Transcriptomic analysis of lung endothelial subsets in experimental sepsis
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ABSTRACT:
PROVIDER: PRJNA716969 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14061700_1.fastq.gz | Fastqsanger.gz | |||
| SRR14061700_2.fastq.gz | Fastqsanger.gz | |||
| SRR14061701_1.fastq.gz | Fastqsanger.gz | |||
| SRR14061701_2.fastq.gz | Fastqsanger.gz | |||
| SRR14061702_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Sepsis affects almost all aspects of endothelial cell function. Lung endothelial subsets, capillaries (capEC) and post capillary venules (PCV), are known to play a pivotal role in maintaining normal homeostasis. The aim of the study is to reveal transcriptional changes in lung endothelial subsets during sepsis. Methods: Sepsis was induced in male C57BL/6 mice by cecal ligation and puncture (CLP). Lung tissues were collected 4 hour after induction of sepsis. Single cell suspension was prepared by enzymatic digestion. Blood endothelial cells (BECs) were enriched by depletion of hematolymphoid cells and epithelial cells by using anti-CD45 and CD326 microbeads. CapEC and PCV were sorted from enriched BECs using fluorescent-labeled antibodies. capEC subset was identified as CD31+Icam1+Vcam1- and PCV subset was identified as CD31+Icam1+Vcam1+. EC subsets were directly sorted into RLT buffer. Total RNA was isolated from the sorted cells with RNeasy Plus Micro kit (Qiagen) and the quality of RNA was checked by Bioanalyzer RNA 6000 pico assay. Sequence library was prepared using SMARTer® Stranded Total RNA-Seq Kit v2-Pico Input Mammalian (Takara Bio USA, Inc.). After library preparation and quality check, the double-stranded-cDNA was sequenced on NextSeq 500 (Illumina) using (read one-index reads-read two, bp): 75-8-8-75 setup. Differentially expression analysis was performed using DESeq2 in R program. Results: Differential expression analysis revealed that lung capEC is transcriptionally different than PCV. capEC and PCV responded differently after induction of sepsis. Enrichment analysis revealed that capEC are more enriched with genes related to regulation of coagulation, vascular permeability, wound healing and lipid metabolic process. On the other hand, PCV are more enriched with genes related to cell chemotaxis, cell-cell adhesion by integrins, chemokine biosynthesis process, regulation of actin filament process, neutrophil homeostasis.
2021-09-22 | GSE169532 | GEO
Project description:Sepsis-induced acute lung injury (ALI), characterized by severe hypoxemia and pulmonary leakage, remains a leading cause of mortality in intensive care units. The exacerbation of ALI during sepsis is largely attributed to uncontrolled inflammatory responses and endothelial dysfunction. Emerging evidences suggest an important role of Z-DNA binding protein 1 (ZBP1) as a sensor in innate immune to drive inflammatory signaling and cell death during infections. However, the role of ZBP1 in sepsis-induced ALI has yet to be defined. We utilized ZBP1 knockout mice and combined single-cell RNA sequencing with experimental validation to investigate ZBP1's roles in the regulation of macrophages and lung endothelial cells during sepsis. We demonstrate that in sepsis, ZBP1 deficiency in macrophages reduces mitochondrial damage and inhibits glycolysis, thereby altering the metabolic status of macrophages. Consequently, this metabolic shift leads to a reduction in the differentiation of macrophages into pro-inflammatory states and decreases macrophage pyroptosis triggered by activation of the NLRP3 inflammasome. These changes significantly weaken the inflammatory signaling pathways between macrophages and endothelial cells, and alleviate endothelial dysfunction and cellular damage. These findings reveal important roles for ZBP1 in mediating multiple pathological processes involved in sepsis-induced ALI by modulating the functional states of macrophages and endothelial cells, thereby highlighting its potential as a promising therapeutic target.
2024-10-10 | GSE278767 | GEO
Project description:The activation of pulmonary endothelial cells (ECs) triggers the occurrence of lung injury and is a hallmark of sepsis-associated acute respiratory distress syndrome(ARDS). Aberrant metabolism favoring glycolysis plays a pivotal role in the pathogenesis of sepsis-induced EC activation. Herein we demonstrate that glycolysis-related histone lactylation, represented by H3K14 lactylation (H3K14la), drives sepsis-associated EC activation and lung injury. Accordingly, H3K14la level is elevated in injured lung tissue and activated ECs. Inhibition of lactate production suppresses both H3K14la levels and EC activation in response to lipopolysaccharide (LPS). We also show that lactate-dependent H3K14la is enriched at the promoters of ferroptosis-related genes, thereby inducing ferroptosis in ECs, and inhibiting ferroptosis effectively ameliorates EC activation. Taken together, elevated lactate in sepsis modulates EC activation and lung injury via histone lactylation and manipulation of glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for the treatment of sepsis-associated ARDS.
2023-01-01 | GSE212087 | GEO
Project description:Endothelial Poldip2 Regulates Sepsis-induced Lung Injury via Rho Pathway Activation
| PRJNA694472 | ENA
Project description:Introduction: Various immune cell types play critical roles in sepsis with numerous distinct subsets exhibiting unique phenotypes even within the same cell population. In this study, we have unveiled the transcriptomic landscape of immune cells in sepsis through single-cell RNA sequencing (scRNA-seq) analysis. We induced sepsis in mice by cecal ligation and puncture. 20 h after the surgery, the spleen and peritoneal lavage were collected. Single-cell suspensions were processed using a 10× Genomics pipeline and sequenced on an Illumina platform. Count matrices were generated using the CellRanger pipeline, which maps reads to the mouse reference transcriptome, GRCm38/mm10. Subsequent scRNA-seq analysis was performed using the R package Seurat. Results: After quality control, we subjected the entire data set to unsupervised classification.Four major clusters were identified as neutrophils, macrophages, B cells, and T cells according to their putative markers. Based on the differentially-expressed genes, we identified activated pathways in sepsis for each cell type. In neutrophils, pathways related to inflammatory signaling, such as NF‐κB and responses to pathogen-associated molecular patterns (PAMPs), cytokines and hypoxia were activated. In macrophages, activated pathways were the ones related to cell aging, inflammatory signaling and responses to PAMPs. In B cells, pathways related to endoplasmic reticulum stress were activated. In T cells, activated pathways were the ones related to inflammatory signaling, responses to PAMPs, and acute lung injury. Next, we further classified each cell type into subsets. Neutrophils consisted of four clusters. Some subsets were activated in inflammatory signaling or cell metabolism, while others possessed immunoregulatory or aging properties. Macrophages consisted of four clusters, including the ones with enhanced aging, lymphocyte activation, extracellular matrix organization, or cytokine activity. B cells consisted of four clusters, including the ones possessing the phenotype of cell maturation or aging. T cells consisted of six clusters, whose phenotypes include molecular translocation or cell activation. Conclusions: Transcriptomic analysis by scRNA-seq has unveiled a comprehensive spectrum of immune cell responses and distinct subsets in the context of sepsis. These findings are poised to enhance our understanding of sepsis pathophysiology, offering avenues for targeting novel molecules, cells, and pathways to combat infectious disease.
2024-01-09 | GSE249975 | GEO
Project description:Rationale: Sepsis is a leading cause of morbidity and mortality; early diagnosis and prediction of progression is difficult to determine. The integration of metabolomic and transcriptomic data in an experimental model of sepsis may be a novel method to identify molecular signatures of clinical sepsis. Objectives: Develop a biomarker panel for earlier diagnosis and prognostic characterization of sepsis patients to inform personalized clinical management and improve understanding of the pathophysiology of sepsis progression. Methods: Mild to severe sepsis, lung injury and death was recapitulated in Macaca fascicularis by intravenous inoculation of Escherichia coli. Plasma samples were obtained at time of challenge and at one, three, and five days later or time of euthanasia. Necropsy was performed and blood, lung, kidney and spleen samples were obtained. An integrative analysis of comprehensive metabolomic and transcriptomic datasets was performed to identify and parameterize a biomarker panel. Measurements and Main Results: Pathogen invasion, respiratory distress, lethargy and mortality was dose dependent. Severe infection and death were associated with metabolomic and transcriptomic changes indicative of mitochondrial, peroxisomal and liver dysfunction. Analysis of reciprocal pulmonary transcriptome and plasma metabolome data revealed an integrated host response that suggested dysregulated fatty acid catabolism resulting from peroxisome-proliferator activated receptor signaling. A representative 4-metabolite model effectively diagnosed sepsis in primates (AUC 0.966) and in two human sepsis cohorts (AUC=0.78 and 0.82). Conclusion: A model to guide early management of patients with sepsis was developed by analysis of reciprocal metabolomic and transcriptomic data in primates that diagnosed sepsis in humans. Transcriptomic analysis of lungs from Cynomolgus macaques challenged with E. coli
2015-07-03 | E-GEOD-59075 | biostudies-arrayexpress
Project description:The vasculature is a key regulator of leukocyte trafficking into the central nervous system (CNS) during inflammatory diseases including multiple sclerosis. However, the impact of endothelial-derived factors on other aspects of CNS immune responses remains unknown. Bioactive lipids, in particular oxysterols downstream Cholesterol-25-hydroxylase (Ch25h) promote neuroinflammation but their functions in the CNS remain unclear. Using a floxed-reporter Ch25h knock-in mice, we traced Ch25h expression to CNS endothelial cells (ECs) and myeloid cells and demonstrated that Ch25h-specific ablation in ECs attenuates experimental autoimmune encephalomyelitis. Mechanistically, inflamed Ch25h-deficient CNS ECs displayed altered lipid metabolism favoring polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) expansion relative to other leukocyte subsets that suppress encephalitogenic T lymphocytes proliferation. Finally, endothelial Ch25h-deficiency combined with mobilization of immature neutrophils into circulation resulted in nearly complete EAE protection. Our findings reveal a central role for CNS endothelial-derived Ch25h in promoting neuroinflammation by regulating expansion of immunosuppressive myeloid cell populations.
2023-01-23 | GSE217431 | GEO
Project description:Opposing roles of dendritic cells subsets in experimental GN
| PRJNA413937 | ENA
Project description:Rationale: Sepsis is a leading cause of morbidity and mortality; early diagnosis and prediction of progression is difficult to determine. The integration of metabolomic and transcriptomic data in an experimental model of sepsis may be a novel method to identify molecular signatures of clinical sepsis. Objectives: Develop a biomarker panel for earlier diagnosis and prognostic characterization of sepsis patients to inform personalized clinical management and improve understanding of the pathophysiology of sepsis progression. Methods: Mild to severe sepsis, lung injury and death was recapitulated in Macaca fascicularis by intravenous inoculation of Escherichia coli. Plasma samples were obtained at time of challenge and at one, three, and five days later or time of euthanasia. Necropsy was performed and blood, lung, kidney and spleen samples were obtained. An integrative analysis of comprehensive metabolomic and transcriptomic datasets was performed to identify and parameterize a biomarker panel. Measurements and Main Results: Pathogen invasion, respiratory distress, lethargy and mortality was dose dependent. Severe infection and death were associated with metabolomic and transcriptomic changes indicative of mitochondrial, peroxisomal and liver dysfunction. Analysis of reciprocal pulmonary transcriptome and plasma metabolome data revealed an integrated host response that suggested dysregulated fatty acid catabolism resulting from peroxisome-proliferator activated receptor signaling. A representative 4-metabolite model effectively diagnosed sepsis in primates (AUC 0.966) and in two human sepsis cohorts (AUC=0.78 and 0.82). Conclusion: A model to guide early management of patients with sepsis was developed by analysis of reciprocal metabolomic and transcriptomic data in primates that diagnosed sepsis in humans.
2015-07-03 | GSE59075 | GEO
Project description:Developmental transcriptome profiling of cardiac vascular endothelial subsets
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