Tachykinin receptors and the airways

doi:10.1016/0024-3205(91)90636-P

Life Sciences

Volume 49, Issue 26, 1991, Pages 1941-1953

https://doi.org/10.1016/0024-3205(91)90636-P Get rights and content

Abstract

The tachykinins, substance P, neurokinin A and neurokinin B, belong to a structural family of peptides. In mammalian airways, substance P and neurokinin A are colocalized to afferent C-fibres. Substance P-containing fibres are close to bronchial epithelium, smooth muscle, mucus glands and blood vessels. Sensory neuropeptides may be released locally, possibly as a result of a local reflex, and produce bronchial obstruction through activation of specific receptors on these various tissues. Three types of tachykinin receptors, namely NK-1, NK-2 and NK-3 receptors, have been characterized by preferential activation by substance P, neurokinin A and neurokinin B respectively. NK-1 and NK-2 receptors were recently cloned. The determination of receptor types involved in the effects of tachykinins in the airways has been done with synthetic agonists and antagonists binding specifically to NK-1, NK-2 and NK-3 receptors. Although the existence of species differences, the conclusion that bronchial smooth muscle contraction is mainly related to activation of NK-2 receptors on bronchial smooth muscle cell has been drawn. The hypothesis of a NK-2 receptor subclassification has been proposed with NK-2A receptor subtype in the guinea-pig airways. Other effects in the airways are related to stimulation of NK-1 receptors on mucus cells, vessels, epithelium and inflammatory cells. A non-receptor-mediated mechanism is also involved in the effect of substance P on inflammatory cells and mast cells.

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Tachykinins encoded by the preprotachykinin A (TAC1) gene such as substance P (SP) and neurokinin A (NKA) are involved in neurogenic inflammatory processes via predominantly neurokinins 1 and 2 (NK1 and NK2) receptor activation, respectively. Endokinins and hemokinins encoded by the TAC4 gene also have remarkable selectivity and potency for the NK1 receptors and might participate in inflammatory cell functions. The aim of the present study was to investigate endotoxin-induced airway inflammation and consequent bronchial hyper-reactivity in TAC1^−/−, NK1^−/− and also in double knockout (TAC1^−/−/NK1^−/−) mice.
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Airway hyper-reactivity was significantly reduced in the TAC1^−/− as well as the TAC1^−/−/NK1^−/− groups. However, LPS-induced histological inflammatory changes (perivascular/peribronchial oedema, neutrophil infiltration and goblet cell hyperplasia), MPO activity and TNF-α concentration were markedly diminished only in TAC1^−/− mice. Interestingly, the concentrations of both cytokines, IL-1β and TNF-α, were significantly greater in the NK1^−/− group.
These data clearly demonstrated on the basis of histology, MPO and cytokine measurements that TAC1 gene-derived tachykinins, SP and NKA, play a significant role in the development of endotoxin-induced murine airway inflammation, but not solely via NK1 receptor activation. However, in inflammatory bronchial hyper-responsiveness other tachykinins, such as hemokinin-1 acting through NK1 receptors also might be involved.
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To cough is a protective defence mechanism that is vital to remove foreign material and secretions from the airways and which in the normal state serves its function appropriately. Modulation of the cough reflex pathway in disease can lead to inappropriate chronic coughing and an augmented cough response. Chronic cough is a symptom that can present in conjunction with a number of diseases including chronic obstructive pulmonary disease (COPD) and asthma, although often the cause of chronic cough may be unknown. As current treatments for cough have proved to exhibit little efficacy and are largely ineffective, there is a need to develop novel, efficacious and safe antitussive therapies. The underlying mechanisms of the cough reflex are complex and involve a network of events, which are not fully understood. It is accepted that the cough reflex is initiated following activation of airway sensory nerves. Therefore, in the hope of identifying novel antitussives, much research has focused on understanding the neural mechanisms of cough provocation. Experimentally this has been undertaken using chemical or mechanical tussive stimuli in conjunction with animal models of cough and clinical cough assessments. This review will discuss the neural mechanisms involved in the cough, changes that occur under pathophysiological conditions and and how current research may lead to novel therapeutic opportunities for the treatment of cough.
Nerve growth factor enhances neurokinin A-induced airway responses and exhaled nitric oxide via a histamine-dependent mechanism
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Citation Excerpt :
The findings lend further evidence for NGF as a factor of importance in induction of airway hyperresponsiveness. Histamine and NKA are endogenous mediators that through binding to cell surface receptors on airway smooth muscle cells induce smooth muscle contraction and bronchoconstriction, hallmarks of asthma [37,38]. In asthmatics, an increased bronchoconstriction to these agonists has been described, but the mechanism for this hyperresponsiveness is unclear [1].
The neurotrophin nerve growth factor (NGF) is elevated in serum and locally in the lung in asthmatics and has been suggested to evoke airway hyperresponsiveness. The aim of this study was to explore mechanisms behind NGF-evoked changes in airway responsiveness. We studied if NGF could evoke increased airway responsiveness to tachykinins, such as neurokinin A (NKA), in a similar way as for histamine and, if so, whether an NGF-evoked increase in NKA airway responsiveness could involve a histamine receptor-dependent mechanism. Contractile responses to cumulative doses of histamine or NKA were studied in guinea-pig tracheal rings in vitro in organ baths. Furthermore, insufflation pressure (IP), pulmonary resistance, lung compliance and exhaled NO (FeNO) were measured in vivo in anaesthetised guinea-pigs challenged with histamine or NKA. NGF pre-treatment in vitro increased the contractile response evoked by histamine, but not by NKA, in tracheal rings. NGF pre-treatment in vivo increased IP, pulmonary resistance and levels of FeNO, and further decreased lung compliance, upon histamine and NKA challenge. The NGF-evoked enhancement of IP, pulmonary resistance, lung compliance as well as FeNO in response to NKA was reversed by the histamine receptor antagonist mepyramine. We suggest that NGF can induce an increase in tachykinin-evoked airway responses and NO formation via a histamine receptor-dependent pathway. This points to an important role for the mast cell in neurotrophin-evoked airway hyperresponsiveness and changes in exhaled NO.
Respiratory Pharmacology and Aerosol Therapy
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Neuronal modulation of lung injury induced by polymeric hexamethylene diisocyanate in mice
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1,6-Hexamethylene diisocyanate biuret trimer (HDI-BT) is a nonvolatile isocyanate that is a component of polyurethane spray paints. HDI-BT is a potent irritant that when inhaled stimulates sensory nerves of the respiratory tract. The role of sensory nerves in modulating lung injury following inhalation of HDI-BT was assessed in genetically manipulated mice with altered innervation of the lung. Knockout mice with a mutation in the low-affinity nerve growth factor receptor (NGFR), which have decreased innervation by nociceptive nerve fibers, and transgenic mice expressing nerve growth factor (NGF) from the lung-specific Clara cell secretory protein (CCSP) promoter, which have increased innervation of the airways, were exposed to HDI-BT aerosol and evaluated at various times after exposure. NGFR knockout mice exhibited significantly more, and CCSP-NGF transgenic mice exhibited significantly less injury and inflammation compared with wild-type mice, indicative of a protective effect of nociceptive nerves on the lung following HDI-BT inhalation. Transgenic mice overexpressing the tachykinin 1 receptor (Tacr1) in lung epithelial cells also showed less severe injury and inflammation compared with wild-type mice after HDI-BT exposure, establishing a role for released tachykinins acting through Tacr1 in mediating at least part of the protective effect. Treatment of lung fragments from Tacr1 transgenic mice with the Tacr1 ligand substance P resulted in increased cAMP accumulation, suggesting this compound as a possible signaling mediator of protective effects on the lung following nociceptive nerve stimulation. The results indicate that sensory nerves acting through Tacr1 can exert protective or anti-inflammatory effects in the lung following isocyanate exposure.
Role of capsaicin-sensitive afferents and sensory neuropeptides in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity in the mouse
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Substance P (SP) and calcitonin gene-related peptide (CGRP) released from capsaicin-sensitive afferents induce neurogenic inflammation via NK₁, NK₂ and CGRP1 receptor activation. This study examines the role of capsaicin-sensitive fibres and sensory neuropeptides in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity with functional, morphological and biochemical techniques in mice. Carbachol-induced bronchoconstriction was measured with whole body plethysmography 24 h after intranasal lipopolysaccharide administration. SP and CGRP were determined with radioimmunoassay, myeloperoxidase activity with spectrophotometry, interleukin-1β with ELISA and histopathological changes with semiquantitative scoring from lung samples. Treatments with resiniferatoxin for selective destruction of capsaicin-sensitive afferents, NK₁ antagonist SR 140333, NK₂ antagonist SR 48968, their combination, or CGRP1 receptor antagonist CGRP(8-37) were performed. Lipopolysaccharide significantly increased lung SP and CGRP concentrations, which was prevented by resiniferatoxin pretreatment. Resiniferatoxin-desensitization markedly enhanced inflammation, but decreased bronchoconstriction. CGRP(8-37) or combination of SR 140333 and SR 48968 diminished neutrophil accumulation, MPO levels and IL-1β production, airway hyperresponsiveness was inhibited only by SR 48968. This is the first evidence that capsaicin-sensitive afferents exert a protective role in endotoxin-induced airway inflammation, but contribute to increased bronchoconstriction. Activation of CGRP1 receptors or NK₁ + NK₂ receptors participate in granulocyte accumulation, but NK₂ receptors play predominant role in enhanced airway resistance.

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MinireviewTachykinin receptors and the airways

Abstract

Regulatory Peptides

Pulm Pharmacol

Eur J Pharmacol

Eur J Pharmacol

Trends Pharmacol Sci

Trends Pharmacol Sci

Trends Pharmacol Sci

J Biol Chem

Eur J Pharmacol

Biochem Biophys Res Comm

Biochem Pharmacol

Neuropharmacology

Eur J Pharmacol

Peptides

J Allergy Clin Immunol

FEBS Lett

Trends Pharmacol Sci

Eur J Pharmacol

Eur J Pharmacol

Neuropeptides

Pulm Pharmacol

Am Rev Respi Dis

J Appl Physiol

Am Rev Respir Dis

Naunyn Schmiedeberg's Arch Pharmacol

Trends NeuroSci.

Trends Neurosci

Acta Physiol Scand

Exp Lung Res

Cell Tissue Res

Lancet

Acta Physiol Scand

Am Rev Respir Dis

Clin Resp Physiol

J Pharmacol Exp Ther

J Pharmacol Exp Ther

Nature (Lond)

Nature (Lond)

Pharmacology

Am Rev Respir Dis

Nature (Lond)

Molec Pharmacol

Science

Nature (Lond)

Br J Pharmacol

Br. J. Pharm.

Minireview
Tachykinin receptors and the airways