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 PGF2α 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).