Sepsis related ACLF mouse model
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ABSTRACT:
PROVIDER: PRJNA950440 | ENA |
REPOSITORIES: ENA
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Project description:Background and aims: Acute-on-chronic liver failure (ACLF) is an acute liver and multisystem failure in patients with previously stable cirrhosis. A common cause of ACLF is sepsis secondary to bacterial infection. Sepsis-associated ACLF involves a loss of differentiated liver function in the absence of direct liver injury, and its mechanism is unknown. We aimed to study the mechanism of sepsis associated ACLF using a novel mouse model. Approach and Results: Sepsis-associated ACLF was induced by cecal ligation and puncture procedure (CLP) in mice treated with thioacetamide (TAA). The combination of TAA and CLP resulted in a significant decrease in liver synthetic function and high mortality. These changes were associated with reduced metabolic gene expression and increased C/EBPβ transcriptional activity. We found that C/EBPβ binding to its target gene promoters was increased. In humans C/EBPβ chromatin binding was similarly increased in ACLF group compared to control cirrhosis. Hepatocyte specific Cebpb knockout mice had reduced mortality and increased gene expression of hepatocyte differentiation markers in TAA/CLP mice, suggesting that C/EBPβ promotes liver failure in these mice. C/EBPβ activation was associated with endothelial dysfunction, characterized by reduced Angiopoietin-1/Angiopoietin-2 ratio and increased endothelial production of HGF. Angiopoietin-1 supplementation or Hgf knockdown reduced hepatocyte C/EBPβ accumulation, restored liver function, and reduced mortality, suggesting that endothelial dysfunction induced by sepsis drives acute-on-chronic liver failure via HGF-C/EBPβ pathway. Conclusion: The transcription factor C/EBPβ is activated in both mouse and human ACLF and is a potential therapeutic target to prevent liver failure in patients with sepsis and cirrhosis.
2023-04-04 | GSE228610 | GEO
Project description:Whole blood from 7 patients with stable cirrhosis, 7 patients with acutely decompensated cirrhosis without ACLF and 17 patients with ACLF (8 related to sepsis and 9 unrelated to sepsis) was sampled into tempus tubes (Applied biosystems, Ambion). The same method was used to sample whole blood from 7 healthy subjects and from 8 patients with septic shock without cirrhosis that were used as comparators.RNA was then extracted using the PerfectPure RNA blood kit (3 PRIME) according to manufactuter instructions. 100 ng of RNA per sample were then hybridized on Human Transcriptome Array 2.0
2021-02-24 | GSE142255 | GEO
Project description:To address the molecular basis of immune-dysfunction in Acute-on-chronic liver failure (ACLF), we carried out gene expression profiling of blood derived neutrophil from ACLF, belonging to both sterile inflammatory and sepsis conditions. Peripheral whole blood was subjected to PMN enrichment by double gradient centrifugation, and RNA isolation was done by TRIZOL method, followed by microarray experiment using Agilent one-color platform. We compared the gene expression of these neutrophils with that of Chronic liver disease (CLD) patients and healthy controls (HC) for baseline relative quantification, and found unique set of upregulated and downregulated genes in ACLF. We validated the expression of the most differentially expressed genes by quantitative RT-PCR and also stratified the patients into survivors and non-survivors, sepsis and sterile-inflammation. We found an upregulated 3-gene signature of ELANE-MPO-CD177 to be associated with 28-day mortality, irrespective of presence or absence of sepsis.
2021-09-28 | GSE156382 | GEO
Project description:Transcriptional response in a sepsis mouse model reflects transcriptional response in sepsis patients
| PRJNA767825 | ENA
Project description:To identify the sncRNAs related to HBV-ACLF, we performed small RNA-seq in plasma exosomes collected from 3 normal subjects, 4 chronic hepatitis B (CHB) patients with flare and 6 HBV-ACLF patients in the discovery cohort.
2022-07-27 | GSE202557 | GEO
Project description:Mortality due to sepsis remains unacceptably high, especially for septic shock patients. Murine models have been used to better understand pathophysiology mechanisms. However, the mouse model is still under debate. Here we investigated the transcriptional response of mice injected with lipopolysaccharide (LPS) and compared it with that of human cells stimulated in vitro with LPS on the one hand, and with that of blood cells in septic patients on the other hand. We identified a molecular signature composed of 2331 genes with an FDR median of 0%. This molecular signature is highly enriched in regulated genes in peritoneal macrophages stimulated with LPS. There is a significant enrichment in several inflammatory signaling pathways, and in disease terms, such as pneumonia, sepsis, systemic inflammatory response syndrome, severe sepsis, an inflammatory disorder, immune suppression, and septic shock. A significant overlap between the genes up-regulated in mouse and human cells stimulated with LPS has been demonstrated. Finally, genes up-regulated in mouse cells stimulated with LPS are enriched in genes up-regulated in human cells stimulated in vitro and in septic patients, who are at high risk of death. Our results support the hypothesis of common molecular and cellular mechanisms between mouse and human sepsis.
2021-12-31 | GSE185150 | GEO
Project description:Streptococcus pneumoniae is a major cause of invasive diseases, such as pneumoniae, meningitis and sepsis resulting in high mortality. The molecular mechanisms and disease developing mechanism underlying pneumococcal infection remain unknown. Previously, we reported that S. pneumoniae β-galactosidase (BgaA) is evolutionarily conserved and contributes to pneumococcal pathogenesis in mouse sepsis model. BgaA is also known to play a role in pneumococcal growth, resistance to human neutrophil opsonophagocytic killing, bacterial adherence to human epithelial cells. In this study, since the detailed role that BgaA plays in sepsis remain unknown, we focused on the role of BgaA in pneumococcal sepsis. Our in vitro assays showed that BgaA promoted bacterial association with human lung epithelial and vascular endothelium cells. BgaA also contributes to pneumococcal survival with human blood by suppressing neutrophils killing, whereas BgaA did not affect pneumococcal survival in mouse blood. In a mouse sepsis model, mice infected with S. pneumoniae bgaA deletion mutant strain exhibited up-regulated host innate immunity pathways, and suppressed tissue damages and blood coagulation as compared to mice infected with the wild-type strain. These results suggest that BgaA works as a multifunctional virulence factor for inducing host tissue damages and blood coagulation. BgaA could be an attractive target for drug and vaccine development.
2022-07-18 | GSE190418 | GEO
Project description:The transcriptomic profiles of circulating neutrophils were compared between patients with ACLF (N=10), patients with CLC (N=10) and HC (N=10). Compared with CLC-neutrophils, the expression of 1022 genes were found to be upregulated in ACLF-neutrophils, and 1101 genes were downregulated. And compared to HC, the expression of 726 genes were up-regulated in ACLF-neutrophils, and 711 genes were down-regulated. The pathway analysis identified mutiple pathways enriched or down-regulated in ACLF-neutrophils when comparing with neutrophils from CLC or HC groups.
2024-02-25 | GSE165024 | GEO
Project description:Clinical study of critically ill patients with sepsis and sepsis-related ARDS with whole blood RNA collected within the first 24 hours of admission Goal of the study was to determine whether biologically relevant genes were identified to be differentially expressed genes in patients with sepsis alone and sepsis with ARDS Prospective observational study, case cohort design
2015-04-01 | E-GEOD-66890 | biostudies-arrayexpress
Project description:Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection. This is best studied in humans and various mouse models, however finding sof these models to not always translate easy to the clinic. In order to improve this transfer, and because sepsis also plays a significant role in vetrenairy medicine, we use the pig as a model organism in sepsis research. We compare two modes of porcine sepsis iduction: fecal infusion and LPS infusion and also compare thse o wha we can find in mice
2023-12-31 | GSE250039 | GEO