Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA203018 | ENA |
REPOSITORIES: ENA
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Project description:The rapid development in septic patients of features of marked immunosuppression associated with increased risk of nosocomial infections and mortality represents the rational for the initiation of immune targeted treatments in sepsis. However, as there is no clinical sign of immune dysfunctions, the current challenge is to develop biomarkers that will help clinicians identify the patients that would benefit from immunotherapy and monitor its efficacy. Using an in vitro model of endotoxin tolerance (ET), a pivotal feature of sepsis-induced immunosuppression in monocytes, we identified using gene expression profiling by microarray a panel of transcripts associated with the development of ET which expression was restored after immunostimulation with interferon-gamma (IFN-M-NM-3). These results were confirmed by qRT-PCR. Importantly, this short-list of markers was further evaluated in patients. Of these transcripts, six (TNFAIP6, FCN1, CXCL10, GBP1, CXCL5 and PID1) were differentially expressed in septic shock patientsM-bM-^@M-^Y blood compared to healthy blood upon ex vivo LPS stimulation and were restored by IFN-M-NM-3. In this study, by combining a microarray approach in an in vitro model and a validation in clinical samples, we identified a panel of six transcripts that could be used for the identification of septic patients eligible for IFNg therapy. The potential value of these markers should now be evaluated in a larger cohort of patients. Upon favorable results, they could serve as stratification tools prior to immunostimulatory treatment and to monitor drug efficacy. PBMCs from 6 healthy donor were left unstimulated (medium) or with 1 shot of LPS (LPS unprimed), 2 shots of LPS (LPS primed) or 2 shots of LPS and Interferon gamma (LPS primed + IFNg).
2013-07-31 | E-GEOD-46914 | biostudies-arrayexpress
Project description:Endotoxin/LPS tolerance is a tightly regulated phenomenon, which, during infection, prevents systemic hyper-inflammation. Here we report for the first time that morphine reversal of endotoxin tolerance resulting in persistent inflammation thus contributing to septicemia and septic shock. We further report that this regulation is mediated by LPS-induced down-regulation of microRNAs 146a and 155. However, only over-expression of miR-146a, but not miR-155 abrogates morphine mediated hyper-inflammation, while antagonizing miR-146a (but not miR-155) augments morphine mediated hyper-inflammation. Hence, miR-146a could be the potential therapeutic target for morphine-mediated abrogation of endotoxin tolerance.
2013-08-01 | GSE42506 | GEO
Project description:Endotoxin/LPS tolerance is a tightly regulated phenomenon, which, during infection, prevents systemic hyper-inflammation. Here we report for the first time that morphine reversal of endotoxin tolerance resulting in persistent inflammation thus contributing to septicemia and septic shock. We further report that this regulation is mediated by LPS-induced down-regulation of microRNAs 146a and 155. However, only over-expression of miR-146a, but not miR-155 abrogates morphine mediated hyper-inflammation, while antagonizing miR-146a (but not miR-155) augments morphine mediated hyper-inflammation. Hence, miR-146a could be the potential therapeutic target for morphine-mediated abrogation of endotoxin tolerance. All treatments done in vivo. Morphine implanted subcuteniously, LPS administered as intraperitoneal injection.
2013-08-01 | E-GEOD-42506 | biostudies-arrayexpress
Project description:The rapid development in septic patients of features of marked immunosuppression associated with increased risk of nosocomial infections and mortality represents the rational for the initiation of immune targeted treatments in sepsis. However, as there is no clinical sign of immune dysfunctions, the current challenge is to develop biomarkers that will help clinicians identify the patients that would benefit from immunotherapy and monitor its efficacy. Using an in vitro model of endotoxin tolerance (ET), a pivotal feature of sepsis-induced immunosuppression in monocytes, we identified using gene expression profiling by microarray a panel of transcripts associated with the development of ET which expression was restored after immunostimulation with interferon-gamma (IFN-γ). These results were confirmed by qRT-PCR. Importantly, this short-list of markers was further evaluated in patients. Of these transcripts, six (TNFAIP6, FCN1, CXCL10, GBP1, CXCL5 and PID1) were differentially expressed in septic shock patients’ blood compared to healthy blood upon ex vivo LPS stimulation and were restored by IFN-γ. In this study, by combining a microarray approach in an in vitro model and a validation in clinical samples, we identified a panel of six transcripts that could be used for the identification of septic patients eligible for IFNg therapy. The potential value of these markers should now be evaluated in a larger cohort of patients. Upon favorable results, they could serve as stratification tools prior to immunostimulatory treatment and to monitor drug efficacy.
2013-07-31 | GSE46914 | GEO
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. Keywords: Septic shock, SIRS, pediatrics, outcome, infection, inflammation
2006-04-30 | GSE4607 | GEO
Project description:Hyporesponsiveness by phagocytes, a well-known phenomenon in sepsis, is frequently induced by low-dose endotoxin-stimulation of Toll-like-receptor-4 (TLR4) but can also be found under sterile inflammatory conditions. We now demonstrate that the endogenous alarmins myeloid-related protein (MRP) 8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner resulting in enhanced survival during murine septic shock. Also during sterile inflammation, polytrauma and burn patients present with initially high MRP serum concentrations identifying these proteins as obvious candidates for triggering secondary hyporesponsiveness in these patients. Interestingly, increased peripartal MRP concentrations prime human neonatal phagocytes for hyporesponsiveness, which was confirmed in murine neonatal endotoxinemia in wildtype and MRP14 -/- mice. Using a comparative bioinformatics analysis between genome-wide response patterns of MRP- and LPS- tolerized monocytes we demonstrated no difference in global gene expression between samples pretreated with either MRP8-MRP14 or LPS. Our data indicate that alarmin-triggered phagocyte tolerance represents a novel regulatory mechanism for the susceptibility of neonates to systemic infections and during sterile inflammation. Human blood monocytes prestimulated with MRP8-MRP14 or LPS and afterwards activated with LPS were selected for RNA extraction and hybridization on Illumina microarrays.
2014-12-12 | E-GEOD-61477 | biostudies-arrayexpress
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.
2008-06-13 | E-GEOD-4607 | biostudies-arrayexpress
Project description:Microbial challenges, such as widespread bacterial infection, induce endotoxin tolerance. This state of hypo-responsiveness to subsequent infections is mainly displayed by monocytes and macrophages. Endotoxin tolerance is generally acquired following a septic episode. In this study, we investigated DNA methylation changes during the acquisition of in vitro tolerance. We identified a set of TET2-mediated demethylation events that are specific to toll like receptor (TLR) 2 and 4 stimulation. Lipopolysaccharide (LPS)-specific demethylation occurs at genomic sites that have low accessibility in quiescent monocytes, concomitantly with the transcriptional activation of many inflammation-related genes, and they are enriched in binding motifs for several signal transducer and activator of transcription (STAT) family members. Indeed, STAT1, STAT3 and STAT5, elements of the JAK2 pathway, are phosphorylated in association with the acquisition of endotoxin tolerance. Inhibition of the JAK2 pathway impairs the activation of tolerized genes at the first encounter with LPS. This supports a crucial role of this pathway in determining the initial response of these genes to bacterial antigens and provides a pharmacological target to prevent exacerbated responses, allowing regulated responses upon subsequent challenges. Finally, we prove the pathological relevance of the JAK2 pathway in monocytes from patients with sepsis.
2021-11-23 | GSE159249 | GEO
Project description:Microbial challenges, such as widespread bacterial infection, induce endotoxin tolerance. This state of hypo-responsiveness to subsequent infections is mainly displayed by monocytes and macrophages. Endotoxin tolerance is generally acquired following a septic episode. In this study, we investigated DNA methylation changes during the acquisition of in vitro tolerance. We identified a set of TET2-mediated demethylation events that are specific to toll like receptor (TLR) 2 and 4 stimulation. Lipopolysaccharide (LPS)-specific demethylation occurs at genomic sites that have low accessibility in quiescent monocytes, concomitantly with the transcriptional activation of many inflammation-related genes, and they are enriched in binding motifs for several signal transducer and activator of transcription (STAT) family members. Indeed, STAT1, STAT3 and STAT5, elements of the JAK2 pathway, are phosphorylated in association with the acquisition of endotoxin tolerance. Inhibition of the JAK2 pathway impairs the activation of tolerized genes at the first encounter with LPS. This supports a crucial role of this pathway in determining the initial response of these genes to bacterial antigens and provides a pharmacological target to prevent exacerbated responses, allowing regulated responses upon subsequent challenges. Finally, we prove the pathological relevance of the JAK2 pathway in monocytes from patients with sepsis.
2021-11-23 | GSE159227 | GEO
Project description:The peripheral whole-blood transcriptome analysis has been used to the identification of biomarkers in different clinical syndromes. The ability to simultaneously measure the gene expression levels of the whole transcriptome is providing a broader view of clinical syndromes such as sepsis. The aim of this study was to assess the gene expression profiles of post-surgical patients with septic shock compared with patients without sepsis.
2014-03-15 | E-MTAB-1548 | biostudies-arrayexpress