Defibrotide mitigates endothelial cell injury induced by plasmas from patients with COVID-19 and related vasculopathies
Copyright © 2023 Elsevier Ltd. All rights reserved..
BACKGROUND AND OBJECTIVES: COVID-19 progression is characterized by systemic small vessel arterial and venous thrombosis. Microvascular endothelial cell (MVEC) activation and injury, platelet activation, and histopathologic features characteristic of acute COVID-19 also describe certain thrombotic microangiopathies, including atypical hemolytic-uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP), and hematopoietic stem cell transplant (HSCT)-associated veno-occlusive disease (VOD). We explored the effect of clinically relevant doses of defibrotide, approved for HSCT-associated VOD, on MVEC activation/injury.
METHODS: Human dermal MVEC were exposed to plasmas from patients with acute TMAs or acute COVID-19 in the presence and absence of defibrotide (5μg/ml) and caspase 8, a marker of EC activation and apoptosis, was assessed. RNAseq was used to explore potential mechanisms of defibrotide activity.
RESULTS: Defibrotide suppressed TMA plasma-induced caspase 8 activation in MVEC (mean 60.2 % inhibition for COVID-19; p = 0.0008). RNAseq identified six major cellular pathways associated with defibrotide's alteration of COVID-19-associated MVEC changes: TNF-α signaling; IL-17 signaling; extracellular matrix (ECM)-EC receptor and platelet receptor interactions; ECM formation; endothelin activity; and fibrosis. Communications across these pathways were revealed by STRING analyses. Forty transcripts showing the greatest changes induced by defibrotide in COVID-19 plasma/MVEC cultures included: claudin 14 and F11R (JAM), important in maintaining EC tight junctions; SOCS3 and TNFRSF18, involved in suppression of inflammation; RAMP3 and transgelin, which promote angiogenesis; and RGS5, which regulates caspase activation and apoptosis.
CONCLUSION: Our data, in the context of a recent clinical trial in severe COVID-19, suggest benefits to further exploration of defibrotide and these pathways in COVID-19 and related endotheliopathies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:225 |
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| Enthalten in: |
Thrombosis research - 225(2023) vom: 30. Mai, Seite 47-56 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Elhadad, Sonia [VerfasserIn] |
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| Links: |
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| Themen: |
438HCF2X0M |
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| Anmerkungen: |
Date Completed 01.05.2023 Date Revised 08.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.thromres.2023.03.009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM355061643 |
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| 245 | 1 | 0 | |a Defibrotide mitigates endothelial cell injury induced by plasmas from patients with COVID-19 and related vasculopathies |
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| 500 | |a Date Revised 08.05.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Ltd. All rights reserved. | ||
| 520 | |a BACKGROUND AND OBJECTIVES: COVID-19 progression is characterized by systemic small vessel arterial and venous thrombosis. Microvascular endothelial cell (MVEC) activation and injury, platelet activation, and histopathologic features characteristic of acute COVID-19 also describe certain thrombotic microangiopathies, including atypical hemolytic-uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP), and hematopoietic stem cell transplant (HSCT)-associated veno-occlusive disease (VOD). We explored the effect of clinically relevant doses of defibrotide, approved for HSCT-associated VOD, on MVEC activation/injury | ||
| 520 | |a METHODS: Human dermal MVEC were exposed to plasmas from patients with acute TMAs or acute COVID-19 in the presence and absence of defibrotide (5μg/ml) and caspase 8, a marker of EC activation and apoptosis, was assessed. RNAseq was used to explore potential mechanisms of defibrotide activity | ||
| 520 | |a RESULTS: Defibrotide suppressed TMA plasma-induced caspase 8 activation in MVEC (mean 60.2 % inhibition for COVID-19; p = 0.0008). RNAseq identified six major cellular pathways associated with defibrotide's alteration of COVID-19-associated MVEC changes: TNF-α signaling; IL-17 signaling; extracellular matrix (ECM)-EC receptor and platelet receptor interactions; ECM formation; endothelin activity; and fibrosis. Communications across these pathways were revealed by STRING analyses. Forty transcripts showing the greatest changes induced by defibrotide in COVID-19 plasma/MVEC cultures included: claudin 14 and F11R (JAM), important in maintaining EC tight junctions; SOCS3 and TNFRSF18, involved in suppression of inflammation; RAMP3 and transgelin, which promote angiogenesis; and RGS5, which regulates caspase activation and apoptosis | ||
| 520 | |a CONCLUSION: Our data, in the context of a recent clinical trial in severe COVID-19, suggest benefits to further exploration of defibrotide and these pathways in COVID-19 and related endotheliopathies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a Defibrotide | |
| 650 | 4 | |a Endothelial cell | |
| 650 | 4 | |a Long COVID | |
| 650 | 4 | |a Thrombosis | |
| 650 | 4 | |a Vasculopathy | |
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| 650 | 7 | |a Anticoagulants |2 NLM | |
| 700 | 1 | |a Redmond, David |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Adrian |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jenny |e verfasserin |4 aut | |
| 700 | 1 | |a Rodriguez, Beatriz Lorenzo |e verfasserin |4 aut | |
| 700 | 1 | |a Racine-Brzostek, Sabrina E |e verfasserin |4 aut | |
| 700 | 1 | |a Subrahmanian, Sandeep |e verfasserin |4 aut | |
| 700 | 1 | |a Ahamed, Jasimuddin |e verfasserin |4 aut | |
| 700 | 1 | |a Laurence, Jeffrey |e verfasserin |4 aut | |
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