Bacterial-Induced Sepsis: A New Treatment Strategy

描述（由申请人提供）：脓毒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）相互作用引发的炎症免疫反应失控引起。细菌诱导的脓毒症与促炎细胞因子的产生、细胞粘附分子的表达、组织损伤以及某些情况下的死亡有关。脂多糖（LPS）已被确定为革兰氏阴性脓毒症发病机制中的关键细菌成分。目前的治疗重点是抗生素控制感染和重症监护支持相关的多器官衰竭。需要新的治疗方案来解决不受管制的炎症免疫反应。据报道，来自牛痘病毒的A52R蛋白在多种TLR配体激活细胞时抑制促炎细胞因子的产生。该蛋白被证明与tlr常见的细胞内信号蛋白结合。我们最近鉴定并表征了一种称为P13的肽，它来源于A52R蛋白，具有与亲本蛋白相似的特性。该项目的I期研究表明，肽P13， I)在体外抑制内皮细胞和肝细胞对LPS的促炎细胞因子的分泌，ii)在体内显著减少LPS诱导的血清中炎症介质的产生，iii)提高注射LPS小鼠的存活率。目前的II期SBIR提案将扩展这些I期研究，并定义优化肽P13治疗的参数（特定目标#1），并提供肽P13在内毒素诱导的脓毒症（特定目标#2）和多微生物脓毒症（特定目标#3）中限制炎症和提高生存率的功效的详细评估。建立肽P13在两种脓毒症模型中的疗效将为肽P13的治疗潜力提供关键评估。

DESCRIPTION (provided by applicant): Sepsis is a disease with increasing morbidity and mortality that 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, tissue damage, and in some cases death. Lipopolysaccaride (LPS) 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 the unregulated inflammatory immune response. The A52R protein from vaccinia virus has been reported to inhibit production of proinflammatory cytokines in response to cell activation by a variety of TLR ligands. The protein was demonstrated to bind to intracellular signaling proteins common to TLRs. We have recently identified and characterized a peptide, termed P13, derived from the A52R protein, with similar properties as the parent protein. Studies conducted during the Phase I portion of this project demonstrated that peptide P13, i) inhibited the in vitro secretion of proinflammatory cytokines by endothelial cells and hepatocytes in response to LPS, ii) functioned in vivo to significantly reduce LPS-induced production of inflammatory mediators in the serum, and iii) enhanced survival in mice injected with LPS. The current Phase II SBIR proposal will expand these Phase I studies and define parameters for optimizing treatment with peptide P13 (specific aim #1), and provide a detailed assessment of the efficacy of peptide P13 in limiting inflammation and enhancing survival in endotoxin-induced sepsis (specific aim #2) and polymicrobial sepsis (specific aim #3). Establishing the efficacy of peptide P13 in both models of sepsis will provide a critical evaluation of the therapeutic potential of peptide P13. New treatment options are needed for patients with bacterial-induced sepsis, a disease with increasing morbidity and mortality. We have identified a novel anti-inflammatory peptide that has demonstrated feasibility to limit inflammation and disease development in an animal model of sepsis. Our current studies will provide a critical evaluation of the therapeutic potential of this peptide as a new treatment strategy for sepsis.