Sepsis decreases lung SVEP1 expression in a murine model
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ABSTRACT:
ORGANISM(S): Mus musculus (mouse)
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PROVIDER: S-BSST942 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:BackgroundBloodstream infections with antibiotic-resistant Pseudomonas aeruginosa are common and increasingly difficult to treat. Pyocins are naturally occurring protein antibiotics produced by P. aeruginosa that have potential for human use.ObjectivesTo determine if pyocin treatment is effective in a murine model of sepsis with P. aeruginosa.MethodsRecombinant pyocins S5 and AP41 were purified and tested for efficacy in a Galleria mellonella infection model and a murine model of P. aeruginosa sepsis.ResultsBoth pyocins produced no adverse effects when injected alone into mice and showed good in vitro antipseudomonal activity. In an invertebrate model of sepsis using G. mellonella, both pyocins significantly prolonged survival from 1/10 (10%) survival in controls to 80%-100% survival among groups of 10 pyocin-treated larvae. Following injection into mice, both showed extensive distribution into different organs. When administered 5 h after infection, pyocin S5 significantly increased survival from 33% (2/6) to 83% (5/6) in a murine model of sepsis (difference significant by log-rank test, P < 0.05).ConclusionsPyocins S5 and AP41 show in vivo biological activity and can improve survival in two models of P. aeruginosa infection. They hold promise as novel antimicrobial agents for treatment of MDR infections with this microbe.
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Project description:BackgroundMechanical ventilation could lead to ventilator-induced lung injury (VILI), but its underlying pathogenesis remains largely unknown. In this study, we aimed to determine the genes which were highly correlated with VILI as well as their expressions and interactions by analyzing the differentially expressed genes (DEGs) between the VILI samples and controls.MethodsGSE11434 was downloaded from the gene expression omnibus (GEO) database, and DEGs were identified with GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using DAVID. Next, we used the STRING tool to construct protein-protein interaction (PPI) network of the DEGs. Then, the hub genes and related modules were identified with the Cytoscape plugins: cytoHubba and MCODE. qRT-PCR was further used to validate the results in the GSE11434 dataset. We also applied gene set enrichment analysis (GSEA) to discern the gene sets that had a significant difference between the VILI group and the control. Hub genes were also subjected to analyses by CyTargetLinker and NetworkAnalyst to predict associated miRNAs and transcription factors (TFs). Besides, we used CIBERSORT to detect the contributions of different types of immune cells in lung tissues of mice in the VILI group. By using DrugBank, small molecular compounds that could potentially interact with hub genes were identified.ResultsA total of 141 DEGs between the VILI group and the control were identified in GSE11434. Then, seven hub genes were identified and were validated by using qRT-PCR. Those seven hub genes were largely enriched in TLR and JAK-STAT signaling pathways. GSEA showed that VILI-associated genes were also enriched in NOD, antigen presentation, and chemokine pathways. We predicted the miRNAs and TFs associated with hub genes and constructed miRNA-TF-gene regulatory network. An analysis with CIBERSORT showed that the proportion of M0 macrophages and activated mast cells was higher in the VILI group than in the control. Small molecules, like nadroparin and siltuximab, could act as potential drugs for VILI.ConclusionIn sum, a number of hub genes associated with VILI were identified and could provide novel insights into the pathogenesis of VILI and potential targets for its treatment.
| S-EPMC8049808 | biostudies-literature
Project description:Oxidative mitochondrial damage is closely linked to inflammation and cell death, but low levels of reactive oxygen and nitrogen species serve as signals that involve mitochondrial repair and resolution of inflammation. More specifically, cytoprotection relies on the elimination of damaged mitochondria by selective autophagy (mitophagy) during mitochondrial quality control. This aim of this study was to identify and localize mitophagy in the mouse lung as a potentially upregulatable redox response to Staphylococcus aureus sepsis. Fibrin clots loaded with S. aureus (1×10(7) CFU) were implanted abdominally into anesthetized C57BL/6 and B6.129X1-Nfe2l2tm1Ywk/J (Nrf2(-/-)) mice. At the time of implantation, mice were given vancomycin (6mg/kg) and fluid resuscitation. Mouse lungs were harvested at 0, 6, 24, and 48h for bronchoalveolar lavage (BAL), Western blot analysis, and qRT-PCR. To localize mitochondria with autophagy protein LC3, we used lung immunofluorescence staining in LC3-GFP transgenic mice. In C57BL/6 mice, sepsis-induced pulmonary inflammation was detected by significant increases in mRNA for the inflammatory markers IL-1? and TNF-? at 6 and 24h, respectively. BAL cell count and protein also increased. Sepsis suppressed lung Beclin-1 protein, but not mRNA, suggesting activation of canonical autophagy. Notably sepsis also increased the LC3-II autophagosome marker, as well as the lung?s noncanonical autophagy pathway as evidenced by loss of p62, a redox-regulated scaffolding protein of the autophagosome. In LC3-GFP mouse lungs, immunofluorescence staining showed colocalization of LC3-II to mitochondria, mainly in type 2 epithelium and alveolar macrophages. In contrast, marked accumulation of p62, as well as attenuation of LC3-II in Nrf2-knockout mice supported an overall decrease in autophagic turnover. The downregulation of canonical autophagy during sepsis may contribute to lung inflammation, whereas the switch to noncanonical autophagy selectively removes damaged mitochondria and accompanies tissue repair and cell survival. Furthermore, mitophagy in the alveolar region appears to depend on activation of Nrf2. Thus, efforts to promote mitophagy may be a useful therapeutic adjunct for acute lung injury in sepsis.
| S-EPMC4284964 | biostudies-literature
Project description:Animal models of sepsis exhibit considerable variability in the temporal development of the physiologic response, which reduces the power of studies, particularly if interventions are tested at arbitrary time points. We developed a biotelemetry-based model of cecal ligation and puncture (CLP) that standardizes the testing of time-sensitive therapies to specific criteria of physiologic deterioration. In this study we seek to further define the variability in physiologic response to CLP sepsis and conduct a cost analysis detailing the potential for reducing animal usage. We have further characterized the variability in physiologic response after CLP in mice and determined peaks in the temporal distribution of points of physiologic decline. Testing therapies at physiologic thresholds reduces the variability found in historical fixed time-based models. Though initial cost is higher with biotelemetry, this is eventually offset by the significantly reduced number of mice needed to conduct physiologically relevant sepsis experiments.
| S-EPMC5529427 | biostudies-literature
Project description:BackgroundPericytes are vascular mural cells and are embedded in the basement membrane of the microvasculature. Recent studies suggest a role for pericytes in lipopolysaccharide (LPS)-induced microvascular dysfunction and mortality, but the mechanisms of pericyte loss in sepsis are largely unknown.MethodsBy using a cecal ligation and puncture (CLP)-induced murine model of sepsis, we observed that CLP led to lung and renal pericyte loss and reduced lung pericyte density and pericyte/endothelial cell (EC) coverage.ResultsUp-regulated Friend leukemia virus integration 1 (Fli-1) messenger ribonucleic acid (RNA) and protein levels were found in lung pericytes from CLP mice in vivo and in LPS-stimulated lung pericytes in vitro. Knockout of Fli-1 in Foxd1-derived pericytes prevented CLP-induced pericyte loss, vascular leak, and improved survival. Disrupted Fli-1 expression by small interfering RNA inhibited LPS-induced inflammatory cytokines and chemokines in cultured lung pericytes. Furthermore, CLP-induced pericyte pyroptosis was mitigated in pericyte Fli-1 knockout mice.ConclusionsOur findings suggest that Fli-1 is a potential therapeutic target in sepsis.
| S-EPMC6217724 | biostudies-literature
Project description: Not available
| S-EPMC9732707 | biostudies-literature
Project description:Bacterial invasion during sepsis induces disregulated systemic responses that could lead to fatal lung failure. The purpose of this study was to relate the temporal dynamics of gene expression to the pathophysiological changes in the lung during the first and second stages of E. coli sepsis in baboons.Using human oligonucleotide microarrays, we have explored the temporal changes of gene expression in the lung of baboons challenged with sublethal doses of E. coli. Temporal expression pattern and biological significance of the differentially expressed genes were explored using clustering and pathway analysis software. Expression of selected genes was validated by real-time PCR. Cytokine levels in tissue and plasma were assayed by multiplex ELISA. Changes in lung ultrastructure were visualized by electron microscopy. We found that genes involved in primary inflammation, innate immune response, and apoptosis peaked at 2 hrs. Inflammatory and immune response genes that function in the stimulation of monocytes, natural killer and T-cells, and in the modulation of cell adhesion peaked at 8 hrs, while genes involved in wound healing and functional recovery were upregulated at 24 hrs.The analysis of gene expression modulation in response to sepsis provides the baseline information that is crucial for the understanding of the pathophysiology of systemic inflammation and may facilitate the development of future approaches for sepsis therapy.
| S-EPMC1819384 | biostudies-literature
Project description:Influenza virus causes a respiratory disease in humans that can progress to lung injury with fatal outcome. The interleukin (IL)-36 cytokines are newly described IL-1 family cytokines that promote inflammatory responses via binding to the IL-36 receptor (IL-36R). The mechanism of expression and the role of IL-36 cytokines are poorly understood. Here, we investigated the role of IL-36 cytokines in modulating the innate inflammatory response during influenza virus-induced pneumonia in mice. The intranasal administration of influenza virus upregulated IL-36? mRNA and protein production in the lungs. In vitro, influenza virus-mediated IL-36? but not IL-36? is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36? was detected in microparticles shed from AECs and promoted the production of pro-inflammatory cytokines and chemokines in respiratory cells. IL-36R-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced early accumulation of neutrophils and monocytes/macrophages, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines, and permeability of the alveolar-epithelial barrier in despite impaired viral clearance. Taken together, these data indicate that IL-36 ligands exacerbate lung injury during influenza virus infection.
| S-EPMC5471142 | biostudies-literature
Project description:Sepsis is a complex medical condition characterized by a systemic inflammatory response in the setting of infection. We hypothesized that combining antibiotics plus an immunosuppressant would protect against the morbidity and mortality of polymicrobial sepsis in mice better than would antibiotics alone. We used a murine cecal-ligation-and-puncture model in which mice were treated either with imipenem plus cyclophosphamide or imipenem alone. Titration to a low cyclophosphamide dose revealed that combination therapy increased survival by 20% compared with imipenem alone (56% vs. 36%, P < 0.001). To investigate the mechanism by which combination therapy did this, we reviewed quantitative and qualitative markers of the systemic immune response, end-organ damage, and the local immune response at the site of injury. Cyclophosphamide treatment was not associated with depletion of peripheral leukocytes or differences in pulmonary damage. However, mice that received combination therapy had higher plasma granulocyte colony-stimulating factor levels than did those treated with antibiotics alone. In addition, mice treated with cyclophosphamide had higher levels of bacterial colonization in intestinal Peyer's patch lymph nodes at 72 h after the septic insult. Intraperitoneal macrophage phenotypes and phagocytosis activity did not differ between groups. We conclude that the inflammatory response plays a significant role in the mortality of polymicrobial sepsis and that the regulation of this element is both feasible and beneficial in this disease model.
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Project description:Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal-dominant) forms with mutations in 1 of 3 gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell-cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase. Although Rho kinase inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo.Our recently generated a model of CCM1 disease (Ccm1(+/-)Msh2(-/-)) was treated with the Rho kinase inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals' brains. For comparison, we also assessed therapeutic effect in previously described Ccm2(+/-)Trp53(-/-) mice treated with the same dose and duration of fasudil and placebo.Fasudil-treated Ccm1(+/-)Msh2(-/-) mice had a significantly decreased prevalence of CCM lesions compared with placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation, and endothelial proliferation and exhibited decreased expression of Rho kinase activation biomarkers. A therapeutic effect was also documented in Ccm2(+/-)Trp53(-/-) mice.This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs and indicates that Rho kinase activation is a critical step in CCM lesion genesis and maturation.
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