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果有关。 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常表现为持续性炎症、免疫抑制 和分解代谢综合征(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，至少在一定程度上是 由于未解决的病理性骨髓生成和随之而来的不同的髓系来源的抑制因子的流行 细胞(MDSCs)。首席调查员(PI)和他的合作者表现出了显著的生产力 在过去的十年里，特别是最近五年，在这个研究领域。公安局的实验室已经进行了 人类和小鼠研究证实这些不同的MDSCs的增强产生与 败血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 伴随着病理性的髓系激活；例如，它们对 巨噬细胞，CD4+和CD8+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，破坏实质细胞，促进炎症。我们 假设microRNAs和免疫代谢相互影响与发育和 这些MDSCs的抑制活性。我们这个应用程序的总体目标就是在此基础上构建 并扩大我们对创伤和脓毒症患者免疫反应的理解，包括理性地 设计旨在治疗或防止严峻临床轨迹的预防性和/或治疗性干预措施 以及败血症或创伤后的长期结果。这包括识别脓毒症和创伤患者 面临死亡风险或长期患病的人群。我们打算：(1)研究具体的机制， 包括表观遗传和代谢变化，到产生或维持病理的MDSC病理生理学 髓系激活。MDSC和造血干细胞和造血祖细胞(HSPC)研究都将是描述性的 和干预性(体外)。例如，MDSC将接受表型分析以及使用CITE-SEQ 10倍基因组学，从骨髓和血液中分离的HSPC将进行表型和功能 分析。通过这些研究，我们将(2)探索不同疾病的病理性髓系细胞激活的独特生物学。 败血症和创伤患者的队列(如不同的患者年龄和性别)；以及(3)考虑可能 影响骨髓间充质干细胞和/或病理性髓系激活的免疫调节疗法，以缓解或预防 CCI/PICS。这个Mira将支持并使PI和他的实验室能够确定为什么脓毒症和创伤 患者进入病理性髓系激活状态，以及如何努力解决这一问题以改善患者预后。

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.