Functional effects of protease-activated receptor-2 stimulation on human airway smooth muscle

Chambers, Linda S.; Black, Judith L.; Poronnik, Philip; Johnson, Patricia A.

doi:10.1152/ajplung.2001.281.6.l1369

Cited by 62 publications

(79 citation statements)

References 38 publications

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“…The observation that instillation of PAR2-AP into the airway doubled the peak airway pressure and increased plateau pressure in wild-type but not PAR2 knockout mice is consistent with reports that PAR2 promotes hyperreactivity in allergic inflammation of the airway in mice (8), that PAR2-AP can increase the contractile response of isolated bronchi from guinea pigs to histamine (32), and that PAR2-AP can induce contraction of human airways and potentiate contractions to histamine (13,14). Our observation that PAR2-AP can trigger leukocyte infiltration into lung is consistent with reports that PAR2-AP can promote leukocyte rolling and arrest on mesenteric (10) and cremasteric vessels (11) and neurogenic inflammation in rat paw (5).…”

Section: Discussionsupporting

confidence: 89%

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Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms

Camerer

Hamilton

et al. 2005

The Journal of Immunology

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Protease-activated receptors (PARs) and tachykinin-immunoreactive fibers are located in the lung as sentries to respond to a variety of pathological stimuli. The effects of PAR activation on the lung have not been adequately studied. We report on the effects of instilling PAR-activating peptides (PAR-APs, including PAR1-, PAR2-, and PAR4-AP) into the lungs of ventilated or spontaneously breathing mice. PAR2-AP, but not PAR1-AP or PAR4-AP, caused a sharp increase in lung endothelial and epithelial permeability to protein, extravascular lung water, and airway tone. No responses to PAR2-AP were detected in PAR2 knockout mice. In bronchoalveolar lavage, PAR2 activation caused 8- and 5-fold increase in MIP-2 and substance P levels, respectively, and a 12-fold increase in the number of neutrophils. Ablation of sensory neurons (by capsaicin) markedly decreased the PAR2-mediated airway constriction, and virtually abolished PAR2-mediated pulmonary inflammation and edema, as did blockade of NK1 or NK2 receptors. Thus, PAR2 activation in the lung induces airway constriction, lung inflammation, and protein-rich pulmonary edema. These effects were either partly or completely neuropeptide dependent, suggesting that PAR2 can cause lung inflammation by a neurogenic mechanism.

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Section: Discussionsupporting

confidence: 89%

“…However, the role of PARs in this tissue has not been completely explored. PAR1 and PAR2 are expressed on bronchial epithelial (12) and smooth muscle cells (13)(14)(15), as well as vascular endothelial and smooth muscle cells (16). A type II alveolar epithelial cell line (A549) also expresses PAR2 (17).…”

mentioning

confidence: 99%

Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms

Camerer

Hamilton

et al. 2005

The Journal of Immunology

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“…The asthmatics had asthma symptoms in the last 12 months and a positive bronchial provocation challenge to either mannitol [23] or to methacholine [24]; these were lung sample donors 19-27 and 28-32, respectively (table 1). The nonasthmatics had a pre-operative diagnosis as given in table 1 and no respiratory physician diagnosis of asthma in their medical records.…”

Section: Asm Cell Culturementioning

confidence: 99%

Histamine and tryptase modulate asthmatic airway smooth muscle GM-CSF and RANTES release

Chhabra¹,

Yz²,

Alkhouri³

et al. 2007

Eur Respir J

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Degranulating mast cells are increased in the airway smooth muscle (ASM) of asthmatics, where they may influence ASM function. The aim of the present study was to determine whether histamine and tryptase modulate ASM cell granulocyte-macrophage colonystimulating factor (GM-CSF) and RANTES (regulated on activation, normal T-cell expressed and secreted) release and also to examine which receptors are involved in this release.Confluent, quiescent ASM cells from asthmatic and nonasthmatic donors were treated with histamine (1 mM-100 mM) with and without histamine receptor antagonist pre-treatment, or the protease-activated receptor (PAR)-2 agonists tryptase (0.5-5 nM) and SLIGKV (100 and 400 mM). The cells were then stimulated with interleukin (IL)-1b and/or tumour necrosis factor (TNF)-a (10 ng?mL -1 ) or left unstimulated for 24 h. Release of GM-CSF and RANTES was determined by ELISA and prostaglandin (PG)E 2 measured by enzyme immunoassay. Neither histamine nor tryptase induced ASM GM-CSF or RANTES secretion. However, histamine increased IL-1b-induced GM-CSF release and markedly reduced TNF-a-induced RANTES release by both asthmatic and nonasthmatic cells to a similar extent, but did not modulate PGE 2 release. All changes involved activation of the histamine H1 receptor as they were partially or fully blocked by chlorpheniramine, but not ranitidine. Tryptase, via its proteolytic activity, also potentiated GM-CSF, but not RANTES, release from asthmatic and nonasthmatic ASM cells induced by both cytokines. PAR-2 involvement in the tryptase potentiation was unlikely because SLIGKV had no effect.In conclusion, mast cells, through histamine and tryptase, may locally modulate airway smooth muscle-induced inflammation in asthma.

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“…An airway segment some 25 mm in length and 2-3 mm internal diameter was removed. Segments were classified as small or medium-sized based on their diameter, location (spanning generations [9][10][11][12][13][14], and the presence of cartilage [17]. Each segment was cannulated and mounted horizontally in an organ bath containing Kreb's solution (mM: NaCl 121, KCl 5.4, MgSO 4 1.2, NaHCO 3 25, NaMOPS (sodium morpholinopropane sulphonic acid, pH 7.3) 5.0, glucose 11.5, CaCl 2 2.5, gassed with 95% O 2 and 5% CO 2 and warmed to 37uC).…”

Section: Methodsmentioning

confidence: 99%

“…Functionally, trypsin can produce rapid and short-lived relaxation of airway smooth muscle (ASM) strip preparations, although findings from different species and/or studies are not uniform [5,[7][8][9][10]; for example, in human ASM, trypsin may cause excitation rather than relaxation [11]. Trypsin activates PAR 2 and PAR 4 [1,2,4] and, since synthetic peptides (PAR-activating peptides, PAR AP) to these receptors also relax ASM preparations, the relaxant effects of trypsin have been attributed to activation of PAR-associated signalling pathways.…”

mentioning

confidence: 99%

Delayed and persistent suppression of bronchoconstriction by trypsin in the airway lumen

Sharma

Goh²,

Asokananthan³

et al. 2006

Eur Respir J

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Mucosal trypsin, a protease-activated receptor (PAR) stimulant, may have an endogenous bronchoprotective role on airway smooth muscle. To test this possibility the effects of lumenal trypsin on airway tone in segments of pig bronchus were tested.Bronchial segments from pigs were mounted in an organ chamber containing Kreb's solution. Contractions were assessed from isovolumetric lumen pressure induced by acetylcholine (ACh) or carbachol added to the adventitia.Trypsin, added to the airway lumen (300 mg?mL), had no immediate effect on smooth muscle tone but suppressed ACh-induced contractions after 60 min, for at least 3 h. Synthetic activating peptides (AP) for PAR 1 , PAR 2 or PAR 3 were without effect, but PAR 4 AP caused rapid, weak suppression of contractions. Lumenal thrombin was without effect and did not prevent the effects of trypsin. Effects of trypsin were reduced by N w -nitro-L-arginine methyl ester but not indomethacin. Trypsin, thrombin and PAR 4 AP released prostaglandin E2. Adventitially, trypsin, thrombin and PAR 4 AP (but not PAR 2 AP) relaxed carbachol-toned airways after ,3 min.The findings of this study show that trypsin causes delayed and persistent bronchoprotection by interacting with airway cells accessible from the lumen. The signalling mechanism may involve nitric oxide synthase but not prostanoids or protease-activated receptors.

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Functional effects of protease-activated receptor-2 stimulation on human airway smooth muscle

Cited by 62 publications

References 38 publications

Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms

Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms

Histamine and tryptase modulate asthmatic airway smooth muscle GM-CSF and RANTES release

Delayed and persistent suppression of bronchoconstriction by trypsin in the airway lumen

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