Cognitive and immune impairments in sepsis survivors

描述（由申请人提供）：每年约有750，000名美国人经历危及生命的严重脓毒症发作。25%到30%的人急性死亡。幸存者的认知功能会减弱此外，许多人将在未来五年内死于免疫能力和感染。这项研究计划将解决败血症的这些晚期后遗症。我们提出的模型将这两种损伤联系起来。全身性炎症导致脑部炎症和脾脏微环境改变。我们问是否有必要维持脑炎症和传出迷走神经功能的损害维持免疫抑制系统的细胞因子。为了支持该模型，并且具有明显的临床意义，我们已经表明，在急性事件明显消退后用细胞因子阻断进行干预可以改善脑和免疫功能。由一个行政核心和3个科学核心支持的三个协调研究项目将探索脑炎症的起源和性质，持续单核细胞功能障碍的性质和原因以及预防严重脓毒症引发的长期发病的最佳治疗方法。 相关性：在严重脓毒症发作后，个体可能会出现认知受损和免疫功能不足，这导致长期预后不良。该研究计划将探索这些持续性损伤，它们之间的联系以及预防或逆转的治疗策略。这些晚期后遗症尚未得到很好的研究，也没有针对性的治疗 项目1：脓毒症存活小鼠的神经系统改变 项目负责人（PL）：布鲁斯沃尔佩 描述（由申请人提供）：脓毒症的幸存者通常会出现持续性认知障碍。我们的初步数据表明，这可以通过在急性、危及生命的免疫激活已经解决时减少全身炎症来改善。在这个项目中，我们将探讨由败血症发作引发的脑炎症，以及TNF，IL-1或HMGB 1或这些的一些组合是否是1）循环中启动脑炎症的关键细胞因子或2）脑内导致组织学和功能损伤的关键细胞因子。此外，我们将探讨全身性炎症是如何传递到大脑的：无论是通过神经回路还是通过激活脑微血管内皮细胞。这些研究将确定连接大脑炎症和全身炎症的途径，并将剖析导致持续认知缺陷的大脑炎症的组成部分。 相关性：脓毒症幸存者通常会出现持续性认知障碍。这项研究将探讨全身性炎症如何导致脑功能障碍。

DESCRIPTION (provided by applicant): Approximately 750,000 Americans each year experience a life-threatening episode of severe sepsis. Twenty five to 30% die acutely. The survivors will experience diminished cognitive function. Moreover, many will die within the next five years due to immunocompetence and infection. This research program will address these late sequelae of sepsis. The model we propose links these two impairments. Systemic inflammation leads to both brain inflammation and an altered splenic microenvironment. We ask whether systemic cytokines are necessary to sustain brain inflammation and whether impairment in the function of the efferent vagus nerve sustains the immunosuppression. In support of this model, and of obvious clinical significance, we have shown that intervening with cytokine blockade after apparent resolution of the acute event improves both brain and immune function. Three coordinated research projects, support by an administrative core and 3 scientific cores will explore the initiation and nature of brain inflammation, the nature and cause of persisting monocyte dysfunction and the optimal therapy to prevent the long term morbidity that is triggered by severe sepsis. RELEVANCE: Following an episode of severe sepsis, individuals may develop impaired cognition and inadequate immune function, which contributes to poor long-term outcome. This research program will explore these persistent impairments, the links between them and therapeutic strategies for their prevention or reversal. These late sequelae have not been well studies, nor targeted therapeutically Project 1: Nervous system alterations in sepsis-surviving mice Project Leader (PL): Bruce Volpe DESCRIPTION (as provided by applicant): Survivors of sepsis often experience persistent cognitive impairment. Our preliminary data show that this can be ameliorated by reducing systemic inflammation at a time when acute, life-threatening immune activation has resolved. In this project, we will explore the brain inflammation that is triggered by an episode of sepsis and whether TNF, IL-1 or HMGB1, or some combination of these is 1) the critical cytokine in the circulation that initiates brain inflammation or 2) a key cytokine within the brain that contribute to histologic and functional damage. Further, we will explore how systemic inflammation is communicated to the brain: whether by neural circuitry or by activation of brain microvascular endothelial cells. These studies will identify pathways connecting brain inflammation to systemic inflammation and will dissect those components of brain inflammation that lead to a persistent cognitive deficit. RELEVANCE: Individuals surviving sepsis often experience persistent cognitive impairment. This study will explore how systemic inflammation causes brain dysfunction.