PREVENTION OF ARTHRITIS WITH DIETARY GLYCINE

某些形式的炎性关节炎涉及自身免疫反应。 进程(1-3)，伴随着枢轴的增加 炎性细胞因子，肿瘤坏死因子-α。我们的实验室已经证明了一种饮食 在其他几种模型中，富含甘氨酸可以防止肿瘤坏死因子α的增加 炎性组织损伤。因此，可以假设甘氨酸会 通过减少巨噬细胞产生的肿瘤坏死因子α来预防关节炎。在……里面 肝损伤研究中，甘氨酸钝化内毒素诱导的小鼠肝损伤 Kupffer细胞中的钙和细胞因子，这一现象被 士的宁依赖于氯化物，就像甘氨酸门控一样 中枢神经系统的氯离子通道。在最初一系列拟议的实验中， 4组Lewis雌性大鼠(每组10只)将在一个 关节炎使用A组链球菌肽聚糖- 多糖(PG-PS)(对照组、甘氨酸5%、PG-PS和甘氨酸+PG-PS)。 在该模型的急性期，炎症在术后1-2天达到高峰 内务部。注射PG-PS，3周后痊愈。随后的静脉注射。 注射PG-PS可100%重新激活慢性炎症。食物 消耗、体重、关节炎指数和脚踝厚度将是 每隔1-3天监测一次，为期6周。当最大的肿胀发生时， 大鼠将被处死，关节组织将被固定用于组织学检查 评估。我们希望饮食中的甘氨酸能够最大限度地减少或预防关节炎。 第二，甘氨酸在PG-PS诱导的关节炎中的剂量反应将是 下定决心。膳食甘氨酸会有所不同(0%到5%)和参数 将对上述内容进行评估。在所有小组中，血液样本将被 收集并测定血清甘氨酸水平。我们预计甘氨酸是 在0.5-1.0毫米范围内对实验性关节炎具有保护作用。第三， 甘氨酸逆转关节炎的能力将得到评估。为了测试这一点 独特的想法，甘氨酸或控制饮食将在 将对炎症和恢复时间进行评估。第四，到 评价机制，脾巨噬细胞和外周血淋巴细胞 在上述4组炎症高峰期分离。 细胞内钙离子、膜电位和关键细胞因子的变化 (肿瘤坏死因子α、干扰素γ、白介素2、白介素4和白介素10)以及 对添加PG-PS的响应。转录因子NFkappaB也将是 它被确定为在TNFpha生产中起关键作用。我们预计甘氨酸 会预防关节炎b激活士的宁敏感的甘氨酸门控 巨噬细胞和/或T淋巴细胞的氯通道使其减少 对炎症激动剂有反应。总的来说，我们期待着这些研究 为了证明饮食中的甘氨酸会阻止细胞因子的释放，减少 发炎，预防关节炎。这项工作是及时和实际的， 将导致简单的饮食干预措施来预防关节炎。

Certain forms of inflammatory arthritis involve autoreactive immunologic processes (1-3), which are accompanied by an increase in the pivotal inflammatory cytokine, TNF-alpha. Our laboratory has shown that a diet rich in glycine can prevent increases in TNFalpha in several other models of inflammatory tissue injury. Thus, it is hypothesized that glycine will prevent arthritis by decreasing TNFalpha production by macrophages. In studies of liver injury, glycine blunted the LPS-induced increased in calcium and cytokines in Kupffer cells, a phenomenon which was blocked by strychnine and was dependent on chloride, just like the glycine-gated chloride channel in the CNS. In a initial series of proposed experiments, 4 groups of Lewis female rats (10 each) will be compared in a model of arthritis using bacterial group A steptococcal peptidoglycan- polysaccharide (PG-PS) (control, glycine 5%, PG-PS and glycine + PG-PS). In the acute phase of this model, inflammation peaks in 1-2 days after the i.a. injection of PG-PS and resolves in 3 weeks. Subsequent i.v. injections of PG-PS causes 100% reactivation of chronic inflammation. Food consumption, body weight, the arthritis index and ankle thickness will be monitored at 1-3 day intervals for 6 weeks. When maximal swelling occurs, rats will be sacrificed and joint tissue will be fixed for histological evaluation. We expect dietary glycine to minimize or prevent arthritis. Second, the dose-response for glycine in PG-PS induced arthritis will be determined. Dietary glycine will be varied (0% to 5%) and the parameters described above will be evaluated. In all groups, blood samples will be collected and serum glycine levels determined. We expect glycine to be protective in experimental arthritis in the 0.5-1.0 Mm range. Third, the ability of glycine to reverse arthritis will be evaluated. To test this unique idea, glycine or control diet will be initiated at the peak of inflammation and the time course of recovery will be evaluated. Fourth, to evaluate mechanism, splenic macrophages and blood lymphocytes will be isolated at the peaks of inflammation in the 4 groups detailed above. Changes in intracellular calcium, membrane potential and key cytokines (TNFalpha, IFNgamma, IL-2, IL-4 and IL-10) will be measured as well as the response to added PG-PS. The transcription factor NFkappaB will also be determined as it is pivotal in TNFalpha production. We expect that glycine will prevent arthritis b activating a strychnine sensitive glycine-gated chloride channel in macrophages and/or T-lymphocytes making them less responsive to inflammatory agonists. Collectively, we expect these studies to demonstrate that dietary glycine will block cytokine release, reduce inflammation and prevent arthritis. This work is timely and practical and will lead to simple, dietary interventions to prevent arthritis.