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

入侵细菌释放的脂多糖（LPS）与人类革兰氏阴性脓毒症中炎症组织损伤的发病机制密切相关。设计抑制内毒素的药物已被提议作为败血症的辅助治疗。脂质a类似物E5564就是这样一种药物，它已被证明可以竞争性地抑制LPS刺激的巨噬细胞释放细胞因子。然而，尽管LPS信号可能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，设计用于抑制LPS的其他药物（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，LPS对宿主防御和炎症损伤的影响可能与主要在患者中观察到的血管外（EV）感染不同。例如，内毒素在血管内激活白细胞可能在IV细菌攻击期间几乎没有保护作用，但可能对它们募集到EV感染病灶很重要。因此，本研究比较了E5564对致死性相似的IV和EV感染的影响。大鼠在IV或EV[支气管或腹腔内]大肠杆菌攻击后接受E5564或安慰剂。E5564降低了IV型大肠杆菌感染的相对死亡风险，并以显著不同的模式增加了EV感染的相对死亡风险。与对照组相比，在IV型和EV型大肠杆菌中，E5564在第4和24小时增加了循环总白细胞和中性粒细胞，但在第4小时减少了肺灌洗中性粒细胞，而在24小时增加了它们。因此，E5564损害组织白细胞募集的能力可能解释了该药物在EV感染模型中缺乏益处或潜在危害的原因。相反，在静脉感染中，对白细胞运输的同样影响可能限制非特异性器官损伤，从而提高生存率。感染部位可能对设计用于改变脓毒症LPS水平的药物有重要影响。

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.