Frontiers reviewAfferent receptors in the airways and cough
Introduction
Coughing can be induced from the larynx and tracheobronchial tree, but not directly from structures above or below these sites. Two types of afferent receptor are found in the mucosa and are primarily involved in cough, rapidly adapting (or irritant) receptors (RARs), so called because they respond with rapid adaptation to a maintained inflation or deflation of the lungs, and C-fibre receptors. There have recently been much discussion and controversy as to the relative role of these two types of receptor in cough (e.g. Karlsson et al., 1988, Fox, 1996, Karlsson, 1996, Widdicombe, 1995, Widdicombe, 1996), but recent research may be leading to a synthesis of views. The issue introduces new concepts about airway sensory mechanisms, and is potentially important in antitussive therapy, because the mechanisms of both peripherally and centrally acting antitussive drugs may depend on the identity of the afferent pathways involved.
There seems to be general agreement that stimulation of RARs produces cough, at least from the larynx, trachea and larger bronchi (Coleridge and Coleridge, 1986, Widdicombe, 1995, Karlsson, 1996). These receptors show a range of mechanical and chemical properties depending on their site, and the reflexes they induce also vary with site (Coleridge and Coleridge, 1986, Widdicombe, 1989). The receptors in the larynx, usually called irritant receptors because they are generally silent in quiet breathing and only activated by mechanical or chemical irritation, can probably cause either an expiratory effort (the expiration reflex) or cough (Sant’Ambrogio and Sant’Ambrogio, 1996); those in the trachea and larger bronchi cause cough; and those deep in the bronchi may produce a deep inspiration or augmented breath (Widdicombe, 1989). These two reflex responses may resemble fragments of a complete cough. In relation to cough, C-fibre receptors have been studied less (Coleridge and Coleridge, 1984, Fox, 1996), and systematic differences in patterns of behaviour and reflex responses have not been related to airway sites: such a study could be important.
This review will concentrate mainly on receptor behaviour in relation to cough, but will not cover in detail the very extensive literature over the past 50 years on receptor physiology in the larynx, tracheobronchial tree and lungs (see Coleridge and Coleridge, 1984, Coleridge and Coleridge, 1986, Widdicombe et al., 1988, Widdicombe, 1989, Fox, 1996, Sant’Ambrogio and Sant’Ambrogio, 1996). It will also neglect other potentially important aspects of cough: the facts that stimulation of receptors that reflexly cause cough may also lead to secretion of mucus which will not only in its turn activate the cough reflex, and will influence the effectiveness of irritant agents that promote cough (Widdicombe, 1997); and may also induce reflexly other changes, such as in blood gas tensions, mucosal vasculature, bronchomuscular tone and the cardiovascular system, which may affect the pattern and strength of the cough reflex.
Section snippets
The larynx
As assessed by single nerve fibre recording, the larynx has a far higher density of sensory receptors than do other sites in the respiratory tract, and a far lower proportion of C-fibre receptors (Sant’Ambrogio and Sant’Ambrogio, 1996). Unfortunately there seem to be no histological studies comparing nerve density in the two regions. Indeed a major deficiency in our knowledge of laryngeal reflexes is a definitive analysis of nerve and receptor histology. On the other hand there has been
Histology
There is a plexus of nonmyelinated sensory nerve fibres in the airway epithelium, especially at the basal level but with projections reaching up towards the tight junctions near the lumen. The fibres can be shown by immunohistological methods to contain substance P (SP, Baluk et al., 1992; Fig. 2) and calcitonin gene-related peptide (CGRP, Baluk et al., 1993), and at least some of them contain neurokinin A (NKA), and probably nitric oxide (Fischer et al., 1993) All disappear on sensory nerve
Pulmonary C-fibre receptors
In spite of an early claim that these receptors can cause cough (Paintal, 1983), most animal results point against the idea (Karlsson et al., 1988). A very large number of studies using selective stimuli to these receptors have never exhibited cough, in any of the several species used. This applies both to anaesthetized and unanaesthetized animals. In practice excitation of pulmonary C-fibre receptors inhibits cough induced mechanically in cats and dogs (Tatar et al., 1988, Tatar et al., 1994;
Conclusions
While there is much evidence that cough can be caused by irritant receptors in the larynx and by RARs in the tracheobronchial tree, the role of C-fibre receptors is more uncertain. They can certainly cause apnoea and rapid shallow breathing, but to establish a subpopulation that can induce cough requires further evidence. If C-fibre receptors when stimulated release tachykinins, this could cause plasma extravasation from postcapillary venules, which would in turn excite RARs and produce cough.
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