Mechanisms of augmented host defenses after mild brain injury

轻度脑损伤后增强宿主防御的机制

• 批准号: 9246802
• 负责人: Daniel G. Remick
• 金额: $ 24.69万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246802
• 关键词: Abdomen; Agonist; Animals; Antimicrobial Resistance; Bacteria; Bacterial Infections; Bacterial Pneumonia; Biological Assay; Blood Coagulation Disorders; Blunt Trauma; Brain Injuries; Candida albicans; Cell Adhesion Molecules; Cell physiology; Chemotaxis; Chest; Clinical; Coagulation Process; Complication; Coupled; Craniocerebral Trauma; Data; Disseminated Intravascular Coagulation; Experimental Designs; FDA approved; Fibrinolysis; Flow Cytometry; Fostering; Grant; Growth; Host Defense; Hour; Immune; Immune response; Incidence; Infection; Inflammation; Injury; Innate Immune Response; Link; Lung; Measures; Mechanics; Modeling; Mus; Nausea; Neuroimmune; Neurotransmitters; Neutrophil Infiltration; Nonpenetrating Wounds; Pathway interactions; Patients; Phagocytes; Phagocytosis; Phagolysosome; Phase; Plasma; Pneumonia; Predisposition; Protocols documentation; Pseudomonas aeruginosa; Publishing; Reactive Oxygen Species; Reagent; Recruitment Activity; Reproducibility; Resources; Risk; Role; Signal Transduction; Streptococcus pneumoniae; Substance P; Substance P Receptor; Tail; Testing; Trauma; Trauma patient; Traumatic Brain Injury; Work; base; chemotherapy; clinically relevant; combat; design; experimental study; extracellular; improved; innovation; killings; macrophage; mild traumatic brain injury; mortality; neutrophil; novel; pathogen; prevent; receptor; response; time interval

We previously published an unexpected finding that mild traumatic brain injury (mTBI) in experimental animals enhances pulmonary defenses against bacterial pneumonia. This finding was validated in patients with mild brain injury who had a lower incidence of pneumonia compared to blunt trauma patients. We show that mTBI enhances innate immune responses and blunts deleterious coagulation responses in a mouse pneumonia model. These findings, coupled with substantial new preliminary data, provide the rationale for our hypothesis that the neuroimmune response to mild traumatic brain injury primes the host so that it will survive a subsequent pathogen challenge. New data demonstrate that the neurotransmitter substance P (SP) is released into the murine lung and plasma within minutes of mTBI. Neurokinin 1 (NK1R) is the preferred receptor of SP and NK1R agonists and an FDA approved NK1R antagonist are available. These reagents will allow us to precisely determine the mechanisms of how mTBI signaling through NK1R augments host responses to improve survival. This experimental design increases scientific reproducibility by both augmenting and blocking the same receptor to prove a cause and effect relationship. Specific aim 1 will determine how SP enhances pulmonary neutrophil recruitment to a pathogen challenge. We will use three distinctly different pathogens, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Candida albicans to identify shared innate immune pathways that foster neutrophil recruitment. Tail trauma will replicate blunt trauma patients and SP function will be manipulated by augmenting or blocking its receptor. The second specific aim will determine the mechanisms of how SP augments phagocytic cell eradication of pathogens from the lung. A novel, recently published flow cytometry assay examines three different phagocytic cell functions simultaneously to provide clear data concerning which function(s) are altered. Inflammation and coagulation are intimately linked, and new data show that mTBI blunts disseminated intravascular coagulation (DIC) during pneumonia by enhancing fibrinolysis. Aim 3 will determine the protective mechanisms provided by SP. These three aims are inter-related which allows efficient use of resources. For example, after trauma and pathogen challenge we can determine in a single mouse how NK1R activation alters neutrophil recruitment, neutrophil function and coagulation responses. These studies are innovative since they challenge existing dogma that TBI only increases susceptibility to pathogens and increases DIC. The studies also have clinical relevance since NK1R antagonists are FDA approved to treat nausea in chemotherapy patients, which may increase their risk of infection. Further, NK1R agonists may augment the hosts’ ability combat pathogens and would serve as a welcome addition to combat the emergence of antimicrobial resistant pathogens.

我们之前发表了一个意外的发现，即实验中的轻度创伤性脑损伤（mTBI） 动物增强肺部对细菌性肺炎的防御能力。这一发现在 与钝性创伤相比，轻度脑损伤患者肺炎的发生率较低 患者。我们证明 mTBI 增强先天免疫反应并减弱有害的凝血 小鼠肺炎模型中的反应。这些发现加上大量新的初步结果 数据，为我们的假设提供了基本原理，即对轻度创伤性脑部的神经免疫反应 损伤使宿主做好准备，使其能够在随后的病原体挑战中生存下来。新数据证明 神经递质物质 P (SP) 在几分钟内释放到小鼠肺和血浆中 的 mTBI。神经激肽 1 (NK1R) 是 SP 和 NK1R 激动剂的首选受体，也是 FDA 批准的 已有批准的 NK1R 拮抗剂可供使用。这些试剂将使我们能够精确地确定 mTBI 信号如何通过 NK1R 增强宿主反应以提高生存率的机制。这 实验设计通过增强和阻断相同的结果来提高科学的可重复性 受体来证明因果关系。具体目标1将决定SP如何增强 肺中性粒细胞募集以应对病原体的攻击。我们将使用三种截然不同的 病原体、铜绿假单胞菌、肺炎链球菌和白色念珠菌进行鉴定 共同的先天免疫途径促进中性粒细胞募集。尾部创伤会复制钝性 创伤患者和 SP 功能将通过增强或阻断其受体来操纵。这 第二个具体目标将确定 SP 如何增强吞噬细胞根除的机制 来自肺部的病原体。最近发表的一种新颖的流式细胞术检测了三种不同的 吞噬细胞同时发挥作用，提供有关哪些功能发生改变的清晰数据。 炎症和凝血密切相关，新数据表明 mTBI 会减弱弥散性 肺炎期间通过增强纤溶作用实现血管内凝血（DIC）。目标 3 将确定 SP提供的保护机制。这三个目标是相互关联的，可以有效地利用 资源。例如，在创伤和病原体攻击后，我们可以确定一只小鼠如何 NK1R 激活改变中性粒细胞募集、中性粒细胞功能和凝血反应。这些 研究具有创新性，因为它们挑战了现有的教条，即 TBI 只会增加易感性 病原体并增加 DIC。这些研究还具有临床意义，因为 NK1R 拮抗剂是 FDA 批准用于治疗化疗患者的恶心，这可能会增加他们感染的风险。 此外，NK1R 激动剂可能会增强宿主对抗病原体的能力，并可作为 欢迎添加抗微生物药物耐药性病原体的出现。