Role of PAR2 in murine pulmonary pseudomonal infection

Moraes, Theo J.; Martin, Raiza; Plumb, Jonathan; Vachon, Éric; Cameron, Cheryl M.; Danesh, Ali; Kelvin, David J.; Ruf, Wolfram; Downey, Gregory P.

doi:10.1152/ajplung.00036.2007

Cited by 49 publications

(50 citation statements)

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“…On one hand, PAR 2 activation by selective agonists in the lung induces signs of inflammation (recruitment of inflammatory cells and cytokine and chemokine release) (13)(14)(15)(16)(17), and endogenous activation of PAR 2 promotes allergic sensitization and the recruitment of inflammatory cells to the airways (17). On the other hand, PAR 2 agonists inhibit LPS-induced granulocyte recruitment, and PAR 2 -deficient mice displayed more severe lung inflammation in a model of bacterial (Pseudomonas aeruginosa) infection (18). Therefore, the exact role of PAR 2 in the lung inflammatory response is unclear (19).…”

Section: Nfluenza Virus Type a (Iav)mentioning

confidence: 99%

Protective Role for Protease-Activated Receptor-2 against Influenza Virus Pathogenesis via an IFN-γ-Dependent Pathway

Khoufache

LeBouder

Morello

et al. 2009

The Journal of Immunology

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Protease-activated receptor-2 (PAR2), a receptor highly expressed in the respiratory tract, can influence inflammation at mucosal surfaces. Although the effects of PAR2 in the innate immune response to bacterial infection have been documented, knowledge of its role in the context of viral infection is lacking. We thus investigated the role of PAR2 in influenza pathogenesis in vitro and in vivo. In vitro, stimulation of PAR2 on epithelial cells inhibited influenza virus type A (IAV) replication through the production of IFN-γ. In vivo, stimulation of PAR2 using specific agonists protected mice from IAV-induced acute lung injury and death. This effect correlated with an increased clearance of IAV in the lungs associated with increased IFN- γ production and a decreased presence of neutrophils and RANTES release in bronchoalveolar fluids. More importantly, the protective effect of the PAR2 agonist was totally abrogated in IFN- γ-deficient mice. Finally, compared with wild-type mice, PAR2-deficient mice were more susceptible to IAV infection and displayed more severe lung inflammation. In these mice higher neutrophil counts and increased RANTES concentration but decreased IFN- γ levels were observed in the bronchoalveolar lavages. Collectively, these results showed that PAR2 plays a protective role during IAV infection through IFN-γ production and decreased excessive recruitment of inflammatory cells to lung alveoli.

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Section: Nfluenza Virus Type a (Iav)mentioning

confidence: 99%

Protective Role for Protease-Activated Receptor-2 against Influenza Virus Pathogenesis via an IFN-γ-Dependent Pathway

Khoufache

LeBouder

Morello

et al. 2009

The Journal of Immunology

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“…Considerando-se que a análise da expressão de PAR-2 no presente estudo foi realizada a partir de amostras do fluido gengival, a expressão encontrada pode refletir a expressão presente em células deste ambiente, tais como linfócitos, neutrófilos, mastócitos e células epiteliais orais (Bohm et al, 1996;Nysted et al, 1996;Lourbakos et al, 1998;Abraham et al, 2000;Lourbakos et al, 2001aLourbakos et al, , 2001bOssovskaya;Bunnett, 2003). Sabe-se que a ativação do receptor PAR-2 nestas células pode levar a secreção de diversas citocinas pró-inflamatórias tais como IL-1, IL-1β, IL-6, IL-8, IFN-γ ,PGE2, e MMP-9 (Lourbakos et al, 2001a(Lourbakos et al, , 2001bShpacovitch et al, 2004;Ossovskaya;Bunnett, 2003;Holzhausen et al, 2006;Lee et al, 2007;. Moraes et al, 2008).…”

Section: Discussionunclassified

Efeito da severidade da doença periodontal sobre a expressão do Receptor Ativado por Protease do Tipo 2 (PAR-2)

Fukushima¹

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“…109,112 C3a and C5a are small proteins that bind to their respective anaphylatoxin receptors C3aR and C5aR, which are G protein-coupled receptors. Similar to protease-activated receptor 2 described above, C3a receptor (C3aR) is also implicated in numerous inflammatory disorders such as asthma, [113][114] arthritis, [115][116] ischemiareperfusion injury 117 118 and many others. There were also reports suggesting that C3a…”

Section: Macmentioning

confidence: 99%

“…The binding affinities (IC 50 ) of SKF63649 (112) and SB290157 (113) [115][116] However, SB290157 (113) had also been reported to show full agonist activity in other assays, especially for cells that had over-expression of C3aR. This compound showed comparable agonist potency to C3a in a calcium release assay using both human and mouse transfected RBL cells, and an enzyme-release assay in differentiated U937 cells.…”

Section: C3ar Non-peptidic Agonists and Antagonistsmentioning

confidence: 99%

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Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

Yau¹

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About 30-40% of all drugs currently in the market place target G-protein coupled receptors, however of the 900 plus GPCRs predicted to exist only about 30 are targeted by approved drugs. Two novel human GPCRs were investigated in this thesis, namely protease-activated receptor 2 (PAR2) and C3a receptor (C3aR). These membranebound receptors are implicated in a variety of diseases in which inflammation is a common component, making them attractive targets for drugs that can treat such disorders. This thesis describes the rational design, synthesis and in vitro assay of ligands targeting these two GPCRs and they will become useful probes for investigating the pathology of inflammatory disorders and may lead to possible future treatments.Chapter 1 of this thesis summarises peptidic and non-peptidic ligands for proteaseactivated receptor and C3a receptor reported in the literature to date, together with their known physiological effects.Chapter 2 examines structure-activity relationships for analogues of the only known potent PAR2 antagonist (GB88) discovered at IMB. The chemical features of GB88 were investigated separately by dividing the molecule into fragments, which were independently varied to study the effect of structure on agonist/antagonist function of the ligands. A potent and selective PAR2 agonist (132) was developed with EC 50 of 0.4 µM in calcium release assays on HT29 cells. Agonist 132 has comparable agonist potency and better ligand efficiency to 2f-LIGRLO-NH 2 , which was previously the most potent PAR2 agonist prior to these studies. In addition, a new PAR2 antagonist was developed (167), which was 2-fold more potent than GB88 in the calcium mobilisation assay.Chapter 3 describes the non-peptidic PAR2 agonist (GB110) and SAR studies for the truncation of this compound that led to the development of new PAR2 antagonists (192, 209, 211, 212). These ligands inhibited the activation of PAR2 induced by 1 µM 2f-LIGRLO-NH 2 with IC 50 0.4-0.6 µM in the calcium release assay.Chapter 4 evaluates the anti-inflammatory properties of newly developed PAR2antagonists (133, 159, 167, 192 -from Chapters 2 & 3) in both in vivo and in vitro experiments. The most potent PAR2 antagonists (167 and 192) were stable in rat plasma and rat liver homogenates and were able to inhibit PAR2 activation induced by peptide agonist 2f-LIGRLO-NH 2 as well as the endogenous activator, trypsin. These iv antagonists have been demonstrated to be anti-inflammatory agents, inhibiting proinflammatory cytokine release (IL6 and TNF-α) and were effective in relieving joint inflammation in rat models of arthritis.Chapter 5 explores various aromatic heterocycles that confer a turn conformation to ligands and this mimics the turn conformation observed for the C-terminus of C3a in its crystal structure. The study investigates how the hydrogen bonding capabilities of heteroatoms in each heterocycle affect the binding and functions of the ligands.Increasing the hydrogen bond acceptor properties of the heterocycle improves binding affinity...

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Role of PAR2 in murine pulmonary pseudomonal infection

Cited by 49 publications

References 54 publications

Protective Role for Protease-Activated Receptor-2 against Influenza Virus Pathogenesis via an IFN-γ-Dependent Pathway

Protective Role for Protease-Activated Receptor-2 against Influenza Virus Pathogenesis via an IFN-γ-Dependent Pathway

Efeito da severidade da doença periodontal sobre a expressão do Receptor Ativado por Protease do Tipo 2 (PAR-2)

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

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