Taurine Chloramine as a Modulator of CNS Inflammation

描述（由申请方提供）：多形性白细胞（PMN，中性粒细胞）是具有卤素依赖性髓过氧化物酶（MPO）的炎性细胞。激活的PMN分泌MPO并在死亡时释放它。MPO产生HOCl/OCl-，其与牛磺酸反应形成牛磺酸一氯胺（Tau-Cl），其是比HOCl/OCl更稳定和选择性的氧化剂。细胞外牛磺酸水平升高通过中性粒细胞相关MPO活性增加炎症部位的Tau-Cl浓度。我们的假设是，预防性给予牛磺酸可以通过形成Tau-Cl和随后抑制促炎介质的产生来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CNS中组织损伤性促炎介质的主要来源，并导致缺血性卒中期间发生的神经损伤。本提案的主要目标是确定Tau-Cl对活化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来自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CNS缺氧缺血模型中使用用于体外研究的大鼠神经胶质细胞培养系统进行评价。此外，暂时性大脑中动脉闭塞的大鼠模型将用于牛磺酸保护免受暂时性局灶性脑缺血导致的CNS损伤的功效的体内研究。完成这些研究不仅对确定Tau-Cl在神经源性细胞中的作用机制（如在缺血性和创伤性脑损伤中发生的）很重要，而且还可能与调节一般炎症反应有关。

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.