Prevention of Apoptotic Cell Death in Sepsis by BCL-2

脓毒症是大多数重症监护病房的主要死亡原因，超过21万人死于 美国每年的压倒性感染(或由此导致的多器官衰竭)。最近 流行病学研究估计，每年有75万人患上脓毒症，花费167亿美元。 研究表明，细胞凋亡是脓毒症细胞死亡的重要机制，而预防 细胞凋亡可提高脓毒症动物模型的存活率。 细胞凋亡可通过受体途径或线粒体途径进行。在某些类型的细胞中 在特定的细胞凋亡刺激下，这两条通路可以连接在一起，使得两条通路都是 在同一间牢房里运作。了解脓毒症中细胞凋亡的死亡机制至关重要，因为 这一知识可以揭示煽动刺激，并使针对责任人的有效治疗成为可能 路径。目前，脓毒症中特有的凋亡途径，即受体对线粒体， 有争议，据报道这两条通路都被激活。我们实验室的初步发现 提示这两条途径可能在脓毒症诱导的淋巴细胞凋亡中起作用 发生在脾的不同解剖区域，与对不同淋巴细胞的影响一致 表型。 与Bcl2一样，丝氨酸苏氨酸激酶Akt是一种癌蛋白，可防止因多种原因引起的细胞死亡 细胞凋亡性刺激。Akt的确切作用机制尚不清楚，但在某些情况下似乎是有效的 其机制与Bc l-2不同。我们实验室的初步研究结果表明 在T细胞中过表达Akt的小鼠淋巴细胞不会发生脓毒症诱导的凋亡，并且 与非转基因动物相比，小鼠的存活率有所提高。 这一建议的指导性假设是：i)脓毒症中淋巴细胞的凋亡是通过两种受体进行的 线粒体介导的途径和，ii)Akt在T细胞中的过表达将阻止淋巴细胞 促进细胞凋亡，提高脓毒症存活率。研究将使用与临床相关的动物模型进行 败血症。此外，还将对患有和不患有危重病人的血液进行转译研究。 败血症。注意，初步研究结果显示脓毒症患者淋巴细胞凋亡增加。 与病情危重的非败血症患者相比。这项提案将提供有关以下方面的重要新信息 脓毒症中淋巴细胞凋亡死亡的机制，并最终可能导致更有效的治疗 这种高度致命的疾病。

Sepsis is the leading cause of death in most intensive care units with over 210,000 people succumbing to overwhelming infection (or the resultant multiple organ failure) in the United States annually. A recent epidemiologic study estimated that 750,000 people develop sepsis annually at a cost of $16.7 billion dollars. Studies show that apoptosis is an important mechanism of cell death in sepsis and that prevention of apoptosis can improve survival in animal models of sepsis. Apoptosis can proceed by either a receptor or mitochondrial mediated pathway. In certain types of cells subjected to particular apoptotic stimuli, the two pathways can be linked such that both pathways are operative in the same cell. Understanding the mechanisms of apoptotic cell death in sepsis is vital because this knowledge may reveal the inciting stimuli and enable an effective therapy aimed at the responsible pathway. Currently, the particular apoptotic pathway operative in sepsis, i.e., receptor versus mitochondrial, is debated and both pathways have been reported to be activated. Preliminary findings in our laboratory indicate that both pathways may be operative in sepsis-induced lymphocyte apoptosis although they appear to be occurring in anatomically different regions of the spleen, consistent with effects on different lymphocyte phenotypes. Like Bcl-2, the serine threonine kinase Akt is an oncoprotein which prevents cell death due to a variety of apoptotic stimuli. The exact mechanism of action of Akt is unknown but in some instances it appears to work by a mechanism that is distinct from that of Bcl-2. Preliminary findings in our laboratory show that lymphocytes from mice that over express Akt in T cells do not undergo sepsis-induced apoptosis and the mice have improved survival compared to non-transgenics. The guiding hypotheses of this proposal are: i) lymphocyte apoptosis in sepsis proceeds via both receptor and mitochondrial mediated pathways and, ii) over-expression of Akt in T cells will prevent lymphocyte apoptosis and improve sepsis survival. Studies will be conducted using a clinically relevant animal model of sepsis. In addition, translational studies will be conducted in blood from critically ill patients with and without sepsis. Note that preliminary findings demonstrate increased lymphocyte apoptosis in patients with sepsis versus critically ill non-septic patients. This proposal will provide important new information regarding mechanisms of apoptotic lymphocyte death in sepsis and may ultimately lead to a more effective therapy for this highly lethal disorder.