Neuronal control of the airways

INTRODUCTION — Airway nerves serve vital roles in the regulation of homeostatic respiration and defensive reflexes that preserve lung capacity for gas exchange. In airway diseases such as allergic rhinitis, asthma, and chronic cough, neuronal dysregulation contributes to disease pathogenesis, with many of the symptoms associated with upper and lower airway disease directly or indirectly related to these changes in neuronal function (figure 1).

Neural control of the upper and lower airways will be reviewed here; other aspects of the pathogenesis of asthma, allergic rhinitis, and chronic obstructive pulmonary disease (COPD) are presented separately. (See "Pathogenesis of asthma" and "Pathogenesis of allergic rhinitis (rhinosinusitis)" and "Chronic obstructive pulmonary disease: Risk factors and risk reduction".)

INNERVATION OF THE UPPER AIRWAY

Afferent innervation — The olfactory nerve (cranial nerve I) provides afferent innervation associated with the sensation of smell. (See "Taste and olfactory disorders in adults: Anatomy and etiology".)

The remaining afferent innervation of the nasal mucosa arises from the ophthalmic (through the ethmoidal nerve) and maxillary branches of the trigeminal nerve. The cell bodies of nonolfactory primary sensory nerves from the nose are located in the trigeminal ganglion. These afferent nerve fibers branch extensively, innervating the epithelium, vessels, and glands of the nasal mucosa. The extensive branching and innervation of multiple effectors in the mucosa, along with synthesis and peripheral transport of neuropeptides with many potential actions in the nose, provide the anatomical substrate necessary for producing axonal reflexes [1,2]. (See 'Axon reflexes' below.)

Reflexes (eg, sneezing, itching, rhinorrhea, and nasal congestion) can be initiated within the nose by a variety of stimuli, including mechanical probing, hypertonic saline, cold and/or dry air, histamine, allergen, nicotine, bradykinin, and capsaicin [2]. Evidence for nasal afferent nerve subtypes that are differentially responsive to inflammatory mediators and irritants has been reported [3]. While both histamine and bradykinin, when applied selectively to the nasal mucosa, initiate reflex-mediated, atropine-sensitive mucus secretion, only histamine readily initiates sneezing in typical patients [4-7]. The data are at least suggestive of the notion that nasal autonomic reflexes and sneezing are differentially regulated by nasal afferent nerve subtypes.

Efferent innervation — Both sympathetic and parasympathetic nerves innervate the vasculature and glands of the nasal mucosa. Sympathetic branches of the upper four cervical nerves meet in the superior cervical ganglia; postganglionic sympathetic nerves travel to the nasal mucosa via branches of the facial nerve (cranial nerve VII). Parasympathetic branches of the trigeminal nerve (cranial nerve V) are relayed to the nasal mucosa via the sphenopalatine ganglion. Studies conducted in animals using selective stimulation of autonomic nerve pathways and pharmacologic studies in human subjects indicate that sympathetic and parasympathetic nerves have opposing actions on their target tissues in the nasal mucosa (table 1 and figure 2).

Parasympathetic nerves and their neurotransmitters mediate mucus secretion and/or vasodilatation. Conversely, sympathetic nerves and sympathetic neurotransmitters have little or no effect on mucus secretion but constrict the blood vessels of the nasal mucosa and the capacitance vessels of the sinuses. The opposing actions of these systems likely determine levels of end-organ function in the nose. Postganglionic nerves might also interact prejunctionally to modulate neurotransmitter release [1,2].

Reflex regulation of upper airway function — The nose filters and conditions inspired air. Reflexes initiated by activation of upper airway afferent nerves preserve and facilitate this conditioning function of the nose. Nasal reflexes also play an important defensive role for the exposed nasal mucosa, hindering infection and clearing inhaled pathogens and irritants either by sneezing or with mucus secretion [8-10]. (See "An overview of rhinitis", section on 'Normal nasal reflexes'.)

Trigeminal afferent nerves terminate bilaterally and centrally in lateral regions of the pons, medulla, and cervical spinal cord, either rostrally in the principal sensory nuclei of the trigeminal nerve or caudally in the spinal trigeminal nuclei. The spinal trigeminal nuclei occupy extensive portions of the brainstem and cervical spinal cord and lie lateral but adjacent to many key structures in the brainstem relevant to the lower airways. The proximity of trigeminal afferent nerve terminations to brainstem structures involved in regulation of lower airway function and respiration may facilitate coordination of respiratory reflexes. This arrangement also provides the anatomical substrate for reflex effects on the lower airways initiated by upper airway irritation [2].

Nasal axon reflexes — Axon reflexes involve the peripheral release of neurotransmitters from sensory nerve terminals without signaling from the central nervous system [11-13]. In the human nose, axon reflexes have been demonstrated in response to capsaicin, hypertonic saline, and bradykinin, which result in mucus secretion, plasma extravasation, substance P release, and inflammatory cell recruitment [1,2,5-10,14-17]. The neurotransmitters mediating these effects have not been identified. However, exogenous neuropeptides induce comparable effects when applied selectively to the human nasal mucosa, and substance P-containing nerve fibers supplied by the trigeminal nerves are known to innervate human nasal mucosa [1,2,8].

INNERVATION OF THE LOWER AIRWAYS

Vagus nerves — The predominant innervation of the lower airways, extending from the larynx to the terminal bronchioles, is provided by afferent and efferent nerve fibers contained within the vagus nerves (cranial nerve X) (figure 3) [18-20].

Vagal sensory afferent nerves — Afferent sensory nerve fibers originate from cell bodies in the jugular (superior vagal) or nodose (inferior vagal) ganglia (collectively termed the vagal ganglia) located at the base of the skull and project to the airway epithelium, subepithelium and smooth muscle, including around glands, autonomic ganglia [21], and within the alveolar airspace distal to airways where they surround capillary beds [22-31]. Within airway epithelium specifically, sensory nerves form a dense plexus with nerve terminals projecting between cells towards the airway lumen where they detect inhaled and endogenous stimuli (picture 1).

Sensory nerves relay input from airways to brainstem centers, with nodose fibers terminating in the nucleus of the solitary tract (nTS) and jugular neurons terminating in the paratrigeminal nucleus (Pa5) [32]. These brainstem centers integrate and relay sensory input to the cerebral cortex, allowing for conscious perception of airway sensory input, and to motor centers involved in subconscious reflex responses such as bronchoconstriction and cough.

Airway afferent nerves can be subclassified based on their neurochemistry, responsiveness to physical and chemical stimuli, myelination, conduction velocity, origin, and sites of termination in the airways and central nervous system (CNS) [18,23,33-39]. No classification scheme fully encapsulates all these features, and considerable overlap exists in the properties of sensory nerve subtypes. In general, sensory nerves are broadly classified as mechanoreceptors or nociceptors (also known as chemoreceptors) based on their responsiveness to either mechanical or chemical stimuli, respectively.

Mechanoreceptors — Three subtypes of airway mechanoreceptors have been described. Of these, the first and second subtypes respond to the dynamic (rapidly adapting receptors [RARs]) and sustained (slowly adapting receptors [SARs]) physical effects of lung inflation (figure 4). RARs can also be activated by bronchoconstrictors such as histamine, acetylcholine, and leukotrienes [36]. The third subtype of airway mechanoreceptor can be localized to the larynx, trachea, and mainstem bronchi and is activated by punctate mechanical stimuli and acid [40].

Mechanoreceptors have an essential role in initiation of cough (see "Causes and epidemiology of subacute and chronic cough in adults", section on 'Causes of chronic cough') and control of respiratory rate and tidal volume. Their activation also influences autonomic nerve activity, most notably the initiation of reflex bronchoconstriction (figure 4). (See 'Reflex regulation of airway smooth muscle' below.)

Nociceptors — Like mechanoreceptors, nociceptors initiate autonomic nerve activity and cough and have unique effects on respiratory patterns when activated. Most airway nociceptors are unmyelinated C fibers that express a variety of cell surface receptors capable of detecting a diverse array of chemical stimuli and inflammatory mediators [18,33,34,41]. For instance, the calcium-permeable ion channels in the transient receptor potential (TRP) channel family are widely expressed by nociceptors and are considered canonical cough receptors given their response to numerous tussive stimuli [42-54].

Examples of TRP receptor subtypes include TRP vanilloid 1 (TRPV1), whose ligands include the active ingredient in chili powder, capsaicin, and citric acid; TRP ankyrin 1 (TRPA1), which responds to endogenous mediators (eg, prostaglandins A2, E2, and D2), extracts from spicy foods (cinnamon, garlic, mustard oil, wasabi), noxious environmental irritants present in air pollution, vehicle exhaust and cigarette smoke (eg, acrolein, isothiocyanates), products of oxidation (4-oxynonenal, 4-hydroxynonenal, ozone), and temperatures below 17°C [55-58]; and TRP vanilloid 4 (TRPV4), which is activated by arachidonic acid and hypotonic solutions [59-63]. Numerous other ligands stimulate nociceptors, including bradykinin, 5-hydroxytryptamine (serotonin), and adenosine triphosphate (ATP) (figure 4), among others. TRPM8 is a cold and menthol receptor that suppresses cough but is mainly expressed in the upper airways [64].

Evidence from animal models suggests that individual receptors activate nociceptor neurons directly while also modifying the function of other surface receptors. For example, TRPV1 and TRPA1 antagonists inhibit prostaglandin E2 and bradykinin-induced coughing in guinea pigs, suggesting TRP channels play a role in G protein coupled receptor (GPCR) signaling in sensory afferents [57,65]. In some cases, cooperative interactions between receptors may occur, such as when TRPV4-mediated sensory nerve activation and TRPV4-induced cough are blocked by antagonists of the purinergic receptor P2X3, suggesting TRPV4’s effects are due to release of the P2X3 ligand ATP [66].

Airway nociceptor nerve terminals contain synaptic vesicles that store and release neurotransmitters and neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide (CGRP), among others. When administered exogenously, these putative neurotransmitters have profound effects in the airways, including initiation of bronchoconstriction, mucus secretion, vasodilation, plasma exudation, and inflammatory cell recruitment [24]. Neuropeptide-containing nerve terminals are thought to be the peripheral terminations of airway C fibers.

Parasympathetic (cholinergic) efferent nerves — Airway efferent nerve fibers consist of preganglionic parasympathetic (cholinergic) nerves that arise bilaterally from the dorsal motor nucleus of the vagus nerve and the nucleus ambiguus in the brainstem and are contained within the vagus nerves bilaterally alongside sensory fibers. Preganglionic parasympathetic nerves synapse on postganglionic parasympathetic nerves embedded in the airway wall in the trachea and extrapulmonary bronchi. These postganglionic parasympathetic nerves are clustered into ganglia containing anywhere from a few neurons to over 100 neurons [22] and give rise to nerve fibers that innervate airway smooth muscle [29], mucus glands [25], blood vessels [27,28], and adjacent parasympathetic neurons [67].

Synaptic transmission between pre- and postganglionic parasympathetic nerves is mediated by the neurotransmitter acetylcholine acting on neuronal nicotinic receptors [22,68]. Activated postganglionic parasympathetic nerves also release acetylcholine, which subsequently stimulates muscarinic receptors on target cells in the airway.

On airway smooth muscle, for example, acetylcholine activates M₃ muscarinic receptors to induce contraction that results in airway narrowing [69]. This mechanism, which is both tonically active at baseline and is rapidly modifiable to facilitate changes in airway caliber, provides the dominant control of bronchoconstriction. Acetylcholine also activates presynaptic inhibitory M₂ muscarinic receptors on parasympathetic neurons that limit further acetylcholine release and thus are critical for regulating the degree of bronchoconstriction [70].

Sympathetic (adrenergic) nerves — Postganglionic sympathetic nerves arise primarily from the superior cervical ganglia and the thoracic sympathetic ganglia bilaterally and project to their ipsilateral airways [71]. Sympathetic nerves release catecholamines, most notably norepinephrine, which activate alpha and beta receptors on airway vasculature to induce vasoconstriction [27,28]. Beta adrenoceptors (primarily beta-2 adrenoceptors) are also widely expressed by human airway smooth muscle and induce smooth muscle relaxation. However, airway sympathetic nerves have no known functional role in the regulation of human airway smooth muscle contractility [29] (in contrast to sympathetic innervation of airway smooth muscle in other species). Rather, catecholamines released into systemic circulation from the adrenal gland appear to be the primary endogenous ligand for airway smooth muscle beta adrenoceptors in humans.

Nonadrenergic noncholinergic (NANC) nerves — NANC nerves are noncholinergic parasympathetic neurons present throughout the trachea and extrapulmonary bronchi that provide the only functionally bronchodilatory innervation of human airway smooth muscle [29,72,73]. NANC-induced bronchorelaxation is mediated by the neurotransmitter nitric oxide (NO), which is synthesized from arginine by the neuronal isoform of NO synthase [74,75].

NANC nerve functions also include regulation of mucus secretion and vasodilatation [25,27,76], as well as release of other neurotransmitters, such as vasoactive intestinal peptide (VIP), that contribute to NANC-mediated relaxation in other species (eg, guinea pig).

Other neurotransmitters (eg, substance P, neurokinin A) have been localized to parasympathetic ganglion neurons innervating the lower airways as well (picture 2 and table 1) [19,29].

Spinal sensory afferent nerves — Spinal afferent sensory nerves arise from cervical and thoracic dorsal root ganglia and provide sparse innervation to the airways and pleura. Spinal sensory nerves have no direct role in airway function, but may contribute indirectly to regulation of airway sympathetic nerve function [77].

Reflex regulation of airway smooth muscle — Although the brainstem centers for vagal sensory afferent and parasympathetic efferent nerves are spatially distinct, connections between these centers allow afferent sensory nerves to modify efferent parasympathetic nerve tone. These connections allow activated sensory nerves to induce parasympathetic nerve acetylcholine release that results in bronchoconstriction. This mechanism, termed "reflex bronchoconstriction" [78-80], is provoked by many stimuli, including inhaled methacholine [81], histamine [82], cold air [83], allergens [84], and exercise [85].

Conversely, activation of other afferent subtypes, including pulmonary mechanoreceptors and skeletal and diaphragmatic sensory nerves, can also induce bronchorelaxation via withdrawal of cholinergic tone [29,86]. The rapid kinetics of cholinergic nerve-mediated responses renders these nerves ideally suited to regulate airway tone on a breath-to-breath basis, such as during exercise to better match demands for gas exchange, or to maximize expiratory airflow with coughing to facilitate airway clearance of inhaled irritants, secretions, or pathogens.

Evidence suggests that reflex bronchodilation through NANC parasympathetic nerve activation also occurs [29,87,88], albeit through a process distinct from cholinergic parasympathetic reflexes described above (see 'Parasympathetic (cholinergic) efferent nerves' above). Unlike reflex bronchoconstriction, which occurs within seconds, onset and reversal of NANC-mediated relaxation occurs over several minutes, possibly as a means for restoring airway patency after the conclusion of defensive reflexes such as coughing [29]. (See 'Nonadrenergic noncholinergic (NANC) nerves' above.)

Axon reflexes — Axon reflexes are well established in extrapulmonary somatic nociceptive C fibers, where release of proinflammatory neuropeptides, such as substance P, result in inflammatory cell recruitment, vascular leak, and neurogenic inflammation. Axonal reflexes have also been described in the lower airways of rodents [65,89-91]; however, their role in the lower airways of humans is less clear [29].

Morphologic studies of the human bronchial mucosa reveal a dense plexus of afferent nerves innervating the epithelium, subepithelium, and smooth muscle layers but a general sparseness of substance P-containing nerve fibers in healthy airways [24,92-94]. However, substance P expressing nerves vary widely among individuals and are increased in airway diseases such as eosinophilic asthma (picture 3) [94]. Thus, axonal reflexes may contribute to airway function and inflammation in specific disease states or in some individuals, but not others. The relevance of these findings in human airways requires further study. (See 'Clinical implications' below.)

CLINICAL IMPLICATIONS

Pharmacologic bronchodilator development — Airway autonomic control was once thought of as a balance between the opposing actions of cholinergic-parasympathetic nerves and adrenergic-sympathetic nerves. Diseases such as asthma, it was inferred, were due to an imbalance of the actions of these autonomic neurotransmitters in the airways. Despite the inaccuracies of this model regarding the role (or lack thereof) of sympathetic nerves in human airways, it formed the conceptual basis for development of two major classes of drugs used in respiratory disease, anticholinergics (muscarinic antagonists) and beta agonists. Indeed, clinical studies have demonstrated that adding an anticholinergic (eg, ipratropium) to a beta-agonist (eg, albuterol) produced a greater bronchodilatory effect than beta-agonists alone during acute asthma exacerbations [95] and that long-acting anticholinergic agents (eg, tiotropium) improved symptoms and lung function over time in patients with asthma [96-100], thus highlighting the synergistic role of cholinergic and adrenergic signaling in airway disease.

Asthma — Asthma is an inflammatory airway disease characterized by variable airflow obstruction and airway hyperresponsiveness, where inhaled stimuli provoke exaggerated airway responses [101]. Neuronal dysregulation contributes to both of these processes. Airway hyperresponsiveness can be demonstrated experimentally in individuals with asthma via inhalation of histamine, bradykinin, prostanoids, cold air, nonisotonic solutions, adenosine, or capsaicin. Accordingly, both airflow obstruction and airway hyperresponsiveness are reduced or abolished by anticholinergics that block M₃ muscarinic receptors, such as ipratropium bromide or atropine, supporting the role of an exaggerated parasympathetic nerve activity in these responses [102-105]. (See 'Parasympathetic (cholinergic) efferent nerves' above.)

Multiple mechanisms contribute to heightened neuronal responsiveness in asthma. Eosinophils, which are common inflammatory cells in airways of a majority of individuals with asthma, preferentially migrate to and physically interact with airway nerves [106,107]. Eosinophil proteins, such as major basic protein, antagonize parasympathetic nerve inhibitory M₂ muscarinic receptors, resulting in dysregulated acetylcholine release and excessive bronchoconstriction [108,109]. Eosinophil cationic protein also increases sensory nerve excitability, which may increase reflex bronchoconstriction and sensory neuropeptide release [110,111]. Other mediators such as histamine, prostaglandin D2, and the cysteinyl leukotrienes enhance neuronal excitability [2,18,19,22], as do the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1b (IL-1b) [112,113] and neuropeptides such as substance P [114].

Similar to other airway cell types in asthma (eg, epithelium, smooth muscle), airway nerves undergo structural and phenotypic remodeling. In bronchoscopic airway biopsies from patients with eosinophilic asthma, epithelial sensory nerve density was doubled compared with healthy individuals. Increased sensory nerve density was associated with worse airflow obstruction and heightened sensitivity to environmental stimuli [94], suggesting nerve remodeling is linked to increased bronchoconstriction and irritant sensitivity in asthma. Neuronal substance P expression was also increased in asthma [115,116], while in animals, allergen exposure similarly increases substance P [94,117,118]. Remodeling of parasympathetic nerves also occurs in human asthma. Bronchial specimens from asthmatic individuals stained for the cholinergic marker vesicular acetylcholine transporter (VAChT) demonstrated significantly increased innervation of airway smooth muscle [119].

Structural neuroplasticity may be mediated by neuronal growth factors, termed neurotrophins.

Neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are found in the airways and serum of allergic patients [120-123]. Allergen challenge induces neurotrophin release in the airways, and allergic asthmatics have high NGF levels in serum relative to atopic nonasthmatics. Given acutely, NGF and BDNF induce airway hyperresponsiveness in animals [124-127]. In transgenic animals, NGF overexpression in the lung produces hyperinnervation and airway hyperresponsiveness in mice [128], while BDNF overexpressed by airway smooth muscle promotes parasympathetic hyperinnervation [119]. NGF also induces neuropeptide gene expression in airway afferent nerves, mimicking the effects of allergen on airway sensory nerves [117,129,130]. Many airway cells are potential sources of neurotrophins, including the airway epithelium, smooth muscle, T cells, and mast cells [131-134].

Neuronal transient receptor potential (TRP) channels are implicated in development of airway hyperresponsiveness in asthma as well [135]. In asthma, airway TRP vanilloid 1 (TRPV1) expression is increased and responsiveness to TRPV1 agonists are potentiated [136,137]. In animals, allergen-induced tracheal contractions are inhibited by the TRPV1 antagonist capsazepine [138]. Interestingly, stimulating TRPV1-expressing neurons in mice promotes airway inflammation, while genetic ablation of TRPV1-expressing or TRP ankyrin 1 (TRPA1)-expressing neurons attenuates airway inflammation and hyperresponsiveness after allergen exposure, suggesting TRP channels have a key role in regulating neuroimmune interactions [135,139]. (See 'Nociceptors' above.)

Nonadrenergic noncholinergic (NANC) nerve dysfunction may also contribute to increased bronchoconstriction in asthma. When airway inflammation is present, NANC nerves fail to bronchodilate during deep inspiration [29,140,141], due in part to attenuated release of nitric oxide (NO) [29,72-75]. Mechanisms that may account for this phenomenon include upregulation of arginase, which depletes the NO precursor arginine, and/or upregulation of glutathione-dependent formaldehyde dehydrogenase (also known as S-nitrosoglutathione [GSNO] reductase) [142-145], which depletes the bronchodilator S-nitrosothiols that is formed from NO and thiol-containing precursors in the airways. Pharmacologic inhibition of NO synthesis similarly prevents bronchodilation during deep inspiration and results in airway hyperresponsiveness to bradykinin [146]. Moreover, mutation of the gene encoding the neuronal isoform of NO synthase is associated with a decreased exhaled NO, increased airways responsiveness, and an increased risk for developing asthma [147,148]. (See 'Nonadrenergic noncholinergic (NANC) nerves' above.)

Chronic cough — Cough reflexes play an essential role in the clearance of inhaled pathogens, aeroallergens, irritants, particulate matter, secretions, and aspirate, and thus they protect the airway mucosa from damage. Impaired and/or insufficient cough reflexes markedly increase the risk for pulmonary infection. Cough therefore helps maintain airway function and lung capacity for gas exchange [40,41].

Chronic cough, however, often serves no physiologic role and adversely impacts quality of life. Cough is defined as chronic when lasting longer than eight weeks and is frequently associated with airway diseases such as lung infections, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, bronchiectasis, and lung cancer. It can also be idiopathic [149]. Notably, it is also one of the most common reasons for consultation with a family doctor or a general respiratory clinician [150]. (See "Causes and epidemiology of subacute and chronic cough in adults", section on 'Causes of chronic cough'.)

Patients with chronic cough often report a heightened cough sensitivity to noxious and innocuous inhaled stimuli (eg, laughing or talking) and a persistent urge to cough. These common unifying features have led to the concept of "cough hypersensitivity," whereby the peripheral and central neuronal pathways that elicit cough become dysregulated [151,152]. Many mechanisms may contribute to increased neuronal excitability in cough hypersensitivity, including increased nociceptor expression by peripheral sensory neurons, de novo expression of cough receptors by nonnociceptive neurons, increased levels of endogenous tussive stimuli, and increased airway epithelial sensory nerve density [153,154]. Experimentally, a variety of proinflammatory mediators have been shown to contribute to nerve sensitization, including leukotrienes, bradykinin, neurokinins, prostanoids, lipid mediators, and ATP.

Exposure to allergen, cigarette smoke, environmental ozone and respiratory virus infections provoke release of sensitizing mediators that are associated with increased cough frequency [155-159].

Evidence suggests that neuronal sensitization in chronic cough is a heterogenous process that results in distinct "neurophenotypes." For instance, while individuals with COPD and chronic idiopathic cough both exhibit a heightened sensitivity to the TRPV1 agonist capsaicin, they have significantly different responses to inhaled prostaglandin E2 [137,160,161]. TRP channels, in particular, are implicated in the heightened cough sensitivity in individuals with chronic idiopathic cough [162], and single-nucleotide polymorphisms of the TRPV1 gene are associated with enhanced susceptibility to cough in current smokers and in subjects with a history of respiratory irritant exposures in the workplace [163]. In models of allergic inflammation, mechanoreceptors, which do not express TRPV1 under normal conditions, undergo phenotypic switching and begin to express TRPV1 to more closely resemble TRPV1-expressing jugular C fibers [164]. On the basis of these findings, TRP channel antagonists have been developed for treatment of chronic cough. These agents effectively block cough induced by specific tussive agents or urge to cough in chronic cough clinical trials [165-167]. These findings underscore the complexity of neuronal mechanisms underlying cough hypersensitivity that are not solely driven by changes in specific TRP receptor activity.

Purinergic P2X3 receptors are another nociceptor implicated in the pathophysiology of chronic cough. P2X3 receptors are heavily expressed by airway sensory nerves and are activated by extracellular ATP [168]. Individuals with chronic cough have increased cough sensitivity to inhaled ATP [169], and extracellular ATP is increased in asthma [170,171]. Furthermore, clinical trials using P2X3 receptor antagonists demonstrated a significant reduction in cough frequency compared with placebo in patients with chronic cough, along with significant improvements in cough-specific quality of life and global ratings of change scores. While promising, these agents await additional regulatory review due in part to the notable adverse effect of loss of taste. Additionally, significant placebo responses in phase III trials raise questions regarding the magnitude of their efficacy [172-174]. (See "Evaluation and treatment of subacute and chronic cough in adults", section on 'Investigational agents'.)

Dysregulation of brainstem and cortical centers may contribute to the development of cough hypersensitivity. In animal studies, injection of capsaicin, substance P, and neurokinin antagonists into the nucleus solitarius affects cough reflex sensitivity [175], suggesting that interactions within the central integrative sites may contribute to excessive cough triggering. This process might also explain how extrapulmonary disorders, such as gastroesophageal reflux disease [176,177], allergic rhinitis [2], and upper respiratory tract infections [178,179], influence pulmonary symptoms such as cough and airway hyperresponsiveness. Furthermore, in the cerebral cortex, reduced activation in regions associated with cough suppression (ie, dorsomedial prefrontal cortex, anterior midcingulate cortex) has been documented using functional magnetic resonance imaging (MRI) in patients with cough hypersensitivity [180], suggesting chronic cough may develop from both increased peripheral and central neuronal excitability and reduced central cough suppression.

Allergic rhinitis — Patients with symptomatic allergic rhinitis have heightened responsiveness to stimuli that activate nasal mucosal afferent nerves [5-7,15,16]. These exaggerated responses are markedly reduced or abolished by atropine pretreatment, confirming the reflexive nature of the responses. Accordingly, nasal ipratropium is approved for treatment of allergic rhinitis [181,182].

Both alpha adrenoceptor agonists (eg, pseudoephedrine) and histamine receptor antagonists (ie, antihistamines) are cornerstones of treatment for allergic rhinitis via their ability to reduce upper airway obstruction [183]. Pharmacologic studies in human subjects indicate that sympathetic nerves tonically sustain upper airway patency through alpha1 adrenoceptor activation [184]. Conversely, histamine, when applied exogenously to the human nasal mucosa, creates nasal blockage in part through histamine H3 receptor-dependent prejunctional inhibition of sympathetic-adrenergic nerves [184].

SUMMARY

●Overview – Nerves innervating the airway mucosa initiate reflexes that contribute to the regulation of airway caliber, mucus production, and the initiation of reflexes, such as sneeze and cough. (See 'Introduction' above.)

●Upper airway innervation and reflexes – Both sympathetic and parasympathetic nerves innervate the vasculature and glands of the nasal mucosa (figure 2). Reflexes can be initiated within the nose by a variety of stimuli, including mechanical probing, hypertonic saline, cold and/or dry air, histamine, allergen, nicotine, bradykinin, and capsaicin. (See 'Innervation of the upper airway' above.)

●Lower airway innervation – The predominant innervation of the lower airways, extending from the larynx to the terminal bronchioles, is provided by afferent and efferent nerve fibers contained within the vagus nerves (cranial nerve X). In general, sensory nerves are broadly classified as mechanoreceptors or nociceptors (also known as chemoreceptors) based on their responsiveness to either mechanical or chemical stimuli, respectively. (See 'Vagus nerves' above.)

The calcium-permeable ion channels in the transient receptor potential (TRP) channel family are widely expressed by nociceptors. Examples of TRP receptor subtypes include TRP vanilloid 1 (TRPV1), whose ligands include the active ingredient in chili powder, capsaicin, and citric acid; TRP ankyrin 1 (TRPA1), which responds to endogenous mediators (eg, prostaglandins A2, E2, and D2), extracts from spicy foods (cinnamon, garlic, mustard oil, wasabi), noxious environmental irritants, and temperatures below 17°C; and TRP vanilloid 4 (TRPV4), which is activated by arachidonic acid and hypotonic solutions. (See 'Nociceptors' above.)

Cholinergic-parasympathetic efferent nerves mediate smooth muscle contraction, whereas nonadrenergic noncholinergic (NANC) nerves mediate smooth muscle relaxation (figure 3). (See 'Reflex regulation of airway smooth muscle' above.)

●Cough reflex – The cough reflex can be initiated by activation of airway mechanoreceptors (eg, by inhaled particulates and accumulated secretions) or airway C fibers. Airway C fibers have nociceptors (eg, TRPV1, TRPA1) that can be activated by bradykinin, capsaicin, and a variety of other endogenous and exogenous irritants. (See 'Mechanoreceptors' above and 'Nociceptors' above.)

Neuronal sensitization in chronic cough is a heterogenous process that results in distinct "neurophenotypes." For instance, while individuals with chronic obstructive pulmonary disease (COPD) and chronic idiopathic cough both exhibit a heightened sensitivity to the TRPV1 agonist capsaicin, they have significantly different responses to inhaled prostaglandin E2. (See 'Chronic cough' above.)

Dysregulation of brainstem and cortical centers may contribute to the development of cough hypersensitivity. In animal studies, injection of capsaicin, substance P, and neurokinin antagonists into the nucleus solitarius affects cough reflex sensitivity, suggesting that interactions within the central integrative sites may contribute to excessive cough. (See 'Chronic cough' above.)

●Neuronal dysregulation in airway disease – In certain diseases, homeostatic and defensive reflexes in the airway mucosa become dysfunctional and/or dysregulated. As examples, elevated parasympathetic-cholinergic tone has been documented in both asthma and COPD, and allergic inflammation is associated with exaggerated sneeze and cough reflexes in allergic rhinitis and asthma. (See 'Clinical implications' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Brendan Canning, PhD, Beatrice Hoffmann, MD, PhD, RDMS, and Maria Belvisi, PhD, who contributed to an earlier version of this topic review.