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引起。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、组织损伤，在某些情况下甚至死亡有关。脂多糖(LPS)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解决不受调控的炎性免疫反应。据报道，痘苗病毒的A52R蛋白可以抑制由多种TLR配体激活的细胞产生的促炎细胞因子。该蛋白被证明与TLRs共同的细胞内信号蛋白结合。我们最近鉴定了一种来源于A52R蛋白的多肽，命名为P13，具有与亲本蛋白相似的性质。在本项目第一阶段进行的研究表明，多肽P13，i)抑制内皮细胞和肝细胞对内毒素的体外分泌促炎细胞因子，ii)在体内显著减少内毒素诱导的血清炎症介质的产生，iii)提高注射内毒素的小鼠的存活率。目前的第二阶段SBIR提案将扩大这些第一阶段研究，并确定优化多肽P13治疗的参数(特定目标#1)，并对多肽P13在内毒素诱导的脓毒症(特定目标2)和多菌败血症(特定目标3)限制炎症和提高存活率方面的有效性进行详细评估。确定多肽P13在两种脓毒症模型中的有效性将为多肽P13的治疗潜力提供关键评估。 细菌引起的脓毒症患者需要新的治疗方案，这种疾病的发病率和死亡率都在增加。我们已经确定了一种新的抗炎肽，它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。我们目前的研究将为这种多肽作为一种新的脓毒症治疗策略的治疗潜力提供一个重要的评估。

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.