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Protease-activated receptor-2 (PAR2) acts as a receptor for trypsin and trypsin-like enzymes. The role of this receptor in airway inflammation is uncertain. In this study we assessed the effect of activation of PAR2 following intranasal administration of the peptide activator of PARZ SLIG RL, over 72 h in mice. The extent of immune cell infiltration into the airways and activities of matrix metalloprotease-2 (MMP-2) and MMP-9 were assessed in bronchoalveolar lavage (BAL) by differential cell counts and gelatin zymography, respectively. SLIGRL did not cause a change in the number or types of cells retrieved in BAL at any time point and did not alter the levels of MMP-2 and MMP-9 present in BAL. In contrast, similar intranasal administration of bacterial lipopolysaccharide (LPS) caused a large influx of neutrophilic polymorphonuclear leukocytes, which was associated with increased MMP-2 at 3 h only and MMP-9 activity from 3-72 h. Simultaneous administration of SLIGRL and LPS transiently potentiated increased MMP-9 activity at 3 h but markedly inhibited neutrophil influx and elevated MMP-2 activity at 3 h. These findings suggest that PAR2 agonists may be useful therapeutic molecules in pulmonary inflammatory diseases.
Protease-activated receptor-2 (PAR2) is a member of a family of four receptors that are activated by serine proteases (1). All members of this receptor family are activated by an extracellular amino acid sequence that is able to bind intramolecularly only after proteolytic removal of a blocking upstream sequence. As such, these receptors act as "sensors" of serine proteases (1). PAR2 is a unique member of this receptor family because it is activated by trypsin and similar enzymes rather than by thrombin, which activates PAR1, PAR3, and PAR4 (1). It is widely held that PAR2 is a receptor for the mast cell-derived serine protease tryptase and that PAR2 may therefore participate in the progression of inflammatory diseases (2). Indeed, intraplantar injection of the hexapeptide SLIGRL (single amino acid code), which mimics the "tethered ligand" region of PAR2 and causes receptor activation, causes an inflammatory response associated with an influx of polymorphonuclear leukocytes (3). However, we have suggested that in some organs, including the lung, PAR2 serves as a detector of inflammatory responses and is coupled to protective rather than destructive pathways (1, 4). Support for this hypothesis...