Physiology and pathophysiology of proteinase-activated receptors (PARs): PARs in the respiratory system: Cellular signaling and physiological/pathological roles

Proteinase-activated receptors (PARs), a family of G protein-coupled receptors, are widely distributed in the mammalian body, playing a variety of physiological/pathophysiological roles. In the respiratory systems, PARs, particularly PAR-2 and PAR-1, are expressed in the epithelial and smooth muscle cells. In addition to the G(q)/(11)-mediated activation of the phospholipase Cbeta pathway, epithelial PAR activation causes prompt and/or delayed prostanoid formation, leading to airway smooth muscle relaxation and/or modulation of an inflammatory process. PAR-2 present in the epithelium and smooth muscle is considered primarily pro-inflammatory in the respiratory system, although PAR-2 may also be anti-inflammatory under certain conditions. In the lung epithelial cells, PAR-2 can also be activated by exogenous proteinases including house dust mite allergens, in addition to various possible endogenous agonist proteinases. Clinical evidence also suggests possible involvement of PARs, particularly PAR-2, in respiratory diseases. PARs thus appear to play critical roles in the respiratory systems, and the agonists/antagonists for PARs may serve as the novel therapeutic strategy for treatment of certain respiratory diseases including asthma.