Bacterial-Induced Sepsis: A New Treatment Strategy

描述（由申请方提供）：脓毒症是一种发病率和死亡率增加的疾病，由细菌或细菌组分与宿主Toll样受体（TLR）相互作用引发的不受控制的炎症免疫应答引起。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、组织损伤以及在某些情况下的死亡相关。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。目前的治疗集中在抗生素控制感染和重症监护支持相关的多器官功能衰竭。需要新的治疗选择来解决不受调节的炎症免疫应答。已经报道来自牛痘病毒的A52R蛋白抑制响应于多种TLR配体的细胞活化的促炎细胞因子的产生。该蛋白质被证明与TLR常见的细胞内信号蛋白结合。我们最近已经确定和表征了一种肽，称为P13，来自A52R蛋白，具有与亲本蛋白相似的性质。在该项目的I期部分期间进行的研究表明，肽P13，i）抑制内皮细胞和肝细胞响应于LPS的促炎细胞因子的体外分泌，ii）在体内起作用以显著减少血清中LPS诱导的炎性介质的产生，和iii）提高注射LPS的小鼠的存活率。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（具体目标#1），并提供肽P13在限制炎症和提高内毒素诱导的脓毒症（具体目标#2）和多微生物脓毒症（具体目标#3）中存活率方面的疗效的详细评估。在两种脓毒症模型中建立肽P13的功效将提供肽P13的治疗潜力的关键评价。 细菌性脓毒症是一种发病率和死亡率不断上升的疾病，需要新的治疗选择。我们已经鉴定了一种新的抗炎肽，其已经证明了在脓毒症动物模型中限制炎症和疾病发展的可行性。我们目前的研究将提供这种肽作为脓毒症新治疗策略的治疗潜力的关键评估。

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.