Skip to main content
Download PDF

Perspective on the human cough reflex

Cough volume 7, Article number: 10 (2011) Cite this article

Abstract

This review dissects the complex human cough reflex and suggests hypotheses about the evolutionary basis for the reflex. A mechanosensory-induced cough reflex conveys through branches of myelinated Aδ nerve fibers is not chemically reactive (i.e., capsaicin, bradykinin); possibly, its evolution is to prevent the harmful effects of aspiration of gastric or particulate contents into the lungs. This became necessary as the larynx moves closer to the opening of the esophagus as human ancestors adapt phonation over olfaction beginning less than 10 million years ago. The second type of cough reflex, a chemosensory type, is carried by unmyelinated C fibers. Supposedly, its origin dates back when prehistoric humans began living in close proximity to each other and were at risk for infectious respiratory diseases or irritant-induced lung injury. The mechanism for the latter type of cough is analogous to induced pain after tissue injury; and, it is controlled by the identical transient receptor potential vanilloid cation channel (TRPV1). The airways do not normally manifest nociceptive pain from a stimulus but the only consistent response that capsaicin and lung inflammation provoke in healthy human airways is cough. TRPA1, another excitatory ion channel, has been referred to as the "irritant receptor" and its activation also induces cough. For both types of cough, the motor responses are identical and via coordinated, precisely-timed and sequential respiratory events orchestrated by complex neuromuscular networking of the diaphragm, chest and abdominal respiratory muscles, the glottis and parts of the brain.

Background

Persistent cough is one of the most common medical complaints that impacts the quality of life and is responsible for a significant proportion of annual ambulatory medical visits and medical expenses in the United States [1]. Involvement of the upper and/or lower airways play pathogenetic roles in cough development and the association of allergy represent an important contributing factor for cough exacerbation. This perspective explores the complexity of coughing and suggests hypotheses about the unique evolutionary basis for the human cough reflex.

Complexity of watching someone cough

Considering a casual connotation, coughing is a reflex-evoked modification of normal breathing patterns [2]. More explicitly, the cough reflex is a multifaceted, precisely timed, neuromuscular phenomenon characterized by the precise concurrent and sequential coordination of the activation patterns of the diaphragm, various muscle groups of the chest wall, cervical muscles, abdominal muscles, laryngeal abductor and adductor muscles, medullary and higher cortical regions of the brain [3, 4]. The complexity of coughing is espoused by television personality Jerry Seinfeld when he informs his friend George Costanza (played by Jason Alexander): "When you cough there are thousands of unseen muscles that suddenly spring into action. It's like watching that fat guy catch a cannonball in his stomach in slow motion" (from The Apology, the 165th episode of the NBC sitcom Seinfeld that was first aired on December 11, 1997).

Accordingly, I am attending a dinner with my wife and observe her walking across the room towards me. As she does so, she aspirates a sliver of ice from a glass of beverage she is drinking. My wife stops walking and her eye brows arch. She informs me later that at that instance she experienced the sensation of an urge to cough. She deftly places a clenched fist to her mouth as her face reddens; her eyes water, narrow and then tighten. Her chin lifts to some extent as her head rears back; perspiration appears on her upper lip. Her stance widens. Her back bends slightly backwards. Her chest expands as she takes in a breath. She holds her breath momentarily only to quickly open her mouth again. Now, her face is cerulean-colored as she forcibly emits a staccato-like exhalation. Then, at the very end of her explosive exhalation, she daintily wipes a small speckle of ice from her lower lip using a pink-colored lace handkerchief that she inconspicuously hides in the cleavage of her dress. As she looks across the room at me, she smiles and nonchalantly lifts both her shoulders and spreads her arms out with the palms facing upwards as if to denote a sense of embarrassment.

Sensory phase of coughing

Mechanosensory Cough

For my wife, it is reasonable to believe that instigation of a cough response is due to stimulation of a mechanically-sensitive 'true cough receptor' that is provoked by the sliver of ice. The premise for the presence of a 'true cough receptor' is explored by Canning et al using the anesthetized guinea pig model, which retains a blunted cough response following noxious stimuli [5, 6]. Mechanical stimulation, postnasal drip, and a water bolus placed into the pharynx will evoke coughing in both human subjects and in animals but not capsaicin [6, 7]. While C-fiber activation initiates coughing in conscious guinea pigs, it does not occur in the anesthetized animal. Anesthesia also attenuates or abolishes coughing in humans [8]. The anesthetized guinea pig model is important because it allows different investigative options, such as examining cough along with recordings from brainstem neurons or vagal afferent neurons, microinjection of drugs into specific brainstem and midbrain structures, selective stimulation of parts of the airways and not others, or extrinsic denervation of only parts of the airways [6]. My wife's coughing commenced with an inspiratory maneuver. In other cases, the mechanosensory-type reflex cough is associated with just a single and short expiratory cough referred to as an 'expiration reflex' [9–11].

Purportedly, the vagal afferent neurons of the true cough receptor are unlike the rapidly adapting receptors (RARs), slowly adapting receptors (SARs) or C-fibers; also, this receptor does not express transient receptor potential vanilloid (TRPV1) and is not sensitive to capsaicin. In contrast to the anesthetized guinea pig model, mechanically-induced coughing in conscious guinea pigs generates impulses carried by low threshold, mechanically sensitive, rapidly adapting receptors (RARs) that travel through myelinated Aδ fibers at conduction velocities of between 4 and 18 m/s [12–17]. These receptors also do not react directly to capsaicin and other chemical stimuli unless the stimulus leads to mechanical distortion of the nerve terminal [18]. RARs promote reflex bronchospasm and mucus secretion through parasympathetic pathways. How the conscious guinea pig cough mechanism applies to my wife's induced-coughing is not sufficiently understood.

Tracheal and laryngeal receptors come in to play as an important defensive role against acid aspiration [19]. The 'true cough receptor' is provoked by acid [6]. The descent of the larynx to a location more approximate to the opening of the esophagus places human ancestors at a greater risk for aspiration. Because of the greater risk for acid aspiration, possibly there is adaptation of a means to provoke coughing via a brainstem sensitizing mechanisms or by direct triggering of afferent esophageal nociceptors projecting from vagal pharyngeal and glossopharyngeal nerves [14, 20]. The ion channel receptor, TRPV1, respond to acid in a more sustained manner than the acid-sensing ion channel-type receptor (ASIC), which tends to produce brief and transient responses to a lowered pH [21].

Chemosensory Cough

Both the chemically- and mechanically-sensitive airway nerves take part in mediating the cough reflex and establishing synapses in the brainstem's caudal two-thirds of the nucleus tractus solitarius [22]. Because the threshold for mechanical activation is more conducive for RARs and SARs than for C-fibers type of nerves, C-fibers consequently respond less to mechanical stimuli than do RARs and SARs. In some animals (i.e., guinea pigs, rabbits, cats, dogs and pigs) glutamate may be the final central nervous system excitatory transmitter during coughing; neurokinins play a more modulatory role [23]. The chemosensory nociceptors reside as a fine plexus within the airway epithelium and walls and send nerve impulses through slowly conducting (< 2 m/s) vagal unmyelinated fibers [24–28]. The sensation of an "urge to cough" is ostensibly associated with activation of bronchopulmonary C-fibers [29, 30]. C-fiber nerves become directly activated, 'sensitized' or 'hyper-activated' by capsaicin, bradykinin, adenosine, PGE2, citric acid, hypertonic saline solution, SO2 and lung inflammation (or inflammatory-type chemicals) [7, 18, 31–33]. The role of lung neuropeptides and neuroinflammation in humans is poorly understood [34–37].

C-fibers actions involve ion channels, ancient sensors of the environment. Hundreds of millions of years ago, ion channels first sense thermal and osmolality stimuli. Later, the ionic channel mechanisms are adapted for other 'environmental' sensations (e.g., hearing, vision and taste). TRPA1, possibly an ''irritant receptor'', is expressed by a subpopulation of unmyelinated afferent C fiber nociceptors and may be linked to TRPV1 to contribute to the transduction of the irritant stimuli [38–43]. Mazzone questions the role of TRPV1 and opines that it is improbable that any TRPV1-expressing cells in other tissues or organs are involved in the cough reflex [18].

Motor Phases of Coughing

The motor pattern of the reflex cough is regulated differently than the motor pattern for tidal breathing [44]. Neuroplastic transformations allow respiratory behaviors having dissimilar spatial and temporal dimensions to instigate a mixture of actions employing comparable respiratory motoneurons [37, 45]. Animal investigations concerning the induction of Fos-like immunoreactive neurons in certain brain stem regions (i.e., the commissural subnucleus of the nucleus tractus solitarius, field of the reticular formation, and nucleus ambiguus) suggest that different reflex responses make use of overlapping neural circuitry [46]. The neural conduit for medullary control of laryngeal adductor muscles actions is contained within a broader neural pathways controlling cough and swallowing [46]. In animal models, there is activation of interneuron pathways located between the medullary nucleus tractus solitarius and the nucleus ambiguus during coughing [46, 47]. Stimulation of the superior laryngeal nerve can evoke different laryngeal adductor muscle responses including coughing, swallowing, gagging, laryngeal spasms, bronchoconstriction, apnea, and retching [46, 47]. The type of the evoked reflex response depends on the considerations of the stimulus used [46, 47].

While conceivably not evident to my wife, the motor side of her cough reflex is spaced by distinctive phases (Figure 1). During the inspiratory phase of cough, my wife's entire glottis is in abduction. The laryngeal motor neurons that begin in my wife's nucleus ambiguus follow vagal and superior laryngeal nerves to excite the motor neurons of her glottis, external intercostal muscles, diaphragm, and other major inspiratory and expiratory respiratory muscles [48]. Her upper airway motoneurons are located at the cranial level; phrenic motoneurons controlling the diaphragm are located in the cervical cord ventral horn; and, her rib cage and abdominal motoneurons are located in the ventral horn of the thoracolumbar segments [49, 50]. If measured, intracellular electrodes would record substantial depolarization of her laryngeal motor neurons during coughing. It seems that a central inspiratory command activates the respiratory motoneurons in an encoded sequential order; the upper airway motoneurons are recruited before those of the diaphragm and the rib cage; this allows the opening of the glottis before the fall in tracheal pressure due to diaphragmatic contraction [49]. The posterior cricoarytenoid muscle activates 40 to 100 milliseconds before the inspiratory activation of the diaphragm [51]. Actions taken by other inspiratory and the laryngeal abductor muscles (e.g., posterior cricoarytenoid muscle) further enlarge the opening of her upper airways [52–60]. My wife's diaphragm and external intercostal muscles contract to expand her chest cavity and lower her intra-thoracic pressure. The crural and costal muscles of her diaphragm act in synchrony throughout inspiration [61]. The contraction of her diaphragm peaks within approximately 1.0 second. As her diaphragm descends, there is some widening of her glottal opening due to tautness placed on her larynx [62].

Figure 1
figure 1

Inspiratory and expiratory flow rates measured over the time course of a coughing event. The figure displays inspiratory and expiratory flow rates measured over the time course of a coughing event. The inspiratory phase of coughing is when an inspiratory maneuver expands the lung volume for sufficient expiratory power. The second, compressive, phase entails narrowing or complete closure of the glottis that allows pressure to build up. During the brief closure, there is isovolume (i.e., no flow) contraction of the chest wall against a closed glottis. During the expulsive phase, there is glottal opening and the explosive release of a burst of air with expiratory cough rejoinders. There is the characteristic cough sound during the latter maneuver.

Full size image

The compressive phase of her cough reflex begins almost immediately after inspiration. Her laryngeal motor neurons are transiently hyperpolarized during the transition between the inspiratory and expiratory compressive phases of her cough; laryngeal motor neurons are repolarized during the expiratory compressive phase [9]. The glottic closure is essential for the process of coughing since the maximal level of intrathoracic pressure attained, and the efficiency of the expiratory cough, depends in great part on the quality of glottic occlusion. The glottic closure reflex is elicited at birth, becomes more active during the first year of life, and gradually decreases in activity with further aging [51]. Very quickly and in the order of perhaps 200 milliseconds and a range between 42 and 1010 milliseconds, the glottic closure takes place as two small laryngeal abductors (posterior cricoarytenoid muscles) quickly relax and her laryngeal adductors (e.g., thyroarytenoid muscles) contract to produce significant narrowing or complete closure of the glottis [3, 63, 64]. The laryngeal sphincter muscles closure is so tight that it can sustain very high intratracheal pressures [65]. Intrapleural pressure may reach more than 100 cm H2O [4, 56, 58, 65, 66]. There is coordinated activity between the posterior cricoarytenoid muscle and the accessory inspiratory muscles (i.e., infrahyoid and intercostal muscles) [51, 57, 67]. Synchronized actions are taken by her expiratory, abdominal and laryngeal adductor muscles. There is further activity by her diaphragm during the compressive phase of the cough reflex that physiologically translates as an isovolume (i.e., no flow) contraction of her chest wall against a closed glottis.

The expulsive phase of the cough reflex begins as the laryngeal adductor muscles (thyroarytenoid and arytenoideus) contract starting a few hundred milliseconds before the diaphragm relaxes and while the abdominal muscles have already relaxed [3, 54, 63]. An effective diaphragmatic force helps my wife to cough. There is inhibition of laryngeal adductor motoneurons, which is important in the generation of explosive expiratory airflow [64]. The posterior cricoarytenoid muscles briefly contract to enlarge the glottic opening but, not as wide as during the inspiratory phase; there is now a strong positive swing of pleural pressure. Her true vocal folds are pulled downwards during the explosive expulsive phase of coughing. The cricothyroid muscle causes vocal fold elongation and increased size of the glottic opening. A transiently relaxed glottis releases a burst of expired air to expel the piece of ice [64]. Finally, the larynx again constricts a bit and her diaphragm relaxes after coughing stops [54, 64].

My wife's true and false cords are participants in coughing since the contraction of the thyroarytenoid muscles alters the position, shape and tension of her false cords. This allows their shelf-like, down-turned free margins to function as a one-way valve to prevent the escape of air from the lower respiratory tract below. In this way, it helps buildup intrathoracic pressure [56]. Her true cords, with their up-turned margins, behave as a one-way valve in the opposite direction, obstructing the entrance of air from above [56]. From a structural point of view, her false cords provide more of an expectorative function for cough, whereas her true cords assume a more protective role against aspiration [56].

My wife's distinctive cough sound is caused by oscillation of the surrounding lung/upper airways' tissues and gases related to the relatively large expiratory airflow velocities during the explosive exhalation [4, 68]. The quality of the cough sound is influenced by airflow speed, changes in resonance of the airway tissues, secretions that are present in the airways and the compliance of the airways [63].

Brainstem Nervous Control of Cough

Multitudes of neural messages are integrated, interconnected and funneled to my wife's brainstem cough centers from peripheral afferent sensors that travel through the vagal internal laryngeal nerve to the medulla and interconnect with neural networks in the cortex. Vagal and glossopharyngeal motoneurons innervate her upper airway muscles; the inspiratory and expiratory bulbospinal pre-motoneurons, of the intermediate and caudal regions of the ventral respiratory group, project nerve impulses to phrenic, intercostal, and abdominal motoneurons [4, 58, 69]. Second-order neurons launch signals to her brain stem nervous systems that influence the normal respiratory cycle but also help carry out coughing [58, 70]. The pontine and rostral ventral respiratory groups, the raphe nuclei and Bötzinger and pre-Bötzinger complexes adjust varied cough discharge patterns [58, 70–72]. Apparently, the pre-Bötzinger complex helps generate inspiratory respiratory rhythm while the retrotrapezoid nucleus/parafacial respiratory group in front of it plays a role for implementing expiratory rhythms. Expiratory neurons, possessing augment firing patterns, span regions of the Bötzinger and pre-Bötzinger complexes to initiate and inhibit premotor neurons of the laryngeal adductor muscles [71, 73–75]. Possibly, an endogenous cough-suppressing neuronal network located within her caudal ventral respiratory region plays some role in modulating the excitability of the cough reflex [37, 69, 76, 77]; there could be some sort of gating mechanism operating at some level [78, 79].

Cortical Nervous Control of Cough

In humans, the cortical participation of the cough reflex is not like any other animal [5]. Accordingly, my wife is capable of controlling her forced exhalation during coughing. She has the ability to voluntarily initiate or inhibit her cough responses without sensory stimulation, during capsaicin inhalation and also with upper respiratory tract infections [32, 60, 80–82]. My wife's cough is lost or severely diminished during general anesthesia or sleep; and, systemic opiates suppress her coughing [7, 30, 33, 60, 83]. Her cough is susceptible to placebo-induced suppression [29, 30, 32, 84]. She notes an "urge-to-cough" that always precedes her actual cough motor maneuver [84]. If she is investigated by imaging studies during voluntary coughing, the findings likely will show brain activity appearing in the ventrolateral sensorimotor cortex, an area responsible for non-respiratory orofacial (i.e., chewing, lip pursing and tongue movements) and respiratory orofacial movements (i.e., speaking, singing, and swallowing) [81]. More recently, Mazzone and colleagues, measured blood oxygen level-dependent (BOLD) responses in human subjects utilizing the technique of event-related functional magnetic resonance imaging and confirmed that the largest areas of imaging during voluntary coughing occurred in cortical areas functionally linked to both respiratory-related orofacial tasks (i.e., speaking and singing) and also non-respiratory orofacial actions (i.e., chewing, lip pursing, and tongue movements) [33].

Discussion

Coughing can be provoked in a variety of animal models, such as the guinea pig, cat, dog and pig [85]. Yet, there are distinctive differences between humans and these animals as well as non-human primates. The distinguishing differences between non-human and human cough reflexes are the results of transformations that take place over millions of years in part responsive to changes in the internal and external environments of evolving humans [5, 20, 86–93]. The scheme utilizing coughing dates back millions of years before when a very primitive mammal first employs this defense [6, 20, 94, 95]. Alternatively, the repositioning of the larynx in the hominid linage may have been a gastrointestinal adaptation in the ape swallowing mechanism because of the separation of the gastrointestinal system from the respiratory tract [96]. The crural diaphragm may have been a gastrointestinal sphincter to defend against gastroesophageal reflux and aspiration [61, 97].

Feasibly over millions of years, the revisionary wings of evolution respond to changes in the hominids' environments as two different cough responses emerge (Figure 2). Over this period of time, genes are duplicated and/or reused, with minor modification, either in the same hominid or a more primitive mammal [98–101]. The regulation of the cough reflex differs greatly from that of tidal breathing [79]. Neuroplastic transformation refigures basic respiratory behaviors, in some very ancient mammal, in order to utilize the same muscles and nerves of normal breathing for the cough reflex [47]. The enlarging brain and changing supralaryngeal tract are important evolutionary drivers for human speech and higher cognitive functions that impacts on the human cough reflex [33, 47, 78, 102–105]. A more archaic Homo sapiens with a larger brain and a changing supralaryngeal tract emerges about 500,000 years ago [106–108]. While the ancestor of the very earliest Homo species may have been chimp-like, it takes serial hominid intermediaries of at least 15-20 "chronospecies", spread out over 6-7 million years, before the modern-type human appears in Africa, between 200,000 and 100,000 years ago [98, 109, 110].

Figure 2
figure 2

Types of Cough Reflex. The pattern of the cough reflex depends on the nature of the evoking stimulus as well as on the part of the respiratory tract stimulated. There are two or more distinctive human cough reflexes with likely different evolutionary histories. The first is the involuntary cough reflex provoked by mechanosensory-responsive Aδ fibers. It is relatively insensitive to chemical stimuli and was derived as a protective mechanism against aspirated gastric content due to the change in the position of the larynx in humans and their primate ancestors. This type of cough reflex evolved a few million to several hundred thousand years ago. An alternative possibility is what has been identified in both conscious and anesthetized guinea pigs and presumably also in humans called the "true cough receptor" as described in originating from low threshold mechanosensitive afferent nerve fibers and is activated by light punctuate mechanical stimulation and rapid changes in pH evoke cough [6, 18]. The rapid changes in pH may hold for the protection against aspiration of gastric acid. The second type of involuntary cough reflex occurs when unmyelinated vagal sensory C-fibers are activated by tissue injury, inflammation or by chemicals such as capsaicin, bradykinin, SO2, and citric acid. The chemically-sensitive cough reflex was possibly a co-evolutionary response by different animal and plant species and occurred over hundreds of millions of years.

Full size image

The foremost driving forces for one type of Homo species cough reflex are modifications of the supralaryngeal tract, decent of the hyoid bone and movement of the larynx closer to the esophageal opening. These changes necessitate a cough defense against aspiration. In an evolutionary sense, the adaption of a neural mechanism such as a 'true cough receptor' (or a similar mechanism) becomes a valuable pulmonary defense. Generating complex sounds utilizing the laryngeal sphincter as a vibratory source is a unique evolutionary adaptation of humans [51]. The distinctiveness of the human glottis is supported by electrophysiological measurements of laryngeal muscles movements during voice maneuvers. In humans, there are peak electrical activities in cortical motor area 4; non-human primates show electrical peaks in cortical motor area 6 [81, 111]. Also, as Homo species evolve, the margins of the human vocal cords lose some of their sharpness; arytenoid cartilages became smaller and vocal folds elongate to produce a wide range of sounds. For my wife's pre-Homo species ancestors, living millions of generations before, the additions of small arytenoid cartilages to the tips of the true vocal cords increases its relative length and maximize its vibratory surfaces [56]. An arytenoid length of 7 compared to a true cord length of 10 (7/10) represents the best cross-sectional area of the glottis; this is when there is ultimate pivotal movement of the arytenoid bodies [56]. The 7/10 ratio allows for the widest laryngeal opening and airways possessing the lowest airflow resistance possible. Such an optimum ratio of arytenoid to vocal cord length is found only in racing animal that need to be able to run fast, such as the gazelle. In contrast, humans who do not depend on flight for protection possess a less efficient 4:10 ratio [56].

For the evolving hominid, the sounds exiting from the mouth are tailored by the "supralaryngeal vocal tract" shaped by two portions that form a right angle to one another (Figure 3) [108]. The earliest hominids likely possesses a supralaryngeal vocal tract having its horizontal dimension longer than its vertical one, making them incapable of producing the full range of sounds made by humans today. Only for the Homo species is there a unique descent of the hyoid bone to well below the mandible [108]. In comparison, the chimpanzee's hyoid bone and larynx position at or near the base of the mandible; and, the chimpanzee's tongue is long and mainly limited to the oral cavity, resulting in a disproportionately shaped supralaryngeal vocal tract. Human ancestors such as Homo erectus and Neanderthal chronospecies possess supralaryngeal vocal tracts intermediate in shape between those of chimpanzees and humans. Over time, the changing positions of the tongue, lips, and larynx alter the overall configuration of the supralaryngeal vocal tract; such transformations place humans at a greater risk for aspiration [96, 108]. The exact impact on the cough reflex of the evolutionary shaping of the supralaryngeal tract and humans' faculties for better cortical control of the muscle movements of the larynx, tongue, mouth and lips have not been adequately explored.

Figure 3
figure 3

The Homo species supralaryngeal tract. The Homo species supralaryngeal tract (right) is characterize by horizontal portion (i.e., mouth and oropharynx) forming a right angle of approximately equal lengths of 1:1 proportion with a vertical segment extending down from the palate to the vocal cords. In comparison, the chimpanzee (left) has a hyoid bone and larynx positioned at or near the base of the mandible; and, the tongue is long and mostly restricted to the oral cavity, resulting in a disproportionate supralaryngeal vocal tract. Human ancestors such as Homo erectus and Neanderthal chronospecies possessed supralaryngeal vocal tracts intermediate in shape between those of chimpanzees and humans. (Adapted from [108]).

Full size image

The growth in the size of the human cortex permits better control of voluntarily speech and song production (and laryngeal muscle movements) as opposed to the limited voluntary control over vocalizations displayed by non-human primates [102, 103, 112–114]. Hundreds of millions of years before, the larger brain size of ancestral mammals compared to their closest extinct mammalian relative is in response to the high resolution of olfaction, prominence of odorant genes and growth of odorant receptors [104]. The relationship between keen olfaction and brain size is changed in the Homo species as they adapt speech over olfaction. The genes regulating brain size and behavior exhibit higher rates of protein evolution in the lineage leading from ancestral primates to humans [112]. The abnormal spindle-like microcephaly-associated gene (ASPM) may have been the evolutionary target for the initial expansion of the hominid cerebral cortex; and, changes regarding human speech are likely accelerated after the FOXP2 regulatory gene reaches its modern normal variant around 100,000 years ago [112, 115–123].

The second type of human cough reflex is adapted as the capacities for speech and cognition evolve and Homo species fashion stronger social connections. There emerges an imperative need to defend against distal lung inflammation or damage as Homo chronospecies move to more enclosed environs where there is a greater possibility of contracting a contagious respiratory tract or parasitic infections and/or being exposed to gaseous-particulate irritant emanations [124, 125]. Pulmonary inflammation often accompanies a contagious respiratory tract infection or following an irritant inhalational exposure [3, 7, 20, 124–127]. The earliest community sites for the ancient Homo species, possibly beginning 400,000 years, are supposedly within caves requiring fire for warmth and for cooking of food [128]. Fire requires the burning of fuels in the forms of biomass, such as wood, animal dung and crop residues [129]. Biomass smoke composed of irritant particles and gases can penetrate deeply into the lung to produce a variety of inflammatory morphologic and biochemical changes.

Teleologically, the lung C-fiber neural responses may permit a broader defensive rejoinder than does just coughing, a warning sign like pain. Possibly, cough associated with respiratory infections is a coevolutionary strategy by primitive viruses coexisting with human predecessors; induction of coughing increases viral contagiousness to enhance viral spread and survival [124, 130]. The coughing part is driven by the virus while neuroinflammation or some other process (in humans) represents a type of innate immunity. Maybe, neuroinflammation corresponds to a first-line inflammatory defense until the actual immune inflammatory response against the respiratory tract infection begins [131, 132]. Unfortunately, while documented in guinea pigs, lung neuroinflammation in humans is not well delineated [127, 133–138].

Summary

A mechanosensory reflex cough, receptive to mechanical and acid stimulations, possibly operates via a mechanism involving the so-called "true cough receptor"; or possibly, there is another mechanism employing other slowly conducting nerve fibers. Pertinent evolutionary adaptations shaping the first type of human reflex cough response comprise modifications of the supralaryngeal tract and descent of the hyoid bone and movement of the larynx to a closer location to the esophageal opening, which increases the risk for aspiration. A second, chemosensory-type reflex cough, originating in some more ancient mammal, involves C-fiber afferent nerves linked to lung inflammation and chemical agents (i.e., capsaicin, bradykinin, etc.). The need for defending against distal lung inflammation or damage emerges as Homo chronospecies move to more enclosed environs where there is a greater possibility of contracting a contagious respiratory tract or parasitic infections and/or exposure to gaseous-particulate irritant emanations. Homo species fashion stronger social connections with the introduction of speech (over olfaction) and the enlargement of the cortical brain size. Homo species (and perhaps an earlier hominid) achieve voluntarily cough initiation and suppression; control of the forced exhalation and the intensity of the cough response; the facility to initiate repeated coughing; a heeding to the integration of psychosocial factors into the cough response; exquisite control of laryngeal muscles actions; a capacity to respond to a variety of cough stimuli; and the perception of airways irritation causing an "urge to cough".

Authors' information

Dr. Stuart M Brooks is currently Adjunct Professor in the College of Public Health, University of South Florida.

Abbreviations

TRPV 1 :

Transient Receptor Potential Cation Channel Subfamily V, Member 1

TRPA 1 :

Transient Receptor Potential Cation Channel, Subfamily A, Member 1

Aδ Nerve Fibers :

A Delta Fibers (Afferent Fibers)

C Nerve Fibers :

Unmyelinated C fibers (Afferent Fibers)

SARs :

Slowly adapting Fibers

RARs :

Rapidly Adapting Receptors

ASIC :

Acid-Sensing Ion Channel-Type Receptor

PGE 2 :

Prostaglandin E2

BOLD :

Blood Oxygen Level-Dependent

FOXP 2 :

Forkhead Box Protein P2

References

  1. Schappert SM, Burt CW: Ambulatory care visits to physicians' offices, hospital outpatient departments, and emergency departments: United States, 2001-2002. 2006, National Center of Health Statistics, 13: 1-66.

    Google Scholar 

  2. Widdicombe JG: Afferent receptors in the airways and cough. Respir Physiol. 1998, 114: 5-15. 10.1016/S0034-5687(98)00076-0.

    Article  CAS  PubMed  Google Scholar 

  3. Poliacek I, Stransky A, Szerda-Prezestaszewska M, Jakus J, Barani H, Tomori Z, Halasova E: Cough and laryngeal muscle discharges in brainstem lesioned anesthetized cats. Physiol Res. 2005, 54: 645-654.

    CAS  PubMed  Google Scholar 

  4. Morris KF, Baekey DM, Nuding SC, Dick TE, Shannon R, Lindsey B: Plasticity in respiratory motor control: Neural network plasticity in respiratory control. J Appl Physiol. 2003, 94: 1242-1252.

    Article  CAS  PubMed  Google Scholar 

  5. Canning BJ: The cough reflex in animals: Relevance to human cough research. Lung. 2008, 186 (Suppl): S23-S28.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Canning BJ, Mazzone SB, Meeker SN, Mori N, Reynolds SM, Undem BJ: Identification of tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol. 2004, 557: 543-558. 10.1113/jphysiol.2003.057885.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Canning BJ: Encoding of the cough reflex. Pulm Pharmacol Ther. 2007, 20: 396-401. 10.1016/j.pupt.2006.12.003.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Nishino T, Hiraga K, Yokokawa N: Laryngeal and respiratory to tracheal irritation at different depths of Enflurane anesthesia in humans. Anesthesiology. 1990, 73: 46-51. 10.1097/00000542-199007000-00008.

    Article  CAS  PubMed  Google Scholar 

  9. Baekey DM, Morris KF, Gestreau C, Li Z, Lindsey BG, Shannon R: Medullary respiratory neurones and control of laryngeal motoneurones during fictive eupnoea and cough in the cat. J Physiol. 2001, 534: 565-581. 10.1111/j.1469-7793.2001.t01-1-00565.x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Polley L, Yaman N, Heaney L, Cardwell C, Murtagh E, Ramsey J, MacMahon J, Costello RW, McGarvey L: Impact of cough across different chronic respiratory diseases. Comparison of two cough-specific health-related quality of life questionnaires. Chest. 2008, 134: 295-302.

    Article  PubMed  Google Scholar 

  11. Tatar M, Hanacek J, Widdicombe JG: The expiration reflex from the trachea and bronchi. Eur Respir J. 2008, 31: 385-390. 10.1183/09031936.00063507.

    Article  CAS  PubMed  Google Scholar 

  12. Riccio MM, Kummer W, Biglari B, Myers AC, Undem BJ: Interganglionic segregation of distinct vagal afferent fibre phenotypes in guinea-pig airways. J Physiol (Lond). 1996, 496: 521-530.

    Article  CAS  Google Scholar 

  13. Lingueglia E: Acid-sensing ion channels in sensory perception. J Biol Chem. 2007, 282: 17325-17329. 10.1074/jbc.R700011200.

    Article  CAS  PubMed  Google Scholar 

  14. Kollarik M, Ru F, Undem BJ: Acid-sensitive vagal sensory pathways and cough. Pulm Pharmacol Ther. 2007, 20: 402-411. 10.1016/j.pupt.2006.11.010.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Benini L, Ferrari M, Sembenin IC, Olivieri M, Miccioloc R, Zuccalib V, Bulighind GM, Fiorinoe F, Ederled A, Casciob V, Vantini I: Cough threshold in reflux oesophagitis: influence of acid and of laryngeal and oesophageal damage. Gut. 2000, 46: 762-767. 10.1136/gut.46.6.762.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Wong CH, Matai R, Morice AH: Cough induced by low pH. Respir Med. 1999, 93: 58-61. 10.1016/S0954-6111(99)90078-1.

    Article  CAS  PubMed  Google Scholar 

  17. Widdicombe JG: Functional morphology and physiology of pulmonary rapidly adapting receptors (RARs). Anat Rec. 2003, 270A: 2-10. 10.1002/ar.a.10003.

    Article  CAS  Google Scholar 

  18. Mazzone SB: An overview of the sensory receptors regulating cough. Cough. 2005, 1: 1-9. 10.1186/1745-9974-1-1.

    Article  Google Scholar 

  19. Nishino T, Isono S, Tanaka A, Ishikawa T: Laryngeal inputs in defensive airway reflexes in humans. Pulm Pharmacol Ther. 2004, 17: 377-381. 10.1016/j.pupt.2004.09.013.

    Article  CAS  PubMed  Google Scholar 

  20. Canning BJ, Farmer DG, Mori N: Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs. Am J Physiol Regul Integr Comp Physiol. 2006, 291: R454-R463. 10.1152/ajpregu.00862.2005.

    Article  CAS  PubMed  Google Scholar 

  21. Waldmann R, Bassilana F, de Weille J, G C, Heurteaux C, Lazdunski M: Molecular cloning of a non-inactivating proton-gated Na+ channel specific for sensory neurons. J Biol Chem. 1997, 272: 20975-20978. 10.1074/jbc.272.34.20975.

    Article  CAS  PubMed  Google Scholar 

  22. Kubin L, Alheid GF, Zuperku EJ, McCrimmon DR: Central pathways of pulmonary and lower airway vagal afferents. J Appl Physiol. 2006, 101: 618-627. 10.1152/japplphysiol.00252.2006.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Canning BJ: Central regulation of the cough reflex: Therapeutic implications. Pulm Pharmacol Ther. 2009, 22: 75-81. 10.1016/j.pupt.2009.01.003.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Lee L-Y: Respiratory sensations evoked by activation of bronchopulmonary C-fibers. Respir Physiol Neurobiol. 2009, 167: 26-35. 10.1016/j.resp.2008.05.006.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Sant'Ambrogio G: Afferent pathways for the cough reflex. Bull Eur Physiopathol Respir. 1987, 23 (Suppl 10): 19s-23s.

    PubMed  Google Scholar 

  26. Undem BJ, Carr MJ: Pharmacology of airway afferent nerve activity. Respir Res. 2001, 2:

    Google Scholar 

  27. Undem BJ, Chuaychoo B, Lee M-G, Weinreich D, Myers AC, Kollarik M: Subtypes of vagal afferent C-fibres in guinea-pig lungs. J Physiol. 2004, 556: 905-917. 10.1113/jphysiol.2003.060079.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Widdicombe JG: Airway receptors. Respir Physiol. 2001, 125: 3-15. 10.1016/S0034-5687(00)00201-2.

    Article  CAS  PubMed  Google Scholar 

  29. Davenport PW, Vovka A, Dukea RK, Bolsera DC, Robertson E: The urge-to-cough and cough motor response modulation by the central effects of nicotine. Pulm Pharmacol Ther. 2009, 22: 82-89. 10.1016/j.pupt.2008.11.013.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Mazzone SB, McLennan L, McGovern AE, Eagan GF, Farrell MJ: Representation of capsaicin-evoked urge to cough in the human brain using functional magnetic resonance imaging. Amer J Respir Crit Care Med. 2007, 176: 327-332. 10.1164/rccm.200612-1856OC.

    Article  Google Scholar 

  31. Canning BJ: Reflex regulation of airway smooth muscle tone. J Appl Physiol. 2006, 101: 971-985. 10.1152/japplphysiol.00313.2006.

    Article  CAS  PubMed  Google Scholar 

  32. Lee LY, Kwong K, Lin YS, Gu Q: Hypersensitivity of bronchopulmonary C-fibers induced by airway mucosal inflammation: cellular mechanisms. Pulm Pharmacol Ther. 2002, 15: 199-204. 10.1006/pupt.2002.0338.

    Article  CAS  PubMed  Google Scholar 

  33. Mazzone SB, Cole LJ, Ando A, Egan GF, Farrell MJ: Investigation of the neural control of cough and cough suppression in humans using functional brain imaging. J Neurosci. 2011, 31: 2948-2958. 10.1523/JNEUROSCI.4597-10.2011.

    Article  CAS  PubMed  Google Scholar 

  34. Watanabea N, S H, Michaelb GJ, Keira S, Spinaa D, Pagea CP, JV P: Immunohistochemical co-localization of Transient Receptor Potential Vanilloid (TRPV) 1 and sensory neuropeptides in the guinea-pig respiratory system. Neuroscience. 2006, 141: 1533-1554. 10.1016/j.neuroscience.2006.04.073.

    Article  CAS  Google Scholar 

  35. Groneberg DA, Quarcoo D, Frossard N, Fischer A: Neurogenic mechanisms in bronchial inflammatory diseases. Allergy. 2004, 59: 1139-1152. 10.1111/j.1398-9995.2004.00665.x.

    Article  CAS  PubMed  Google Scholar 

  36. Guo A, Vulchanova L, Wang J, Li X, R E: Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding site. Eur J Neurosci. 2001, 11: 946-958.

    Article  Google Scholar 

  37. Canning BJ: Anatomy and neurophysiology of the cough reflex: ACCP evidence-based clinical practice guidelines. Chest. 2006, 129: 33S-47S. 10.1378/chest.129.1_suppl.33S.

    Article  PubMed  Google Scholar 

  38. Birrell MA, Belvisi MG, Grace M, Sadofsky L, Faruqi S, Hele DJ, Maher SA, Freund-Michel V, Morice AH: TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am J Respir Crit Care Med. 2009, 180: 1042-1047. 10.1164/rccm.200905-0665OC.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Taylor-Clark TE, McAlexander MA, Nassenstein C, Sheardown SA, Wilson S, Thornton J, Carr MJ, Undem BJ: Relative contributions of TRPA1 and TRPV1 channels in the activation of vagal bronchopulmonary C-fibres by the endogenous autacoid 4-oxononenal. J Physiol. 2008, 586: 3447-3459. 10.1113/jphysiol.2008.153585.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. McNamara CR, Mandel-Brehm J, Bautista DM, J S, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM: TRPA1 mediates formalin-induced pain. PNAS. 2007, 104: 13525-13530. 10.1073/pnas.0705924104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Bautista DM, Jordt S-E, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D: TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006, 124: 1269-1282. 10.1016/j.cell.2006.02.023.

    Article  CAS  PubMed  Google Scholar 

  42. Brooks SM: Irritant-Induced Chronic Cough: a TRPpathy. Lung. 2008, 186: S88-S93. 10.1007/s00408-007-9068-0.

    Article  CAS  PubMed  Google Scholar 

  43. Materazzi S, Nassini R, Gatti R, Trevisani M, Geppetti P: Pharmacology and therapeutics of cough. Cough sensors. II. Transient receptor potential membrane receptors on cough sensors. Handbook of Experimental Pharmacology. 2009, 187: 49-61. 10.1007/978-3-540-79842-2_3.

    Article  CAS  PubMed  Google Scholar 

  44. Bolser DC, Davenport PW: Functional organization of the central cough generation mechanism. Pulm Pharmacol Ther. 2002, 15: 221-225. 10.1006/pupt.2002.0361.

    Article  CAS  PubMed  Google Scholar 

  45. Widdicombe JG: Neurophysiology of the cough reflex. Eur Respir J. 1995, 8: 1193-1202. 10.1183/09031936.95.08071193.

    Article  CAS  PubMed  Google Scholar 

  46. Ambalavanar R, Tanaka Y, Selbie WS, Ludlow CL: Neuronal activation in the medulla oblongata during selective elicitation of the laryngeal adductor response. J Neurophysiol. 2004, 92: 2920-2932. 10.1152/jn.00064.2004.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Gestreau C, Dutschmann M, Obled S, Bianchi AL: Activation of XII motoneurons and premotor neurons during various oropharyngeal behaviors. Respir Physiol Neurobiol. 2005, 147: 159-176. 10.1016/j.resp.2005.03.015.

    Article  PubMed  Google Scholar 

  48. Suárez AA, Pessolano FA, Monteiro SG, Ferreyra G, Capria ME, Mesa L, Dubrovsky A, De Vito EL: Peak Flow and Peak Cough Flow in the Evaluation of Expiratory Muscle Weakness and Bulbar Impairment in Patients with Neuromuscular Disease. Amer J Phys Med Rehab. 2002, 81: 506-511. 10.1097/00002060-200207000-00007.

    Article  Google Scholar 

  49. Hilaire G, Duron B: Maturation of the mammalian respiratory system. Physiol Rev. 1999, 79: 325-360.

    CAS  PubMed  Google Scholar 

  50. Gacek RR: Localization of laryngeal motor neurons in the kitten. Laryngoscope. 1975, 85: 1841-1861. 10.1288/00005537-197511000-00007.

    Article  CAS  PubMed  Google Scholar 

  51. Brasnu DF: Recurrent laryngeal nerve paralysis: Current concepts and treatment: Part I-Phylogenesis and physiology. Ear Nose and Throat Journal. 2000, 1-20.

    Google Scholar 

  52. Addington WR, Stephens RE, Widdicombe JG, Ockey RR, Anderson JW, Miller SP: Electrophysiologic latency to the external obliques of the laryngeal cough expiration reflex in humans. Am J Phys Med Rehabil. 2003, 82: 370-373.

    PubMed  Google Scholar 

  53. Hadjikoutis S, Wiles CM, Eccles R: Cough in motor neuron disease: a review of mechanisms. QJM. 1999, 92: 487-494. 10.1093/qjmed/92.9.487.

    Article  CAS  PubMed  Google Scholar 

  54. Poliacek I, Stransky A, Jakus J, Barani H, Tomori Z, Halasova E: Activity of the laryngeal abductor and adductor muscles during cough, expiration and aspiration reflexes in cats. Physiol Res. 2003, 52: 749-762.

    CAS  PubMed  Google Scholar 

  55. Sant'Ambrogio G, Sant'Ambrogio FB: Role of laryngeal afferents in cough. Pulm Pharmacol. 1996, 9: 309-314. 10.1006/pulp.1996.0040.

    Article  PubMed  Google Scholar 

  56. Sasaki CT: Anatomy and development and physiology of the larynx. Shaker and Goyal GI Motility online-Part 1 Oral cavity, pharynx and esophagus. Edited by: Goyal R, Shaker R. 2008, London: Nature Publishing Group, 2006, [http://www.nature.com/gimo/contents/pt1/full/gimo7.html]

    Google Scholar 

  57. Shah MD, Shah SM: The applied physiology of cough. Indian J Pediatr. 2001, 68 (Suppl 2): S3-10.

    PubMed  Google Scholar 

  58. Shannon R, Baekey DM, Morris KF, Lindsey BG: Ventrolateral medullary respiratory network and a model of cough motor pattern generation. J Appl Physiol. 1998, 84: 2020-2035.

    CAS  PubMed  Google Scholar 

  59. Widdicombe JG: Respiratory reflexes from the trachea and bronchi of the cat. J Physiol. 1954, 123: 55-70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Widdicombe JG, Eccles R, Fontanac G: Supramedullary influences on cough. Resp Physiol Neurobiol. 2006, 152: 320-328. 10.1016/j.resp.2006.02.018.

    Article  Google Scholar 

  61. Pickering M, Jones JFX: The diaphragm: two physiological muscles in one. J Anat. 2002, 201: 305-312. 10.1046/j.1469-7580.2002.00095.x.

    Article  PubMed Central  PubMed  Google Scholar 

  62. Martin-Harris B: Coordination of respiration and swallowing. Shaker and Goyal GI Motility online-Part 1 Oral cavity, pharynx and esophagus. Edited by: Goyal R, R S. 2008, London: Nature Publishing Group, 2006, [http://www.nature.com/gimo/contents/pt1/full/gimo10.html]

    Google Scholar 

  63. Piirila P, Sovijarvi AR: Objective assessment of cough. Eur Respir J. 1995, 8: 1949-1956. 10.1183/09031936.95.08111949.

    Article  CAS  PubMed  Google Scholar 

  64. Shiba K, Nakazawa K, Ono K, Umezaki T: Multifunctional laryngeal premotor neurons: their activities during breathing, coughing, sneezing, and swallowing. J Neuroscience. 2007, 27: 5156-5162. 10.1523/JNEUROSCI.0001-07.2007.

    Article  CAS  PubMed  Google Scholar 

  65. Shaker G: Reflex interaction of pharynx, esophagus, and airway. Shaker and Goyal GI Motility online-Part 1 Oral cavity, pharynx and esophagus. Edited by: Goyal R, R S. 2008, London: Nature Publishing Group, 2006, [http://www.nature.com/gimo/contents/pt1/full/gimo11.html]

    Google Scholar 

  66. Morris JB, Symanowicz PT, Olsen JE, Thrall RS, Cloutier MM, Hubbard AK: Immediate sensory nerve-mediated respiratory responses to irritants in healthy and allergic airway-diseased mice. J Appl Physiol. 2003, 94: 1563-1571.

    Article  CAS  PubMed  Google Scholar 

  67. Gacek RR, Malmgren LT, Lyon MJ: Localization of adductor and abductor motor nerve fibers to the larynx. Ann Otol. 1977, 86: 770-776.

    Google Scholar 

  68. Fontana GA, Widdicombe JG: What is cough and what should be measured?. Pulm Pharmacol Therap. 2007, 20: 307-312. 10.1016/j.pupt.2006.11.009.

    Article  CAS  Google Scholar 

  69. Poliacek I, Corrie LW-C, Wang C, Rose MJ, Bolser DC: Microinjection of DLH into the region of the caudal ventral respiratory column in the cat: evidence for an endogenous cough-suppressant mechanism. J Appl Physiol. 2007, 102: 1014-1021.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Baekey DM, Morris KF, Nuding SC, Segers LS, Lindsey BG, Shannon R: Medullary raphe neuron activity is altered during fictive cough in the decerebrate cat. J Appl Physiol. 2003, 94: 93-100.

    Article  PubMed  Google Scholar 

  71. Bongianni F, Mutolo D, Fontana GA, Pantaleo T: Discharge patterns of Bötzinger complex neurons during cough in the cat. Am J Physiol Regul Integr Comp Physiol. 1998, 274: R1015-R1024.

    CAS  Google Scholar 

  72. Rybak A, O'Connor RO, Ross A, Shevtsova NA, Nuding SC, Segers LS, Shannon R, Dick TE, Dunin-Barkowski WL, Orem JM, et al: Reconfiguration of the pontomedullary respiratory network: A computational modeling study with coordinated in vivo experiments. J Neurophysiol. 2008, 100: 1770-1799. 10.1152/jn.90416.2008.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Jiang C, Lipski J: Extensive monosynaptic inhibition of ventral respiratory group neurons by augmenting neurons in the Bötzinger complex in the cat. Exp Brain Res. 1990, 81: 631-

    Article  Google Scholar 

  74. Ono K, Shiba K, Nakazawa K, Shimoyama I: Synaptic origin of the respiratory-modulated activity of laryngeal motoneurons. Neurosci. 2006, 140: 1079-1088. 10.1016/j.neuroscience.2006.02.063.

    Article  CAS  Google Scholar 

  75. Jürgens U, Ehrenreicha L: The descending motorcortical pathway to the laryngeal motoneurons in the squirrel monkey. Brain Research. 2007, 1148: 90-95.

    Article  PubMed  CAS  Google Scholar 

  76. Canning BJ, Widdicombe JG: Innervation of the airways: Introduction. Respir Physiol. 2001, 125: 1-2. 10.1016/S0034-5687(00)00200-0.

    Article  CAS  PubMed  Google Scholar 

  77. Morice AH, Fontana GA, Belvisi MG, Birring SS, Chung KF, Dicpinigaitis PV, Kastelik JA, McGarvey LP, Smith JA, Tatar M, Widdicombe JG: ERS Taskforce: The diagnosis and management of chronic cough. Eur Respir J. 2004, 24: 481-492. 10.1183/09031936.04.00027804.

    Article  CAS  PubMed  Google Scholar 

  78. Haxhiu MA, Kc P, Moore CT, Acquah SS, Wilson CG, Zaidi SI, Massari VJ, Ferguson DG: Brain stem excitatory and inhibitory signaling pathways regulating bronchoconstrictive responses. J Appl Physiol. 2005, 98: 1961-1982. 10.1152/japplphysiol.01340.2004.

    Article  CAS  PubMed  Google Scholar 

  79. Bolser DC, Poliacek I, Jakus J, Fuller DD, Davenport PW: Neurogenesis of cough, other airway defensive behaviors and breathing: A holarchical system?. Resp Physiol Neurobiol. 2006, 152: 255-265. 10.1016/j.resp.2006.01.008.

    Article  Google Scholar 

  80. Hutchings HA, Morris S, Eccles R, Jawad MS: Voluntary suppression of cough induced by inhalation of capsaicin in healthy volunteers. Respir Med. 1993, 87: 379-382. 10.1016/0954-6111(93)90052-2.

    Article  CAS  PubMed  Google Scholar 

  81. Simonyan K, Saad ZS, Loucks TMJ, Poletto CJ, Ludlow CL: Functional neuroanatomy of human voluntary cough and sniff production. Neuroimage. 2007, 15: 401-409.

    Article  Google Scholar 

  82. Lasserson D, Mills K, Arunachalam R, Polkey M, Moxham J, Kalra L: Differences in motor activation of voluntary and reflex cough in humans. Thorax. 2006, 61: 699-705. 10.1136/thx.2005.057901.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. O'Connell F: Central pathways for cough in man-unanswered questions. Pulm Pharmacol Ther. 2002, 15: 295-301. 10.1006/pupt.2002.0344.

    Article  PubMed  CAS  Google Scholar 

  84. Davenport PW, Sapienza CM, Bolser DC: Psychophysical assessment of the urge-to-cough. Eur Respir Rev. 2002, 12: 249-253.

    Google Scholar 

  85. Bolser DC: Experimental models and mechanisms of enhanced coughing. Pulm Pharmacol Ther. 2004, 7: 383-388.

    Article  CAS  Google Scholar 

  86. Adams L, Schneider DA, Schertel ER, Strong EB, Green JF: Respiratory reflexes in the anesthetized miniature swine. Respir Physiol. 1987, 70: 343-357.

    Article  CAS  PubMed  Google Scholar 

  87. Belvisi MG, Hele DJ: Animal models of cough. Cough: Causes, Mechanisms and Therapy. Edited by: Chung KF, Widdicombe JG, Boushey HA. 2003, Oxford: Blackwell Publishing Ltd, 217-222.

    Chapter  Google Scholar 

  88. Coleridge JC, Coleridge HM: Afferent vagal C fibre innervation of the lungs and airways and its functional significance. Rev Physiol Biochem Pharmacol. 1984, 99: 1-110. 10.1007/BFb0027715.

    CAS  PubMed  Google Scholar 

  89. House A, Celly C, Skeans S, Lamca J, Egan RW, Hey JA, Chapman RW: Cough reflex in allergic dogs. Eur J Pharmacol. 2004, 492: 251-258. 10.1016/j.ejphar.2004.03.053.

    Article  CAS  PubMed  Google Scholar 

  90. Müller GB: Evo-Devo: Extending the evolutionary synthesis. Nature Reviews Genetics. 2007, 8: 943-949.

    Article  PubMed  CAS  Google Scholar 

  91. Javorka K, Kulisek V, Calkovska A: Defensive Reflexes of the Respiratory System in Anaesthetized Rabbits during High Frequency Jet Ventilation. Experimental Physiology. 1994, 79: 967-973.

    Article  CAS  PubMed  Google Scholar 

  92. Lewisa CA, Ambrosea C, Bannera K, Battrama C, Butlera K, Giddingsa J, Moka J, Nasrab J, Winnya C, Polla C: Animal models of cough: Literature review and presentation of a novel cigarette smoke-enhanced cough model in the guinea-pig. Pulm Pharmacol Ther. 2007, 20: 325-333. 10.1016/j.pupt.2006.12.001.

    Article  CAS  Google Scholar 

  93. Tatar M, Pecova R, Karcolova D: Sensitivity of the cough reflex in awake guinea pigs, rats and rabbits. Bratisl Lek Listy. 1997, 98: 539-543.

    CAS  PubMed  Google Scholar 

  94. Stephens RE, Addington WR, Widdicombe JG: Effect of acute unilateral middle cerebral artery infarcts on voluntary cough and the laryngeal cough reflex. Am J Phys Med Rehabil. 2003, 82: 379-383.

    PubMed  Google Scholar 

  95. Niimi A, Matsumoto H, Ueda T, Takemura M, Suzuki K, Tanaka E, Chin K, Mishima M, Amitani R: Impaired cough reflex in patients with recurrent pneumonia. Thorax. 2003, 58: 152-153. 10.1136/thorax.58.2.152.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Nishimura T, Oishi T, Suzuki J, Matsuda K, Takahashi T: Development of the supralaryngeal vocal tract in Japanese macaques: implications for the evolution of the descent of the larynx. Am J Phys Anthrol. 2008, 135: 182-194. 10.1002/ajpa.20719.

    Article  Google Scholar 

  97. Ruben JA, Bennett AF, Hisaw FL: Selective factors in the origin of the mammalian diaphragm. Paleobiology. 1987, 13: 54-59.

    Google Scholar 

  98. Carroll SB: Endless Forms Most Beautiful-The New Science of Evo Devo and the Making of the Animal Kingdom. 2005, New York, London: WM Norton & Company, 1

    Google Scholar 

  99. Cavalli-Sforza LL, Feldman MW: The application of molecular genetic approaches to the study of human evolution. Nat Genet. 2003, 33: 266-275. 10.1038/ng1113.

    Article  CAS  PubMed  Google Scholar 

  100. Rothchild I: The yolkless egg and the evolution of Eutherian viviparity. Biology of Reproduction. 2003, 6: 337-357.

    Google Scholar 

  101. Sneddon LU: Evolution of nociception in vertebrates: comparative analysis of lower vertebrates. Brain Res Rev. 2004, 46: 123-130. 10.1016/j.brainresrev.2004.07.007.

    Article  CAS  PubMed  Google Scholar 

  102. Brown S: Contagious heterophony: a new theory about the origins of music. Musicae Scientiae. 2007, 11: 3-26.

    Article  Google Scholar 

  103. Brown S, Ngan E, Liotti M: A Larynx Area in the Human Motor Cortex. Cerebral Cortex. 2008, 18: 837-845.

    Article  PubMed  Google Scholar 

  104. Rowe TB, Macrini TE, Luo Z-X: Fossil evidence on origin of the mammalian brain. Science. 2011, 332: 955-957. 10.1126/science.1203117.

    Article  CAS  PubMed  Google Scholar 

  105. Bolser DC: Central mechanisms II: Pharmacology of brainstem pathways. Pharmacology and Therapeutics of Cough. Edited by: Chung KF, Widdicombe J. 2009, Berlin, Heidelberg: Springer, 187: 203-217. 10.1007/978-3-540-79842-2_10. [F. Hofmann M (Series Editor) Handbook of Experimental Pharmacology]

    Chapter  Google Scholar 

  106. Harpending H, Batzer MA, Gurven M, Jorde LB, Rogers AR, ST S: Genetic traces of ancient demography. PNAS USA. 1998, 95: 1961-1967. 10.1073/pnas.95.4.1961.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Lieberman DE, McBratney BM, Krovitz G: The evolution and development of cranial form in Homosapiens. PNAS. 2002, 99: 1134-1139. 10.1073/pnas.022440799.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Lieberman P, McCarthy R: Tracking the evolution of language and speech: Comparing Vocal Tracts to Identify Speech Capabilities. Expedition Magazine. 2007, 49: 15-20. 2

    Google Scholar 

  109. Enard WM, Przeworski SE, Fisher CSL, Lai V, Wiebe T, Kitano AP, Monaco AP, Pääbo S: Molecular evolution of FOXP2, a gene involved in speech and language. Nature Genetics. 2002, 418: 869-872.

    CAS  Google Scholar 

  110. Pilbeam D: Genetic and Morphological Records of the Hominoidea and Hominid Origins: A Synthesis. Mol Phylog Evol. 1996, 5: 155-168. 10.1006/mpev.1996.0010.

    Article  CAS  Google Scholar 

  111. Simonyan K, Ostuni J, Ludlow CL, Horwitz B: Functional but not structural networks of the human laryngeal motor cortex show left hemispheric lateralization during syllable but not breathing production. J Neurosci. 2009, 29: 14912-14923. 10.1523/JNEUROSCI.4897-09.2009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM, Lahn BT: Accelerated Evolution of Nervous System Genes in the Origin of Homo sapiens. Cell. 2004, 119: 1027-1040. 10.1016/j.cell.2004.11.040.

    Article  CAS  PubMed  Google Scholar 

  113. Simonyan K, Jürgens U: Afferent cortical connections of the motor cortical larynx area in the rhesus monkey. Neurosci. 2005, 130: 133-149. 10.1016/j.neuroscience.2004.08.031.

    Article  CAS  Google Scholar 

  114. Zhang J, Webb DM, Podlaha O: Accelerated Protein Evolution and Origins of Human-Specific Features: FOXP2 as an Example. Genetics. 2002, 162: 1825-1835.

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG: ASPM is a major determinant of cerebral cortical size. Nat Genet. 2002, 32: 316-320. 10.1038/ng995.

    Article  CAS  PubMed  Google Scholar 

  116. Evans PD, Anderson JR, Vallender EJ, Gilbert SL, Malcom CM, Dorus S, Lahn BT: Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Human Molecular Genetics. 2004, 13: 489-494. 10.1093/hmg/ddh055.

    Article  CAS  PubMed  Google Scholar 

  117. Kouprina N, Pavlicek A, Mochida GH, Solomon G, Gersch W, Yoon Y-H, Collura R, Ruvolo M, Barrett JC, Woods CG, Walsh CA, Jurka J, Larionov V: Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion. PLoS Biology. 2004, 2: 0653-0663.

    Article  CAS  Google Scholar 

  118. Mekel-Bobrov N, Gilbert SL, Evans PD, Vallender EJ, Anderson JR, Hudson RR, Tishkoff SA, Lahn BT: Ongoing Adaptive Evolution of ASPM, a Brain Size Determinant in Homo sapiens. Science. 2005, 309: 1720-1722. 10.1126/science.1116815.

    Article  CAS  PubMed  Google Scholar 

  119. Zhang J: Evolution of the Human ASPM Gene, a Major Determinant of Brain Size. Genetics. 2003, 165: 2063-2070.

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Coop G, Bullaughey K, Luca F, Przeworski M: The Timing of Selection at the Human FOXP2 Gene. Mol Biol Evol. 2008, 25: 1257-1259. 10.1093/molbev/msn091.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Krause J, Lalueza-Fox C, Orlando L, Enard W, Green RE, Burbano HA, Hublin J-J, Hänni C, Fortea J, de la Rasilla M, Bertranpetit J, Rosas A, Pääbo S: The Derived FOXP2 Variant of Modern Humans Was Shared with Neanderthals. Curr Biol. 2007, 17: 1908-1912. 10.1016/j.cub.2007.10.008.

    Article  CAS  PubMed  Google Scholar 

  122. Lieberman P: The FOXP2 gene, human cognition and language. Integrative Approaches to Human Health and Evolution. 2006, 115-126. April 18-20, 2005; Madrid, Spain. Elsevier B.V.

    Google Scholar 

  123. Shua W, Chob JY, Jiangc Y, Zhangc M, Weiszf D, Elderd GA, Schmeidlerd J, De Gasperid R, Gama Sosad MA, Rabidou D, Santuccij AC, Perld D, Morriseya E, Buxbaumc JD: Altered ultrasonic vocalization in mice with a disruption in the FoxP2 gene. PNAS. 2005, 102: 9643-9648. 10.1073/pnas.0503739102.

    Article  CAS  Google Scholar 

  124. Challen JJ, Taylor EW: Retroviruses, ascorbate, and mutations, in the evolution of Homo sapiens. Free Radical Biology and Medicine. 1998, 25: 130-132. 10.1016/S0891-5849(98)00034-3.

    Article  Google Scholar 

  125. Bjørnstada ON, Harvillb ET: Evolution and emergence of Bordetella in humans. Trends in Microbiology. 2005, 13: 355-359. 10.1016/j.tim.2005.06.007.

    Article  CAS  Google Scholar 

  126. Calixto JB, Medeiros R, Fernandes ES, Ferreira J, Cabrini DA, Campos MM: Kinin B1 receptors: key G-protein-coupled receptors and their role in inflammatory and painful processes. Br J Pharmacol. 2005, 143: 803-818.

    Article  CAS  Google Scholar 

  127. Carr MJ, Undem BJ: Pharmacology of vagal afferent nerve activity in guinea pig airways. Pulm Pharmacol Ther. 2003, 16: 45-52. 10.1016/S1094-5539(02)00179-7.

    Article  CAS  PubMed  Google Scholar 

  128. Roebroeks W, Villa P: On the earliest evidence for habitual use of fire in Europe. PNAS. 2011, 108: 5209-5214. 10.1073/pnas.1018116108.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Smith KR: Inaugural article: National burden of disease in India from indoor air pollution. Proceedings of the National Academy of Sciences of the United States of America. 2000, 97: 13286-13293. 10.1073/pnas.97.24.13286.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  130. Bell PJL: Viral eukaryogenesis: was the ancestor of the nucleus a complex DNA virus?. J Mol Evol. 2001, 53: 251-256. 10.1007/s002390010215.

    Article  CAS  PubMed  Google Scholar 

  131. Burgel P-R, Nadel JA: Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur Respir J. 2008, 32:

    Google Scholar 

  132. Myou S, Fujimura M, Kita T, Katayama N, Abo M, Yoshimi Y, Nishitsuji M, Nomura S, Nakao S: Sensory neuropeptides are not involved in acetaldehyde-induced bronchoconstriction in guinea-pigs. J Auton Pharmacol. 2001, 21: 139-143. 10.1046/j.1365-2680.2001.00217.x.

    Article  CAS  PubMed  Google Scholar 

  133. Öckinger J, Serrano-Fernández P, Möller S, Ibrahim SM, Olsson T, Jagodic M: Definition of a 1.06-Mb Region Linked to Neuroinflammation in Humans, Rats and Mice. Genetics. 2006, 173: 1539-1154. 10.1534/genetics.106.057406.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  134. Baluk P: Neurogenic inflammation in skin and airways. J Investig Dermatol Symp Proc. 1997, 2: 76-81.

    Article  CAS  PubMed  Google Scholar 

  135. Barnes PJ: Neurogenic inflammation and asthma. J Asthma. 1992, 29: 165-180. 10.3109/02770909209099025.

    Article  CAS  PubMed  Google Scholar 

  136. Lee M-G, Undem BJ, Brown C, Carr MJ: Effect of Nociceptin in Acid-evoked Cough and Airway Sensory Nerve Activation in Guinea Pigs. Am J Respir Crit Care Med. 2006, 173: 271-275. 10.1164/rccm.200507-1043OC.

    Article  CAS  PubMed  Google Scholar 

  137. Kwong K, Wu ZX, Kashon ML, Krajnak KM, Wise PM, Lee LY: Chronic smoking enhances tachykinin synthesis and airway responsiveness in guinea pigs. Am J Respir Cell Mol Bio. 2001, 25: 299-305.

    Article  CAS  Google Scholar 

  138. Mutoh T, Bonham AC, Joad JP: Substance P in the nucleus of the solitary tract augments bronchopulmonary C fiber reflex output. Am J Physiol Regul Integr Comp Physiol. 2000, 279: R1215-1223.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Colleges of Public Health and Medicine, University of South Florida, Tampa, Florida

    Stuart M Brooks

Authors
  1. Stuart M Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stuart M Brooks.

Additional information

Competing interests

The author declares that they have no competing interests.

Authors’ original submitted files for images

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Brooks, S.M. Perspective on the human cough reflex. Cough 7, 10 (2011). https://doi.org/10.1186/1745-9974-7-10

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1745-9974-7-10

Keywords

  • Human evolution
  • Cough mechanisms
  • Transient receptor potential vanilloid cation channel (TRPV1)
  • Mechanosensory Cough
  • Chemosensory Cough
  • Urge to cough

Cough

ISSN: 1745-9974