Nosocomial pneumonias impair cognitive function

项目摘要/摘要 重症监护病房的患者长期健康威胁的风险很高，包括认知障碍。这个 直到最近，在对重症监护患者进行大规模认知评估后，才发现了相关性 出院后的幸存者。有关于许多人的推荐信、评论和行动呼吁 过去十年有关这场公共卫生危机的重症监护网站和期刊。研究表明， 牵连的精神错乱是长期认知缺陷的良好预测指标；然而，病因和分子 导致突发性认知障碍的机制尚不清楚。 在过去的4年里，我们的研究发现，重症监护病房的患者感染了 细菌性肺炎使支气管肺泡灌洗液、血浆、肺泡灌洗液中细胞毒性淀粉样蛋白水平升高， 还有脑脊液。在从细菌收集的脑脊液中孵育的啮齿动物脑片 肺炎阳性患者表现出海马区长时程增强受抑。相比之下，突触 细菌肺炎阴性患者脑脊液中孵育的切片强化明显。 此外，使用针对Aβ和𝜏的选择性抗体从脑脊液或血浆中进行免疫纯化 低聚物注射到啮齿动物体内，这些细胞毒素会诱导神经元树突棘回缩，降低脊椎 密度，并损害动物的学习。 我们之前的体外研究表明，在对铜绿假单胞菌感染的反应中，肺 内皮细胞产生和释放包括Aβ和𝜏在内的细胞毒素及其细胞毒性和生物活性 这些物种中的大多数依赖于细菌的毒力。这些内皮衍生的细胞毒素会损害 内皮屏障的完整性，阻碍损伤后的血管修复，重要的是，它们被释放到 体内的体循环。因此，在这场竞争性更新中，研究旨在检验这一假设 细菌性肺炎所致肺内皮源性淀粉样蛋白包括病理性A、β和𝜏 能够传播和发起聚合。这项工作解决了一种新的机制，其基础是 通过系统地量化体外、啮齿动物和大鼠体内内皮细胞释放的细胞毒素来结束器官功能障碍 病人样本。

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 decade on this public health crisis. Studies have implicated delirium as a good predictor for long-term cognitive deficit; however, the causative and molecular mechanisms leading to abrupt cognitive impairment are unclear. In the past 4 years, our studies have discovered that patients in the intensive care unit who contracted bacterial pneumonia have elevated levels of cytotoxic amyloids in the bronchoalveolar lavage fluid, plasma, and the cerebrospinal fluid. Rodent brain slices incubated in the cerebrospinal fluids collected from bacterial pneumonia-positive patients show dampened hippocampal long-term potentiation. In comparison, synaptic strengthening is prominent in slices incubated in bacterial pneumonia-negative patients’ cerebrospinal fluid. Moreover, immunopurified from the cerebrospinal fluid or plasma using selective antibodies against Aβ and 𝜏 oligomers and injected into rodents, these cytotoxins induce neuronal dendritic spine retraction, reduce spine density, and impair animal learning. Our previous in vitro studies have implicated that in response to Pseudomonas aeruginosa infection, lung endothelium produces and releases cytotoxins including Aβ and 𝜏 species, and the cytotoxicity and bioactivity of these species are dependent upon the bacterial virulence. These endothelium-derived cytotoxins damage endothelial barrier integrity, hinder vascular repair following injury and, importantly, they are released into the systemic circulation in vivo. Thus, in this competitive renewal, the studies are designed to test the hypothesis that bacterial pneumonia-elicited lung endothelium-derived amyloids include pathological Aβ and 𝜏 species capable of dissemination and initiating aggregation. This work addresses a novel mechanism underlying the end organ dysfunction by systemically quantify cytotoxins released from endothelium in vitro, in rodents, and in patient specimens.