A novel therapeutic target in various lung diseases: airway proteases and protease-activated receptors

Protease-activated receptors (PAR), which are G protein-coupled receptors, have 4 members, PAR-1 to PAR-4. PARs are activated by proteolysis of a peptide bond at the N-terminal domain of the receptor. PARs are widely distributed throughout the airways. Their activity is modulated by airway proteases of endogenous and exogenous origin, which can either activate or disable the receptors. The regulation of PAR activity by proteases is important under pathological conditions when the activity of proteases is increased. Moreover, various inflammatory mediators, such as cytokines, growth factors, or prostanoids, alter the PAR expression level. Elevated PAR levels are observed in various lung disorders, and their significance in the development of pathological situations in the lung is currently intensively investigated. Consequences of PAR activation can be either beneficial or deleterious, depending on the PAR subtype. PAR-1 has been shown to be an important player in the development of pulmonary fibrosis. Thus, PAR-1 represents an exciting target for clinical intervention in fibrotic diseases. PAR-2 contributes to allergic airway inflammation. However, the question whether the impact of PAR-2 is beneficial or deleterious is still under intensive discussion. Therefore, precise information concerning the participation of PAR-2 in various lesions is required. Moreover, it is necessary to generate selective PAR- and organ-targeted approaches for treating the diseases. A thorough understanding of PAR-induced cellular events and the consequences of receptor blockade may help in the development of novel therapeutic strategies targeted to prevent lung destruction and to avoid deterioration of conditions of patients with inflammatory or fibrotic lung diseases.