Endothelial Poldip2 Regulates Sepsis-induced Lung Injury via Rho Pathway Activation
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ABSTRACT:
PROVIDER: PRJNA694472 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13517700_1.fastq.gz | Fastqsanger.gz | |||
| SRR13517700_2.fastq.gz | Fastqsanger.gz | |||
| SRR13517701_1.fastq.gz | Fastqsanger.gz | |||
| SRR13517701_2.fastq.gz | Fastqsanger.gz | |||
| SRR13517702_1.fastq.gz | Fastqsanger.gz |
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Project description:We report the effect of Poldip2 knock-down on gene expression in human pulmonary endothelial cells with and without TNF-alpha challenge.
2021-03-27 | GSE165410 | GEO
Project description:AimsSepsis-induced lung injury is associated with significant morbidity and mortality. Previously, we showed that heterozygous deletion of polymerase δ-interacting protein 2 (Poldip2) was protective against sepsis-induced lung injury. Since endothelial barrier disruption is thought to be the main mechanism of sepsis-induced lung injury, we sought to determine if the observed protection was specifically due to the effect of reduced endothelial Poldip2.Methods and resultsEndothelial-specific Poldip2 knock-out mice (EC-/-) and their wild-type littermates (EC+/+) were injected with saline or lipopolysaccharide (18 mg/kg) to model sepsis-induced lung injury. At 18 h post-injection mice, were euthanized and bronchoalveolar lavage (BAL) fluid and lung tissue were collected to assess leucocyte infiltration. Poldip2 EC-/- mice showed reduced lung leucocyte infiltration in BAL (0.21 ± 0.9×106 vs. 1.29 ± 1.8×106 cells/mL) and lung tissue (12.7 ± 1.8 vs. 23 ± 3.7% neutrophils of total number of cells) compared to Poldip2 EC+/+ mice. qPCR analysis of the lung tissue revealed a significantly dampened induction of inflammatory gene expression (TNFα 2.23 ± 0.39 vs. 4.15 ± 0.5-fold, IκBα 4.32 ± 1.53 vs. 8.97 ± 1.59-fold), neutrophil chemoattractant gene expression (CXCL1 68.8 ± 29.6 vs. 147 ± 25.7-fold, CXCL2 65 ± 25.6 vs. 215 ± 27.3-fold) and a marker of endothelial activation (VCAM1 1.25 ± 0.25 vs. 3.8 ± 0.38-fold) in Poldip2 EC-/- compared to Poldip2 EC+/+ lungs. An in vitro model using human pulmonary microvascular endothelial cells was used to assess the effect of Poldip2 knock-down on endothelial activation and permeability. TNFα-induced endothelial permeability and VE-cadherin disruption were significantly reduced with siRNA-mediated knock-down of Poldip2 (5 ± 0.5 vs. 17.5 ± 3-fold for permeability, 1.5 ± 0.4 vs. 10.9 ± 1.3-fold for proportion of disrupted VE-cadherin). Poldip2 knock-down altered expression of Rho-GTPase-related genes, which correlated with reduced RhoA activation by TNFα (0.94 ± 0.05 vs. 1.29 ± 0.01 of relative RhoA activity) accompanied by redistribution of active-RhoA staining to the centre of the cell.ConclusionPoldip2 is a potent regulator of endothelial dysfunction during sepsis-induced lung injury, and its endothelium-specific inhibition may provide clinical benefit.
| S-EPMC9612795 | biostudies-literature
Project description:Poldip2 is a multifunctional protein whose roles are only partially understood. The previous Poldip2 knockout mouse generated by the gene trap model suffers from two limitations: perinatal lethality in homozygotes and constitutive Poldip2 inactivation. To overcome these limitations, we developed a new conditional floxed Poldip2 mouse. Here, we correctly targeted floxed Poldip2 mice to produce an endothelial-specific by crossing it with CDH5 ERT2 Cre mouse. Additionally, we also produced smooth-muscle specific Poldip2 knockout mice by crossing the flox'ed Poldip2 mice with SM22A-Cre mice. The Poldip2_EC-/- and Poldip2_SMC-/-mice were viable and showed remarkably reduced Poldip2 expression. To characterize the effect of Poldip2 ablation in the ECs and in the SMCs, we performed a RNA-seq study using the carotid arteries of these mice.
2024-01-24 | GSE165939 | 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:Poldip2 is a multifunctional protein whose roles are only partially understood. The previous Poldip2 knockout mouse generated by the gene trap model suffers from two limitations: perinatal lethality in homozygotes and constitutive Poldip2 inactivation. To overcome these limitations, we developed a new conditional floxed Poldip2 mouse. Here, we correctly targeted floxed Poldip2 mice to produce a new constitutive knockout line by crossing with a Cre deleter. In contrast to the gene trap model, many homozygous knockout mice were viable, in spite of having no Poldip2 expression. To characterize the effect of Poldip2 ablation in the vasculature, we performed a RNA-seq study using the carotid arteries of these mice.
2021-12-20 | GSE165274 | GEO
Project description:To study the function of AMD-associated gene POLDIP2 in retinal pigment epithelial (RPE) cells, we used CRISPR/Cas to knockout POLDIP2 in the human RPE cell line ARPE19. We then performed RNA-seq to profile the transcriptome of wildtype ARPE19 and POLDIP2 knockout.
2022-10-01 | GSE207158 | GEO
Project description:Sepsis is a serious systemic inflammatory reaction, which often leads to acute lung injury, and then affects lung function. This study aimed to explore the molecular mechanism of the interaction between il1b+ alveolar resident macrophages and pulmonary endothelial cells during sepsis induced lung injury using single-cell RNA sequencing technology.
2025-04-10 | PXD062802 |
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:Excessive endothelial pro-inflammatory response is an early hallmark in sepsis-induced acute lung injury (ALI). Xuebijing (XBJ) as a Chinese traditional medicine is widely used for treating sepsis in the clinic. However, the molecular mechanism of the beneficial effectiveness of XBJ remains unclear. Our present study showed that XBJ inhibited phosphorylation-dependent activation of ATP citrate lyase (ACLY), thereby suppressing the acetylation-dependent nuclear translocation of transcription factor MYB. Thus, as the downstream target gene of MYB, the expression of retinoic acid inducible gene I (RIG-I) was downregulated, leading to the inhibition of NF-κB signaling and EC pro-inflammatory and coagulation activation, which further alleviated sepsis-associated ALI. Moreover, XBJ compounds Quercetin, Ferulic Acid, Kaempferol and Paeoniflorin all showed inhibitory effects on the activation of the downstream MYB/RIG-I signaling by binding to ACLY protein. Our study revealed the novel regulatory mechanism of XBJ in sepsis-induced EC dysfunction and ALI via ACLY/MYB/RIG-I axis, providing theoretical basis for the clinical application of XBJ and shedding insight into novel therapeutic targets for treating sepsis.
2025-03-01 | GSE279126 | GEO
Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common life-threatening critical syndrome with no effective pharmacotherapy. Extracellular vesicles (EVs) are considered as a new way of long-distance communication between cells. Our previous research using an ex vivo perfused human ALI model suggested that endothelial cell-derived EVs (EC-EVs) mediate the development of ALI/ARDS. However, how EC-EVs aggravate lung injury remains largely unknown. Here we demonstrated that EC-EVs released under inflammatory stimulation are preferentially taken up by monocytes and reprogram the differentiation of monocytes towards M1 type macrophage. These findings demonstrate a previously unidentified mechanism by which distant infections could lead to ALI/ARDS, providing novel targets and strategies for the prevention and treatment of sepsis-related ALI/ARDS.
2024-03-20 | GSE236215 | GEO