Rapid communication

Autoradiographic mapping of substance p receptors in lung

Release of neuropeptides, including tachykinins and calcitonin gene-related peptide, from sensory nerves via and axon or local reflex may have inflammatory effects in the airways. This neurogenic inflammation may be initiated by activation of sensory nerves by inflammatory mediators and irritants. Neurogenic inflammation is well developed in rodents and may contribute to the inflammatory response to allergens, infections and irritants in animalmodels. However, the role of neurogenic inflammation in airway inflammatory diseases, such as asthma and COPD is still uncertains, as there is still little direct evidence for the involvement of sensory neuropeptides in human airways. Initial clinical studies using strategies to block neurogenic inflammation have not been encouraging, but it is important to study more severe forms of airway disease in more prolonged studies in the future to explore the role of neurogenic inflammation.

A smoking-induced inflammatory reaction in the airways and lung parenchyma, comprised mainly of neutrophils and alveolar macrophages, has long been accepted to be the major cause of COPD in smokers. Recent reports have underlined the role of the T lymphocyte as a potentially important factor in the inflammatory process leading to COPD. It has been found that, in the airways and the lung parenchyma, the presence of T cells, predominantly CD8+ T cells, can distinguish between smokers with and without COPD. In addition to T cells, other inflammatory cell types such as neutrophils and macrophages are probably essential in the initial inflammatory process leading to the breakdown of lung tissue, perhaps producing peptides eventually recognized by T cells as antigenic. This would provide an explanation for the T-cell inflammation. Once activated, T cells are present in the lung, and their effector functions would include the attraction and enhancement of the inflammatory function in other inflammatory cells like neutrophils and macrophages. It seems likely that, only when all inflammatory cell types (ie, CD4+, CD8+, neutrophils, and macrophages) are present in the lung, the airways remodeling and parenchymal destruction characteristic of COPD will ensue. If T cells are responsible for the lung injury and progression of COPD, it would resemble a response to an antigenic stimulus originating in the lung. If that were the case, COPD could be considered to be an autoimmune disease triggered by smoking.

We investigated, in ferret trachea in vitro, the binding characteristics and the inhibition of non-adrenergic, non-cholinergic (NANC) neural mucus secretion of four tachykinin receptor antagonists: the non-peptide tachykinin NK₁ receptor antagonists CGP 49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-(quinolin-μ-ylmethyl amino) piperidine), CGP 55000 ((2R,4S)-2-benzyl-1-(3,5-bistrifluoromethyl-benzoyl)-4-(quinolinyl-methylamino)piperidine) and CP 99,994 ((+)-(2S,3S)-3-methoxybenzyl amino)-2-phenylpiperidine), and the peptide tachykinin NK₂ receptor antagonist MEN 10,627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2β–5β)). CGP 49823, CGP 55000 and CP 99,994 concentration-dependently displaced [¹²⁵I]Bolton–Hunter substance P binding in tracheal membranes with Hill coefficients not different from unity and IC₅₀ values of 1.4, 1.7 and 1.3 nM, respectively. In contrast, MEN 10,627 displaced binding according to a two-site model, with IC₅₀s of 0.2 nM and 1.3 μM. Electrical stimulation of tracheal segments with adrenoceptor and cholinoceptor blockade increased output of the mucus marker ³⁵SO₄ by 59% above baseline (representing the NANC neural secretory response). CGP 49823, CGP 55000 or CP 99,994 concentration-dependently inhibited NANC neural secretion with IC₅₀ values of 30, 8 and 120 nM, respectively. In contrast, MEN 10,627 (3 μM) did not inhibit secretion. The NK₁ antagonists, but not the NK₂ antagonist, inhibited [Sar⁹]substance P-induced secretion, while none of the antagonists affected acetylcholine-induced secretion. We conclude that NANC neural secretion in ferret trachea in vitro is a useful test system for tachykinin NK₁ receptor antagonists with therapeutic potential in conditions of the airways in which tachykininergic mechanisms and mucus hypersecretion are implicated in pathophysiology, for example asthma and chronic bronchitis.

The distribution of intraepithelial nerve fibres and neuroendocrine cells within the surface and glandular epithelium of human nasal mucosa and larynx was examined using immunohistochemical techniques. Neuronal structures were immunostained for the general neuroendocrine marker protein gene-product (PGP) 9.5, and the two neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) using immunofluorescence and streptavidin–biotin-peroxidase complex (S-ABC) methods. Intraepithelial nerve fibres with free nerve endings contained PGP 9.5 and were found within the respiratory surface epithelium of the nasal mucosa and the squamous epithelium of the larynx. A subpopulation of these nerve fibres showed positive immunoreactivties with antibodies against SP and CGRP. Nerve fibres within the ductal epithelium of subepithelial excretory ducts passing the basal membrane and reaching the luminal part were detected. These nerve fibres showed CGRP-like immunoreactivity but not for SP. A dense network of nerve fibres within the squamous surface epithelium was detected in the subglottic and epiglottic region containing CGRP and SP in a small subpopulation of nerve fibres. Single intraepithelial taste buds in the epiglottic region and neuroendocrine cells within the subglottic epithelium expressed PGP 9.5.