Overview of neural pathways in allergy and asthma

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Abstract

Three groups of airway sensory nervous receptor may be involved in the pathophysiological changes in asthma and allergy. Those most active will be the C-fibre receptors, the rapidly adapting receptors, and Aδ-nociceptive receptors. All are stimulated or sensitised by the inflammatory and immunological changes. The C-fibre receptors may mediate the axon reflex neurogenic inflammation—bronchoconstriction, mucus secretion and mucosal hyperaemia due to neuropeptide release—but the evidence for this process in humans, unlike rodents, is scanty. Activation of the receptors will also cause central nervous reflexes. The pathways for these reflexes in the brainstem, where their interactions, and the chemical neurotransmitters involved, are beginning to be delineated. The resulting reflexes include bronchoconstriction, mucus secretion and mucosal vasodilatation, responses that will amplify any similar changes due to neurogenic inflammation. The cough reflex depends on the interaction of the three basic reflex pathways. The reflexes show plasticity at peripheral, ganglionic and central nervous levels, and it is unlikely that results in acute experiments on healthy animals will apply quantitatively to humans with asthma.

Introduction

Before the advent of immunology, asthma used to be considered a disease of the autonomic nervous system. The evidence was mainly based of the partial effectiveness of atropinic drugs in overcoming bronchoconstriction and mucus secretion, and the fact that tightness of the chest and cough were characteristic symptoms and these had to be nervously mediated. The evidence for nervous mechanisms in animal models of asthma and airway allergy has since been abundantly studied and established, but similar studies are seldom practical in humans and here the conclusions are largely inferential.

Inflammatory and immunological reactions in the airways excite at least three types of sensory receptor. (Note that in this paper the term ‘receptor’ will be mainly applied to ‘sensory nervous receptors’, its original use, and only occasionally to ‘pharmacological receptors’ in cell membranes.) This excitation causes local tissue responses, or neurogenic inflammation, and also sets up reflexes via the central nervous system (CNS) including cough and changes in breathing. In turn these reflexes also produce secondary responses in the target tissues of the airways, smooth muscle, mucus glands and the vasculature, which interact with the primary changes due to the local pathology. The whole system exhibits much flexibility and plasticity.

Section snippets

Sensory receptors in the lungs

Of the five main groups of sensory receptor in the airway (all probably with subgroups depending on both location and physiology), all connect to afferent fibres up the vagus nerves, but only three seem to play a primary role in asthma [1], [2], [3], [4], [5]. Of the other two, the slowly adapting pulmonary stretch receptors (SARs) lie in the airway smooth muscle and are relatively insensitive to local chemical changes [2]. Although they reflexly influence the pattern of breathing, the cough

Neurogenic inflammation

Activation of sensory nerves may, via an axon reflex, release neuropeptides which cause local tissue responses which in turn amplify the direct effects of inflammation and its mediators [21], [22]. This neurogenic inflammation is independent of, although it may interact with, the reflex effects of stimulation of the sensory receptors. It has been described for many tissues and, although it seems established for rodent airways, whether it plays a part in human asthma remains controversial.

Central nervous system

The CNS pathways and interactions of the airway nerves involved in asthma have recently been extensively studied [5], [27], [28], [29], [30]. Many of these studies have been directed towards the cough reflex and its control and, therefore, although they have a clear relationship to asthma, may not be as relevant as the CNS control of airway smooth muscle and other effector tissues, about which we know less. Fig. 4 shows a tentative diagram of how the afferent and motor systems of airway

C-fibre receptors

A large literature shows that, in anaesthetized animals, selective C-fibre receptor stimulants cause reflex rapid shallow breathing and, if the stimulus is large and sudden, a preceding apnoea [1], [4], [37]. The extent to which this reflex contributes to the respiratory changes is asthma is unclear. In mild asthma there may be hyperventilation, and the C-fibre reflex could contribute to this response.

Whether C-fibre receptors cause cough is more controversial [1], [17], [19]. Indeed in both

Plasticity

Until recently nearly all the animal experiments on neural mechanisms in asthma and allergy have been with acute experiments, often with healthy tissues or with those only transiently rendered pathological. An expanding body of evidence suggests that these results, while valid, may not be quantitatively applicable to chronic diseases.

In the airway wall, the mechanical sensitivity of RARs can be enhanced by, for example, antigen stimulation in sensitised animals [40]. C-fibre receptors may also

Conclusion

Animal experiments establish that airway sensory nerves are sensitised or stimulated in inflammatory and allergic conditions. Both their local activities (neurogenic inflammation) and their central nervous reflexes would amplify the mucosal changes due to asthma. In chronic conditions they could be sensitised even more, with resultant hyperreactivity. The extent to which these processes apply to humans remains, in general, to be investigated.

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