Protease-Activated Receptor-2 Peptides Activate Neurokinin-1 Receptors in the Mouse Isolated Trachea

Abey, Hugh T; Fairlie, David P.; Moffatt, James D.; Balzary, Rowan W.; Cocks, T. M.

doi:10.1124/jpet.105.097121

Cited by 22 publications

(22 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to PAR 2 s, PAR 2 -APs are known to activate NK 1 receptors (Abey et al, 2006). However, f-LIGRL-induced reductions in LPS-induced neutrophilia were unaffected by administration of a NK 1 receptor antagonist, indicating that these receptors were not involved in PAR 2 -AP-induced reductions in LPS-induced neutrophilia.…”

mentioning

confidence: 83%

“…NK 1 Receptor Antagonists Did Not Inhibit Responses to PAR 2 -APs. As PAR 2 -APs have been reported to activate NK 1 receptors (Abey et al, 2006), experiments were performed to determine whether a NK 1 receptor antagonist, L-703606, altered f-LIGRL-induced decreases in LPS-induced BAL neutrophil numbers. Similar to previous observations, LPS caused a marked increase in the number of BAL neutrophils, and f-LIGRL reduced this effect by 65 Ϯ 3% (Fig.…”

Section: Lps Model Of Acute Airway Inflammationmentioning

confidence: 99%

“…f-LIGRL seems more suited to in vivo investigations because it is a more potent activator of PAR 2 than SLIGRL and is resistant to degradation by aminopeptidases (Kawabata et al, 2004). Partially scrambled analogs of SLIGRL and f-LIGRL, such as LSIGRL and f-LRGIL, do not activate PAR 2 receptors and are regularly used as control peptides in experiments involving PAR 2 -activating peptides (PAR 2 -APs) (Abey et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibitory Influence of Protease-Activated Receptor 2 and E-Prostanoid Receptor Stimulants in Lipopolysaccharide Models of Acute Airway Inflammation

Peters

Mann²,

Henry³

2010

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Protease-activated receptors (PARs) are widely expressed throughout the respiratory tract, and PAR 2 has been investigated as a potential drug target for inflammatory airway diseases. The primary focus of this study was to determine the extent to which PAR 2 -activating peptides modulate lipopolysaccharide (LPS)-induced airway neutrophilia in mice and establish the underlying mechanisms. Intranasal administration of LPS induced dose-and time-dependent increases in the number of neutrophils recovered from bronchoalveolar lavage (BAL) fluid of mice. Coadministration of the PAR 2 -activating peptide f-LIGRL inhibited LPS-induced neutrophilia at 3 and 6 h after inoculation. PAR 2 -mediated inhibition of LPS-induced neutrophilia was mimicked by prostaglandin E 2 (PGE 2 ) and butaprost[selective E-prostanoid (EP 2 ) receptor agonist], and blocked by parecoxib (cyclooxygenase 2 inhibitor) and 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) (EP 1 /EP 2 receptor antagonist). PAR 2 -activating peptides also blunted early increases in the levels of the key neutrophil chemoattractants keratinocyte-derived chemokine and macrophage inflammatory protein 2 (MIP-2) in the BAL of LPS-exposed mice. However, neither PAR 2 -activating peptides nor PGE 2 inhibited LPSinduced generation of MIP-2 in cultures of primary murine alveolar macrophages In summary, PAR 2 -activating peptides and PGE 2 suppressed LPS-induced neutrophilia in murine airways, independently of an inhibitory action on MIP-2 generation by alveolar macrophages.

show abstract

mentioning

confidence: 83%

Section: Lps Model Of Acute Airway Inflammationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitory Influence of Protease-Activated Receptor 2 and E-Prostanoid Receptor Stimulants in Lipopolysaccharide Models of Acute Airway Inflammation

Peters

Mann²,

Henry³

2010

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Third, the delayed responses mediated by SLIGKV-NH 2 could be by a mechanism other than by PAR-2. This could perhaps involve cross-reactivity with other receptors (1). As a final consideration, it is known that the posttranslational modifications of PAR-2 can change the ability of proteases to activate PAR-2.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory and proliferative responses of human proximal tubule cells to PAR-2 activation

Vesey¹,

Kruger²,

Poronnik³

et al. 2007

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Despite the abundant expression of protease-activated receptor (PAR)-2 in the kidney, its relevance to renal physiology is not well understood. A role for this receptor in inflammation and cell proliferation has recently been suggested in nonrenal tissues. The aims of this study were to demonstrate that human proximal tubule cells (PTC) express functional PAR-2 and to investigate whether its activation can mediate proinflammatory and proliferative responses in these cells. Primary human PTC were cultured under serum-free conditions with or without the PAR-2-activating peptide SLIGKV-NH2 (up to 800 μM), a control peptide, VKGILS-NH2 (200 μM), or trypsin (0.01–100 nM). PAR-2 expression (RT-PCR), intracellular Ca2+ mobilization (fura-2 fluorimetry), DNA synthesis (thymidine incorporation), fibronectin production (ELISA, Western blotting), and monocyte chemotactic protein (MCP)-1 secretion (ELISA) were measured. Trypsinogen expression in kidney and PTC cultures was determined by immunohistochemistry and Western blotting. In the kidney PTC were the predominant cell type expressing PAR-2. SLIGKV-NH2, but not VKGILS-NH2, stimulated a rapid concentration-dependent mobilization of intracellular Ca2+ and ERK1/2 phosphorylation and, by 24 h, increases in DNA synthesis, fibronectin secretion, and MCP-1 secretion. These delayed responses appeared to be independent of ERK1/2. Trypsin produced similar rapid but not delayed responses. Trypsinogen was weakly expressed by PTC in the kidney and in culture. In summary, PTC are the main site of PAR-2 expression in the human kidney. In PTC cultures SLIGKV-NH2 initiates proinflammatory and proliferative responses. Trypsinogen expressed within the kidney has the potential to contribute to PAR-2 activation in certain circumstances.

show abstract

“…The few published works show conflicting results on the effects of PAR-2 activation on airway epithelial ion transport, with one group referring to increased chloride secretion after stimulation of basolateral PAR-2, and no effect of apical PAR-2 activation [20], while another group found no change in short circuit current when basolateral PAR-2 was activated [1]. The effects of PAR-2 activation on ion transport in models of airway inflammation have received even less attention.…”

Section: Introductionmentioning

confidence: 96%

Allergic sensitization enhances anion current responsiveness of murine trachea to PAR-2 activation

Rievaj

Davidson

Nadeem

et al. 2011

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor possibly involved in the pathogenesis of asthma. PAR-2 also modulates ion transport in cultured epithelial cells, but these effects in native airways are controversial. The influence of allergic inflammation on PAR-2-induced changes in ion transport has received little attention. Here, we studied immediate changes in transepithelial short circuit current (I (sc)) induced by PAR-2 activation in the tracheas of naive and allergic mice. Activation of PAR-2 with an apically added activation peptide (AP) induced a small increase in I (sc), while a much larger increase was observed following basolateral AP addition. In ovalbumin-sensitized and -challenged animals used as a model of allergic airway inflammation, the effect of basolateral AP addition was enhanced. Responses to basolateral AP in both naive and allergic mice were not decreased by blocking sodium absorption with amiloride or CFTR function with CFTR(inh)172 but were reduced by the cyclooxygenase inhibitor indomethacin and largely blocked (>80%) by niflumic acid, a calcium-activated chloride channels' (CaCC) blocker. Allergic mice also showed an enhanced response to ATP and thapsigargin. There was no change in mRNA expression of Par-2 or of the chloride channels Ano1 (Tmem16a) and Bestrophin 2 in tracheas from allergic mice, while mRNA levels of Bestrophin 1 were increased. In conclusion, basolateral PAR-2 activation in the mouse airways led to increased anion secretion through apical CaCC, which was more pronounced in allergic animals. This could be a protective mechanism aimed at clearing allergens and defending against mucus plugging.

show abstract

Protease-Activated Receptor-2 Peptides Activate Neurokinin-1 Receptors in the Mouse Isolated Trachea

Cited by 22 publications

References 37 publications

Inhibitory Influence of Protease-Activated Receptor 2 and E-Prostanoid Receptor Stimulants in Lipopolysaccharide Models of Acute Airway Inflammation

Inhibitory Influence of Protease-Activated Receptor 2 and E-Prostanoid Receptor Stimulants in Lipopolysaccharide Models of Acute Airway Inflammation

Proinflammatory and proliferative responses of human proximal tubule cells to PAR-2 activation

Allergic sensitization enhances anion current responsiveness of murine trachea to PAR-2 activation

Contact Info

Product

Resources

About