Stephenson D, Rash K, Smalstig B, Roberts E, Johnstone E, Sharp J, Panetta J, Little S, Kramer R, Clemens J
Graduate Program in Medical Neurobiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Glia. 1999 Aug;27(2):110-28. doi: 10.1002/(sici)1098-1136(199908)27:2<110::aid-glia2>3.0.co;2-c.
Many recent studies have emphasized the deleterious role of inflammation in CNS injury. Increases in free fatty acids, eicosanoids, and products of lipid peroxidation are known to occur in various conditions of acute and chronic CNS injury, including cerebral ischemia, traumatic brain injury, and Alzheimer's disease. Although an inflammatory response can be induced by many different means, phospholipases, such as cytosolic phospholipase A(2) (cPLA(2)), may play an important role in the production of inflammatory mediators and in the production of other potential second messengers. cPLA(2) hydrolyzes membrane phospholipids and its activity liberates free fatty acids leading directly to the production of eicosanoids. We investigated the cellular localization of cytosolic phospholipase A(2) in the CNS following: (1) focal and global cerebral ischemia, (2) facial nerve axotomy, (3) human cases of Alzheimer's disease, (4) transgenic mice overexpressing mutant superoxide dismutase, a mouse model of amyotrophic lateral sclerosis, and (5) transgenic mice overexpressing mutant amyloid precursor protein, which exhibits age-related amyloid deposition characteristic of Alzheimer's disease. We show that in every condition evaluated, cytosolic phospholipase A(2) is present in reactive glial cells within the precise region of neuron loss. In conditions where neurons did not degenerate or are protected from death, cytosolic phospholipase A(2) is not observed. Both astrocytes and microglial cells are immunoreactive for cytosolic phospholipase A(2) following injury, with astrocytes being the most consistent cell type expressing cytosolic phospholipase A(2). The presence of cytosolic phospholipase A(2) does not merely overlap with reactive astroglia, as reactive astrocytes were observed that did not exhibit cytosolic phospholipase A(2) immunoreactivity. In most conditions evaluated, inflammatory processes have been postulated to play a pivotal role and may even participate in neuronal cell death. These results suggest that cytosolic phospholipase A(2) may prove an attractive therapeutic target for neurodegeneration.
最近许多研究都强调了炎症在中枢神经系统损伤中的有害作用。已知在急性和慢性中枢神经系统损伤的各种情况下，包括脑缺血、创伤性脑损伤和阿尔茨海默病，游离脂肪酸、类花生酸和脂质过氧化产物都会增加。尽管炎症反应可通过多种不同方式诱导，但磷脂酶，如胞质磷脂酶A2（cPLA2），可能在炎症介质的产生以及其他潜在第二信使的产生中起重要作用。cPLA2水解膜磷脂，其活性释放游离脂肪酸，直接导致类花生酸的产生。我们研究了胞质磷脂酶A2在以下情况下在中枢神经系统中的细胞定位：（1）局灶性和全脑缺血，（2）面神经切断术，（3）人类阿尔茨海默病病例，（4）过表达突变型超氧化物歧化酶的转基因小鼠，一种肌萎缩侧索硬化症小鼠模型，以及（5）过表达突变型淀粉样前体蛋白的转基因小鼠，其表现出与阿尔茨海默病相关的年龄依赖性淀粉样沉积特征。我们发现，在评估的每种情况下，胞质磷脂酶A2都存在于神经元丢失的精确区域内的反应性胶质细胞中。在神经元未退化或受到死亡保护的情况下，未观察到胞质磷脂酶A2。损伤后星形胶质细胞和小胶质细胞对胞质磷脂酶A2均有免疫反应，星形胶质细胞是表达胞质磷脂酶A2最一致的细胞类型。胞质磷脂酶A2的存在不仅仅与反应性星形胶质细胞重叠，因为观察到一些反应性星形胶质细胞没有表现出胞质磷脂酶A2免疫反应性。在评估的大多数情况下，炎症过程被认为起关键作用，甚至可能参与神经元细胞死亡。这些结果表明，胞质磷脂酶A2可能是神经退行性变的一个有吸引力的治疗靶点。
