Innate immune suppression following experimental injury

实验性损伤后的先天免疫抑制

• 批准号: 8588809
• 负责人: Kristin C. Greathouse
• 金额: $ 0.09万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588809
• 关键词: Academic Medical Centers; Adult; Adverse effects; Affect; Animal Model; Bladder; Bone Marrow; Care given by nurses; Cell physiology; Cells; Child; Childhood; Clinical; Clinical Trials; Communicable Diseases; Contracts; Critical Illness; Critically ill children; Defect; Development; Ensure; Evaluation; FDA approved; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Health Care Costs; Hospitalization; Immune; Immune response; Immunization; Immunobiology; Immunosuppression; Infection; Infection prevention; Inflammatory; Injury; Intensive Care; Intensive Care Units; Intervention; Investigation; Justice; Knowledge; Laboratories; Leukocytes; Lipopolysaccharides; Measures; Mentors; Mentorship; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Myeloid Progenitor Cells; Nosocomial Infections; Nurses; Operative Surgical Procedures; Outcome; Partial Hepatectomy; Patients; Phagocytes; Play; Positioning Attribute; Predisposition; Prevention; Production; Public Health; Research Training; Risk; Role; Scientist; Severities; Surgical Injuries; TNF gene; Techniques; Testing; Therapeutic; Training; Translational Research; Trauma; Tumor Necrosis Factor-alpha; Urinary tract infection; Uropathogenic E. coli; Whole Blood; antimicrobial; career; clinically relevant; clinically significant; cost; cytokine; design; granulocyte; high risk; immune function; improved; indium arsenide; injured; innate immune function; killings; macrophage; microbial; migration; monocyte; mortality; mouse model; neutrophil; novel; pathogen; prevent; public health relevance; response; tool

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.

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) 在危重成人和儿童的健康相关费用、发病率和死亡率中占很大比例。研究表明，危重疾病可诱发具有临床意义的先天免疫抑制，从而增加 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，使用标准实验室测试无法确定患者先天免疫功能的缺陷。此外，目前还没有经过批准的针对增强先天免疫功能和降低 NI 易感性的疗法。早期实验证据表明，在患有 NI 的严重受伤儿童中，当 LPS 离体刺激时，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。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？危重病人全血中白细胞的生产能力。除了产生细胞因子外，吞噬细胞功能对于清除感染也至关重要，但尚未在创伤性损伤的情况下进行探索。为了评估吞噬细胞功能，我们计划测量全血中白细胞在损伤诱导的免疫抑制（部分肝切除）小鼠模型中执行吞噬和杀伤的关键抗菌功能的能力，并假设吞噬细胞功能在损伤后也受到抑制。然后我们计划确定 GM-CSF 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发的医院感染（尿路感染）严重程度的能力。因此，研究培训计划的目标是：1）表征吞噬细胞针对已知医院病原体的先天免疫功能； 2) 评估GM-CSF对吞噬细胞抗菌功能的影响； 3)确定GM-CSF在我们的损伤诱导的免疫抑制动物模型中降低NI严重程度的能力。研究结果将为后续专注于检测和降低危重患者 NI 风险的研究提供信息。 生病的孩子。申请人的职业目标是在主要学术医疗中心的儿科重症监护环境中进行跨学科转化研究。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，并提供先天免疫细胞功能实验室测量的全面培训。该培训将为作为一名护士科学家开启成功的职业生涯提供工具，专注于改善患有 NI 高风险的危重儿童的护理结果。