INFECTIOUS ARTHRITIS AND CARTILAGE DESTRUCTION

感染性关节炎和软骨破坏

基本信息

批准号：
3155461
负责人：
DAVID J SCHURMAN
金额：
$ 18.27万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-07-01 至 1995-06-30
项目状态：
已结题

项目摘要

The long-term objectives of this proposal are to define the biochemical mechanisms underlying continued cartilage degradation in staphylococcal septic arthritis and to develop therapeutic regimens to prevent post-infectious inflammatory cartilage destruction. The experimental rationale is based on our results showing that staphylococcal joint infection results in the rapid onset of cartilage degradation and in persistent cartilage destruction in spite of early antibiotic treatment. Addition of an anti-inflammatory agent with antibiotic therapy decreases but does not override the processes of cartilage degradation. The results of these studies are applicable to rheumatology, orthopaedics and infectious diseases. The hypothesis to be tested is that reduction of inflammatory post-infectious cartilage degradation is analogous to treatment of cancer in which a combination of therapeutic modalities are required to achieve successful results. The multifactorial approach includes synovial lavage to decrease the levels of debris and inflammatory exudate. The efficacy of wash techniques will be expanded by application of systemic and intra-articular agents to block cartilage degradation and synovial inflammation. The Specific Aims are to: (1) Characterize the Staphylococcal-induced cartilage degradation following antibiotic and NSAID therapy in conjunction with lavage at 2, 4 and 7 days after infection. Analysis of the cartilage will be carried out (la) at 10 days post-infection to establish short-term proteoglycan losses and (lb) at three weeks, seven weeks and three months post-infection to determine long-term events; (2) Extend the combination treatment by analyzing the effects of adding two different proteinase inhibitors in the lavage solution, one an analog of tissue inhibitor of metalloproteinase (TIMP-like) and the other, alpha 2-macroglobulin; (3) Extend the combination treatment by adding transforming growth factor beta to enhance cartilage repair and by adding antibodies to purified staphylococcal cartilage degrading factor (Staph Factor) in vitro and in vivo; (4) Expand wash techniques and induce reparative properties to the cartilage and synovium by adding insulin, epidermal growth factor and insulin-like growth factor I to (4a) cartilage explant cultures challenged with Staph Factor and (4b) in the infected joint in a lavage solution at a stage after bacteria are killed and inflammation has subsided. Experiments will use in vitro and in vivo models of Staphylococcal infectious arthritis. Effects of antibiotic and anti-inflammatory therapies coupled with (a) proteinase inhibitors and (b) growth factors will be assessed by quantitation of cartilage proteoglycan synthesis and degradation.

该提案的长期目标是确定软骨持续退化的生化机制葡萄球菌化脓性关节炎并制定治疗方案防止感染后炎症软骨破坏。这实验原理基于我们的结果表明葡萄球菌关节感染导致软骨迅速发生退化和持续的软骨破坏，尽管早期抗生素治疗。添加抗炎剂抗生素治疗会减少但不会覆盖该过程软骨退化。这些研究结果适用于风湿病学、骨科和传染病。要检验的假设是减少炎症感染后软骨退化类似于癌症的治疗其中需要结合多种治疗方式来实现成功的结果。多因素方法包括滑膜灌洗减少碎片和炎症渗出物的水平。功效洗涤技术的应用将通过系统性和关节内药物可阻止软骨退化和滑膜退化炎。具体目标是： (1) 描述抗生素和抗生素后葡萄球菌引起的软骨退化 NSAID 治疗与术后 2、4 和 7 天联合灌洗感染。第 10 天将进行软骨分析 (la) 感染后建立短期蛋白多糖损失和（磅）感染后三周、七周和三个月确定长期事件； (2)通过分析延长联合治疗灌洗液中添加两种不同蛋白酶抑制剂的效果溶液，一种金属蛋白酶组织抑制剂的类似物（TIMP 样）和另一个，α2-巨球蛋白； (3) 延长添加转化生长因子β的联合治疗增强软骨修复并通过添加抗体纯化体外和体内葡萄球菌软骨降解因子（Staph Factor）体内； (4) 扩大洗涤技术并诱导修复性能软骨和滑膜添加胰岛素、表皮生长因子和胰岛素样生长因子 I 至 (4a) 软骨外植体培养物在灌洗中用葡萄球菌因子和 (4b) 在受感染的关节中进行攻击在细菌被杀死并且炎症发生后的阶段解决平息了。实验将使用葡萄球菌的体外和体内模型传染性关节炎。抗生素和抗炎作用与 (a) 蛋白酶抑制剂和 (b) 生长因子相结合的疗法将通过软骨蛋白多糖合成的定量来评估降解。