Recombinant human thrombomodulin treatment against endotoxemia-induced myocardial injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE131437 | GEO | 2022/09/01
REPOSITORIES: GEO
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Project description:Recombinant humant thrombomodulin treatment against endotoxemia-induced acute respiratory distress syndrome (ARDS).
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Project description:Previously we had shown in a mouse model of bronchial asthma that thrombomodulin (TM; CD141; BDCA3) can convert immunogenic conventional dendritic cells into tolerogenic dendritic cells while inducing its own expression on the cell surface. Thrombomodulin+ dendritic cells are tolerogenic while thrombomodulin- dendritic cells are pro-inflammatory and immunogenic. Here we hypothesized that thrombomodulin treatment of dendritic cells would modulate inflammatory gene expression. Murine bone marrow derived dendritic cells were treated with soluble thrombomodulin and expression of surface markers was determined. Treatment with thrombomodulin reduces the expression of maturation markers and increases the expression of TM on the DC surface. Thrombomodulin treated and control dendritic cells were sorted into thrombomodulin+ and thrombomodulin- dendritic cells before their mRNA was analyzed by microarray. mRNAs encoding pro-inflammatory genes and dendritic cells maturation markers were reduced while cell cycle genes were increased in thrombomodulin-treated and thrombomodulin+ dendritic cells compared to control dendritic cells and thrombomodulin- dendritic cells. We compared the effects on global gene expression of treating dendritic cells with soulble thrombomodulin to no treatment, and dendritic cells separated into thrombomodulin+ and thrombomodulin- dendritic cell subsets.
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2024-01-24 | GSE231707 | GEO
Project description:Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis. Here, we identify thrombomodulin signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, thrombomodulin is rapidly upregulated and maintained throughout all phases of the senescent program in aged mammalian tissues and in senescent cell models. Mechanistically, thrombomodulin activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescent program and ensuring senescent cell viability. Therapeutically, thrombomodulin signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic thrombomodulin signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.
2023-05-22 | GSE228941 | GEO
Project description:Myocardial infarction is a leading cause of mortality worldwide 1 . While advances have been made
in acute treatment, an incomplete understanding of remodelling processes has limited the
effectiveness of therapies to reduce late-stage mortality 2 . Here, we generate an integrative high-
resolution map of human cardiac remodelling after myocardial infarction using single-cell gene
expression, chromatin accessibility, and spatial transcriptomic profiling of multiple physiological
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continuum following ischemic injury. In total, our study provides an integrative molecular map of
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Project description:IntroductionRecent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM). rTM has been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan, and is currently undergoing a phase III clinical trial in the United States.MethodsHistone H3 levels in plasma of healthy volunteers and patients with sepsis and DIC were measured using enzyme-linked immunosorbent assay. Male C57BL/6 mice were injected intravenously with purified histones, and pathological examinations were performed. The protective effects of rTM against histone toxicity were analyzed both in vitro and in mice.ResultsHistone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. These levels were higher in non-survivors than in survivors. Extracellular histones triggered platelet aggregation, leading to thrombotic occlusion of pulmonary capillaries and subsequent right-sided heart failure in mice. These mice displayed symptoms of DIC, including thrombocytopenia, prolonged prothrombin time, decreased fibrinogen, fibrin deposition in capillaries, and bleeding. Platelet depletion protected mice from histone-induced death in the first 30 minutes, suggesting that vessel occlusion by platelet-rich thrombi might be responsible for death during the early phase. Furthermore, rTM bound to extracellular histones, suppressed histone-induced platelet aggregation, thrombotic occlusion of pulmonary capillaries, and dilatation of the right ventricle, and rescued mice from lethal thromboembolism.ConclusionsExtracellular histones cause massive thromboembolism associated with consumptive coagulopathy, which is diagnostically indistinguishable from DIC. rTM binds to histones and neutralizes the prothrombotic action of histones. This may contribute to the effectiveness of rTM against DIC.
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Project description:Recombinant Anti-thrombin treatment against endotoxemia-induced acute respiratory distress syndrome (ARDS).
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Project description:Cardiac injury following myocardial infarction exhibits a circadian pattern, yet the underlying mechanism remains unclear. To elucidate genes governing circadian variation of myocardial injury, we conducted transcriptomic profiling of left-ventricular tissues from mice or humans experiencing myocardial injury at different daytimes. Through comprehensive analyses, including transgenic mouse models and functional studies, we identified BMAL1 as a pivotal transcription factor modulating diurnal variation of myocardial injury. Remarkably, we discovered that BMAL1 regulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with HIF2A. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2F/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1. Furthermore, we confirmed amphiregulin (AREG) as a transcriptional target of the BMAL1/HIF2A heterodimer, critical for modulating circadian variation of myocardial injury. Finally, targeting the BMAL1/HIF2A-AREG pathway via timed AREG administration or enhancing circadian rhythm pharmacologically offered significant cardioprotection, implicating this pathway in treating ischemic heart disease.
2024-03-20 | GSE255307 | GEO