Pathogenesis of sepsis-induced dysfunction of innate immunity

脓毒症引起的先天免疫功能障碍的发病机制

• 批准号: 10609788
• 负责人: Xiao-Di Tan
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609788
• 关键词: Acetyltransferase; Achievement; Anti-Inflammatory Agents; Attenuated; Burn Trauma; Caring; Cause of Death; Cells; Cellular Metabolic Process; Clinical; Coupled; Critical Illness; Data; Deacetylase; Development; Diabetes Mellitus; Disease; Effector Cell; Environment; Epigenetic Process; Functional disorder; Goals; Health; Healthcare Systems; Homeostasis; Hospitals; Host Defense; Immune; Immune System Diseases; Immune response; Immunity; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Intensive Care Units; Investigation; Knowledge; Lead; Life; Link; Lung; Macrophage Activation; Mediating; Medical; Metabolic; Metabolism; Modality; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; Natural Immunity; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Patients; Phagocytes; Phenotype; Physicians; Play; Prognostic Marker; Regimen; Resolution; Role; Sepsis; Signal Transduction; Sirtuins; Site; Surgical complication; Testing; Therapeutic; Time; Tissues; Trauma; Traumatic injury; United States Department of Veterans Affairs; Veterans; Work; adaptive immunity; cecal ligation puncture; clinical application; cost; cytokine; gain of function; loss of function; macrophage; mortality; novel; older patient; organ injury; pathogen; polymicrobial sepsis; programs; septic; severe burns; tissue injury

Our long-term goal is to study molecular mechanisms underlying pathogenesis of sepsis, a potentially life-threatening illness caused by severe traumatic injury and trauma infections. Sepsis is the most costly condition for VA hospitals to treat. When sepsis becomes severe, it has a high mortality rate even with appropriate care. Sepsis is associated with overwhelming inflammatory response and dysregulation of innate immunity, which can lead to persistent inflammation and multiple organ failure. The mechanisms by which this pathophysiological problem occurs remain unknown. Evidence shows that macrophages play an important role in the innate immune response. They undergo polarization to M1 phenotype (i.e. inflammatory macrophages) and M2 phenotype (i.e. anti-inflammatory macrophages) in inflammation depending on local environments. Currently, the exact phenotype of macrophages in inflammatory sites during sepsis is not clear. The molecular mechanisms underlying polarization of macrophages in sepsis is unknown. Furthermore, the impact of macrophage polarization in pathogenesis of sepsis-associated immune dysregulation and tissue injury has not been elucidated. Thus, we will focus on filling these knowledge gaps in this project. In preliminary studies, we found that polymicrobial sepsis is associated with increase in M1-like macrophages in mouse lungs. M1 macrophage activation is coupled with increase in levels of Sirt6, a key regulator for cell metabolism. Furthermore, loss-of-function and gain-of-function studies revealed the link between Sirt6 and M1 macrophage activation. Therefore, we will study whether Sirt6 plays an important role in septic insult-induced M1 macrophage activation and tissue injury, and if so, we will study the molecular mechanism by which Sirt6 promotes M1 macrophage activation. To this end, we will execute the following studies. Specific Aim 1 will determine the role of Sirt6 in M1 macrophage activation under cytokine-stimulation and septic condition. Specific Aim 2 will study how Sirt6 potentiates M1 macrophage activation in inflammation. Specific Aim 3 will examine whether Sirt6-associated signal axis in macrophages impacts pathogenesis of sepsis. Achievement of these specific aims will provide novel information regarding how severe inflammation in sepsis causes imbalance of M1-M2 macrophage activation, which may ultimately lead to development of strategies for maintaining macrophage homeostasis in patients with sepsis. Data derived from the proposed work will expand our knowledge on mechanisms underlying progression of sepsis to persistent inflammation and multiple organ injury. Sepsis is a common and serious complication for surgery patients in the Department of Veterans Affairs Healthcare System. Thus, the subject matter of this proposal is timely important and links to clinical application for management of VA patients with critical illness.

我们的长期目标是研究败血症的发病机理的分子机制，这是一种潜在的 严重的创伤和创伤感染引起的威胁生命的疾病。败血症是最昂贵的 VA医院可以治疗的条件。当败血症变得严重时，即使 适当的护理。败血症与天生的压倒性炎症反应和失调有关 免疫力，可能导致持续的炎症和多器官衰竭。这个机制 病理生理问题尚不清楚。证据表明巨噬细胞起着重要的作用 在先天免疫反应中的作用。它们经历了极化对M1表型（即炎症 巨噬细胞）和M2表型（即抗炎巨噬细胞）在炎症中取决于局部 环境。当前，败血症期间炎症部位的巨噬细胞的确切表型尚不清楚。 败血症中巨噬细胞极化的分子机制尚不清楚。此外， 巨噬细胞极化对败血症相关免疫失调和组织的发病机理的影响 伤害尚未阐明。因此，我们将专注于填补该项目中的这些知识差距。在 初步研究，我们发现多数型败血症与M1样巨噬细胞的增加有关 小鼠肺。 M1巨噬细胞激活与SIRT6水平的增加相结合，SIRT6的水平是细胞的关键调节剂 代谢。此外，功能丧失和功能性研究揭示了SIRT6和M1之间的联系 巨噬细胞激活。因此，我们将研究SIRT6在化粪池侮辱引起的 M1巨噬细胞激活和组织损伤，如果是这样，我们将研究SIRT6的分子机制 促进M1巨噬细胞激活。为此，我们将执行以下研究。具体目标1将 确定在细胞因子刺激和化粪池条件下SIRT6在M1巨噬细胞激活中的作用。 具体目标2将研究SIRT6在炎症中如何增强M1巨噬细胞的激活。具体的目标3将 检查巨噬细胞中与SIRT6相关的信号轴是否会影响败血症的发病机理。成就 这些特定目的中将提供有关败血症导致严重炎症的新信息 M1-M2巨噬细胞激活的不平衡，这可能最终导致发展的策略 维持败血症患者的巨噬细胞稳态。从拟议的工作中得出的数据将 扩展我们对败血症发展到持续炎症和的机制的知识 多器官损伤。败血症是部门手术患者的常见而严重的并发症 退伍军人事务医疗系统。因此，该提议的主题及时重要，并与 临床应用于患有危重疾病的VA患者。

项目成果

In Inflamed Intestinal Tissues and Epithelial Cells, Interleukin 22 Signaling Increases Expression of H19 Long Noncoding RNA, Which Promotes Mucosal Regeneration.

• DOI: 10.1053/j.gastro.2018.03.058
• 发表时间: 2018-07
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Geng H;Bu HF;Liu F;Wu L;Pfeifer K;Chou PM;Wang X;Sun J;Lu L;Pandey A;Bartolomei MS;De Plaen IG;Wang P;Yu J;Qian J;Tan XD
• 通讯作者: Tan XD