Mechanisms of Immune Dysfunction after Trauma and Surgical Sepsis

项目总结/摘要 创伤和外科败血症是世界范围内发病和死亡的主要原因之一。这两 急性损伤可导致免疫功能障碍，然后导致持续的危重病状态。这 免疫功能障碍表现为过度的全身炎症反应， 功能障碍;同时抑制免疫防御，使患者易受 继发感染。我们对激活和传播这些反应的机制的理解是 远远没有完成。许多针对脓毒症免疫反应的失败临床试验证明了这一点 了解创伤和脓毒症免疫反应调节机制的重要性。 我们的策略利用最先进的模型和技术来询问创伤的"免疫学"， 脓毒症的机制在未来五年，我们将实施三个相互关联的战略。第一、 我们将把基础科学发现转化为败血症和创伤的机制小鼠模型。我们将 重点关注人类和小鼠对创伤和败血症的免疫反应方面。 免疫学领域的基本发现比以往任何时候都要快。我们将重点 注意了解这些发现如何与脓毒症的综合宿主免疫反应相关， 多系统创伤其次，我们将“反向翻译”在危重病人（包括 那些来自我们自己的广泛的人类创伤数据库和生物库）到我们的动物模型，以了解 对人类的观察结果的机械含义。第三，我们将测试修改有希望的代理， 我们的模型中的治疗目标，以获得对我们的机制的可翻译性的概念验证洞察力。 research. 未来5年的计划开始有三个具体目标。(1)我们将建立一个完整的角色观 内毒素（LPS）传感途径的免疫反应，多微生物，腹腔内败血症。做 这一点，我们将纳入最近发现的Caspase-11（Caspase-4/5在人类），最近描述的 细胞内LPS受体，用于研究宿主对腹腔内脓毒症的反应。我们假设，高 移动族蛋白1（HMGB1）将在脓毒症中Caspase-11的上游和下游发挥重要作用。（二） 我们将确定IL-33-先天性淋巴细胞2组（ILC2）轴在2型免疫应答中的作用 这是创伤引起的免疫功能紊乱的一部分。我们有令人兴奋的初步数据表明IL-33 水平与损伤后最初24小时内人类中的2型细胞因子水平相关。(3)我们将测试 可溶性鸟苷酸环化酶活化作为改变脓毒症中免疫应答的靶点的功效。 这些重点领域中的每一个都代表了我们正在进行的转化研究计划的“下一步”。随着新 发现（包括来自我们自己的计划）出现，我们将准备好"转向"追求新的 有前途的研究方向。我们将特别敏感的发现，告诉我们如何优化 我们的临床前模型

Project Summary/Abstract Trauma and Surgical Sepsis are among the leading causes of morbidity and death worldwide. Both of these acute insults can lead to immune dysfunction that then contributes to a state of persistent critical illness. This immune dysfunction is manifested by an excessive systemic inflammatory response that can lead to organ dysfunction; and a simultaneous suppression of immune defenses that renders patients susceptible to secondary infections. Our understanding of the mechanisms that activate and propagate these responses is far from complete. The many failed clinical trials targeting the immune response in sepsis stand as testament to the importance of understanding the mechanisms that regulate the immune response to trauma and sepsis. Our strategy utilizes state-of-the-art models and techniques to interrogate the “immunology” of trauma and sepsis at the mechanistic level. Over the next five years, we will pursue three inter-related strategies. First, we will translate basic science discoveries into our mechanistic mouse models of sepsis and trauma. We will focus on aspects of the immune response to trauma and sepsis that overlap between humans and mice. Fundamental discoveries in the field of immunology are emerging faster than ever before. We will focus attention on understanding how these discoveries relate to the integrated host immune response to sepsis and multi-system trauma. Second, we will “reverse translate” discoveries made in critically ill humans (including those from our own extensive human trauma database and biobank) into our animal models to understand the mechanistic implications of the observations made in humans. Third, we will test agents that modify promising therapeutic targets in our models to acquire proof-of-concept insight into the translatability of our mechanistic research. Plans for the next 5 years begin with three specific goals. (1) We will establish an integrated view of the role of endotoxin (LPS) sensing pathways in the immune response to poly-microbial, intra-abdominal sepsis. To do this we will incorporate recent discoveries on Caspase-11 (Caspase-4/5 in humans), a recently described intracellular LPS receptor, into studies on the host response to intra-abdominal sepsis. We postulate that High Mobility Group Box 1 (HMGB1) will play a major role both up- and down-stream of Caspase -11 in sepsis. (2) We will define the role of the IL-33 - innate lymphocyte cell group 2 (ILC2) axis in the type 2 immune response that is known to be part of trauma- induced immune dysfunction. We have exciting preliminary data that IL-33 levels correlate with type 2 cytokine levels in humans within the first 24 h after injury. (3) We will test the efficacy of soluble guanylyl cyclase activation as a target to modify the immune response in sepsis. Each of these areas of focus represent the “next steps” in our ongoing translational research program. As new discoveries (including from within our own program) emerge we will be ready to “pivot” to pursue new promising research directions. We will be especially sensitive to discoveries that inform us on how to optimize our pre-clinical models.