Cognitive and immune impairments in sepsis survivors

描述（由申请人提供）：大约75万美国人每年经历一次危及生命的严重败血症。25%到30%的患者急性死亡。幸存者的认知功能会减弱。此外，许多人将在未来五年内因免疫能力低下和感染而死亡。本研究计划将解决这些败血症的晚期后遗症。我们提出的模型将这两种损伤联系起来。全身性炎症导致脑炎症和脾脏微环境改变。我们想知道系统性细胞因子是否对维持脑炎症是必要的，以及传出迷走神经功能的损害是否维持了免疫抑制。为了支持这个模型，并且具有明显的临床意义，我们已经证明在急性事件明显解决后干预细胞因子阻断可以改善大脑和免疫功能。由一个行政核心和三个科学核心支持的三个协同研究项目将探索脑炎的起源和性质，持续单核细胞功能障碍的性质和原因，以及预防严重败血症引发的长期发病率的最佳治疗方法。

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.