Department of Pharmacology, University of Valencia, Av. Vicent Andres Estelles s/n, 46100 Burjasot, Valencia, Spain.
Eur J Pharmacol. 2010 May 25;634(1-3):184-91. doi: 10.1016/j.ejphar.2010.02.028. Epub 2010 Feb 23.
Carbon monoxide-releasing molecules can counteract inflammatory responses. The aim of this study was to investigate whether tricarbonylchloro(glycinate)ruthenium (II) (CORM-3) is able to control the effector phase of experimental arthritis. Arthritis was induced in C57Black-6 mice by an intraperitoneal injection of serum from arthritic K/BxN mice. CORM-3 was administered intraperitoneally at 10 mg/kg/day (5 mg/kg twice a day) from days 0 to 10 and animals were sacrificed on day 11. Serum levels of osteocalcin and prostanoids were measured by enzyme-linked immunosorbent assay and radioimmunoassay. Gene expression was determined by real-time PCR. Histological analysis was performed and protein expression was examined by immunohistochemistry. Treatment with CORM-3 reduced the macroscopic score in hind paws, the migration of inflammatory cells and erosion of cartilage and bone. CORM-3 increased the levels of osteocalcin in the serum and reduced PGD2 levels, whereas PGE2 and 6-ketoPGF1alpha were not affected. In synovial tissues, we also observed a significant reduction in gene expression of interleukin-1beta, receptor activator of nuclear factor kappaB ligand (RANKL), matrix metalloproteinase (MMP)-9 and MMP-13. CORM-3 induced HO-1 expression in joint tissues but inhibited high mobility group box 1 (HMGB1), hematopoietic-prostaglandin D2 synthase (H-PGDS) and lipocalin-type prostaglandin D2 synthase (L-PGDS), as well as RANKL and intercellular adhesion molecule-1. COX-2 expression was not affected by CORM-3 treatment. We have shown that CORM-3 decreases the inflammatory response and protects against the degradation of cartilage and bone in the arthritic mice. Pharmacological CO delivery represents a novel strategy to regulate the effector phase of arthritis.
一氧化碳释放分子可以对抗炎症反应。本研究旨在探讨三羰基氯（甘氨酸）钌（II）（CORM-3）是否能够控制实验性关节炎的效应期。通过向关节炎 K/BxN 小鼠腹腔内注射关节炎血清，在 C57Black-6 小鼠中诱导关节炎。从第 0 天到第 10 天，每天腹腔内给予 CORM-3 10mg/kg（每天两次给予 5mg/kg），第 11 天处死动物。通过酶联免疫吸附试验和放射免疫测定法测定血清骨钙素和前列腺素水平。通过实时 PCR 测定基因表达。进行组织学分析并通过免疫组织化学检查蛋白质表达。用 CORM-3 治疗可降低后爪的宏观评分、炎性细胞的迁移以及软骨和骨的侵蚀。CORM-3 增加了血清中的骨钙素水平并降低了 PGD2 水平，而 PGE2 和 6-酮-PGF1alpha 不受影响。在滑膜组织中，我们还观察到白细胞介素-1β、核因子 kappaB 受体激活剂配体（RANKL）、基质金属蛋白酶（MMP）-9 和 MMP-13 的基因表达显著降低。CORM-3 诱导关节组织中 HO-1 的表达，但抑制高迁移率族盒 1（HMGB1）、造血前列腺素 D2 合酶（H-PGDS）和脂氧合酶型前列腺素 D2 合酶（L-PGDS）以及 RANKL 和细胞间黏附分子-1。CORM-3 处理不影响 COX-2 的表达。我们已经表明，CORM-3 可降低关节炎小鼠的炎症反应并防止软骨和骨降解。药理学 CO 输送代表了一种调节关节炎效应期的新策略。
