Airway inflammation and tachykinins: prospects for the development of tachykinin receptor antagonists

Joos, Guy; Swert, Katelijne O. De; Pauwels, Romain

doi:10.1016/s0014-2999(01)01323-1

Cited by 60 publications

(45 citation statements)

References 121 publications

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“…However, recently it was reported that in smalldiameter human bronchi, tachykinins also cause contraction via NK 1 R stimulation (4). Moreover, functional evidence for the presence of NK 3 R exists in both animal and human airways (24,38,40,43). Although most functional studies suggest that the NK 3 R subtype is not directly involved in airway smooth muscle constriction (2, 13, 14, 53), an NK 3 R antagonist was mildly potent at inhibiting a neurokinin A-induced contraction in human bronchus (51).…”

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confidence: 99%

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

Mizuta

Gallos

Zhu

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Emala CW Sr. Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 294: L523-L534, 2008. First published January 18, 2008 doi:10.1152/ajplung.00328.2007.-Neuropeptide tachykinins (substance P, neurokinin A, and neurokinin B) are present in peripheral terminals of sensory nerve fibers within the respiratory tract and cause airway contractile responses and hyperresponsiveness in humans and most mammalian species. Three subtypes of neurokinin receptors (NK 1R, NK2R, and NK3R) classically couple to G q protein-mediated inositol 1,4,5-trisphosphate (IP3) synthesis and liberation of intracellular Ca 2ϩ , which initiates contraction, but their expression and calcium signaling mechanisms are incompletely understood in airway smooth muscle. All three subtypes were identified in native and cultured human airway smooth muscle (HASM) and were subsequently overexpressed in HASM cells using a human immunodeficiency virus-1-based lentivirus transduction system. Specific NKR agonists {NK 1R, [Sar 9 ,Met(O2) 11 ]-substance P; NK 2 R, [␤-Ala 8 ]-neurokinin A(4 -10); NK 3 R, senktide} stimulated inositol phosphate synthesis and increased intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) in native HASM cells and in HASM cells transfected with each NKR subtype. These effects were blocked by NKR-selective antagonists (NK 1R, L-732138; NK2R, GR-159897; NK 3R, SB-222200). The initial transient and sustained phases of increased [Ca 2ϩ ]i were predominantly inhibited by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB) or the store-operated Ca 2ϩ channel antagonist SKF-96365, respectively. These results show that all three subtypes of NKRs are expressed in native HASM cells and that IP 3 levels are the primary mediators of NKR-stimulated initial [Ca 2ϩ ] i increases, whereas store-operated Ca 2ϩ channels mediate the sustained phase of the [Ca 2ϩ ]i increase. intracellular calcium; ryanodine; actin; myosin; lentivirus 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). At least three subtypes of neurokinin receptors (NK 1 R, NK 2 R, and NK 3 R) have been characterized, which exhibit preferential affinity for the endogenous neuropeptides substance P, neurokinin A, and neurokinin B, respectively (33). All three receptor subtypes are members of the seven-transmembrane domain receptor superfamily that couple to G q proteins (50).Classically, the expression of NK 1 R and NK 2 R has been described in both the nervous system and p...

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confidence: 99%

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

Mizuta

Gallos

Zhu

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…They may be released by a variety of stimuli (eg, allergen, ozone) and have various effects including smooth muscle contraction; facilitation of cholinergic neurotransmission; submucosal gland secretion; vasodilatation; increase in vascular permeability; stimulation of mast cells, B and T lymphocytes, and macrophages; chemoattraction of eosinophils and neutrophils; and the vascular adhesion of neutrophils. 1 Tachykinins mediate their effects by stimulation of tachykinin NK 1 , NK 2 and NK 3 receptors.…”

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confidence: 99%

“…Elevated levels of tachykinins have been recovered from the airways of patients with asthma, and airway inflammation leads to an upregulation of tachykinin NK 1 and NK 2 receptors. 1 In guinea pigs, the tachykinin NK 1 receptor is involved in both the antigen-induced airway hyperresponsiveness to histamine and the infiltration of inflammatory cells. 3 Substance P also exerts several proinflammatory actions on macrophages [4][5][6][7] ; even an autocrine function of this peptide has been suggested.…”

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confidence: 99%

The role of the tachykinin NK1 receptor in airway changes in a mouse model of allergic asthma

Swert

Tournoy

Joos

et al. 2004

Journal of Allergy and Clinical Immunology

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Background: Tachykinins are present in sensory nerves and in nonneuronal cells like macrophages. Human data suggest a role for these peptides in asthma, but the exact role of tachykinins and their receptors in allergic airway inflammation is still a matter of debate. Objective: The aim of this study was to determine the role of the tachykinin NK 1 receptor in allergic airway responses in a mouse model. Methods: Tachykinin NK 1 receptor wild-type and knockout animals were sensitized intraperitoneally to ovalbumin and subsequently exposed from days 14 to 21 to aerosolized ovalbumin (1%). On day 22, the immunologic and histologic changes were evaluated, and lung function measurements were performed. Results: Mice lacking the tachykinin NK 1 receptor and their wild-type litter mates developed inflammatory cell infiltrates in the airways and ovalbumin-specific IgE on sensitization and exposure to ovalbumin compared with saline-exposed controls. No differences were detected between wild-type and knockout mice. The substance P content of alveolar macrophages was not influenced by ovalbumin or by the lack of the NK 1 receptor. Ovalbumin-induced hyperresponsiveness was not observed, but at baseline, the knockout mice were more reactive despite similar morphology. Ovalbumin induced more goblet cell hyperplasia in wild-type animals compared with knockout animals. No differences in airway wall thickness were observed. Conclusion: These data suggest that tachykinin NK 1 receptors do not affect allergic airway inflammation or endogenous substance P content of alveolar macrophages but influence baseline responsiveness and promote features of remodeling such as goblet cell

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“…Tachykinins may be released by a variety of stimuli (e.g. cigarette smoke, ozone) and they generate a range of effects that are potentially relevant in the pathogenesis of asthma [1]. Their effects are mediated through specific receptors, the tachykinin NK 1 , NK 2 and NK 3 receptors.…”

Section: Introductionmentioning

confidence: 99%

“…cigarette smoke, ozone) and they generate a range of effects that are potentially relevant in the pathogenesis of asthma [1]. Their effects are mediated through specific receptors, the tachykinin NK 1 , NK 2 and NK 3 receptors. In the airways, tachykinin NK 1 receptors, the high affinity receptors for substance P, are mainly involved in proinflammatory effects while NK 2 receptors, preferential receptors for neurokinin A, are considered to be important in smooth muscle contraction.…”

Section: Introductionmentioning

confidence: 99%

Role of the tachykinin NK1 receptor in mediating contraction to 5-hydroxytryptamine and antigen in the mouse trachea

Swert

Lefebvre

Pauwels

et al. 2007

Pulmonary Pharmacology & Therapeutics

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Airway inflammation and tachykinins: prospects for the development of tachykinin receptor antagonists

Cited by 60 publications

References 121 publications

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

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

The role of the tachykinin NK1 receptor in airway changes in a mouse model of allergic asthma

Role of the tachykinin NK1 receptor in mediating contraction to 5-hydroxytryptamine and antigen in the mouse trachea

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