ArticleJCI insight2021
Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 33 citations in OpenAlex.
- Defibrotide Therapy for SARS-CoV-2 ARDS.Chest · 2022Trial
- Epigenetic Regulation of the NET Formation-Blood-Brain Barrier Axis in Ischemic Stroke: Mechanisms, Therapeutic Targets and Translational Perspectives.Neurology international · 2026Review
- Neutrophils and NETosis in polycystic ovary syndrome: unraveling the immuno-metabolic thromboinflammatory axis.European journal of medical research · 2026Review
- Cardioprotective effects of the extracellular chaperone clusterin in acute myocardial infarction.European journal of clinical investigation · 2025Article
- Identification and validation of hub genes related to neutrophil extracellular traps-mediated cell damage and immune recruitment during abdominal aortic aneurysm.Scientific reports · 2025Article
- Defibrotide for Protecting Against and Managing Endothelial Injury in Hematologic Malignancies and COVID-19.Biomolecules · 2025Review
- Article
- Identification and Validation of Hub Genes Related to Neutrophil Extracellular Traps-Mediated Cell Damage During Myocardial Infarction.Journal of inflammation research · 2024Article
- Emerging therapeutic strategies targeting extracellular histones for critical and inflammatory diseases: an updated narrative review.Frontiers in immunology · 2024Review
- Inhibition of neutrophil extracellular trap formation alleviates vascular dysfunction in type 1 diabetic mice.Science advances · 2023Article
- The Polyanionic Drug Suramin Neutralizes Histones and Prevents Endotheliopathy.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- Defibrotide modulates pulmonary endothelial cell activation and protects against lung inflammation in pre-clinical models of LPS-induced lung injury and idiopathic pneumonia syndrome.Frontiers in immunology · 2023Article
- Bystander effect of SARS-CoV-2 spike protein on human monocytic THP-1 cell activation and initiation of prothrombogenic stimulus representing severe COVID-19.Journal of inflammation (London, England) · 2022Article
- Endothelial Cell-Activating Antibodies in COVID-19.Arthritis & rheumatology (Hoboken, N.J.) · 2022Article
- Exploratory Investigation of the Plasma Proteome Associated with the Endotheliopathy of Trauma.International journal of molecular sciences · 2022Article
- Endothelial Dysfunction Induced by Extracellular Neutrophil Traps Plays Important Role in the Occurrence and Treatment of Extracellular Neutrophil Traps-Related Disease.International journal of molecular sciences · 2022Review
- Cardiovascular signatures of COVID-19 predict mortality and identify barrier stabilizing therapies.EBioMedicine · 2022Article
- Do Circulating Histones Represent the Missing Link among COVID-19 Infection and Multiorgan Injuries, Microvascular Coagulopathy and Systemic Hyperinflammation?Journal of clinical medicine · 2022Article
- Defibrotide inhibits NET-mediated thrombosis in APS models.Nature reviews. Rheumatology · 2022Article
- Fundamentals in Covid-19-Associated Thrombosis: Molecular and Cellular Aspects.Frontiers in cardiovascular medicine · 2021Review
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Authors and funding
16 authors at 3 institutions in 3 countries.
Funding
Abstract
Neutrophil-mediated activation and injury of the endothelium play roles in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap-derived [NET-derived] histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the US Food and Drug Administration-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.