Nosocomial pneumonias impair cognitive function

项目总结/摘要 重症监护病房的患者面临长期健康威胁的风险很高，包括认知障碍。的 最近，在对重症患者进行大规模随访认知评估后， 幸存者从医院出院后。有许多推荐，评论和呼吁采取行动 在过去的2-3年里，重症监护网站和期刊上都有关于这场公共卫生危机的报道。但 导致突然认知障碍的致病机制尚不清楚-它们不能归因于年龄， 性别、相对脑缺氧、麻醉剂和镇静剂。 医院获得的细菌如铜绿假单胞菌在血管内皮细胞损伤过程中损害内皮细胞功能。 最终导致急性肺损伤的感染最近的研究表明，在铜绿假单胞菌感染后， 内皮细胞产生并释放可在细胞间传递的细胞毒性淀粉样蛋白。具有访问 到全血循环的内皮，这些细胞毒性淀粉样蛋白可能传播。事实上， 在重症监护病房的医院获得性肺炎患者的血液和脑脊液中可检测到。 此外，当应用于脑切片时，来自内皮的细胞毒性淀粉样蛋白损害神经活动 和突触信息传递。 该项目利用了垂直整合的方法，从使用不同的细菌 染色和培养的细胞，体外脑切片记录和体内动物行为研究。这些研究 设计以检验医院获得性肺炎诱导CSF中淀粉样蛋白积累的假设， 导致LTP抑制和学习缺陷。总之，研究系统地研究了一种可能的 肺-脑轴，其中原发性肺部感染诱导细胞毒性淀粉样蛋白的产生，其扩散到 脑脊液中，并有助于认知障碍。这项工作解决了一个新的机制， 终末器官功能障碍，这是明显的过程中，并在之后，危重病。机械性的认识 研究内皮源性细胞毒性对脑功能的影响将揭示新的治疗方法， 认知能力下降

PROJECT SUMMARY/ABSTRACT Patients in intensive care units are at high risk for long-term health threats including cognitive impairment. The correlation was only recently revealed after large-scale follow-up cognitive assessments on intensive patient survivors after their discharge from the hospital. There are testimonials, reviews and calls-to-action on many critical care websites and in journal issues over the last 2-3 years on this public health crisis. However, the causative mechanisms that lead to abrupt cognitive impairment are unclear—they are not attributable to age, gender, relative brain hypoxia, anesthetics and sedatives. Nosocomial bacteria such as Pseudomonas aeruginosa impair endothelial cell function during the course of infection that culminates in acute lung injury. Recent studies implicate that after P. aeruginosa infection, endothelial cells produces and releases cytotoxic amyloids that are transmissible among cells. Having access to the endothelium of whole blood circulation, these cytotoxic amyloids likely propagate. In fact, the amyloids are detectable in the blood and cerebrospinal fluid of nosocomial pneumonia patients in intensive care units. Further, when applied to brain slices, the cytotoxic amyloids derived from endothelium impair neural activity and synaptic information transfer. This project takes advantage of vertically integrated approaches, ranging from the use of different bacteria stains and cultured cells, to in vitro brain slice recordings and in vivo animal behavior studies. The studies are designs to test the hypothesis that nosocomial pneumonias induce amyloid protein accumulation in CSF, resulting in LTP suppression and learning deficit. Altogether, studies systematically examine a possible lung-brain axis, where a primary lung infection induces production of cytotoxic amyloids that spread to the cerebrospinal fluid and contribute to cognitive impairment. This work addresses a novel mechanism underlying the end organ dysfunction that is evident during, and in the aftermath of, critical illness. Mechanistic insight into endothelium-derived cytotoxicity to brain function will reveal novel therapeutic approaches to prevent cognitive decline.