Mechanisms of Immune Dysfunction after Trauma and Surgical Sepsis

项目摘要/摘要 创伤和外科脓毒症是全世界发病率和死亡率的主要原因之一。这两个都是 急性侮辱可能会导致免疫功能障碍，进而导致持续的危重疾病状态。这 免疫功能障碍表现为过度的全身炎症反应，可导致器官 功能障碍；同时抑制免疫防御，使患者容易患上 继发性感染。我们对激活和传播这些反应的机制的理解是 这还远远没有完成。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。 我们的策略使用最先进的模型和技术来询问创伤和 机械性水平的脓毒症。在未来五年，我们将推行三个相互关联的战略。第一, 我们将把基础科学发现转化为脓毒症和创伤的机械小鼠模型。我们会 重点关注人类和小鼠之间重叠的创伤和败血症的免疫反应。 免疫学领域的基础性发现正在以前所未有的速度涌现。我们将专注于 注意了解这些发现如何与脓毒症的综合宿主免疫反应和 多系统创伤。第二，我们将“反向翻译”在危重人类身上所做的发现(包括 这些来自我们自己的广泛的人类创伤数据库和生物库)进入我们的动物模型，以了解 在人类身上所观察到的机械论含义。第三，我们将测试修改Promising的代理 我们模型中的治疗目标，以获得对我们机械的可译性的概念验证洞察 研究。 未来五年的计划从三个具体目标开始。(一)树立完整的角色观 针对多微生物、腹内脓毒症的免疫反应中的内毒素(LPS)感知通路的研究。去做 我们将结合关于Caspase-11(人类的Caspase-4/5)的最新发现，最近描述了一种 细胞内的内毒素受体，用于研究宿主对腹内脓毒症的反应。我们假设高中生 运动蛋白组框1(HMGB1)在脓毒症中将在Caspase-11的上游和下游发挥重要作用。(2) 我们将确定IL-33先天淋巴细胞组2(ILC2)轴在2型免疫反应中的作用 众所周知，这是创伤引起的免疫功能障碍的一部分。我们有令人兴奋的初步数据，IL-33 损伤后24小时内的水平与人类的2型细胞因子水平相关。(3)我们将测试 以可溶性鸟苷酸环化酶激活为靶点改变脓毒症免疫反应的有效性。 这些重点领域中的每一个都代表着我们正在进行的翻译研究计划的“下一步”。作为新的 发现(包括从我们自己的计划中)出现时，我们将准备“转向”以追求新的发现 前景看好的研究方向。我们将对通知我们如何优化的发现特别敏感 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.