Innate immune suppression following experimental injury

描述(由申请人提供)：在重症监护病房(ICU)住院期间的医院感染(NI)在与健康相关的费用、发病率和死亡率中占很大比例，严重受伤的成人和儿童。研究表明，危重疾病可导致一种临床上显著的先天免疫抑制，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御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，目前还没有针对增强先天免疫功能和降低对NI易感性的已获批准的治疗方法。早期的实验证据表明，当在体外受到内毒素刺激时，全血中的白细胞产生促炎细胞因子肿瘤坏死因子α(TNF？)的能力降低。发生医院感染的重伤儿童。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)能提高肿瘤坏死因子？危重病人全血白细胞的生产能力。除了细胞因子的产生，吞噬细胞的功能在清除感染方面也是至关重要的，在创伤损伤的情况下还没有被研究过。为了评估吞噬细胞功能，我们计划在损伤诱导免疫抑制(肝部分切除)的小鼠模型中，测量全血中白细胞执行吞噬和杀伤等关键抗菌功能的能力，并假设创伤后吞噬细胞功能也受到抑制。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性医院感染(尿路感染)的严重程度的能力。因此，研究培训方案的目的是：1)表征吞噬细胞对已知医院病原体的固有免疫功能；2)评估GM-CSF对吞噬细胞抗菌功能的影响；3)在我们的创伤诱导免疫抑制动物模型中确定GM-CSF减轻NI严重程度的能力。这些发现将为后续的研究提供参考，这些研究的重点是检测和降低重症医院感染的风险。 生病的孩子。申请者的职业目标是在一个主要的学术医学中心的儿科重症监护环境中进行跨学科的转化性研究。培训计划和跨学科指导团队经过精心设计，以确保完成研究目标，并提供关于先天免疫细胞功能的实验室测量的全面培训。这一培训将提供工具，以护士科学家的身份开始成功的职业生涯，专注于改善患有医院感染的高风险危重儿童的护理结果。 公共卫生相关性：从这项建议中获得的知识可以影响公众的健康，并通过提供新的方法来监测先天性免疫功能，以确定重症监护病房患者感染医院感染的最高风险，从而降低医疗保健成本。此外，通过研究一种免疫调节剂来改善免疫功能，降低医院感染的风险，可能会影响公众健康。

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. PUBLIC HEALTH RELEVANCE: Knowledge gained from this proposal could impact the health of the public and reduce health care costs by providing new methods for monitoring of innate immune function to identify intensive care unit patients at highest risk for contracting a nosocomial infection. In addition, public health could be affected through the investigation of an immune modulating agent for the purposes of improving immune function to decrease nosocomial infection risk.