Gilroy D W, Tomlinson A, Greenslade K, Seed M P, Willoughby D A
Royal London School of Medicine and Dentistry.
Inflammation. 1998 Oct;22(5):509-19. doi: 10.1023/a:1022350111213.
Selective cyclooxygenase 2 (COX 2) inhibitors NS-398 and nimesulide were investigated for their effects on patellar cartilage and bone content in a model of Mycobacterium tuberculosis (M.tb)-induced monoarticular arthritis in the rat. The protective/destructive properties of these nonsteroidal antiinflammatory drugs (NSAIDs) were compared with piroxicam, known to accelerate cartilage breakdown and reduce bone erosion in this model in comparison to untreated arthritic controls. Male CFHB Wistar rats were injected intraarticularly with heat killed M.tb into the left stifle joint, resulting in loss of patellar cartilage glycosaminoglycans (GAG), bone erosion and inflammation. The right stifle joint received saline. Animals were dosed daily, p.o., with NS-398 (1, 10 mg/kg), nimesulide (0.5, 5 mg/kg) or piroxicam (10 mg/kg). Four days after M.tb injection, patellar GAG content, bone weight and joint swelling were measured in drug-treated animals and untreated arthritic controls. Changes in the left joint were compared to the right. The expression and distribution of COX 2 protein was determined by immunocytochemistry in synovial tissue from arthritic controls over the time course. Focal accumulations of inflammatory cells were positively immunolabelled for COX 2 in the synovium from the left stifle joint of untreated arthritic animals, 6 h after injection of M.tb. Labeling of inflammatory cell infiltrates increased and was widespread in the synovium at 24 h. By day 4 fibroblasts were positively labelled for COX 2 in addition to polymorphonuclear and mononuclear leukocytes. Piroxicam and nimesulide at the higher dose significantly exacerbated M.tb-induced cartilage GAG loss while NS-398 was without effect. Both COX 2 inhibitors did not alter M.tb-induced patellar bone loss. In contrast, piroxicam significantly reduced bone loss. All COX inhibitors significantly reduced joint swelling. In conclusion, the selective inhibition of COX 2 may result in the amelioration of synovitis with a lowered risk of NSAID-induced cartilage damage in rheumatic disease.
在大鼠结核分枝杆菌（M.tb）诱导的单关节炎模型中，研究了选择性环氧化酶2（COX 2）抑制剂NS - 398和尼美舒利对髌软骨和骨含量的影响。将这些非甾体抗炎药（NSAIDs）的保护/破坏特性与吡罗昔康进行比较，已知与未治疗的关节炎对照组相比，吡罗昔康在该模型中会加速软骨破坏并减少骨侵蚀。将雄性CFHB Wistar大鼠的左膝关节腔内注射热灭活的M.tb，导致髌软骨糖胺聚糖（GAG）丢失、骨侵蚀和炎症。右膝关节注射生理盐水。动物每天口服给予NS - 398（1、10 mg/kg）、尼美舒利（0.5、5 mg/kg）或吡罗昔康（10 mg/kg）。在注射M.tb四天后，测量药物治疗动物和未治疗的关节炎对照组的髌GAG含量、骨重量和关节肿胀情况。将左关节的变化与右关节进行比较。在整个时间过程中，通过免疫细胞化学法测定关节炎对照组滑膜组织中COX 2蛋白的表达和分布。在注射M.tb 6小时后，未治疗的关节炎动物左膝关节滑膜中炎症细胞的局灶性聚集对COX 2呈阳性免疫标记。在24小时时，炎症细胞浸润的标记增加并在滑膜中广泛分布。到第4天，除了多形核白细胞和单核白细胞外，成纤维细胞对COX 2也呈阳性标记。高剂量的吡罗昔康和尼美舒利显著加剧了M.tb诱导的软骨GAG丢失，而NS - 398没有效果。两种COX 2抑制剂均未改变M.tb诱导的髌骨质丢失。相比之下，吡罗昔康显著减少了骨质丢失。所有COX抑制剂均显著减轻了关节肿胀。总之，选择性抑制COX 2可能会改善滑膜炎，同时降低风湿性疾病中NSAID诱导的软骨损伤风险。
