The role of tachykinin receptor antagonists in the prevention of bronchial hyperresponsiveness, airway inflammation and cough
European Respiratory Journal
The excitatory nonadrenergic noncholinergic (NANC) system, involving various neuropeptides of the tachykinin family, such as substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and calcitonin gene-related peptide (CGRP), as transmitters, has now been well characterized. In airways, SP, NKA and CGRP are co-localized in the sensory unmyelinated C-fibres, which innervate all compartments of the airway wall from the trachea down to the bronchioles. C-fibre endings are found within the
... within the epithelium. They form a dense plexus in the subepithelial lamina propria, supply the glands, ramify within the smooth muscle layer and make direct contacts with postganglionic parasympathetic neurons, located in the local ganglion. In the trachea, this sensory innervation is almost exclusively derived from sensory vagal neurons, supplied by the jugular ganglion, whilst that of the lung is of mixed origin with a predominating vagal and a smaller spinal contribution [1-5]. The NANC system can be activated by different stimuli, which affect the chemosensitive C-fibre afferents in airways and lead to a local release of tachykinins that are responsible for several biological effects in the bronchopulmonary system: bronchospasm; increase in vascular permeability from postcapillary venules; stimulation of glandular secre-tion; facilitation of cholinergic neurotransmission; and recruitment and activation of some types of inflammatory cells. Sensory nerves also mediate respiratory defence reflexes, such as coughing, sneezing and secretion of mucus ( fig. 1 ). From these data, it has been hypothesized that abnormal stimulation of the sensory nerve terminals, e.g. induced by epithelial shedding as seen in asthma, results in enhanced release of tachykinins in the airway wall with subsequent exaggeration of inflammation. This concept of "neurogenic inflammation" introduces sensory nerve fibres as important components in the pathogenesis of asthma. The biological actions of tachykinins are mediated via three types of receptors, denoted neurokinins 1-3 (NK 1 , NK 2 and NK 3 ), which have the highest affinity for SP, NKA and NKB, respectively. This receptor classification has been established from receptor-binding and functional studies. It has now been recognized that the expression of tachykinin NK 3 receptors is confined mainly to the central and peripheral nervous system, whilst tachykinin NK 1 and tachykinin NK 2 receptors are expressed both in the central and peripheral nervous system and in target organs, including airways       . According PHARMACOLOGICAL REVIEW The role of tachykinin receptor antagonists in the prevention of bronchial hyperresponsiveness, airway inflammation and cough. C. Advenier, V. Lagente, E. Boichot. ©ERS Journals Ltd 1997. ABSTRACT: Several recent observations suggest that tachykinins, such as substance P and neurokinin A, might be involved in the pathogenesis of bronchopulmonary alterations. Progress in investigations on the physiological and pathological roles of tachykinins has been greatly facilitated by the availability of a number of highly selective nonpeptide antagonists for tachykinin neurokinin 1, 2 and 3 (NK 1 , NK 2 and NK 3 ) receptors. The use of selective tachykinin NK 2 receptor antagonists suggests that tachykinin NK 2 receptor stimulation plays an important role in the development of airway hyperresponsiveness in the guinea-pig. Others studies have also indicated that tachykinin NK 1 -receptors are involved in immediate or delayed neurogenic inflammation including microvascular leakage and the subsequent increase in plasma protein extravasation. A role for the sensory neuropeptide system has also been proposed in cough, as shown by the observation that the antitussive effect of tachykinin NK 2 receptor antagonists has clearly been demonstrated in several experimental conditions, but the effect of tachykinin NK 1 receptor antagonists is still debated. Taken together, the results obtained with the various selective receptor antagonists provide pharmacological evidence that tachykinins play a role in delayed bronchopulmonary alterations and suggest that tachykinin receptor antagonists may be useful for investigating mechanisms and possibly reducing airway functional alterations in asthmatic patients.