Innate immune suppression following experimental injury

描述（由申请人提供）：重症监护病房（ICU）住院期间的院内感染（NI）是重伤成人和儿童健康相关成本、发病率和死亡率的重要组成部分。研究表明，危重疾病可诱导一种具有临床意义的先天免疫抑制形式，从而增加对NI的易感性。先天免疫细胞对病原体入侵的反应是抵抗NI的第一道防线。目前，患者的先天免疫功能缺陷不能用标准的实验室测试来确定。此外，目前还没有批准的靶向增强先天免疫功能和降低NI易感性的治疗方法。早期实验证据表明，在发生NI的严重损伤儿童中，全血白细胞在体外受到LPS刺激时产生促炎细胞因子肿瘤坏死因子α (TNF?)的能力降低。也有初步证据表明免疫刺激剂粒细胞-巨噬细胞集落刺激因子（GM-CSF）可以改善TNF？危重病人全血白细胞的生产能力。除了细胞因子的产生外，吞噬细胞的功能在清除感染中也至关重要，但尚未在创伤性损伤的背景下进行探讨。为了评估吞噬细胞功能，我们计划在损伤诱导的免疫抑制（部分肝切除术）小鼠模型中测量全血中白细胞执行吞噬和杀伤关键抗菌功能的能力，并假设吞噬细胞功能也在损伤后受到抑制。然后，我们计划确定GM-CSF的免疫刺激是否会改善该模型中的吞噬细胞功能。此外，我们将评估GM-CSF降低手术损伤后实验诱导的医院感染（尿路感染）严重程度的能力。因此，研究培训计划的目标是：1)表征吞噬细胞对已知医院病原体的先天免疫功能；2)评价GM-CSF对吞噬细胞抑菌功能的影响；3)在损伤性免疫抑制动物模型中测定GM-CSF降低NI严重程度的能力。这些发现将为后续的研究提供信息，这些研究的重点是在危急情况下检测和降低NI的风险

DESCRIPTION (provided by applicant): Nosocomial infections (NI) during hospitalization in the intensive care unit (ICU) are a significant proportion of health-related cost, morbidity, and mortality in critically injured adults and children. Studies have shown that critical illness can induce a clinically significant form of innate immune suppression that increases susceptibility to NI. Innate immune cell responses to pathogen invasion are the first line of defense against NI. Currently, defects in innate immune function in patients cannot be determined using standard laboratory tests. Additionally, there are no approved therapies targeted to enhance innate immune function and reduce susceptibility to NI. Early experimental evidence indicates there is a reduced ability leukocytes from whole blood, when stimulated by LPS ex vivo, to produce the pro-inflammatory cytokine tumor necrosis factor alpha (TNF?) in critically injured children who develop NI. There is also preliminary evidence that the immunostimulating agent granulocyte-macrophage colony stimulating factor (GM-CSF) can improve TNF? production capacity in leukocytes from whole blood of the critically ill. In addition to cytokine production, phagocyte function is also vitally important in clearance of infection and has not been explored in the context of traumatic injury. To evaluate phagocyte function we plan to measure the ability of leukocytes in whole blood to perform the critical antimicrobial functions of phagocytosis and killing in a mouse model of injury-induced immune suppression (partial hepatectomy), and hypothesize that phagocyte function is also suppressed following injury. We then plan to determine whether immunostimulation with GM-CSF will improve phagocyte function in this model. Moreover, we will evaluate the ability of GM-CSF to reduce the severity of experimentally induced nosocomial infection (urinary tract infection) following surgical injury. Therefore, the objectives of the research training proposal are: 1) to characterize innate immune functions of phagocytes against known nosocomial pathogens; 2) to evaluate the effects of GM-CSF on the antimicrobial functions of phagocytes and; 3) determine ability the of GM-CSF to reduce the severity of NI in our animal model of injury- induced immune suppression. The findings will inform subsequent studies focused on detecting and reducing risk for NI in critically ill children. The applicant's career goal is to conduct interdisciplinary translational research ina pediatric intensive care setting of a major academic medical center. The training plan and interdisciplinary mentorship team have been carefully crafted to ensure completion of the study aims, and to provide comprehensive training in laboratory measures of innate immune cell function. This training will provide the tools to launch a successful career as a nurse-scientist focused on improving nursing care outcomes for critically ill children at high risk for developing NI.