Taurine Chloramine as a Modulator of CNS Inflammation

牛磺酸氯胺作为中枢神经系统炎症的调节剂

• 批准号: 6613786
• 负责人: MICHAEL R QUINN
• 金额: $ 26.81万
• 依托单位: NEW YORK STATE CNCL FOR MTL HYGIENE PLNG
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613786
• 关键词: astrocytes; cell line; central nervous system; cytokine; gene expression; genetic transcription; glia; glioma; immunocytochemistry; inflammation; laboratory rat; macrophage inflammatory proteins; monocyte chemoattractant protein 1; neutrophil; nitric oxide synthase; northern blottings; polymerase chain reaction; prostaglandin E; prostaglandin endoperoxide synthase; taurine; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Polymorphonuclear leukocytes (PMN, neutrophils) are inflammatory cells that possess halide-dependent myeloperoxidase (MPO). Activated PMN secrete MPO and release it upon death. MPO produces HOCl/OCl-, which reacts with taurine to form taurine monochloramine (Tau-Cl), a more stable and selective oxidant than HOCl/OCl. Elevated levels of extracellular taurine increase Tau-Cl concentrations at the site of inflammation via PMN associated MPO activity. It is our hypothesis that prophylactic administration of taurine may attenuate tissue damage resulting from aberrant inflammatory responses through formation of Tau-Cl and subsequent inhibition of the production of proinflammatory mediators. Astrocytes and microglia are a major source of tissue damaging proinflammatory mediators in the CNS and contribute to the neural damage that occurs during ischemic stroke. The primary goals of this proposal are to establish the inhibitory effects of Tau-Cl on the production of inflammatory mediators by activated glial cells and to determine the molecular mechanisms(s) through which Tau-Cl exerts this effect. This will be accomplished using primary cultures of rat astrocytes and microglia, and clonal cell lines derived from glial cells. The ability of Tau-Cl to inhibit production of proinflammatory mediators will be evaluated in a model of CNS hypoxic ischemia using culture systems of rat glial cells for in vitro studies. In addition, a rat model of transient middle cerebral artery occlusion will be used for in vivo studies of the efficacy of taurine to protect against the CNS damage that results from transient focal cerebral ischemia. Completion of these studies is not only important to determining the mechanism of Tau-Cl action in cells of neural origin, as occurs in ischemic and traumatic brain injury, but may also be relevant to modulating inflammatory responses in general.

描述（由申请人提供）： 多形核白细胞（PMN，中性粒细胞）是具有卤化物依赖性髓过氧化物酶（MPO）的炎症细胞。激活的 PMN 会分泌 MPO 并在死亡时释放。 MPO 产生 HOCl/OCl-，与牛磺酸反应形成牛磺酸一氯胺 (Tau-Cl)，这是一种比 HOCl/OCl 更稳定、选择性更强的氧化剂。细胞外牛磺酸水平升高，通过 PMN 相关的 MPO 活性增加炎症部位的 Tau-Cl 浓度。我们的假设是，预防性施用牛磺酸可以通过形成 Tau-Cl 并随后抑制促炎介质的产生，减轻异常炎症反应引起的组织损伤。星形胶质细胞和小胶质细胞是中枢神经系统中组织损伤性促炎介质的主要来源，并导致缺血性中风期间发生的神经损伤。该提案的主要目标是确定 Tau-Cl 对激活的神经胶质细胞产生炎症介质的抑制作用，并确定 Tau-Cl 发挥这种作用的分子机制。这将使用大鼠星形胶质细胞和小胶质细胞的原代培养物以及源自神经胶质细胞的克隆细胞系来完成。 Tau-Cl抑制促炎介质产生的能力将在中枢神经系统缺氧缺血模型中使用大鼠神经胶质细胞培养系统进行体外研究进行评估。此外，短暂性大脑中动脉闭塞的大鼠模型将用于体内研究牛磺酸预防短暂性局灶性脑缺血引起的中枢神经系统损伤的功效。完成这些研究不仅对于确定 Tau-Cl 在神经源细胞中的作用机制（如缺血性和创伤性脑损伤中发生的情况）很重要，而且还可能与调节一般炎症反应有关。