Influence Of Site, Severity, And Type Of Infection On Ef

细菌内毒素的释放与人类革兰氏阴性脓毒症时炎性组织损伤的发病机制密切相关。抑制内毒素的药物已被提出作为脓毒症的辅助治疗。E5564是一种类脂A类似物，已被证明具有竞争性抑制内毒素刺激的巨噬细胞释放细胞因子的作用。然而，虽然内毒素信号可以刺激对宿主有害的炎症介质，但这种反应也可能具有适应性保护功能。事实上，其他旨在抑制内毒素的药物(如抗内毒素抗体)在脓毒症动物模型中是有益的，但在大型临床脓毒症试验中并未显示出有益的效果。在经常使用血管内(IV)细菌攻击的动物模型中，内毒素对宿主防御和炎性损伤的影响可能不同于主要在患者身上观察到的血管外(EV)感染。例如，在静脉细菌攻击期间，内毒素对白细胞的血管内激活可能没有什么保护作用，但可能对它们重新聚集到EV感染的病灶很重要。因此，这项研究比较了E5564与类似的致死性IV和EV感染的效果。大鼠在静脉或EV[支气管或腹膜内]大肠杆菌攻击后接受E5564或安慰剂治疗。E5564降低了感染IV型大肠杆菌的相对死亡风险，而增加了EV感染的相对死亡风险，模式明显不同。与对照组相比，在IV和EV大肠杆菌中，E5564在4小时和24小时时循环总白细胞和中性粒细胞增加，而在4小时时肺灌洗液中中性粒细胞减少，而在24小时时增加，因此，E5564抑制组织中白细胞募集的能力可能解释了该药在EV感染模型中缺乏益处或潜在危害的原因。相反，在IV感染中，对白细胞运输的同样影响可能会限制非特异性器官损伤，从而提高存活率。感染部位可能对设计用来改变脓毒症中内毒素水平的药物有重要影响。 这个项目已经完成，手稿正在准备中。

Lipopolysaccharide (LPS) release from invading bacteria has been closely associated with the pathogenesis of the inflammatory tissue injury occurring during gram-negative sepsis in humans. Agents designed to inhibit endotoxin have been proposed as adjunctive therapy for sepsis. E5564, a lipid A analogue, is one such agent which has been shown to competitively inhibit LPS stimulated cytokine release from macrophages. However, although LPS signaling may stimulate inflammatory mediators harmful to the host, this response may also have an adaptive protective function. In fact, other agents (e.g. antiendotoxin antibodies) designed to inhibit LPS which were beneficial in animal models of sepsis, have not shown beneficial effects in large clinical sepsis trials. It is possible that in animal models that have frequently employed intravascular (IV) bacterial challenges, the effects of LPS on host defense and inflammatory injury are different than during the extravascular (EV) infection primarily observed in patients. For instance, the intravascular activation of leukocytes by endotoxin may have little protective effect during IV bacterial challenge but may be important for their recruitment to an EV nidus of infection. This study therefore compared the effects of E5564 with similarly lethal IV and EV infection. Rats received E5564 or placebo after IV or EV [intrabronchial or intraperitoneal] E. coli challenges. E5564 decreased the relative risk of death with IV E. coli and increased it with EV infection in patterns that were significantly different. Compared to controls, in both IV and EV E. coli, E5564 increased circulating total leukocytes and neutrophils at 4 and 24 h combined but decreased lung lavage neutrophils at 4 h while increasing them at 24 h. Thus, the ability of E5564 to impair tissue leukocyte recruitment may explain the lack of benefit or potential harm associated with the agent in this model of EV infection. Conversely, in IV infections, the same affect on leukocyte trafficking may limit non-specific organ injury and thereby improve survival. Site of infection may have an important impact on agents designed to alter LPS levels in sepsis. This project has been completed and a manuscript is in preparation.