Gene expression profiling of neutrophils from patients with cirrhosis and acute on chronic liver failure (ACLF)
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PROVIDER: PRJNA596431 | ENA |
REPOSITORIES: ENA
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Project description:Neutrophils were isolated (using Ficoll, Dextran and water to lyse the red cells) from whole blood of 5 healthy subjects, 5 patients with stable cirrhosis and 5 patients with ACLF. RNA was then extracted and amplified 100 ng of RNA per sample were then hybridized on ClarionS array (Affymetrix, Thermofischer scientific)
2021-02-24 | GSE142254 | GEO
Project description:Gene expression profiling patients with cirrhosis and acute on chronic liver failure (ACLF)
| PRJNA596427 | ENA
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: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:BACKGROUND: The molecular mechanisms driving the progression from early chronic liver disease (eCLD) to cirrhosis and, finally, acute-on-chronic liver failure (ACLF) are largely unknown. Thus, the aim of this work is to develop a network-based approach to investigate molecular pathways driving progression from eCLD to ACLF. We created 9 liver-specific biological networks capturing key pathophysiological processes potentially related to CLD. We used these networks as framework to perform gene set enrichment analyses(GSEA) and create dynamic profiles of disease progression. RESULTS: Principal component analyses revealed that samples clustered according to the disease stage. GSEA analyses of the defined processes showed an up-regulation of inflammation, fibrosis and apoptosis networks throughout disease progression. Interestingly, we did not find significant gene expression differences between CC and DC, while ACLF showed acute expression changes in all the defined liver-related networks. The analyses of disease progression patterns identified ascending and descending expression profiles associated to ACLF onset. Functional analyses showed that ascending profiles were associated to inflammation, fibrosis, apoptosis, senescence and carcinogenesis networks, while descending profiles were mainly related to oxidative stress and genetic factors. We confirmed by qPCR the up-regulation of 4 genes of the ascending profile CXCL-6, KRT-18, SPINK-1, and ITGA2, and validated our findings on an independent patient’s cohort. CONCLUSION: ACLF is characterized by a specific hepatic gene expression pattern related to inflammation, fibrosis, apoptosis, senescence and carcinogenesis processes. Moreover, the observed profile is significantly different from that of compensated and decompensated cirrhosis, supporting thus the hypothesis that ACLF should be considered a distinct entity.
2021-09-11 | GSE139602 | GEO
Project description:Background&aims: Patients with acute decompensation (AD) of cirrhosis progressing to acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated with increased circulating levels of small-molecule metabolites. To investigate whether these alterations reflect inadequate cell energy output, we assessed mitochondrial morphology and central metabolic pathways with emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from AD patients with and without ACLF. Methods: The study included samples from AD patients (102 without and 126 with ACLF) along with 41 healthy subjects. Leukocyte mitochondria ultrastructure was visualized by transmission electron microscopy and cytosolic and mitochondrial metabolic fluxes were determined by assessing NADH/FADH 2 production from various substrates. Plasma GDF15 and FGF21 were determined by Luminex and acylcarnitines by LC-MS/MS. Gene expression was analyzed by RNA-seq and PCR-based glucose metabolism profiler array. Results: Mitochondrial ultrastructure in patients with advanced cirrhosis was distinguished by cristae rarefication and swelling. The number of mitochondria per leukocyte was higher in patients, accompanied by a reduction in their size. Increased FGF21 and C:6- and C:8-carnitines predicted mortality whereas GDF15 strongly correlated with a gene set signature related to leukocyte activation. Metabolic flux analyses revealed increased energy production in mononuclear leukocytes from patients with preferential involvement of extra-mitochondrial pathways, supported by upregulated expression of genes encoding enzymes of the glycolytic and pentose phosphate pathways. In ACLF patients, mitochondrial function analysis uncovered two break-points in the TCA cycle at the isocitrate dehydrogenase and succinate dehydrogenase level, which were bridged by anaplerotic reactions involving glutaminolysis and nucleoside metabolism. Conclusions: Our findings provide evidence at the cellular, organelle and biochemical levels that severe mitochondrial dysfunction governs immunometabolism in leukocytes from patients with AD cirrhosis and ACLF.
2021-11-03 | GSE180014 | 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:Background and aims: Acute-on-chronic liver failure (ACLF) is characterized by rapid deterioration of liver function and organ failure, whereby immunoparesis and susceptibility to infections often precipitate this syndrome. Here we characterized the events triggering immune dysfunction in monocytes within alcoholic liver disease. Methods: We evaluated the frequency of monocyte subsets, their intracellular IL10 production, surface HLA-DR expression, and phagocytic and oxidative burst capacity in patients with decompensated cirrhosis, -alcoholic hepatitis or ACLF. RNAsequencing of ACLF patient-derived CD14+ monocytes were performed either immediately or after 12-hour culture in the presence or absence of plasma from ACLF patients. In this in vitro model of ACLF induction in CD14+ monocytes we characterized the early molecular, immunological and functional changes. Results: Besides a redistribution of monocyte subset composition, ACLF patient-derived monocytes featured elevated frequencies of IL-10-producing cells, reduced HLA-DR expression and impaired phagocytic- and oxidative burst capacity. RNAsequencing revealed a reprogramming of ACLF monocytes, whereby they undergo a transition from a pro-inflammatory to an immunosuppressive- and altered metabolic status. Culturing healthy monocytes in the presence of ACLF plasma, blunted their phagocytic capacity and triggered a gene expression pattern comparable to ACLF patients. Conversely, culturing patient monocytes in normal plasma restored their phagocytic capacity. Finally, plasma IL-10 levels correlated with patient survival. Conclusion: ACLF monocytes featured a defective immunosuppressive and -glycolytic profile, an attribute which could be mimicked by culturing healthy monocytes in the presence of ACLF patient plasma. Our data implicate a role for IL-10 signaling pathways in triggering monocytes dysfunction and opens up new avenues for therapeutic targeting.
2019-02-06 | GSE93265 | GEO
Project description:BACKGROUND/ AIMS: Severe forms of alcoholic liver disease are associated with increased susceptibility to infections largely due to immune dysfunction. In this study, we analyze the phenotypic, molecular and functional profiles of the mononuclear phagocyte system of patients with cirrhosis, severe alcoholic hepatitis (sAH) or acute-on-chronic liver failure (ACLF). RESULTS: sAH and ACLF patients display a severe impairment of the TH1-promoting IL-12p70/IFNgamma/CXCL10 axis. Furthermore, the CD14+ monocytes and classical dendritic cells of these patients are unable to mount an appropriate pro-inflammatory response after stimulation with PAMPs associated with gram-negative bacteria or fungal pathogens. These cells also have reduced polyfunctionality, which is associated with a higher risk of subsequent infection. Finally, we show that CD14+ monocytes of sAH and ACLF patients display a similar transcriptional profile characterized by immunosuppressive features. This was accompanied with changes in chromatin accessibility in enhancer regions of key immune and metabolic genes. CONCLUSIONS: Altered transcriptional program and functional properties of monocytes from sAH and ACLF patients has strong epigenetic determinants.
2020-08-02 | GSE135285 | GEO