PREVENTION OF APOPTOTIC CELL DEATH IN SEPSIS BY BCL-2

描述(摘自摘要)：脓毒症的定义是全身性的 感染引起的炎症反应，是发病率和 美国年死亡率超过17.5万人的死亡率 独自一人。宿主对脓毒症的反应是一种错综复杂的相互作用 炎症和抗炎过程，包括凝固级联， 补体系统、激肽系统和许多其他系统。免疫防御是 在脓毒症中也被激活；并且有招募和激活 粒细胞、淋巴细胞和单核细胞。最近的研究表明， 脓毒症引起循环中淋巴细胞的显著减少。 通过全身组织中淋巴细胞的广泛凋亡。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，也是可能的 这种淋巴细胞的丧失是过度的，并损害宿主的能力 根除感染。最近，抗凋亡蛋白bcl-2已经被 显示可以防止细胞因大量不同的刺激而死亡 包括缺氧、电离辐射、氧化损伤和兴奋性毒素。这个 这项调查的目的是继续他们的初步观察 证明在T细胞中选择性过表达bcl2的转基因小鼠 淋巴细胞对淋巴细胞的凋亡有完全的保护作用，提高了 在脓毒症中存活。这些发现表明，防止 脓毒症时淋巴细胞死亡可能会提高存活率。转基因小鼠在 哪种bcl2选择性地在T、B淋巴细胞或T和B淋巴细胞中过表达 将受雇于败血症。RAG-1小鼠的淋巴细胞转移实验， 在成熟的T和B细胞中完全缺乏的，也将被检测。 RAG-1小鼠将被输注过表达bcl2的T或B淋巴细胞 并记录了对细胞凋亡和存活的影响。Bc1-2‘S的作用机制 此外，还将调查保护效果。最后，尸检样本来自 将对死于脓毒症或其他原因的患者进行相关检查 Bc1-2‘S表达与淋巴细胞凋亡的关系及可能机制 细胞凋亡的机制，如caspase激活和细胞色素c的释放。

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.