Bacterial-Induced Sepsis: A New Treatment Strategy

描述（由申请人提供）：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）相互作用引起的不受控制的炎症免疫反应引起。细菌诱导的脓毒症与促炎细胞因子的产生、细胞粘附分子的表达和细胞凋亡的诱导有关。脂多糖（IPS）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炎症反应和相关的细胞凋亡。我们最近鉴定并鉴定了一种从免疫调节的A52R痘苗病毒蛋白中提取的肽，该肽i)在对多种TLR配体（包括LPS）的反应中抑制促炎细胞因子的体外分泌，ii)在小鼠中耳炎症模型中显著减少细菌诱导的炎症，iii)在初步的体外研究中减少LPS诱导的细胞凋亡。我们建议在这项I期研究中测试这种肽作为一种治疗方法的可行性，以减少lps诱导的脓毒症中的炎症和细胞凋亡。实验将在体外检查肽在限制内皮细胞活化和凋亡方面的作用，以响应LPS（特异性目的#1），以及肽在LPS诱导的脓毒症小鼠模型中的体内有效性（特异性目的#2）。如果成功，这些研究将为继续评估肽作为革兰氏阴性细菌引起的败血症的新治疗策略提供证据。

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.