Lan Rommel S, Stewart Geoffrey A, Henry Peter J
Department of Pharmacology, QEII Medical Centre, The University of Western Australia, Nedlands, Western Australia 6009, Perth, Australia.
Pharmacol Ther. 2002 Sep;95(3):239-57. doi: 10.1016/s0163-7258(02)00237-1.
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.
蛋白酶激活受体（PARs）是G蛋白偶联的七跨膜结构域受体，充当细胞酶传感器。这些受体通过氨基末端的蛋白水解切割而被激活，使新形成的“拴系配体”与受体的第二个细胞外环之间相互作用，从而赋予细胞信号传导功能。PARs也可被模拟拴系配体的小肽激活。在呼吸道中，PARs可能受内源性蛋白酶（如气道胰蛋白酶和肥大细胞组织蛋白酶）以及外源性蛋白酶（包括吸入性气传变应原，如来自屋尘螨粪便颗粒的变应原）的调节。已在呼吸道的多种细胞类型中鉴定出免疫反应性PARs，据报道PAR激活可刺激细胞有丝分裂并促进组织炎症。PARs的激活同时刺激支气管舒张剂和抗炎介质的释放，这可能有助于诱导细胞保护并将与严重慢性气道炎症相关的组织损伤降至最低。此外，气道炎症反应与上皮PAR表达增加以及细胞外空间中PAR激活和PAR失活蛋白酶浓度升高有关。在此基础上，PARs可能在气道稳态中发挥调节作用，并可能参与呼吸道炎症性疾病，如哮喘和慢性阻塞性肺疾病。进一步聚焦于新开发的PAR激动剂和拮抗剂在适当气道炎症模型中的作用的研究，将有助于更好地了解PARs在呼吸病理生理学中的作用及其作为治疗靶点的潜力。
