Bacterial-Induced Sepsis: A New Treatment Strategy

描述(申请人提供)：败血症是一种发病率和死亡率不断上升的疾病，由细菌或细菌成分与宿主Toll样受体(TLRs)相互作用引发的失控炎症免疫反应所致。细菌诱导的脓毒症与促炎细胞因子的产生、细胞黏附分子的表达和诱导细胞凋亡有关。脂多糖(IPS)已被认为是革兰氏阴性脓毒症发病机制中的关键细菌成分。目前的治疗重点是控制感染的抗生素和相关多器官衰竭的重症监护支持。需要新的治疗方案来同时解决炎症反应和相关的细胞凋亡。我们最近已经发现并鉴定了一种源自免疫调节A52R痘苗病毒蛋白的多肽，即i)可在体外抑制包括内毒素在内的多种TLR配体作用下促炎细胞因子的分泌，ii)在体内显著降低细菌诱导的中耳炎模型中的炎症反应，以及iii)在初步的体外研究中减少内毒素诱导的细胞凋亡。在这项第一阶段研究中，我们建议测试这种多肽作为一种治疗方法的可行性，以减少在脂多糖诱导的脓毒症中出现的炎症和细胞凋亡。实验将在体外检测多肽在限制脂多糖诱导的脓毒症小鼠模型中的内皮细胞激活和凋亡方面的作用(特定目的#1)和体内效果(特定目的#2)。如果成功，这些研究将为继续评估多肽作为治疗革兰氏阴性细菌引起的脓毒症的新策略提供证据。 细菌引起的脓毒症是一种发病率和死亡率不断上升的疾病，新的治疗方案是必要的。我们已经确定了一种新的治疗多肽，已经在实验室证明了显著的效果，现在将在脓毒症的动物模型上进行测试。如果成功，这些研究将为继续评估这种多肽作为一种新的脓毒症治疗策略提供基础。

DESCRIPTION (provided by applicant): Sepsis, a disease with increasing morbidity and mortality, results from an uncontrolled inflammatory immune response initiated by the interaction of bacteria or bacterial components with host Toll-like receptors (TLRs). Bacterial-induced sepsis is associated with production of proinflammatory cytokines, expression of cell adhesion molecules, and induction of cell apoptosis. Lipopolysaccaride (IPS) has been identified as a critical bacterial component in the pathogenesis of gram-negative sepsis. Current treatments focus on antibiotics for controlling infection and intensive care support for associated multi-organ failure. New treatment options are needed that address both the inflammatory response and the associated cell apoptosis. We have recently identified and characterized a peptide, derived from the immunoregulatory A52R vaccinia virus protein, that i) inhibits the in vitro secretion of proinflammatory cytokines in response to a variety of TLR ligands, including LPS, ii) functions in vivo to significantly reduce bacterial-induced inflammation in a mouse model of middle ear inflammation, and iii) in preliminary in vitro studies reduces LPS-induced cell apoptosis. We propose in this Phase I study to test the feasibility of this peptide as a treatment to reduce both the inflammation and cell apoptosis seen in LPS-induced sepsis. Experiments will examine in vitro the peptide effect in limiting endothelial cell activation and apoptosis in response to LPS (specific aim #1) and the in vivo effectiveness of the peptide in a mouse model of LPS-induced sepsis (specific aim #2). If successful, these studies will provide evidence for continued assessment of the peptide as a new treatment strategy for gram-negative bacterial-induced sepsis. New treatment options are necessary for patients with bacterial-induced sepsis, a disease with increasing morbidity and mortality. We have identified a novel therapeutic peptide that has demonstrated significant effects in the laboratory and will now be tested in an animal model of sepsis. If successful, these studies will provide the foundation for continued assessment of this peptide as a new treatment strategy for sepsis.