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

感染部位、严重程度和类型对 Ef 的影响

• 批准号: 6993911
• 负责人: Peter Q Eichacker
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6993911
• 关键词: analog; bacterial disease; biological signal transduction; blood toxicology; cell migration; drug screening /evaluation; endotoxins; host organism interaction; inhibitor /antagonist; laboratory rat; leukocyte activation /transformation; lipopolysaccharides; pathologic process; septicemia; virulence

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.

入侵细菌释放的脂多糖（LPS）与人类革兰氏阴性败血症期间发生的炎症组织损伤的发病机制密切相关。已提出设计用于抑制内毒素的药物作为脓毒症的辅助治疗。 E5564 是一种脂质 A 类似物，已被证明可以竞争性抑制 LPS 刺激的巨噬细胞释放细胞因子。然而，虽然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，其他旨在抑制脂多糖的药物（例如抗内毒素抗体）对脓毒症动物模型有益，但在大型临床脓毒症试验中尚未显示出有益效果。在经常采用血管内 (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) 感染期间不同。例如，内毒素对白细胞的血管内激活在静脉注射细菌攻击期间可能几乎没有保护作用，但对于将其募集到EV感染病灶可能很重要。因此，本研究将 E5564 与类似致死性 IV 和 EV 感染的效果进行了比较。大鼠在 IV 或 EV [支气管内或腹膜内] 大肠杆菌攻击后接受 E5564 或安慰剂。 E5564 降低了 IV 型大肠杆菌导致的死亡相对风险，并增加了 EV 感染导致的相对死亡风险，但模式存在显着差异。与对照相比，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，但在 4 小时时减少肺灌洗中性粒细胞，而在 24 小时时增加。因此，E5564 损害组织白细胞募集的能力可能解释了在这种 EV 感染模型中与该药物相关的益处或潜在危害的缺乏。相反，在静脉注射感染中，对白细胞运输的相同影响可能会限制非特异性器官损伤，从而提高生存率。感染部位可能对改变脓毒症 LPS 水平的药物产生重要影响。 该项目已经完成，正在准备手稿。