Institute of Pharmacology and Toxicology, University Hospital, Friedrich Schiller University, Drackendorfer Str. 1, 07747 Jena, Germany.
Arthritis Res Ther. 2011 Jun 20;13(3):R97. doi: 10.1186/ar3372.
Endothelins are involved in tissue inflammation, pain, edema and cell migration. Our genome-wide microarray analysis revealed that endothelin-1 (ET-1) and endothelin-2 (ET-2) showed a marked up-regulation in dorsal root ganglia during the acute phase of arthritis. We therefore examined the effects of endothelin receptor antagonists on the development of arthritis and inflammatory pain in monoarthritic mice.
Gene expression was examined in lumbar dorsal root ganglia two days after induction of antigen-induced arthritis (AIA) using mRNA microarray analysis. Effects of drug treatment were determined by repeated assessment of joint swelling, pain-related behavior, and histopathological manifestations during AIA.
Daily oral administration of the mixed ET(A) and ET(B) endothelin receptor antagonist bosentan significantly attenuated knee joint swelling and inflammation to an extent that was comparable to dexamethasone. In addition, bosentan reduced inflammatory mechanical hyperalgesia. Chronic bosentan administration also inhibited joint swelling and protected against inflammation and joint destruction during AIA flare-up reactions. In contrast, the ET(A)-selective antagonist ambrisentan failed to promote any detectable antiinflammatory or antinociceptive activity.
Thus, the present study reveals a pivotal role for the endothelin system in the development of arthritis and arthritic pain. We show that endothelin receptor antagonists can effectively control inflammation, pain and joint destruction during the course of arthritis. Our findings suggest that the antiinflammatory and antinociceptive effects of bosentan are predominantly mediated via the ET(B) receptor.
内皮素参与组织炎症、疼痛、水肿和细胞迁移。我们的全基因组微阵列分析显示，内皮素-1（ET-1）和内皮素-2（ET-2）在关节炎急性期在背根神经节中表现出明显的上调。因此，我们研究了内皮素受体拮抗剂对单关节炎小鼠关节炎和炎性疼痛发展的影响。
使用 mRNA 微阵列分析，在诱导抗原诱导性关节炎（AIA）后两天检查腰椎背根神经节中的基因表达。通过反复评估关节肿胀、与疼痛相关的行为以及 AIA 期间的组织病理学表现来确定药物治疗的效果。
每天口服混合 ET(A)和 ET(B)内皮素受体拮抗剂波生坦可显著减轻膝关节肿胀和炎症，其程度可与地塞米松相媲美。此外，波生坦还减轻了炎症性机械性痛觉过敏。慢性波生坦给药还可抑制关节肿胀，并在 AIA 发作反应期间预防炎症和关节破坏。相比之下，ET(A)-选择性拮抗剂安立生坦未能促进任何可检测到的抗炎或镇痛活性。
因此，本研究揭示了内皮素系统在关节炎和关节炎性疼痛发展中的关键作用。我们表明，内皮素受体拮抗剂可有效控制关节炎过程中的炎症、疼痛和关节破坏。我们的发现表明，波生坦的抗炎和镇痛作用主要通过 ET(B)受体介导。
