Cough, airway sensory nerves and cough receptors

Cough receptors are located in the very peripheral ends of axons of neurons involved in the sensory innervation of the airways that rise towards the central nervous system in the vagus nerve. The nuclei of these nerves are in the jugular or nodose ganglia. If the receptors are activated with sufficient intensity, an action potential would then be generated and travel through the vagus nerve and synapses in the medulla where the cough reflex is processed (Bonvini & Belvisi, 2017). The cough reflex arc (Figure 1) constitutes the afferent, central, and efferent pathways. The afferent impulses go to the medulla, which coordinates the autonomic functions of breathing. The central pathway, which coordinates coughing, is situated in the upper brain stem and pons. The efferent pathway sends signals from the cough centre to the muscles, abdominal wall, and diaphragm via the phrenic, vagus, and spinal motor nerves (Bonvini & Belvisi, 2017). The central nervous system (CNS) interprets signals from the vagal afferent nerves and elicit changes in the breathing rate and depth and autonomic flow to airway smooth muscles. However, urge of coughing and feeling of dyspnoea may result if certain afferent nerves in the airways are activated. If the sensory nervous system becomes dysregulated in illnesses (e. g. rhinitis, bronchitis, asthma, and COPD), it may cause bronchospasm, urge of coughing, and dyspnoea (Mazzone & Undem, 2016).
The airway afferent nerve system is generally classified by the fibre conduction velocities. C-fibres are the slowest in conducting signals and then followed by B-fibres, which are autonomous (Table 1). A-fibres are the fastest, which are further classified as Aδ, Aγ and Aβ, from the slowest to the fastest in conduction. However, since Aγ fibres are efferent autonomic nerves, the ranking of vagal sensory nerves in the order of increasing conduction velocity are C-, Aδ, and Aβ fibres. C-fibres respond to potentially damaging mechanical forces, as well as inflammatory mediators and acidic chemicals (Mazzone & Undem, 2016). There are two types of C-fibres, namely, pulmonary and bronchial. Pulmonary C-fibres respond to chemical stimulants with short latency when delivered through the right atrial injection into the pulmonary circulation. On the other hand, bronchial C-fibres are in the large airways and respond to chemical stimulants with short latency injected directly into the systemic circulation. A-fibres generally respond to mechanical forces with low thresholds. Aδ fibres lead to cough and serve almost exclusively the larynx, trachea, and bronchi. They do not respond to tissue distention, airway smooth muscle contraction, and inflammatory mediators. However, they are sensitive to mechanical stimulation of, and sudden acidity in, the epithelium. If the pH decreases gradually, the acid-sensing mechanism adapts to it before signal conductance occurs (Mazzone & Undem, 2016). Aβ fibres respond to the lung distention and deflation during breathing. The mechano-sensitive Aβ fibres are subcategorised as rapidly-adapting receptors (RARs) and slowly-adapting receptors (SARs). RARs are activated by lung deflation, bronchospasm, and changes in dynamic lung compliance. SARs’ action potential conduction velocities are faster than RARs and have a different distribution in the airways. SARs also respond to the mechanical forces that occur during tidal breathing (Figure 2 and Table 1) (Mazzone & Undem, 2016).
Transient receptor potential (TRP) channels are a group of ion channels consisting of 28 members that are expressed by many types of cells. TRP-vanilloid-1 (TRPV1), TRP-ankyrin-1 (TRPA1), and TRP-melastatin-8 (TRPM8) are the most important TRP channels related to cough. Capsaicin strongly activates most vagal C-fibres through the TRPV1 receptors, which are sensitive to acid and heat too. TRPA1 is expressed in C-fibre afferent neurons and colocalised with TRPV1. Therefore, inhalation of TRPV1 or TRPA1 agonists will cause coughing. TRPA1 can be activated by natural molecules (e.g. allyl isothiocyanate, allicin, cannabinol) and environmental irritants (e.g. acrolein, hypochlorite, hydrogen peroxide). TRPM8 is a receptor for menthol and cold temperatures but it constitutes only about 15% of bronchopulmonary C-fibres (Bonvini & Belvisi, 2017; Mazzone & Undem, 2016).
Inhalation of acidic aerosols leads to coughing in human and laboratory animals because they can activate all C-fibres in the airways through TRPV1 receptors. A-fibres can also be activated by acidic stimuli. Acid-sensing ion channels (ASIC) also contribute to acid-induced action potential discharge. Other endogenous compounds that can stimulate action potential discharge are bradykinin, histamine (secondary to ATP release), serotonin, adenosine, and prostaglandins (PG) so inhalation of PGD2, and PGF can cause cough (Mazzone & Undem, 2016).
Considering patients that inhale therapeutic aerosols, it is understood that the stimulus threshold for coughing is significantly lower in patients with pulmonary diseases (Wong & Morice, 1999). Further those with chronic cough have a continuous urge to cough. These conditions indicate that the affected airways have higher basal vagal afferent activity and sensory hypersensitivity. Autacoids (e.g. chemokines, cytokines, purines, eicosanoids) and ATP present in inflammatory airway diseases can stimulate the C-fibres in the respiratory tract to induce coughing. ATP receptor antagonists can decrease coughing frequency through inhibiting the stimulation of airway nodose C-fibres by ATP (Mazzone & Undem, 2016). For example, AF-219 works by blocking ATP receptors P2X3 and P2X2,3 thereby reducing frequency of coughs in a phase 2 clinical trial (Abdulqawi et al., 2015). Touch-sensitive airway mechanosensitive afferent receptors respond vigorously to light punctate mechanical stimuli. These cough receptors are located on many nodose-derived A-fibres in large airways (e.g., larynx, trachea, and main bronchi) (Bonvini & Belvisi, 2017).
Airway inflammation increases the release of various neurotrophic factors that can interact with receptors at the nerve terminals and leads to gene expression changes in the distal vagal ganglia. For example, allergic inflammation may cause phenotypic changes in SAR and PAR neurons to express TRPV1 ion channels, which are normally absent. These nerves consequently become sensitive to capsaicin and other endogenous TRPV1-activating stimuli. Airway inflammation may also upregulate the functional TRPV1 channels in tracheal Aδ neurons that normally do not express these them. Nodose C-fibre neurons may develop responsiveness to neurokinins under similar circumstances. Due to these phenotypic changes, stimuli that are normally inert may potentially cause coughing, bronchospasm, and dyspnoea. Large-diameter RAR/SAR neurons as well as tracheal Aδ neurons start to express neuropeptides, such as substance P, and express and transport peptides such as calcitonin gene-related peptide (CGRP) and neurokinins
(Mazzone & Undem, 2016). Peripheral tissue inflammation or neuropathic injury may increase excessive neuronal activity in the central nerves that result in central sensitisation (Mazzone & Undem, 2016).