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This Article Full Text Full Text (PDF) All Versions of this Article: 288/4/L734    most recent 00173.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Lee, Y.C. G. Articles by Light, R. W. Search for Related Content PubMed PubMed Citation Articles by Lee, Y.C. G. Articles by Light, R. W.

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

¹Centre for Respiratory Research, University College London, United Kingdom; ²Pulmonary and Critical Care Medicine, Vanderbilt University; ³St. Thomas Hospital, Nashville, Tennessee; ⁴Asthma and Allergy Research Institute & Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Australia; and ⁵Respiratory Division-Heart Institute (InCor), University of São Paulo, São Paulo, Brazil

Submitted 12 May 2004 ; accepted in final form 15 November 2004

Pleural inflammation underlies many pleural diseases, but its pathogenesis remains unclear. Proteinase-activated receptor-2 (PAR₂) 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 PAR₂-activating peptide (SLIGRL-NH₂) at 10, 100, and 1,000 µM 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- release. Known physiological activators of PAR₂, tryptase, trypsin, and coagulation factor Xa, also stimulated dose-dependent MIP-2 release from mesothelial cells in vitro. Dexamethasone inhibited the PAR₂-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.

proteinase-activated receptor; pleura