LPS induces pulmonary microvascular endothelial cell barrier dysfunction by upregulating ceramide production

Jiang, Jianjun; Ouyang, Huijuan; Zhou, Qun; Tang, Sihui; Pu, Fang; Xie, Guangyuan; Yang, Jin; Sun, Guan

doi:10.1016/j.cellsig.2022.110250

Cited by 7 publications

(3 citation statements)

References 69 publications

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“…In addition to being a component of cell membranes, ceramide functions as a second messenger to regulate numerous cellular processes, including apoptosis, proliferation, migration, and autophagy . Ceramide is elevated in numerous pathological conditions, such as neurodegenerative disorders, endothelial dysfunction, cancer, and bowel inflammation, and contributes to these pathological processes. − Therefore, it is interesting to further investigate ceramide metabolism regulation by naringenin, which will help to fully understand the biological role of naringenin.…”

Section: Discussionmentioning

confidence: 99%

Naringenin Inhibits Acid Sphingomyelinase-Mediated Membrane Raft Clustering to Reduce NADPH Oxidase Activation and Vascular Inflammation

Ding,

Zhu,

et al. 2024

J. Agric. Food Chem.

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Macrophage inflammation and oxidative stress promote atherosclerosis progression. Naringenin is a naturally occurring flavonoid with antiatherosclerotic properties. Here, we elucidated the effects of naringenin on monocyte/macrophage endothelial infiltration and vascular inflammation. We found naringenin inhibited oxidized low-density lipoprotein (oxLDL)-induced pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α toward an M2 macrophage phenotype and inhibited oxLDL-induced TLR4 (Toll-like receptor 4) membrane translocation and downstream NF-κB transcriptional activity. Results from flow cytometric analysis showed that naringenin reduced monocyte/macrophage infiltration in the aorta of high-fat-diet-treated ApoE-deficient mice. The aortic cytokine levels were also inhibited in naringenin-treated mice. Further, we found that naringenin reduced lipid raft clustering and acid sphingomyelinase (ASMase) membrane gathering and inhibited the TLR4 and NADPH oxidase subunit p47phox membrane recruitment, which reduced the inflammatory response. Recombinant ASMase treatment or overexpression of ASMase abolished the naringenin function and activated macrophage and vascular inflammation. We conclude that naringenin inhibits ASMase-mediated lipid raft redox signaling to attenuate macrophage activation and vascular inflammation.

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Section: Discussionmentioning

confidence: 99%

Naringenin Inhibits Acid Sphingomyelinase-Mediated Membrane Raft Clustering to Reduce NADPH Oxidase Activation and Vascular Inflammation

Ding,

Zhu,

et al. 2024

J. Agric. Food Chem.

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“… 48 SPT long chain subunits 1 ( SPTLC1 ) is a key subunit in the enzymatic activity of the SPT complex and is closely associated with vascular development and systemic sphingolipid homeostasis. 49 Jiang et al 50 found that inhibition of SPTLC1 expression in lung microvascular endothelial cells significantly reduced SPT expression and inhibited LPS-induced ceramide production, thereby inducing endothelial barrier dysfunction. Medler et al 51 found that inhibition of SPTLC1 expression in lung endothelial cells inhibited TNF-α (plus actinomycin) induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Screening of Lipid Metabolism-Related Genes as Diagnostic Indicators in Chronic Obstructive Pulmonary Disease

Jiang,

Peng,

Dai

et al. 2023

COPD

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Objective It has been observed that local and systemic disorders of lipid metabolism occur during the development of chronic obstructive pulmonary disease (COPD), but no specific mechanism has yet been identified. Methods The mRNA microarray dataset GSE76925 of COPD patients was downloaded from the Gene Expression Omnibus database and screened for differentially expressed genes (DEGs). Lipid metabolism-related genes (LMRGs) were extracted from the Kyoto Encyclopedia of Genes and Genomes database and Molecular Signature Database. The DEGs were intersected with LMRGs to obtain differentially expressed lipid metabolism-related genes (DeLMRGs). GO enrichment analysis and KEGG pathway analysis were performed on DeLMRGs, and protein-protein interaction networks were constructed and screened to identify hub genes. The GSE8581 validation set and further ELISA experiments were used to validate key DeLMRG expression. Results Differential analysis of dataset GSE76925 identified 587 DEGs, of which 62 genes were up-regulated and 525 were down-regulated. Taking the intersection of 587 DEGs with 1102 LMRGs, 20 DeLMRGs were obtained, including 1 up-regulated gene and 19 down-regulated genes. 10 hub genes were screened by cytohubba plugin, including 9 down-regulated genes PLA2G4A, HPGDS, LEP, PTGES3, LEPR, PLA2G2D, MED21, SPTLC1 and BCHE , as well as the only up-regulated gene PLA2G7 . Validation of the identified 10 DeLMRGs using the validation set GSE8581 revealed that BCHE and PLA2G7 expression levels differed between the two groups. We further constructed the ceRNA network of BCHE and PLA2G7 . Cell experiments also showed that PLA2G7 expression was up-regulated and BCHE expression was down-regulated in CSE-treated RAW264.7 and THP-1 cells. Conclusion Based on a comprehensive bioinformatic analysis of lipid metabolism genes, we identified BCHE and PLA2G7 as potentially significant biomarkers of COPD. These biomarkers may represent promising targets for COPD diagnosis and treatment.

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“…The lung is the most vulnerable target organ under septic conditions, and acute lung injury (ALI) is the most common complication of sepsis (4). Pulmonary microvascular endothelial cells (PMVECs) are the first target in sepsis-induced ALI, and many pathophysiological changes are initiated thereafter (5). Recent advancement in the study of endothelial cell damage has shown that further reducing endothelial shear stress caused by large volume resuscitation after hemorrhagic shock leads to persistent tissue hypoxia and increased microvascular endothelial permeability (6).…”

Section: Introductionmentioning

confidence: 99%

HYDROGEN PREVENTS LIPOPOLYSACCHARIDE-INDUCED PULMONARY MICROVASCULAR ENDOTHELIAL CELL INJURY BY INHIBITING STORE-OPERATED Ca2+ ENTRY REGULATED BY STIM1/ORAI1

Li,

Chen,

Shu

et al. 2023

Shock

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Background Sepsis is a type of life-threatening organ dysfunction that is caused by a dysregulated host response to infection. The lung is the most vulnerable target organ under septic conditions. Pulmonary microvascular endothelial cells (PMVECs) play a critical role in acute lung injury (ALI) caused by severe sepsis. The impairment of PMVECs during sepsis is a complex regulatory process involving multiple mechanisms, in which the imbalance of calcium (Ca2+) homeostasis of endothelial cells is a key factor in its functional impairment. Our preliminary results indicated that hydrogen gas (H2) treatment significantly alleviates lung injury in sepsis, protects PMVECs from hyperpermeability, and decreases the expression of plasma membrane stromal interaction molecule 1 (STIM1), but the underlying mechanism by which H2 maintains Ca2+ homeostasis in endothelial cells in septic models remains unclear. Thus, the purpose of the present study was to investigate the molecular mechanism of STIM1 and Ca2+-release-activated- Ca2+ channel protein1 (Orai1) regulation by H2 treatment and explore the effect of H2 treatment on Ca2+ homeostasis in lipopolysaccharide (LPS)-induced PMVECs and LPS-challenged mice. Methods We observed the role of H2 on LPS-induced ALI of mice in vivo. The lung wet/dry (W/D) weight ratio, total protein in the bronchoalveolar lavage (BAL) fluid and Evans blue dye (EBD) assay were used to evaluate the pulmonary endothelial barrier damage of LPS-challenged mice. The expression of STIM1 and Orai1 were also detected using epifluorescence microscopy. Moreover, we also investigated the role of H2- rich medium in regulating PMVECs under LPS treatment, which induced injury similar to sepsis in vitro. The expression of STIM1 and Orai1 as well as the Ca2+ concentration in PMVECs were examined. Results In vivo, we found that H2 alleviated ALI of mice through decreasing lung W/D weight ratio, total protein in the BAL fluid and permeability of lung. In addition, H2 also decreased the expression of STIM1 and Orai1 in pulmonary microvascular endothelium. In vitro, LPS treatment increased the expression levels of STIM1 and Orai1 in PMVECs, while H2 reversed these changes. Furthermore, H2 ameliorated Ca2+ influx under sepsis-mimicking conditions. Treatment with the sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA) inhibitor, thapsigargin (TG), resulted in a significant reduction in cell viability as well as a reduction in the expression of junctional proteins, including VE-cadherin and occludin. Treatment with the store-operated Ca2+ entry (SOCE) inhibitor, YM-58483 (BTP2), increased the cell viability and expression of junctional proteins. Conclusions The present study suggested that H2 treatment alleviates LPS-induced PMVEC dysfunction by inhibiting SOCE mediated by STIM1 and Orai1 in vitro and in vivo.

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LPS induces pulmonary microvascular endothelial cell barrier dysfunction by upregulating ceramide production

Cited by 7 publications

References 69 publications

Naringenin Inhibits Acid Sphingomyelinase-Mediated Membrane Raft Clustering to Reduce NADPH Oxidase Activation and Vascular Inflammation

Naringenin Inhibits Acid Sphingomyelinase-Mediated Membrane Raft Clustering to Reduce NADPH Oxidase Activation and Vascular Inflammation

Screening of Lipid Metabolism-Related Genes as Diagnostic Indicators in Chronic Obstructive Pulmonary Disease

HYDROGEN PREVENTS LIPOPOLYSACCHARIDE-INDUCED PULMONARY MICROVASCULAR ENDOTHELIAL CELL INJURY BY INHIBITING STORE-OPERATED Ca2+ ENTRY REGULATED BY STIM1/ORAI1

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