Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism

Steinhoff, Martin; Vergnolle, Nathalie; Young, Steven H.; Tognetto, Michele; Amadesi, Silvia; Ennes, Helena S.; Trevisani, Marcello; Hollenberg, Morley D.; Wallace, John L.; Caughey, George H.; Mitchell, Sharon E.; Williams, Lynda M.; Geppetti, Pierangelo; Mayer, Emeran A.; Bunnett, Nigel W.

doi:10.1038/72247

Cited by 864 publications

(865 citation statements)

References 39 publications

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“…121,123 TRPV4 is extensively co-localised with PAR2 (proteinase-activated receptor 2), which sensitizes thoracolumbar spinal afferents to the gut during neurogenic inflammation. 124 Activation of PAR2, by proteases released by mast cell degranulation, can lead to behavioural hypersensitivity and increased afferent firing via sensitization of TRPV4. 123,125 TRPA1 is the third TRP channel known to have a key role in setting the sensitivity of vascular afferents.…”

Section: Trp Channels In Vascular Afferentsmentioning

confidence: 99%

Extrinsic primary afferent signalling in the gut

Brookes

Spencer

Costa

et al. 2013

Nat Rev Gastroenterol Hepatol

236

207

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Visceral sensory neurons activate reflex pathways that control gut function and also give rise to important sensations, such as fullness, bloating, nausea, discomfort, urgency and pain. Sensory neurons are organised into three distinct anatomical pathways to the central nervous system (vagal, thoracolumbar and lumbosacral). Although remarkable progress has been made in characterizing the roles of many ion channels, receptors, and second messengers in visceral sensory neurons, the basic aim of understanding how many classes there are, and how they differ, has proven difficult to achieve. We suggest that there are just five structurally distinct types of sensory endings in the gut wall that account for essentially all of the primary afferent neurons in the three pathways. Each of these five major structural types of endings seems to show distinctive combinations of physiological responses. These types are: 'intraganglionic laminar' endings in myenteric ganglia; 'mucosal' endings located in the subepithelial layer; 'muscular mucosal' afferents, with mechanosensitive endings close to the muscularis mucosae; 'intramuscular' endings, with endings within the smooth muscle layers; and 'vascular' afferents, with sensitive endings primarily on blood vessels. 'Silent' afferents might be a subset of inexcitable 'vascular' afferents, which can be switched on by inflammatory mediators.Extrinsic sensory neurons comprise an attractive focus for targeted therapeutic intervention in a range of gastrointestinal disorders.2

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Section: Trp Channels In Vascular Afferentsmentioning

confidence: 99%

Extrinsic primary afferent signalling in the gut

Brookes

Spencer

Costa

et al. 2013

Nat Rev Gastroenterol Hepatol

236

207

View full text Add to dashboard Cite

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“…However the precise mechanism and the specific inflammatory cells and Mast cells release histamine and tryptase, both of which have been detected in the airways of cough patients [59,60]. In an experimental model of itch, tryptase is known to activate the proteinase activated receptor (PAR-2) located on the C-fibre nerve terminal, releasing substance P which in turn sensitises the mast cell to release TNFα which in known to sensitize nociceptor function [64]. Neuropeptides such as substance P and neurokinin A are elevated in the airways of asthmatic patients with cough [65] and airway levels of calcitoningene-related peptide (CGRP) are positively correlated with capsaicin cough reflex sensitivity [66].…”

Section: Inflammation Cough Reflex Sensitisation and Airway Sensory mentioning

confidence: 99%

Are there clinical features of a sensitized cough reflex?

McGarvey

McKeagney²,

Polley

et al. 2009

Pulmonary Pharmacology & Therapeutics

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Key words: sensory hyperresponsiveness, hyperreactivity, cough reflex, receptor AbstractCough reflex hypersensitization is a key feature in patients with troublesome cough. The clinical consequence of this hypersensitive state is typified by bouts of coughing often triggered by low threshold stimuli encountered by the patient during normal daily activities including exposure to aerosols, scents and odours, a change in air temperature and when talking or laughing. These features are often perceived by cough patients to be the most disruptive aspect of their condition and undoubtedly contribute to impaired quality of life.Patients with troublesome cough may describe a range of additional symptoms and sensations including an 'urge to cough' or the feeling of an 'itch' at the back of the throat, or a choking sensation and occasionally chest pain or breathlessness. It is uncertain if these features arise due to the processes responsible for cough reflex sensitisation or as a direct consequence of the underlying cough aetiology. In an attempt to understand the clinical features of a sensitized cough reflex, the spectrum of symptoms typically described by cough patients will be reviewed and possible underlying mechanisms considered. Since an intact cough reflex is crucial to airway protection, anti-tussive treatment that attenuates the hypersensitive cough state rather than abolishing the cough reflex completely would be preferable. Identifying such agents remains a clinical, scientific and pharmacological challenge.

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“…Immunoreactive PAR2 was more strongly expressed in the expected cell types in the airways of PAR2tg mice compared with PAR2wt(tg) animals, as detected with an Ab to human PAR2, which confirms overexpression of the protein. Although the PAR2tg animals expressed human rather than mouse PAR2, the cleavage site for trypsin and tryptase are identical for the human and rodent receptors, both of which respond to trypsin and tryptase (25,31,32,35).…”

Section: Par2 Mediates Allergic Inflammation Of the Airwaysmentioning

confidence: 99%

Protease-Activated Receptor 2 Mediates Eosinophil Infiltration and Hyperreactivity in Allergic Inflammation of the Airway

Schmidlin

Amadesi

Dabbagh³

et al. 2002

The Journal of Immunology

303

258

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Trypsin and mast cell tryptase can signal to epithelial cells, myocytes, and nerve fibers of the respiratory tract by cleaving proteinase-activated receptor 2 (PAR2). Since tryptase inhibitors are under development to treat asthma, a precise understanding of the contribution of PAR2 to airway inflammation is required. We examined the role of PAR2 in allergic inflammation of the airway by comparing OVA-sensitized and -challenged mice lacking or overexpressing PAR2. In wild-type mice, immunoreactive PAR2 was detected in airway epithelial cells and myocytes, and intranasal administration of a PAR2 agonist stimulated macrophage infiltration into bronchoalveolar lavage fluid. OVA challenge of immunized wild-type mice stimulated infiltration of leukocytes into bronchoalveolar lavage and induced airway hyperreactivity to inhaled methacholine. Compared with wild-type animals, eosinophil infiltration was inhibited by 73% in mice lacking PAR2 and increased by 88% in mice overexpressing PAR2. Similarly, compared with wild-type animals, airway hyperreactivity to inhaled methacholine (40 μg/ml) was diminished 38% in mice lacking PAR2 and increased by 52% in mice overexpressing PAR2. PAR2 deletion also reduced IgE levels to OVA sensitization by 4-fold compared with those of wild-type animals. Thus, PAR2 contributes to the development of immunity and to allergic inflammation of the airway. Our results support the proposal that tryptase inhibitors and PAR2 antagonists may be useful therapies for inflammatory airway disease.

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Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism

Cited by 864 publications

References 39 publications

Extrinsic primary afferent signalling in the gut

Extrinsic primary afferent signalling in the gut

Are there clinical features of a sensitized cough reflex?

Protease-Activated Receptor 2 Mediates Eosinophil Infiltration and Hyperreactivity in Allergic Inflammation of the Airway

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