Defibrotide mitigates endothelial cell injury induced by plasmas from patients with COVID-19 and related vasculopathies.

Autor: Elhadad S; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, United States of America., Redmond D; Division of Regenerative Medicine, Hartman Institute fort Therapeutic Organ Regeneration, Ansary Stem Cell Institute, United States of America., Tan A; Genomics Resources Core Facility, Weill Cornell Medicine, United States of America., Huang J; Division of Regenerative Medicine, Hartman Institute fort Therapeutic Organ Regeneration, Ansary Stem Cell Institute, United States of America., Rodriguez BL; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, United States of America., Racine-Brzostek SE; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, United States of America., Subrahmanian S; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America., Ahamed J; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America., Laurence J; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, United States of America. Electronic address: jlaurenc@med.cornell.edu.
Jazyk: angličtina
Zdroj: Thrombosis research [Thromb Res] 2023 May; Vol. 225, pp. 47-56. Date of Electronic Publication: 2023 Mar 23.
DOI: 10.1016/j.thromres.2023.03.009
Abstrakt: 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.
Competing Interests: Declaration of competing interest JL has received grants from Jazz Pharmaceuticals, manufacturer of defibrotide, and grants and honoraria from Alexion, Inc. and Omeros, Inc. The remaining authors declare no competing financial interests.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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