Taurine Chloramine as a Modulator of CNS Inflammation

描述(申请人提供)：多形核白细胞(PMN，中性粒细胞)是一种炎性细胞，具有卤化物依赖的髓过氧化物酶(MPO)。激活的PMN分泌MPO，并在死亡时释放它。MPO产生HOCl/OCL-，与牛磺酸反应生成牛磺酸一氯胺(Tau-Cl)，这是一种比HOCl/OCL更稳定和选择性更高的氧化剂。细胞外牛磺酸水平的升高通过PMN相关的MPO活性增加了炎症部位的Tau-Cl浓度。我们的假设是，预防性应用牛磺酸可能通过形成Tau-Cl和随后抑制促炎介质的产生来减轻由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组织损伤性促炎介质的主要来源，并在缺血性中风期间导致神经损伤。本研究的主要目的是确定牛磺酸-氯对活化的神经胶质细胞产生炎症介质的抑制作用，并确定牛磺酸-氯发挥这种作用的分子机制(S)。这将使用大鼠星形胶质细胞和小胶质细胞的原代培养，以及来自神经胶质细胞的克隆细胞系来实现。在中枢神经系统缺氧缺血模型中，将使用大鼠神经胶质细胞培养系统进行体外研究，以评估Tau-Cl抑制促炎介质产生的能力。此外，还将利用暂时性大脑中动脉闭塞的大鼠模型进行体内研究，研究牛磺酸对暂时性局灶性脑缺血引起的中枢神经系统损伤的保护作用。这些研究的完成不仅对确定Tau-Cl在神经源性细胞中的作用机制非常重要，就像在缺血和创伤性脑损伤中所发生的那样，而且可能与调节一般的炎症反应有关。

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.