Role of protease-activated receptors in airway function: a target for therapeutic intervention?

Protease-activated receptors (PARs) are G-protein-coupled, seven transmembrane domain receptors that act as cellular enzyme sensors. These receptors are activated by the proteolytic cleavage at the amino terminus, enabling interaction between the newly formed "tethered ligand" and the second extracellular loop of the receptor to confer cellular signalling. PARs can also be activated by small peptides that mimic the tethered ligand. In the respiratory tract, PARs may be regulated by endogenous proteases, such as airway trypsin and mast cell tryptase, as well as exogenous proteases, including inhaled aeroallergens such as those from house dust mite faecal pellets. Immunoreactive PARs have been identified in multiple cell types of the respiratory tract, and PAR activation has been reported to stimulate cellular mitogenesis and to promote tissue inflammation. Activation of PARs concurrently stimulates the release of bronchorelaxant and anti-inflammatory mediators, which may serve to induce cytoprotection and to minimise tissue trauma associated with severe chronic airways inflammation. Furthermore, airway inflammatory responses are associated with increased epithelial PAR expression and elevated concentrations of PAR-activating, and PAR-inactivating, proteases in the extracellular space. On this basis, PARs are likely to play a regulatory role in airway homeostasis, and may participate in respiratory inflammatory disorders, such as asthma and chronic obstructive pulmonary disease. Further studies focussing on the effects of newly developed PAR agonists and antagonists in appropriate models of airway inflammation will permit better insight into the role of PARs in respiratory pathophysiology and their potential as therapeutic targets. (C) 2002 Elsevier Science Inc. All rights reserved.