Pathogenesis of sepsis-induced dysfunction of innate immunity

我们的长期目标是研究脓毒症发病机制的分子机制，脓毒症是一种潜在的疾病 严重外伤和外伤感染引起的危及生命的疾病。败血症是最昂贵的 VA 医院治疗的条件。当脓毒症变得严重时，即使有脓毒症，死亡率也很高 适当的护理。脓毒症与压倒性的炎症反应和先天性失调有关 免疫，这可能导致持续炎症和多器官衰竭。其机制 发生的病理生理问题仍不清楚。有证据表明巨噬细胞发挥着重要作用 在先天免疫反应中的作用。它们经历极化为 M1 表型（即炎症 炎症中的M2表型（即抗炎巨噬细胞）取决于局部 环境。目前，脓毒症期间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。此外， 巨噬细胞极化对脓毒症相关免疫失调和组织发病机制的影响 受伤情况尚未明确。因此，我们将在这个项目中专注于填补这些知识空白。在 初步研究，我们发现多种微生物败血症与 M1 样巨噬细胞的增加有关 小鼠肺。 M1 巨噬细胞的激活与 Sirt6 水平的增加相结合，Sirt6 是细胞的关键调节因子 新陈代谢。此外，功能丧失和功能获得研究揭示了 Sirt6 和 M1 之间的联系 巨噬细胞激活。因此，我们将研究Sirt6是否在脓毒症损伤诱发中发挥重要作用。 M1巨噬细胞激活和组织损伤，如果是的话，我们将研究Sirt6的分子机制 促进 M1 巨噬细胞活化。为此，我们将开展以下研究。具体目标 1 将 确定 Sirt6 在细胞因子刺激和脓毒症条件下 M1 巨噬细胞激活中的作用。 具体目标 2 将研究 Sirt6 如何增强炎症中 M1 巨噬细胞的激活。具体目标 3 将 检查巨噬细胞中 Sirt6 相关信号轴是否影响脓毒症的发病机制。成就 这些具体目标将提供有关脓毒症严重炎症如何引起的新信息 M1-M2 巨噬细胞激活的不平衡，这可能最终导致制定策略 维持脓毒症患者巨噬细胞稳态。从拟议工作中获得的数据将 扩展我们对脓毒症进展为持续性炎症的潜在机制的了解 多器官损伤。脓毒症是外科手术患者常见且严重的并发症 退伍军人事务医疗保健系统。因此，本提案的主题具有及时的重要意义并链接到 VA危重症患者管理的临床应用。

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.