Mechanisms of Immune Dysfunction after Trauma and Surgical Sepsis

创伤和手术败血症后免疫功能障碍的机制

• 批准号: 10183268
• 负责人: TIMOTHY R BILLIAR
• 金额: $ 63.28万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183268
• 关键词: Acute; Animal Model; Area; Attention; Basic Science; CD14 Antigen; Caspase; Cells; Cessation of life; Clinical Trials; Critical Illness; Data; Databases; Endotoxins; Functional disorder; Goals; HMGB1 Protein; Human; Immune System Diseases; Immune Targeting; Immune response; Immunologics; Immunology; Immunosuppression; Injury; Intra-abdominal; Lead; Lymphocyte; Modeling; Morbidity - disease rate; Mus; Operative Surgical Procedures; Organ; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Pre-Clinical Model; Research; Role; Secondary to; Sepsis; Soluble Guanylate Cyclase; Stream; Techniques; Testing; Translating; Trauma; biobank; cytokine; efficacy testing; improved outcome; insight; mouse model; programs; response; secondary infection; severe injury; systemic inflammatory response; therapeutic target; translational research program

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.

项目概要/摘要 创伤和手术脓毒症是全世界发病和死亡的主要原因。 急性损伤会导致免疫功能障碍，进而导致持续的危重疾病。 免疫功能障碍表现为过度的全身炎症反应，可导致器官损伤 功能障碍；同时抑制免疫防御，使患者容易受到感染 我们对激活和传播这些反应的机制的理解是 许多失败的针对败血症免疫反应的临床试验就是证明。 了解调节对创伤和败血症的免疫反应的机制的重要性。 我们的策略利用最先进的模型和技术来探究创伤和创伤的“免疫学” 在接下来的五年里，我们将采取三个相互关联的策略。 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。 重点关注人类和小鼠对创伤和败血症的免疫反应的重叠方面。 免疫学领域的基本发现正在以前所未有的速度出现，我们将重点关注。 关注了解这些发现如何与败血症和宿主的综合免疫反应相关 其次，我们将“反向翻译”在危重病人（包括重症患者）身上的发现。 来自我们自己广泛的人类创伤数据库和生物库的数据）进入我们的动物模型，以了解 第三，我们将测试改变有希望的药物的机制。 我们模型中的治疗目标，以获得对我们机制的可转化性的概念验证见解 研究。 （一）建立统一的角色观 内毒素（LPS）传感途径对多种微生物、腹内脓毒症的免疫反应。 我们将结合 Caspase-11（人类中的 Caspase-4/5）的最新发现，这是最近描述的一种 细胞内脂多糖受体，进入宿主对腹内脓毒症反应的研究，我们假设高。 Mobility Group Box 1 (HMGB1) 将在败血症中的 Caspase -11 上游和下游发挥重要作用 (2)。 我们将定义 IL-33 - 先天淋巴细胞组 2 (ILC2) 轴在 2 型免疫反应中的作用 已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表明 IL-33。 损伤后 24 小时内的水平与人类 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激活作为改变脓毒症免疫反应目标的功效。 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”。 发现（包括来自我们自己的计划）的出现，我们将准备“转向”追求新的 我们将对那些告诉我们如何优化的发现特别敏感。 我们的临床前模型。