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Whole blood transcriptomics reveals G-CSF as a mediator of cardiopulmonary bypass- induced systemic inflammatory response syndrome

ABSTRACT: Objectives: Systemic inflammatory response syndrome (SIRS) is a frequent complication of cardiopulmonary bypass (CPB). SIRS is associated with significant morbidity and mortality, but its pathogenesis remains incompletely understood, and as a result biomarkers are lacking, and treatment remains expectant and supportive. This study aimed to understand the pathophysiological mechanisms driving SIRS induced by CPB and identify novel therapeutic targets that might reduce systemic inflammation and improve patient outcomes. Methods: 21 patients undergoing cardiac surgery and CPB were recruited, and blood was sampled before, during and after surgery. SIRS was defined using the American College of Chest Physicians/Society of Critical Care Medicine criteria. We performed immune cell profiling, whole blood transcriptomics and measured individual mediators in plasma/serum to characterise SIRS induced by CPB. Results: Nineteen patients fulfilled criteria for SIRS, with a mean duration of 2.7 days. Neutrophil numbers rose rapidly with CPB and remained elevated for at least 48 hours afterwards. Transcriptional signatures associated with neutrophil activation and degranulation were enriched during CPB. We identified a network of cytokines governing these transcriptional changes, including granulocyte colony stimulating factor (G-CSF), a regulator of neutrophil production and function. Conclusions: We identified neutrophils and G-CSF as major regulators of CPB induced systemic inflammation. Short-term targeting of G-CSF could provide a novel therapeutic strategy to limit neutrophil mediated inflammation and tissue damage in SIRS induced by CPB.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253782 | GEO | 2024/02/28

REPOSITORIES: GEO

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Project description:Goal of the experiment: To identify correlated genes, pathways and groups of patients with systemic inflammatory response syndrome and septic shock that is indicative of biologically important processes active in these patients. Background: We measured gene expression levels and profiles of children with systemic inflammatory response syndrome (SIRS) and septic shock as a means for discovering patient sub-groups and gene signatures that are active in disease-affected individuals and potentially in patients with poor outcomes. Methods: Microarray and bioinformatics analyses of 123 microarray chips representing whole blood derived RNA from controls, children with SIRS, and children with septic shock. Results: A discovery-based filtering approach was undertaken to identify genes whose expression levels were altered in patients with SIRS or septic shock. Clustering of these genes identified 3 Major and several minor sub-groups of patients with SIRS or septic shock. The three groups differed with respect to incidence of septic shock and trended toward differences in mortality. Statistical analyses demonstrated that 6,435 gene probes were differentially regulated between the three patient sub-groups (false discovery rate < 0.001%). Of these gene probes, 623 gene probes within 7 major gene ontologies accounted for the majority of group differentiation. Network analyses of these 623 gene probes demonstrated 5 major gene networks that were differentially expressed between the 3 groups. Statistical comparison of septic shock survivors and non-survivors identified one major gene network that was under expressed in a high fraction of the non-survivors and identified potential biomarkers for poor outcome. Conclusions: This is the first genome-level demonstration of pediatric patient sub-groups with SIRS and septic shock. The sub-groups differ clinically and differentially express 5 major gene networks. We have identified gene signatures and potential biomarkers associated with poor outcome in children with septic shock. These data represent a major advancement in our genome-level understanding of pediatric SIRS and septic shock. Experiment Overall Design: Children < 10 years of age admitted to the pediatric intensive care unit and meeting the criteria for either SIRS or septic shock were eligible for the study. SIRS and septic shock were defined based on pediatric-specific criteria. We did not use separate categories of "sepsis" or "severe sepsis". Patients meeting criteria for "sepsis" or "severe sepsis" were placed in the categories of SIRS and septic shock, respectively, for study purposes. Control patients were recruited from the outpatient or inpatient departments of the participating institutions using the following exclusion criteria: a recent febrile illness (within 2 weeks), recent use of anti-inflammatory medications (within 2 weeks), or any history of chronic or acute disease associated with inflammation. Experiment Overall Design: After obtaining informed consent, blood samples were obtained on Day 1 of the study, and when possible on Day 3 of the study. Blood samples were divided for RNA extraction and isolation of serum. Severity of illness was calculated based on the PRISM III score. Organ failure was defined based on pediatric-specific criteria. Annotated clinical and laboratory data were collected daily while in the intensive care unit. Study patients were placed in the study categories of SIRS or Septic Shock on Day 1 of the study. On Day 3 of the study, patients were classified as SIRS, Septic Shock, or SIRS resolved (no longer meeting criteria for SIRS). All study patients were followed for 28 days to determine mortality or survival. Clinical, laboratory, and biological data were entered and stored using a web-based data base developed locally.

Project description:Cardiopulmonary bypass (CPB), the mechanical support required during the majority of cardiac surgeries, causes significant systemic inflammation and multi-organ dysfunction that is especially severe in neonatal patients. Currently, the limited understanding of the molecular mechanisms that underlie CPB-associated inflammation presents a significant barrier to the development of therapeutic interventions. To address this knowledge gap, we performed mRNA sequencing of total circulating leukocytes from neonatal patients undergoing CPB. The transcriptional signatures across 7 time points ranging from pre-CPB, during CPB, to 24 hours post-CPB were found to be dominated by myeloid cells, particularly monocytes. INTERLEUKIN-8 (IL8) and TUMOR NECROSIS FACTOR-α (TNFα) were two inflammatory cytokines specifically and robustly upregulated in the leukocytes from both CPB patients and piglets exposed to CPB. To delineate the mechanism how CPB activates cytokine production, we exposed THP-1 cells, a human monocyte cell line, in vitro to CPB-like conditions including artificial surfaces, high shear stress and cooling/rewarming. The in vitro CPB data recapitulated the in vivo CPB condition in that IL8 and TNFα were strongly upregulated. Shear stress was the major driver of cytokine expression as compared to the temperature or plastic exposure. Extracellular calcium influx was found essential for the shear-stress mediated upregulation of cytokines via the MEK/ERK/AP-1 and Calcineurin/NFAT pathways. After being exposed to CPB conditions, a subpopulation of THP-1 cells died by apoptosis and TNFα-mediated necroptosis, the latter form of which potentially contribute to the post-CPB tissue injuries. Together, our study is the first to elucidate the shear-stress modulated molecular mechanisms leading to systemic inflammation in pediatric CPB and the link between inflammation and organ damage. Calcium signaling pathways and TNFα signaling are novel targets for therapeutic development to improve clinical outcomes. To our knowledge, these are also the first data to implicate necroptosis in CPB and show that shear stress can activate necroptosis.

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Whole blood transcriptomics reveals G-CSF as a mediator of cardiopulmonary bypass- induced systemic inflammatory response syndrome

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