Bunnett Nigel W
Department of Surgery, University of California at San Francisco, San Francisco, California 94143-0660, USA.
Semin Thromb Hemost. 2006 Apr;32 Suppl 1:39-48. doi: 10.1055/s-2006-939553.
Certain serine proteases that originate from the circulation (coagulation factors), inflammatory cells (mast cell tryptase, neutrophil granzyme A, and proteinase 3), and epithelial and neuronal tissues (trypsins) can specifically regulate cells by cleaving protease-activated receptors (PARs), a family of four G-protein-coupled receptors. Proteases cleave PARs on multiple cell types to reveal tethered ligand domains that bind to and activate the cleaved receptors. The proteases that activate PARs are often generated and secreted during injury and inflammation, and PARs orchestrate tissue responses to these insults, including hemostasis, inflammation, nociception, and repair mechanisms. Agonists of PARs, notably PAR2, induce inflammation in many tissues that is characterized by hyperemia, extravasation of plasma proteins, granulocyte infiltration, and alterations in epithelial permeability. These effects are mediated in part by the release of neuropeptides substance P and calcitonin gene-related peptide from sensory nerve fibers in peripheral tissues. Proteases that activate PAR2 also induce the release of neuropeptides from the central projections of these nerves in the dorsal horn of the spinal cord, where they participate in pain transmission. Accumulating evidence from PAR-deficient mice indicates that these mechanisms may contribute to experimental models of disease and raise the possibility that protease inhibitors and PAR antagonists may be useful therapies for a variety of inflammatory and painful conditions.
某些源自循环系统（凝血因子）、炎症细胞（肥大细胞类胰蛋白酶、中性粒细胞颗粒酶A和蛋白酶3）以及上皮和神经组织（胰蛋白酶）的丝氨酸蛋白酶，可通过裂解蛋白酶激活受体（PARs，一类包含四个G蛋白偶联受体的家族）来特异性调节细胞。蛋白酶可在多种细胞类型上裂解PARs，从而暴露出与裂解后的受体结合并激活该受体的拴系配体结构域。激活PARs的蛋白酶通常在损伤和炎症过程中产生并分泌，而PARs可协调组织对这些损伤的反应，包括止血、炎症、痛觉感受和修复机制。PARs的激动剂，尤其是PAR2，可在许多组织中诱导炎症，其特征为充血、血浆蛋白外渗、粒细胞浸润以及上皮通透性改变。这些效应部分是由外周组织中感觉神经纤维释放神经肽P物质和降钙素基因相关肽所介导的。激活PAR2的蛋白酶还可诱导这些神经在脊髓背角的中枢投射释放神经肽，这些神经肽参与疼痛传递。来自PAR缺陷小鼠的越来越多的证据表明，这些机制可能与疾病的实验模型有关，并增加了蛋白酶抑制剂和PAR拮抗剂可能成为治疗多种炎症和疼痛性疾病的有用疗法的可能性。
