FASEB J：慢性炎症性疾病的新疗法

昆士兰大学分子生物科学研究所研究人员发现一个潜在的新方法可以治疗慢性炎症性疾病，如关节炎。教授David Fairlie和他的同事们已开发出一种实验性治疗方法，该方法已经被证明能有效减少关节炎模型症状和疾病发展。

Fairlie教授说，刺激人体内免疫细胞分泌的蛋白酶在消化、抵抗感染和伤口愈合中发挥重要作用。但在慢性炎症性疾病如关节炎中，这些不断刺激免疫细胞所释放的酶呈高浓度会引起炎症，导致组织损伤。Fairlie教授和他的团队已经开发出阻止这种刺激免疫细胞的实验用化合物，并能成功地减少实验模型中慢性炎症性关节炎。

如果该治疗化合物可以转移到人类身上，它有可能减少慢性炎症性疾病对健康和经济影响。近四百万澳大利亚人患有慢性关节疼痛包括骨关节炎、类风湿关节炎和痛风等。这新研究结果发表在Federation of American Societies For Experimental Biology Journal杂志上。

编译自：Possible new approach to fighting chronic inflammatory diseases

doi:10.1096/fj.11-201004
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An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats

Rink-Jan Lohman*, Adam J. Cotterell*, Grant D. Barry*, et al.

Multiple serine proteases exert proinflammatory actions by signaling through protease-activated receptor-2 (PAR2) on the cell surface. Although inhibitors of individual proteases are anti-inflammatory, we sought to discover whether the first potent antagonist of their common target PAR2 might be beneficial in treating chronic arthritis-like inflammatory disease. Using a fluorescence assay, a novel compound, GB88, was shown to antagonize PAR2-induced intracellular Ca²⁺ release in human monocyte-derived macrophages, being 1000 times more potent than a control compound, ENMD-1068 (IC₅₀ 1.6±0.5 μM vs. 1.2±0.4 mM, respectively). In Wistar rats, GB88 was orally bioavailable (F=55%, T_max 4 h, C_max 1.7 μM, 10 mg/kg). GB88 inhibited the acute paw edema induced in Wistar rats by intraplantar λ-carrageenan or PAR2 agonists 2-furoyl-LIGRLO-NH₂ or mast cell β-tryptase, without inhibiting proteolytic activity of tryptase in vitro. In the chronic collagen-induced model of arthritis in rats, GB88 (10 mg/kg) was disease modifying and ameliorated pathological and histopathological changes (edema, pannus formation, synovial hyperplasia, collagen degradation, macrophage invasion, mast cell degranulation) compared to untreated arthritic controls. The results suggest that an orally active PAR2 antagonist is effective in treating chronic arthritis in rats through inhibiting macrophage infiltration, mast cell degranulation, and β-tryptase-PAR2 signaling in joint inflammation.—Lohman, R.-J., Cotterell, A. J., Barry, G. D., Liu, L., Suen, J. Y., Vesey, D. A., Fairlie, D. P. An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats.