The role of tachykinin receptor antagonists in the prevention of bronchial hyperresponsiveness, airway inflammation and cough

Abstract

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 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][2][3][4][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 secretion; 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 [5][6][7][8][9][10]. According 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. PHARMACOLOGICAL REVIEW

Capsaicin responsiveness in asthma and COPD

“…In our laboratory measurement of capsaicin sensitivity in over 200 healthy volunteers, as well as in a smaller group of stable asthmatic patients in whom cough was not a reported complaint, demonstrated no significant diVerence in cough reflex sensitivity between these two groups. Our findings are consistent with those of previous investigations 2 3 and support the well documented dissociation between cough and bronchoconstriction, 4 responses that are controlled by distinct neural pathways.…”

“…It is becoming increasingly clear that patients and their doctors do not always share the same perceptions of what is important in asthma management and what constitutes a successful outcome of asthma care. The AIR study 4 shows that patients are particularly concerned with functional outcomes-what matters most to them is what they can and can't do because of their asthma, and how their asthma prevents them from doing the things they want to do. Although there is obviously an overlap with other outcome measures such as symptoms, patients frequently modify their lifestyle to prevent symptoms occurring, so asthma may disproportionately impair their quality of life even in the absence of reported symptoms.…”

Inhibiting Effect of Ammonia on Citric Acid‐Induced Cough in Pigs: A Possible Involvement of Substance P

“…Both capsaicin and citric acid are thought to act through the release of neurokinins, especially substance P, from Cfibers. Furthermore, neurokinin receptor (NK1, NK2, NK3) antagonists inhibit the cough reflex, and in guinea pigs, cats, and humans, citric acid-induced coughing is enhanced by inhibitors of two enzymes involved in substance P degradation: neutral endopeptidase and angiotensin-converting enzyme (Ujiie et al 1993;Fox et al 1996;Sekizawa et al 1996;Advenier et al 1997;Bolser et al 1997). These facts support the view that substance P plays a role in the cough reflex.…”

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

“…TACHYKININS ARE STORED AND RELEASED from unmyelinated pulmonary C fibers in airways (8,30,31,44) and evoke inflammatory peripheral effects including vasodilation, plasma extravasation, leukocyte adhesion, facilitation of cholinergic neurotransmission, and epithelial cell secretion in the airways (1,12,16), which are referred to as neurogenic inflammation. Local release of tachykinins from peripheral sensory nerves may also lead to airway contractile responses and hyperresponsiveness in human and most mammalian species (32,42).…”