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Activation of proteinase-activated receptor-2 in mesothelial cells induces pleural inflammation

Lee, YCG; Knight, DA; Lane, KB; Cheng, DS; Koay, MA; Teixeira, LR; Nesbitt, JC; ... Light, RW; + view all (2005) Activation of proteinase-activated receptor-2 in mesothelial cells induces pleural inflammation. AM J PHYSIOL-LUNG C , 288 (4) L734 - L740. 10.1152/ajplung.00173.2004.

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Abstract

Pleural inflammation underlies many pleural diseases, but its pathogenesis remains unclear. Proteinase-activated receptor-2 (PAR(2)) is a novel seven-transmembrane receptor with immunoregulatory roles. We hypothesized that PAR2 is present on mesothelial cells and can induce pleural inflammation. PAR2 was detected by immunohistochemistry in all ( 19 parietal and 11 visceral) human pleural biopsies examined. In cultured murine mesothelial cells, a specific PAR(2)-activating peptide (SLIGRL-NH2) at 10, 100, and 1,000 mu M stimulated a 3-, 42-, and 1,330-fold increase of macrophage inflammatory protein (MIP)-2 release relative to medium control, respectively ( P < 0.05 all) and a 2-, 32-, and 75-fold rise over the control peptide ( LSIGRL-NH2, P < 0.05 all). A similar pattern was seen for TNF-alpha release. Known physiological activators of PAR(2), tryptase, trypsin, and coagulation factor Xa, also stimulated dose-dependent MIP-2 release from mesothelial cells in vitro. Dexamethasone inhibited the PAR(2)-mediated MIP-2 release in a dose-dependent manner. In vivo, pleural fluid MIP-2 levels in C57BL/6 mice injected intrapleurally with SLIGRL-NH2 (10 mg/kg) were significantly higher than in mice injected with LSIGRL-NH2 or PBS ( 2,710 +/- 165 vs. 880 +/- 357 vs. 88 +/- 46 pg/ml, respectively; P < 0.001). Pleural fluid neutrophil counts were higher in SLIGRL-NH2 group than in the LSIGRL-NH2 and PBS groups ( by 40- and 26-fold, respectively; P < 0.05). This study establishes that activation of mesothelial cell PAR2 potently induces the release of inflammatory cytokines in vitro and neutrophil recruitment into the pleural cavity in vivo.

Type: Article
Title: Activation of proteinase-activated receptor-2 in mesothelial cells induces pleural inflammation
DOI: 10.1152/ajplung.00173.2004
Keywords: proteinase-activated receptor, pleura, KAPPA-B ACTIVATION, RESPIRATORY EPITHELIAL-CELLS, THROMBIN RECEPTOR, PLATELET ACTIVATION, RABBIT MODEL, IN-VITRO, ENDOTOXIN, RELEASE, INTERLEUKIN-8, MECHANISM
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/91327
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