Single-nucleus transcriptomic profiling of the diaphragm during mechanical ventilation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1124550 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29428972_1.fastq.gz | Fastqsanger.gz | |||
| SRR29428972_2.fastq.gz | Fastqsanger.gz | |||
| SRR29428973_1.fastq.gz | Fastqsanger.gz | |||
| SRR29428973_2.fastq.gz | Fastqsanger.gz | |||
| SRR29428974_1.fastq.gz | Fastqsanger.gz |
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Project description:Mechanical ventilation contributes to diaphragm atrophy and muscle weakness, which is referred to as ventilator-induced diaphragmatic dysfunction (VIDD).Through snRNA seq, we demonstrated that diaphragm fibrosis resulting from FAP proliferation, EMT, immune cell infiltration, and diaphragm atrophy which are induced by phrenic nerve ending loss are the underlying causes of VIDD.
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Project description:Ventilator-induced diaphragm dysfunction (VIDD), a dysfunction of the diaphragm muscle caused by prolonged mechanical ventilation (MV), is an important factor that hinders successful weaning from ventilation. We evaluated the effects of electrical stimulation of the diaphragm muscle (pulsed current with off-time intervals) on genetic changes during 12 hours of MV (E-V12). Rats were divided into four groups: control, 12-hour MV, sham operation, and E-V12 groups. Transcriptome analysis using an RNA microarray revealed that 12-hour MV caused upregulation of genes promoting muscle atrophy and downregulation of genes facilitating muscle synthesis, suggesting that 12-hour MV is a reasonable method for establishing a VIDD rat model. Of the genes upregulated by 12-hour MV, 18 genes were not affected by the sham operation but were downregulated by E-V12. These included genes related to catabolic processes, inflammatory cytokines, and skeletal muscle homeostasis. Of the genes downregulated by 12-hour MV, 6 genes were not affected by the sham operation but were upregulated by E-V12. These included genes related to oxygen transport and mitochondrial respiration. These results suggested that 12-hour MV shifted gene expression in the diaphragm muscle toward muscle degradation and that electrical stimulation counteracted this shift by suppressing catabolic processes and increasing mitochondrial respiration.
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Project description:Mechanical ventilation contributes to diaphragm atrophy and muscle weakness, which is referred to as ventilator-induced diaphragmatic dysfunction (VIDD). The pathogenesis of VIDD has not been fully understood until recently. The aim of this study was to investigate the effects of 24 h of mechanical ventilation on fibro-adipogenic progenitor (FAP) proliferation, endothelial-mesenchymal transition (EndMT), and immune cell infiltration driving diaphragm fibrosis in a rabbit model. The rabbits were anaesthetized and randomly divided into two groups (n = 3 each group): a control group and an experimental group. Diaphragm nuclei for sequencing were prepared by dissociating and filtering muscle tissue. 10X Genomics Platform for single-nucleus RNA sequencing (snRNA-seq) was used to profile the cells. Normalization and clustering were performed by Seurat, and clusters were manually annotated as different cell types. In this study, we performed differentially expressed genes (DEGs) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, pseudotime analysis and high dimensional weighted gene coexpression network analysis (hdWGCNA) to identify the key genes and signaling pathways related to the pathogenesis of VIDD. We further performed quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting to verify the results of snRNA-seq. The snRNA-seq results showed that acute postmechanical ventilation diaphragm cell changes included an increase in the proportion of fibroblasts and a decrease in the proportion of myofibres. The DEGs, KEGG, hdWGCNA and pseudotime analyses demonstrated that fibro-adipogenic progenitor (FAP) proliferation, endothelial-mesenchymal transition (EndMT) and immune cell infiltration are the three main processes involved in early stage of fibrosis development, among which Pdgfd, Sema3a, Cxcr2, are the corresponding regulatory genes. Glycolysis and the gene Pfkfb3 are also important metabolic factors for fibrosis formation. Negr1 and Mef2c are involved in phrenic nerve ending loss and diaphragm fibre atrophy. The qRT-PCR data showed that the mRNA levels of the genes Pdgfd, Cxcr2, Pfkfb3 and Negr1 were significantly greater in the experimental group than in the control group (P < 0.01), and the expression levels of Sema3a and Mef2c were significantly lower (P < 0.01). Despite limitations, including the lack of functional evaluations to confirm ventilator-induced diaphragm dysfunction (VIDD) and the absence of data validating diaphragm unloading during ventilation, our findings suggest that FAP proliferation and immune cell infiltration may play a role in the early stage of driving diaphragm fibrosis during mechanical ventilation. However, future studies are needed to confirm these findings and investigate the potential mechanisms underlying them.
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Project description:To investigate the effect of mechanical ventilation and mechanical ventilationon with PEEP application on diaphragmatic dysfunction, we established a model of mechanical ventilation on New Zealand rabbit, in which rabbits in the experimental group were ventilated with/without PEEP application for 48 hours continuously
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Project description:To explore the downstream mechanisms of Notch2 induced M2 macrophage polarization during mechanical ventilation, the BMDMs-treated with exosomes for non-cyclical-stretched or cyclical-stretced epithelial cells for 12 h were subjected to RNA-seq.
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Project description:This series contain mouse and rat lung samples treated with mechanical ventilation and corresponded controls.
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Project description:Children have a lower incidence and mortality from acute lung injury than adults, and infections are the most common event associated with acute lung injury (ALI). To study the effects of age on susceptibility to ALI, we investigated the responses to microbial products combined with mechanical ventilation in juvenile (21 day) and adult (16 week-old) mice. We hypothesized that the increased incidence and severity of lung injury associated with increasing age is due in large part to acquired changes in the way in which inflammatory responses are activated in the lungs in response to microbial products and mechanical ventilation. Juvenile (21 day) and adult (16 week) C57BL/6 mice were treated with an aerosol of E. coli 0111:B4 lipopolysaccharide (LPS) (20 mL of 0.1 mg/mL) for 30 minutes in a sealed aerosol chamber, immediately followed by mechanical ventilation (LPS+MV) using tidal volume = 15 mL/kg, rate = 80 breaths/min, FiO2 = 30% and positive end expiratory pressure = 2 cm H2O for the duration of the study period time = 2 hours. Comparison groups included mice treated with LPS or mechanical ventilation (MV) alone, and untreated age-matched controls. There were N = 4 animals per group except the juvenile mice treated with MV alone and LPS+MV where there were N = 3. Each sample was an individual animal, therefore there were 30 samples. Mice treated with LPS alone were placed into a sealed aerosol chamber as stated above, and then allowed to breath spontaneously with free access to food and water for the duration of the study period time = 2 hours. Mice treated with MV alone were treated with the mechanical ventilation protocol stated above for the duration of the study period time = 2 hours. At the end of the study period, the mice were euthanized, and the lungs were immediately removed and placed into RNAlater (Ambion, Austin, TX) for at least 24 hr prior to isolation of total lung mRNA.
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