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.

项目摘要/摘要 创伤和外科败血症是全球发病和死亡的主要原因之一。这两个 急性损伤会导致免疫功能障碍，从而导致持续的危重疾病。这 免疫功能障碍表现为过度的全身炎症反应，可能导致组织 功能障碍；并简单地抑制免疫防御措施，使患者容易受到影响 继发感染。我们对激活和传播这些反应的机制的理解是 远离完成。针对败血症的免疫反应的许多失败的临床试验作为遗嘱 了解调节对创伤和败血症免疫反应的机制的重要性。 我们的战略利用最先进的模型和技术来审问创伤的“免疫学”和 机械水平的败血症。在接下来的五年中，我们将采取三种相互关联的策略。第一的， 我们将将基础科学发现转化为败血症和创伤的机械小鼠模型。我们将 专注于对人类和小鼠之间重叠的创伤和败血症的免疫反应的各个方面。 免疫学领域的基本发现比以往任何时候都更快。我们将集中精力 注意这些发现与综合宿主对败血症的免疫反应的关系 多系统创伤。其次，我们将“反向翻译”在重病人类中提出的发现（包括 从我们自己广泛的人类创伤数据库和生物库中的那些人）到我们的动物模型中 人类观察的机械含义。第三，我们将测试可以修改承诺的代理商 我们模型中的治疗目标，以获取概念概念的见解 研究。 未来5年的计划以三个特定目标开始。 （1）我们将建立对角色的综合观点 内毒素（LPS）感应途径在对多微生物，腹内败血症的免疫反应中。做 我们将在Caspase-11（人类中的caspase-4/5）上纳入最新发现，这是最近描述的 细胞内LPS受体，研究宿主对腹内败血症的反应。我们假设那个高 Mobility Group Box 1（HMGB1）将在败血症中的caspase -11的上流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IL-33的令人兴奋的初步数据 受伤后的前24小时内，水平与人类的2型细胞因子水平相关。 （3）我们将测试 固体瓜尼环酶激活的疗效是改变败血症中免疫反应的靶标。 这些重点领域中的每一个都代表了我们正在进行的翻译研究计划中的“下一步”。作为新 发现（包括来自我们自己的计划中）我们将准备“枢转”购买新的 有希望的研究指示。我们将对发现如何优化的发现特别敏感 我们的临床前模型。