Reflexes from airway rapidly adapting receptors

Abstract

Rapidly adapting receptors (RARs) occur throughout the respiratory tract from the nose to the bronchi. They have thin myelinated nerve fibres, an irregular discharge and adapt rapidly to a maintained volume stimulus, but often slowly to a chemical stimulus. They are polymodal, responding to mechanical and chemical irritant stimuli, and to many inflammatory and immunological mediators. RARs show very varied sensitivities to different stimuli, and diverse reflex responses. Those in the larynx are usually called ‘irritant’ receptors. They probably cause cough, the expiration reflex and other laryngeal reflexes: cardiovascular, mucus secretion, bronchoconstrictor and laryngoconstrictor. Those in the trachea and larger bronchi are very mechanosensitive; they cause cough, bronchoconstriction and airway mucus secretion. Those in the larger bronchi are more chemosensitive; they may cause cough, but also stimulate hyperventilation, augmented breaths, mucus secretion, bronchoconstriction and laryngeal closure. Most of the stimuli to RARs also affect other airway receptors, especially those with C-fibre afferents, and the total reflex response will be the additive affect of all these reflexes.

Introduction

The term ‘irritant receptor’ is frequently used to describe a set of rapidly adapting receptors (RARs) found within the respiratory tract (nose, nasopharynx, larynx and tracheobronchial tree), and responding to various irritants (Sant'Ambrogio et al., 1984); indeed ‘irritable’ might be a preferable term (J.C.C. Coleridge, personal communication). While RARs adapt rapidly to a maintained mechanical stimulus, their response to a chemical one is often long-lasting. Many authors prefer the expression RAR, that has the advantage of being a neurophysiologically accepted term. These endings are not usually very active in quiet breathing in anaesthetized experimental animals, but can readily be recruited by inhalation of appropriate irritants, rapid changes in airway volume and intraluminal mechanical stimuli, or by the release of inflammatory or immunological mediators (Widdicombe, 2001). RARs in the lungs are sensitised by airway smooth muscle contraction and by decreases in lung compliance (Sellick and Widdicombe, 1970).

Although we do not have details of the fine structure of RARs (Widdicombe, 2001), we have both light and electron microscopic evidence on the presence within the airway epithelium of nerve endings most probably afferent. Degeneration studies on these fibres after unilateral cervical vagotomy below the nodose ganglion in cats establishes their afferent nature (Das et al., 1979, Baluk et al., 1992). On the vagotomized side there is a diffuse degeneration of fibres, especially in the hilar bronchi compared with the trachea. On the other hand postganglionic parasympathetic efferent fibres were not affected. One cannot say to what extent the epithelial fibres are parts of RARs or of C-fibre receptors: presumably both.

An important characteristic of RARs is their rapid adaptation to a maintained mechanical stimulus, which distinguishes them from slowly adapting receptors (SARs). This factor is commonly measured by obtaining the values of the initial discharge frequency (Fi) of the receptors when the applied stimulation is fully completed, and the lower ‘adapted’ steady state discharge (Fss) sometime (usually 1 or 2 s) after the stimulus has been introduced. The difference between the two values, when expressed as a percentage of Fi, is called the adaptation index (AI) (Widdicombe, 1954b). However, considering the different effects of volume and pressure inflation on adaptation, it seems potentially misleading to rely on the adaptation index alone to identify an SAR or an RAR. The AI should be used only as an approximate guideline, and the AI of SARs may overlap with that found for RARs.

Further differences between RARs and SARs include: slower conduction velocities of the nerve fibres of RARs, irregularity of nerve impulse discharge of RARs, patterns of firing in relation to the respiratory cycle, chemosensitivities, and locations in the wall of the trachea. They have different reflex actions on breathing and bronchomotor tone (Widdicombe, 2001). Thus many factors may have to be considered in distinguishing between the two types of receptor.

These receptors have been located in airways from the nose to the cartilaginous bronchi with a diameter of at least 0.3 mm in dogs and cats. As in the case of SARs, RARs are not distributed along the tracheobronchial tree in a uniform manner, but are more frequent in the larger airways (Mortola et al., 1975, Lee et al., 1992).

The greater concentration of RARs in the carina and hilar airways may provide a better arrangement of the defence mechanisms against irritants of various natures entering through the upper airways and/or the oesophagus. Cough, the expiration reflex, and swallowing are some of the defence mechanisms that can be recruited.

The receptive fields of RARs in the trachea and the extrapulmonary bronchi in the dog are distributed around the entire circumference (Sant'Ambrogio et al., 1978). This distribution is definitely different from that of the SARs which are exclusively located within the trachealis muscle in the posterior wall of the trachea and extrapulmonary bronchi. RARs and SARs thus represent distinct and independent entities (Widdicombe, 2001).

Conduction velocities of the fibres from RARs are consistent with small (Aδ) myelinated fibres and overlap with those of fibres from SARs; a similar conclusion can be derived from the vagal blocking temperatures for RARs and SARs.

RARs can be activated either by gross deformation of the airways (such as those induced by a large distension or collapse of the lung) or by discrete probing of the airway mucosa. The two types of response can sometimes be separated for RARs in the extrathoracic trachea; the latter, but not the former, may be abolished by removing the airway epithelium (Sant'Ambrogio et al., 1978). This result may imply a multibranching structure for the endings, consistent with their irregular discharge.

The respiratory modulation of RARs, when present, is irregular in both its timing within the respiratory cycle and within each burst of discharge. Short bursts of activity are more often seen at peak inflation or at pressures attained at lower lung volumes. This observation indicates that transpulmonary pressure is an important factor in their activation (see below).

A variety of inhaled substances in the form of gases (ammonia, ethyl ether, sulphur dioxide, etc.), aerosols, smokes and fumes can stimulate RARs. The actions of several of them on airway receptors vary in different species: for instance, cigarette smoke is more effective in rabbits than in dogs, and sulphur dioxide can be used to block SARs in rabbits but is ineffective in dogs.

These differences may depend on the amount of mucus being secreted, which could itself stimulate the RARs or could provide an insulating barrier to some of the endings. Any change of activity in RARs (and also in SARs) can also produce local and even distant effects on bronchomotor tone. For instance, an inhaled substance affecting lung compliance would change receptor activity in a very proximal airway whenever the corresponding transmural pressure is altered. For a similar reason an RAR (and also an SAR) could be affected by a resistance change in the upper airway (e.g. a laryngoconstriction) leading to a change in transmural pressure anywhere along the tracheobronchial tree.

As several studies have revealed, RARs do not constitute a well-defined population of similar individual receptors; marked differences occur and have in some instances been attributed to the ganglionic origin of the cell bodies of the fibres being investigated. Major defining characteristics occur for the responses of fibres originating from the nodose and jugular ganglia, respectively (Riccio et al., 1996). These findings open up new perspectives for the development of our knowledge of lower airway afferent innervation. We could hypothesize that fibres of the jugular ganglion are the ones that mediate bronchoconstriction while those in the nodose ganglion mediate cough, or vice versa.