as to the identity of a given afferent
nerve type. It is therefore desirable to consider multiple characteristics when defining an
airway afferent fiber.
In guinea pigs (and likely true for all mammals) airway sensory nerves can be broadly
functionally classified as either primarily mechanically sensitive (low threshold
mechanosensors) or primarily chemically sensitive (chemosensors or alternatively,
nociceptors) (Fig1). Low threshold mechanoreceptors are readily activated by one or
more mechanical stimuli, including lung inflation, bronchospasm or light touch, but
generally do not respond directly to chemical stimuli unless the stimulus acts upon
airway structural cells to result in mechanical distortion of the nerve terminal [5-8].
Conversely, chemosensors are typically activated directly or sensitized by a wide range
of chemicals, including capsaicin, bradykinin, adenosine, PGE2, but are relatively
insensitive to mechanical stimuli [9,10]. This broad delineation, however, may not be
strictly correct as at least some low threshold mechanosensors also directly respond to
chemical stimuli, including acid and ATP, although these mediators may still activate the
nerve terminal via mechanical mechanisms [11,12]. Subtypes of both the
mechanosensors and chemosensors are readily identified (described below). Regardless
of the afferent fiber, the majority of airway afferent nerves originate in the vagal sensory
ganglia (nodose or jugular) [13,14]. A small population of fibers (believed to be a
subpopulation of chemosensitive nerves) may have their origin in dorsal root ganglia
adjacent to the upper thoracic spinal cord [15]. Little is known about the role of spinal
afferents in airway defense.
ow threshold mechanosensors
Two classic types of low threshold mechanosensors have been described in the
intrapulmonary airways of a number of mammalian species, namely the rapidly adapting
receptors (RARs) and slowly adapting receptors (SARs) [8,9,16-20]. However, when
comparing only a limited number of phenotypic traits RARs and SARs may appear
indistinguishable (Table 1). Thus, RARs and SARs both originate in the nodose ganglia,
terminate in the intrapulmonary airways and lung parenchyma, conduct action potentials
in the Aβ-range (10–20 m/s) and are sensitive to many mechanical stimuli, including
changes in lung volume, airway smooth muscle constriction and airway wall
oedema[9,12,17-21]. Accordingly, RARs and SARs may both display activity when the
lungs are inflated [9,16-19]. RARs and SARs are also both generally insensitive to a wide
range of chemical stimuli, unless the stimulus evokes coincidental changes in airway
smooth muscle tone, mucus secretion or airway wall volume [8,17,19].
Table 1. Properties of low threshold mechanosensor subtypes innervating the guinea pig airways.
Nevertheless, RARs and SARs can be differentiated by comparing their individual
mechanical activation profiles, mechanical adaptation properties, central termination
patterns and the reflexes that each precipitate (Table 1). Thus, RARs may be activated
during both inflation and deflation of the lungs (including lung collapse) [9,17]. SARs, on
the other hand, display activity during tidal inspirations, peaking just prior to the
initiation of expiration [9,16]. As their names suggest, RARs display rapid adaptation
(i.e., a rapid reduction in the number of action potentials) during sustained lung
inflations, whereas SARs adapt slowly to this stimulus [9,17]. It is important to note,
however, that this rapid adaptation shown by RARs during sustained lung inflations is
unlikely an electrophysiological property of the nerve terminal but rather relates to the
nature of the stimulus. RARs typically adapt slowly to other types of mechanical stimuli,
including dynamic lung inflations, bronchospasm and lung collapse [12,19]. Finally,
activation of RARs evokes tachypnea and airway smooth muscle constriction, whereas
SARs are likely the primary afferent fibers involved in the Hering-Breuer reflex, which
terminates inspiration and initiates expiration when the lungs are adequately
inflated [16,17]. SAR activation also inhibits cholinergic drive to the airway smooth
muscle, resulting in a reduction in airway tone [8]. The different reflexes that are evoked
by these afferent nerve subtypes likely reflect the distinct brainstem neurons innervated
by RARs and SARs [reviewed in 22].
A third type of low threshold mechanosensor has been described in the guinea pig
airways [12]. These fibers also originate from the nodose ganglia, but are primary
located in the extrapulmonary airways (larynx, trachea and large bronchi) and are quite
distinct to RARs and SARs (Figure 2; Table 1). Extrapulmonary low threshold
mechanosensors are exquisitely sensitive to punctate mechanical stimuli (such as touch)
but are insensitive to physiologically-relevant tissue stretching, changes in luminal
pressure or airway smooth muscle constriction [12]. Extrapulmonary low threshold
mechanosensors are also readily differentiated from their intrapulmonary counterparts
by a much slower conduction velocity (~5 m/sec, Aδ-range) and a lack of sensitivity to
the purinergic agonist ATP [12]. During sustained punctate mechanical stimulation,
extrapulmonary mechanosensors display rapid adaptation, although again this likely
reflects some property of the mechanics of the stimulus in relation to tissue surrounding
the nerve terminal rather than reflecting electrophysiological adaptation [23].
Circumstantial evidence suggests that analogous fibers may be present in the
extrapulmonary airways of cats, dogs and humans [2,24-30]. It is presently unknown
whether this mechanosensor subtype is activated during normal breathing.
hemosensors
Chemically-sensitive airway afferent fibers are found throughout the airways and lungs
and are generally quiescent in the normal airways, becoming recruited during airways
inflammation or irritation. Airway chemosensors are derived from both the nodose and
jugular vagal ganglia, as well as from the dorsal root ganglia [13-15]. As described
above, chemosensors are typically defined by the ability of a variety of chemicals to
directly activate the nerve terminal (i.e., not secondarily to structural alterations within
the tissue; Table 2). However, care needs to be taken when differentiating an airway
chemosensor form other airway afferent nerve subtypes. For example, often airway
chemosensors are stereotypically defined by their responsiveness to the irritant chemical
capsaicin and, hence, the expression of the capsaicin receptor (TRPV1). This definition,
however, is not strictly accurate, as at least some species possess capsaicin-insensitive,
TRPV1-negative chemosensors [31]. Alternatively, it may be assumed that all airway
chemosensors are C-fiber type nociceptors. This is also incorrect, as airway (and other
visceral) chemosensors that conduct action potentials in the Aδ-fiber range have been
identified (analogous to somatic Aδ-nociceptors) [13,32,33]. Furthermore, due to the
overwhelming number of studies conducted in guinea pigs, chemically-sensitive fibers
are often presumed to express tachykinins (substance P and/ or neurokinin A) (Fig 2).
Guinea pigs are perhaps unique amongst mammals and express a high density of
tachykinin-containing airway C-fibers, especially in their extrapulmonary airways[34-36].
Indeed, in the airways of most mammalian species (and in the guinea pig
intrapulmonary airways) the majority of C-fiber chemosensors do not express
tachykinins [35,36]. Given these reasons, airway chemosensors are sometimes thought
of as high threshold mechanosensors. Within this group are fibers that are not readily
excited by mechanical stimulation (bronchoconstriction, lung inflations light touch, etc),
but can be activated using severe mechanical manipulations (lung hyperinflation, forceful
punctate stimuli etc) and one or more chemical stimuli (capsaicin, bradykinin, adenosine
etc).
airway afferent nerves and cough
The identity of the afferent nerve fiber subtype that is primarily responsible for evoking
reflex coughing has been the subject of much debate. Studies in experimental animals
and in humans show clearly that multiple types of mechanical and chemical stimuli can
(under the right experimental conditions) evoke coughing [1,12,24-30,37,38]. This
would argue that multiple afferent nerve subtypes (mechanosensors and chemosensors)
might be involved in the production of reflex coughing. However, not all stimuli evoke
cough under all conditions [3,12]. This might suggest divergence between multiple reflex
pathways or the existence of primary and secondary cough afferent pathways (discussed
below).
Rapidly adapting receptors (RARs) and chemosensors
RARs have long been presumed to be the primary afferent nerve fibers that evoke
defensive cough in the airways [1,4,5,39]. Indeed, it has been proposed that coughing
can be initiated following the activation of RARs by airway smooth muscle constriction,
mucous accumulation, mechanical irritation and even capsaicin and bradykinin
application (due to the resulting airway obstruction) [1,4,17]. However, several
observations argue against the role of classic RARs as the primary cough-provoking
afferent fibers. For example, many stimuli that produce robust activation of RARs (e.g.
thromboxane, leukotriene C4 (LTC4), histamine, neurokinins, methacholine) are
ineffective or only modestly effective at evoking cough [17,28,40-42]. Moreover, in
some coughing species (e.g., guinea pigs) many RARs are spontaneously active
throughout the respiratory cycle and yet cough is only induced in response to very
specific stimuli [8,12,14,19].
Evidence also supports a role of airway chemosensitive nerve fibers in the cough reflex.
For example, stimuli that are known to activate airway chemosensors, such as capsaicin,
bradykinin and citric acid, are amongst the most potent tussigenic agents in conscious
animals and humans [12,26,38,43,44]. However, capsaicin and bradykinin do not evoke
cough in anesthetized animals or humans, even though cough can be evoked in these
same animals by mechanically probing the airway mucosa [12,25,27]. In fact, in
anesthetized animals acute capsaicin challenge has been shown to inhibit breathing and,
as a consequence, inhibit cough evoked by mechanical stimulation of the
airways [12,25,27]. These conflicting observations have lead to suggestions that in
conscious animals cough-evoked by chemosensor stimuli relies on cortical processing of
the stimulus, in which the activation of a subset of airway chemosensors generate the
conscious perception of airway irritation and promote the urge to cough [3]. Indeed, it is
interesting that capsaicin-evoked cough can be consciously suppressed in human
subjects [45]. If this hypothesis is correct, then chemosensor-mediated cough may not
strictly be reflexive in nature. Rather, the perception of airway irritation may induce the
conscious/ voluntary decision to cough. The true respiratory reflex response that is
evoked by airway chemosensor stimulation may in fact be rapid inhibition of respiratory
activity, which is observed during anesthesia and perhaps over-ridden (unless the reflex
is robustly activated) by voluntary control in the conscious state.
