Pathological Myeloid Activation After Sepsis and Trauma

点击翻译按钮获取中文摘要

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.