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Editorials Neurogenic Inflammation in Human Airways

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Editorials Neurogenic Inflammation in Human Airways Thorax 1995;50:217-219 217 Thorax: first published as 10.1136/thx.50.3.217 on 1 March 1995. Downloaded from THORAX Editorials Neurogenic inflammation in human airways: is it important? Numerous peptides have been demonstrated in airway which is present in both upper and lower human nerves and endocrine cells.' Among the best studied are airways. substance P and neurokinin A which are peptides contained A considerable amount of research has been carried within sensory airway nerves. Both are members of the out on the effects of exogenously administered sensory tachykinin peptide family. The tachykinins are potent vaso- neuropeptides on the upper and lower airways. Studies on dilators and contractors of smooth muscle which are co- human lower airways have focused on changes in airway localised with calcitonin gene-related peptide, a sensory calibre. 2 Inhalation ofsubstance P and neurokinin A causes neuropeptide with important vasodilator properties.2 In dose-dependent bronchoconstriction, neurokinin A being studies on rodent airways substance P and neurokinin A more potent than substance P and asthmatic subjects being have been implicated as neurotransmitters which mediate more responsive than normal subjects.2' 28 The contractile the excitatory part of the non-adrenergic non-cholinergic effect of substance P and neurokinin A is reduced in (NANC) nervous system. These non-cholinergic excitatory asthmatic patients pretreated with disodium cromoglycate nerves can be activated by mechanical and chemical stimuli or nedocromil sodium, suggesting that indirect mech- - as stimulation of cells and/or - for example, histamine, bradykinin generating anti- anisms such inflammatory http://thorax.bmj.com/ dromic impulses and a local axon reflex which leads to nerves are involved.2429 Pretreatment with anticholinergics non-cholinergic bronchoconstriction, plasma protein extra- offers only slight protection, whereas antihistamines have vasation, and vasodilatation."34 Jancso et al first used the no effect on the bronchoconstriction caused by neurokinin term "neurogenic inflammation" to describe the increase A.'0" The exact mechanism by which substance P and in vascular permeability, plasma extravasation, and tissue neurokinin A contract human airways in vivo remains swelling which occurred in the skin and conjunctiva when to be determined. Apart from bronchoconstriction, other sensory nerves were stimulated by topical administration potentially important lower airway effects of the sensory - an effect ofirritants such as capsaicin, hypertonic saline, mustard oil neuropeptides include mucus hypersecretion on October 4, 2021 by guest. Protected copyright. and formaldehyde, or by antidromic electrical stimulation.5 which has been studied on human bronchi in vitro'2 - and In studies on animal and isolated human airways the the enhancement of microvascular permeability - an effect effects observed following stimulation with tachykinins which has been extensively studied in rodents.' At present include smooth muscle contraction, stimulation of sub- in vivo data on these effects in man are lacking. mucosal gland secretion, vasodilatation, and increased vas- The effect of exogenously administered substance P, cular permeability. 134 Moreover, the sensory neuropeptides neurokinin A, and calcitonin gene-related peptide has have important proinflammatory effects such as the stimu- also been studied in the nose. Topical administration of lation ofT lymphocyte proliferation, stimulation of macro- substance P and neurokinin A increases nasal airway re- phages, mast cells and eosinophils, and the chemo- sistance in a dose-dependent fashion, substance P being attraction of eosinophils and neutrophils.8 Since the more potent than neurokinin A and methacholine.334 The description of these effects the original concept of neuro- increase in nasal airway resistance is more pronounced in genic inflammation put forward by Jancso and coworkers patients with allergic rhinitis than in control subjects." has been broadened by some authors to include the various Furthermore, in patients with allergic rhinitis, nasal chal- components of the efferent function ofthe sensory nerves.9 lenge with substance P or neurokinin A increases the In view of their multiple effects the sensory neuropeptides amount of protein and albumin recovered, which is taken have been implicated in the pathogenesis of several airway as evidence in favour of plasma protein extravasation.'4 disorders including rhinitis and asthma.10-'2 Substance P also increases the percentage of neutrophils The sensory neuropeptides substance P and neurokinin recovered from nasal lavage.'4'5 In contrast, application of A and their receptors have been localised to upper and calcitonin gene-related peptide to the nasal mucosa does lower human airways. 1"-16 Compared with rodents the nerve not stimulate glandular or plasma protein extravasation, fibres containing substance P are less dense in human which is in agreement with animal studies showing that airway tissue. Studies on necroscopic tissue, broncho- calcitonin gene-related peptide does not affect baseline alveolar lavage fluid, and induced sputum have, how- plasma protein extravasation.'6 ever, suggested an increased amount of substance P in In animal airways neutral endopeptidase was found to the airways of asthmatic patients compared with normal be the major enzyme responsible for degradation ofsensory subjects. 1'19The major enzyme responsible for degradation neuropeptides. After inhalation of thiorphan or phos- of substance P and neurokinin A is neutral endopeptidase phoramidon (two inhibitors of the degrading enzyme 21828oos, Germonpre, Pauwels neutral endopeptidase) the bronchoconstrictor effect of effect ofcapsaicin was more pronounced late in the season, neurokinin A was enhanced both in normal and asthmatic suggesting that sensory nerves become more responsive subjects. These studies offered functional proof for an during exposure to pollen. Moreover, capsaicin produced involvement of neutral endopeptidase in the in vivo break- nasal blockage only at the end of the pollen season. In line Thorax: first published as 10.1136/thx.50.3.217 on 1 March 1995. Downloaded from down of inhaled neurokinin A in man.262737 Neutral en- with previous observations, capsaicin had no effect on the dopeptidase was also found to be involved in the upper albumin levels in nasal lavage fluid before the pollen season airway response to exogenously administered substance P; and no change occurred in this parameter during the pollen oral administration of the neutral endopeptidase inhibitor season. Hyperalgesia therefore occurs during the pollen acetorphan potentiated the effects of substance P on nasal season but, as no changes in vascular permeability oc- airway resistance. As in the patients with asthma, no curred, the involvement of neurogenic inflammation in difference was observed between the normal subjects and allergic rhinitis was questioned. the subjects with allergic rhinitis.3" Moreover, angiotensin Several questions still remain unanswered. Firstly, effects converting enzyme also seems to be involved in the break- other than vascular permeability may be more important down of exogenously administered substance P in patients - for instance, in a study on 16 adults with chronic non- with allergic rhinitis.3" allergic rhinitis Lacroix et al found an enhanced vascular Substance P and neurokinin A are thus present in human response to capsaicin compared with normal subjects.48 airway nerves and, when exogenously applied, have potent Both nasal vascular responses and subjective discomfort excitatory actions on both upper and lower human airways. were considerably reduced after the fifth application of Neutral endopeptidase is present in the airways and is capsaicin and these changes in nasal response were ac- involved in the breakdown of exogenously administered companied by a 50% reduction in the content of calcitonin substance P. It is not known, however, whether sensory gene-related peptide in nasal biopsy specimens.48 Secondly, nerves release substance P and neurokinin A in airway upper and lower airways have a different structure and disorders such as asthma and rhinitis. behave differently towards inflammatory mediators (for One approach to this problem has been to measure the example, histamine) and pharmacological agents (for ex- amount of substance P released into nasal or broncho- ample, methacholine). One therefore has to be cautious in alveolar lavage fluid. Increased amounts of substance extrapolating findings from the nose to the lower airways P have been recovered from nasal and bronchoalveolar and there is a need to develop methods for the non-invasive lavage fluid after the administration of allergen in the nose measurement of plasma protein extravasation in the lower or through the bronchoscope.'839 lThese findings suggest human airways. Thirdly, attention should be paid to the that sensory neuropeptides can, indeed, be released from longer term effects of the sensory neuropeptides such as sensory nerves into the airways during an allergic reaction. upregulation of cytokine expression and the influence on Another approach has been the use of the neurotoxin bronchial responsiveness"" which may be as important as capsaicin. Capsaicin is an important pharmacological tool the immediate bronchoconstrictor and vascular effects. which has been used mainly in animal studies. It is the Finally, as potent and specific antagonists for the neuro- pungent ingredient
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