Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PARs in the Respiratory System: Cellular Signaling and Physiological/Pathological Roles

Abstract

Abstract. 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 Cb 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.

Mold Allergen, Pen c 13, Induces IL-8 Expression in Human Airway Epithelial Cells by Activating Protease-Activated Receptor 1 and 2

“…We previously showed that Pen c 13 activates PAR-1 and PAR-2 through activation of phospholipase C␤ via G q/11 ␣ protein, a common pathway for G protein-coupled receptors, and produces inositol triphosphate, followed by Ca 2ϩ mobilization (34). We therefore investigated whether Pen c 13 induced IL-8 release via phospholipase C activation and found that this was the case.…”

Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation

“…Many common environmental irritants and aeroallergens, such as extracts from house dust mites, cockroaches, and numerous fungal species, have been reported to exhibit protease activity (2,23,30,31), which is implicated in bronchial inflammation, likely due in part to the release of inflammatory cytokines from BECs (5,8). Although proteases can exert their effects on cell function in several ways, specific G protein-coupled receptors, termed protease-activated receptors (PARs), have been identified, and these have been shown to mediate many of the physiological responses of cells to proteases (14,31). Accordingly, we tested whether proteases in HDE contribute to the dust-induced inflammatory response in BECs, in lung tissue slices, and in a murine model of airway disease, and whether this response is mediated through PARs.…”

Signal Transduction for Proteinase-Activated Receptor-2-Triggered Prostaglandin E2 Formation in Human Lung Epithelial Cells

“…PAR 2 is extensively but unevenly distributed in the mammalian body, including the nervous, circulatory, gastrointestinal, and respiratory systems, modulating a variety of functions under physiological and/or pathological conditions (Cocks et al, 1999;Cicala et al, 2001a;Kawabata et al, 2001aKawabata et al, ,b, 2004Vergnolle et al, 2001;Ossovskaya and Bunnett, 2004;Sekiguchi and Kawabata, 2004a,b;Kawabata and Kawao, 2005). PAR 2 , like other PARs, couples to G q/11 protein that mediates activation of phospholipase C ␤ followed by formation of inositol triphosphate and diacylglycerol and also seems to trigger activation of other multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) cascades in distinct cell types (Ossovskaya and Bunnett, 2004;Sekiguchi and Kawabata, 2004).…”

“…In the respiratory system, PAR 2 plays a dual role, being both anti-inflammatory/protective and proinflammatory (Cocks et al, 1999;Cicala et al, 2001b;Moffatt et al, 2002;Schmidlin et al, 2002;Kawabata and Kawao, 2005). PAR 2 is expressed in airway epithelial cells, and stimulation of PAR 2 with PAR 2 -activating peptides or trypsin causes epithelial prostaglandin E 2 (PGE 2 )-dependent relaxation in the isolated tracheal and bronchial tissues from humans, guinea pigs, rats, and mice (Cocks et al, 1999;Lan et al, 2001).…”