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脓毒症发病机制的分子机制， 由严重创伤和创伤感染引起的危及生命的疾病。败血症是最昂贵的 当脓毒症变得严重时，即使在治疗期间， 适当的照顾。脓毒症与压倒性炎症反应和先天性免疫缺陷相关。 免疫力，这可能导致持续性炎症和多器官衰竭。这种机制， 发生的病理生理问题仍不清楚。有证据表明，巨噬细胞在 在先天免疫反应中的作用。它们经历向M1表型的极化（即炎性 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.目前，脓毒症炎症部位巨噬细胞的确切表型尚不清楚。 脓毒症中巨噬细胞极化的分子机制尚不清楚。而且 巨噬细胞极化在脓毒症相关免疫失调和组织病理学中作用 伤害尚未得到澄清。因此，我们将专注于填补本项目中的这些知识空白。在 初步研究，我们发现多微生物败血症与M1样巨噬细胞的增加有关， 小鼠肺。M1巨噬细胞活化与Sirt 6水平的增加相结合，Sirt 6是细胞增殖的关键调节因子。 新陈代谢.此外，功能丧失和功能获得研究揭示了Sirt 6和M1之间的联系。 巨噬细胞活化因此，我们将研究Sirt 6是否在脓毒性胰岛素诱导的 M1巨噬细胞激活和组织损伤，如果是这样，我们将研究Sirt 6 促进M1巨噬细胞活化。为此，我们将进行以下研究。具体目标1将 确定Sirt 6在丝氨酸刺激和脓毒症条件下M1巨噬细胞活化中的作用。 具体目标2将研究Sirt 6如何在炎症中增强M1巨噬细胞活化。第3章将 检查巨噬细胞中Sirt 6相关信号轴是否影响败血症的发病机制。成就 这些特定的目的将提供新的信息，关于严重的炎症败血症如何导致 M1-M2巨噬细胞活化的不平衡，这可能最终导致开发 维持脓毒症患者的巨噬细胞稳态。从拟议工作中获得的数据将 扩大我们对脓毒症进展为持续性炎症的潜在机制的认识， 多器官损伤脓毒症是外科病人常见的严重并发症， 退伍军人事务医疗保健系统。因此，本提案的主题是及时的重要事项，并与 临床应用于危重VA患者的管理。

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.

在发炎的肠道组织和上皮细胞中，白介素22信号传导增加了H19长的非编码RNA的表达，从而促进粘膜再生。

• 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