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Deciphering how anesthetics increase host susceptibility to microbial infection

破译麻醉剂如何增加宿主对微生物感染的易感性

基本信息

批准号：
8462202
负责人：
Nancy Elizabeth Freitag
金额：
$ 7.3万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462202
关键词：
Anesthesia procedures Anesthetics Animals Area Bacteria Bacterial Infections Bacterial Model Bacterial Translocation Biological Models Cell physiology Cells Communication Data Development Drug Targeting Effector Cell Foundations Frequencies Future Health Hospital Costs Hospitals Host resistance Human Immune Immune response Immune system Immunity In Vitro Individual Infection Ketamine Link Listeria monocytogenes Modeling Molecular Mus Natural Immunity Nervous system structure Neuraxis Nosocomial Infections Operative Surgical Procedures Organ Organism Outcome Pathway interactions Patients Pentobarbital Pharmaceutical Preparations Pilot Projects Population Predisposition Production Propofol Reporting Research Resistance to infection Risk Salmonella typhimurium Serum Severities Signal Transduction Site Streptococcus pyogenes Superoxides Tissues Work adaptive immunity base cell mediated immune response chemokine cytokine design extracellular immune clearance immune function improved intravenous administration macrophage microbial monocyte mouse model novel pathogen research study tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Anesthetic administration is associated with a significantly increased risk of infection in hospital patients undergoing surgery. While several studies have reported linkages between commonly used anesthetics and decreased immune cell function, little is currently known regarding the molecular mechanisms by which drugs that target the nervous system influence host immune responses. An improved understanding of pathways of communication between the nervous and immune systems would clarify how specific anesthetics place individuals at greater risk for microbial infection. The facultative intracellular bacterial pathogen Listeria monocytogenes (Lm) has served for decades as a powerful model system for deciphering host responses to microbial infection, and the organism continues to serve as tool for elucidating new paradigms of innate and adaptive immunity. Based on the well-established mouse model of Lm infection, experiments outlined within this proposal will use Lm to elucidate the mechanisms by which commonly used surgical anesthetics, such as propofol, dramatically increase host susceptibility to microbial infection. Preliminary data indicates that intravenous administration of anesthetics to mice prior to Lm infection increased bacterial burdens in target organs by more than 10,000-fold in comparison to none drug-treated animals. Propofol, the most commonly used anesthetic in human surgeries, was found to reduce the clearance of bacteria from mouse target organs and to alter host innate immune signaling. The working hypothesis of this proposal is that propofol and possibly other anesthetic agents increase host susceptibility to microbial infection by enhancing bacterial translocation across host barriers while also impeding the recruitment of innate immune effector cells to sites of bacterial infection. Experiments in Aim 1 will examine the impact of anesthetic exposure on multiple facets of host immunity to Lm infection, including cytokine and chemokine signaling and monocyte recruitment to sites of bacterial infection. Aim 2 experiments will determine if propofol exposure has broad effects towards increasing host susceptibility to other microbial pathogens, specifically bacteria that occupy different intracellular and extracellular replication niches within the host. The outcome of these pilot studies will be a deeper understanding of how anesthetic agents suppress host immunity, and the data generated will form the basis for future collaborative projects designed to decipher the pathways that link the central nervous system with host immune function. This novel area of research has the potential to ultimately reduce the frequency and severity of post-surgical infections via the recognition of host immune responses negatively impacted by anesthetic exposure and by recognition of the types of infections for which anesthesia increases host susceptibility.

描述（由申请人提供）：麻醉剂给药与接受手术的住院患者感染风险显著增加相关。虽然有几项研究报道了常用麻醉剂和免疫细胞功能下降之间的联系，但目前对靶向神经系统的药物影响宿主免疫反应的分子机制知之甚少。对神经系统和免疫系统之间的通信途径的更好理解将澄清特定麻醉剂如何使个体处于更大的微生物感染风险中。兼性细胞内细菌病原体单核细胞增生李斯特菌（Listeria monocytogenes，Lm）几十年来一直充当用于破译宿主对微生物感染的反应的强大模型系统，并且该生物体继续充当用于阐明先天性和适应性免疫的新范例的工具。基于完善的Lm感染小鼠模型，本提案中概述的实验将使用Lm来阐明常用的外科麻醉剂（如丙泊酚）显著增加宿主对微生物感染的易感性的机制。初步数据表明，在Lm感染之前对小鼠静脉注射麻醉剂使靶器官中的细菌负荷增加了10，000倍以上。异丙酚是人类手术中最常用的麻醉剂，被发现可以减少细菌从小鼠靶器官中的清除，并改变宿主的先天免疫信号。该提议的工作假设是，丙泊酚和可能的其他麻醉剂通过增强细菌穿过宿主屏障的移位同时也阻碍先天免疫效应细胞向细菌感染部位的募集来增加宿主对微生物感染的易感性。目的1中的实验将检查麻醉剂暴露对宿主对Lm感染的免疫的多个方面的影响，包括细胞因子和趋化因子信号传导以及单核细胞募集到细菌感染部位。目标2实验将确定丙泊酚暴露是否对增加宿主对其他微生物病原体的易感性具有广泛影响，特别是在宿主内占据不同细胞内和细胞外复制龛的细菌。这些试点研究的结果将是对麻醉剂如何抑制宿主免疫力的更深入了解，所产生的数据将成为未来合作项目的基础，这些合作项目旨在破译将中枢神经系统与宿主免疫功能联系起来的途径。这一新的研究领域有可能通过识别麻醉暴露对宿主免疫反应的负面影响以及识别麻醉增加宿主易感性的感染类型，最终降低术后感染的频率和严重程度。