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.
|Journal||American journal of physiology : lung cellular and molecular physiology|
|Publication status||Published - 2005|
Lee, Y. C., Knight, D. A., Lane, K. B., Cheng, D. S., Koay, M. A., Teixeira, L. R., ... Light, R. W. (2005). Activation of proteinase-activated receptor-2 in mesothelial cells induces pleural inflammation. American journal of physiology : lung cellular and molecular physiology, 288(4), 734-740. https://doi.org/10.1152/ajplung.00173.2004