Pathological Myeloid Activation After Sepsis and Trauma

摘要 脓毒症和严重创伤与具有挑战性的临床轨迹以及令人沮丧的长期结局有关 出院后。在外科重症监护病房（SICU），败血症和 创伤患者可发展为慢性危重病（CCI;长期急性护理和慢性护理住院 未解决的器官功能障碍）。CCI经常表现为持续性炎症、免疫抑制 和卡他综合征（PICS）。患有PICS的SICU幸存者反复感染，认知能力差 表现，身体功能障碍和自我报告的生活质量差。这些条件，至少部分， 由于未解决的病理性骨髓生成和随后的不同骨髓源性抑制基因的流行， 细胞（MDSC）。首席研究员（PI）和他的合作者已经证明了显着的生产力 在过去的十年里，特别是在过去的五年里，在这个研究领域。PI的实验室进行了 人和鼠研究证实这些不同MDSC的增强产生与 脓毒症和创伤的预后不佳。该实验室还发现了这些MDSC的关键区别， 伴随病理性骨髓活化;例如，它们对免疫系统有强效的免疫抑制作用， 巨噬细胞，CD 4+和CD 8 + T细胞;同时，它们产生炎性细胞因子，反应性一氧化氮， 氧化物（NO）、氧化和过氧化产物，其损害实质细胞并促进炎症。我们 假设microRNA和免疫代谢相互影响， 这些MDSC的抑制活性。我们对这个应用程序的总体目标是建立在这个基础上 扩大我们对创伤和脓毒症患者免疫反应的理解，包括合理地 设计旨在治疗或预防严峻临床轨迹的预防性和/或治疗性干预 以及脓毒症或创伤后的长期结果。这包括识别败血症和创伤患者 面临死亡风险或长期患病的人群。我们打算：（1）审查具体机制， 包括表观遗传和代谢变化，与MDSC病理生理学相关， 骨髓激活MDSC和造血干祖细胞（HSPC）研究均为描述性研究 和介入性（离体）。例如，MDSC将经历表型分析以及CITE-seq，使用 10 X Genomics，从骨髓和血液中分离的HSPC将进行表型和功能鉴定。 分析.通过这些研究，我们将（2）探索不同的骨髓细胞病理性激活的独特生物学特性， 脓毒症和创伤患者的队列（例如不同的患者年龄和性别组）;以及（3）考虑可能的 影响MDSC和/或病理性骨髓活化的免疫调节疗法，以减轻或预防 CCI/PICS。该MIRA将支持并使PI及其实验室能够确定脓毒症和创伤 患者进入病理性骨髓活化，以及如何解决这一问题以改善患者的预后。

ABSTRACT Sepsis and severe trauma are linked with challenging clinical trajectories as well as dismal long-term outcomes following hospital discharge. In surgical intensive care units (SICUs), an alarming percentage of sepsis and trauma patients can develop chronic critical illness (CCI; prolonged acute-care and chronic-care hospitalization with unresolved organ dysfunction). CCI frequently manifests as a persistent inflammation, immunosuppression and catabolism syndrome (PICS). SICU survivors suffering from PICS have repeat infections, poor cognitive performance, physical dysfunction and self-reported poor quality of life. These conditions, at least in part, are due to an unresolving pathologic myelopoiesis and ensuing prevalence of distinct myeloid-derived suppressor cells (MDSCs). The principal investigator (PI) and his collaborators have demonstrated significant productivity over the last decade, especially in the last five years, in this research field. The PI’s laboratory has conducted human and murine research to establish that enhanced production of these distinct MDSCs is associated with poor outcomes in sepsis and trauma. The laboratory has also discovered key distinctions in these MDSCs’ accompanying pathologic myeloid activation; for example, they are potently immunosuppressive towards macrophages, CD4+ and CD8+ T cells; while concurrently, they produce inflammatory cytokines, reactive nitric oxide (NO), oxidation and peroxidation products that damage parenchymal cells and promote inflammation. We hypothesize that microRNAs and immunometabolism affect each other in relation to the development and suppressive activity of these MDSCs. Our overarching goal for this application is to build upon this foundation and expand our understanding of the patient immune response to trauma and sepsis, including rationally designing prophylactic and/or therapeutic interventions aimed at treating or preventing grim clinical trajectories and long-term outcomes following sepsis or trauma. This includes identifying sepsis and trauma patient populations at risk of dying or having long-term morbidity. We intend: (1) to examine specific mechanisms, including epigenetic and metabolic changes, to MDSC pathophysiology that engender or maintain pathologic myeloid activation. MDSC and hematopoietic stem and progenitor cell (HSPC) studies will be both descriptive and interventional (ex vivo). For example, MDSCs will undergo phenotypic analysis as well as CITE-seq using 10X Genomics, and HSPCs isolated from bone marrow and blood will undergo phenotypic and functional analysis. With these studies, we will (2) explore the unique biology of pathologic myeloid cell activation in different cohorts of sepsis and trauma patients (such as different patient age and sex groups); and (3) consider possible immunomodulative therapies that affect MDSCs and/or pathologic myeloid activation to mitigate or prevent CCI/PICS. This MIRA would support and enable the PI and his laboratory to determine why sepsis and trauma patients enter pathologic myeloid activation, and how to work towards resolving this to improve patient outcomes.