Mechanisms of augmented host defenses after mild brain injury

我们之前发表了一项意外的发现，在实验性脑损伤中， 动物增强肺部对细菌性肺炎的防御。这一发现得到了验证， 与钝性创伤相比，肺炎发生率较低的轻度脑损伤患者 患者我们发现，mTBI增强先天免疫反应和钝化有害凝血 小鼠肺炎模型中的反应。这些发现，加上大量的新的初步 数据，为我们的假设提供了理论基础，即对轻度脑外伤的神经免疫反应 损伤使宿主准备好，以便它将在随后的病原体挑战中存活。新数据显示 神经递质P物质（SP）在几分钟内释放到小鼠肺和血浆中， mTBI。神经激肽1（NK1R）是SP和NK1R激动剂的优选受体，并且FDA 批准的NK1R拮抗剂可用。这些试剂将使我们能够精确地确定 mTBI如何通过NK1R信号传导增强宿主反应以改善存活的机制。这 实验设计通过增加和阻断相同的 受体来证明因果关系。具体目标1将决定SP如何增强 肺中性粒细胞对病原体攻击的募集。我们将使用三个明显不同的 病原菌，铜绿假单胞菌，肺炎链球菌，白色念珠菌，以确定 共同的先天免疫途径，促进中性粒细胞的招募。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。的 第二个具体的目标将确定SP如何增强吞噬细胞清除的机制。 肺部的病原体一种新的，最近发表的流式细胞术检测检查三个不同的 吞噬细胞同时发挥功能，以提供关于哪些功能被改变的明确数据。 炎症和凝血密切相关，新的数据表明，mTBI使播散性钝化， 通过增强纤维蛋白溶解，在肺炎期间发生血管内凝血（DIC）。目标3将决定 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，我们可以确定在一只小鼠中， NK1R活化改变中性粒细胞募集、中性粒细胞功能和凝血反应。这些 研究是创新的，因为它们挑战了现有的教条，即TBI只会增加对 病原体和增加DIC。这些研究也具有临床相关性，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激动剂可以增强宿主对抗病原体的能力，并将作为一种免疫抑制剂。 这是一个值得欢迎的补充，以打击耐药性病原体的出现。

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.