PREVENTION OF APOPTOTIC CELL DEATH IN SEPSIS BY BCL-2

描述（改编自摘要）：脓毒症定义为全身性 感染引起的炎症反应是发病的主要原因， 美国每年有超过175，000人死亡 一个人宿主对脓毒症的反应是一个复杂的相互作用， 炎症和抗炎过程，包括凝血级联反应， 补体系统、激肽系统和许多其他系统。免疫防御是 在败血症中也被激活;并且有募集和激活 粒细胞、淋巴细胞和单核细胞。最近的研究表明， 脓毒症引起循环淋巴细胞显著减少， 通过全身组织中淋巴细胞的大量凋亡。虽然 推测脓毒症诱导的淋巴细胞凋亡可能是有益的， 在脓毒症中，通过下调炎症反应， 淋巴细胞的损失是过度的，损害了宿主的能力， 根除感染最近，抗凋亡蛋白BCL-2已被发现， 可以防止大量不同刺激导致的细胞死亡 包括缺氧、电离辐射、氧化损伤和兴奋性毒素。的 这项调查的目的是继续他们的初步观察， 证明了在T细胞中选择性过表达BCL-2的转基因小鼠， 淋巴细胞对淋巴细胞凋亡有完全的保护作用， 脓毒症中的生存。这些研究结果表明， 脓毒症中淋巴细胞死亡可提高存活率。转基因小鼠构建体 其中BCL-2在T、B或T和B淋巴细胞中选择性过表达 将用于败血症。Rag-1小鼠中的淋巴细胞转移实验， 其完全缺乏成熟T和B细胞。 Rag-1小鼠将输注过表达BCL-2的T或B淋巴细胞 并记录对细胞凋亡和存活的影响。BCL-2的机制 也将研究保护效果。最后， 将对死于败血症或其他原因的患者进行检查， BCL-2的表达与淋巴细胞凋亡的关系 细胞凋亡的机制，如半胱天冬酶激活和细胞色素c释放。

DESCRIPTION (adapted from the abstract): Sepsis is defined as the systemic inflammatory response from infection and is a major cause of morbidity and mortality with an annual death rate of over 175,000 people in the United States alone. The host response to sepsis is an intricate interplay of numerous inflammatory and anti-inflammatory processes including the coagulation cascade, complement system, kinin system, and many others. Immunologic defenses are activated in sepsis as well; and there is recruitment and activation of granulocytes, lymphocytes, and monocytes. Recent studies demonstrate that sepsis causes a marked decrease in circulating lymphocytes which is accompanied by extensive apoptosis of lymphocytes in tissues throughout the body. Although it is speculated that sepsis-induced apoptosis of lymphocytes may be beneficial in sepsis by down-regulating the inflammatory response, it is also possible that loss of lymphocytes is excessive and impairs the ability of the host to eradicate the infection. Recently, the anti- apoptotic protein BCL-2 has been shown to prevent cell death from a remarkable number of diverse stimuli including hypoxia, ionizing radiation, oxidant injury and excitotoxins. The aims of this investigation are to pursue their initial observations demonstrating that transgenic mice which selectively overexpress BCL-2 in T lymphocytes have complete protection against lymphocyte apoptosis and improved survival in sepsis. These findings indicate that strategies which prevent lymphocyte death in sepsis may improve survival. Transgenic mouse constructs in which BCL-2 is selectively overexpressed in T, B, or both T and B lymphocytes will be employed in sepsis. Lymphocyte transfer experiments in Rag-1 mice, which are totally deficient in mature T and B cells, will be examined also. Rag-1 mice will be transfused with T or B lymphocytes that overexpress BCL-2 and effects on apoptosis and survival recorded. Mechanisms of BCL-2's protective effect will be investigated as well. Finally, autopsy sample from patient who died of sepsis or other causes will be examined to correlate BCL-2's expression with lymphocyte apoptosis and gain insight into possible mechanisms of apoptosis such as caspase activation and cytochrome c release.