Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria

0375991 - BC 2013 RIV US eng J - Journal Article
Francischetti, I.M.B. - Oliveira, C. J. - Ostera, G. R. - Yager, S. B. - Debierre-Grockiego, F. - Carregaro, V. - Jaramillo-Gutierrez, G. - Hume, J. C. C. - Jiang, L. - Moretz, S. E. - Lin, Ch. K. - Ribeiro, J.M.C. - Long, C. A. - Vickers, B. K. - Schwarz, R. T. - Seydel, K. B. - Iacobelli, M. - Ackerman, H. C. - Srinivasan, P. - Gomes, R. B. - Wang, X. - Monteiro, R.Q. - Kotsyfakis, Michalis - Sa-Nunes, A. - Waisberg, M.
Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria.
Arteriosclerosis Thrombosis and Vascular Biology. Roč. 32, č. 3 (2012), s. 786-798. ISSN 1079-5642. E-ISSN 1524-4636
Institutional research plan: CEZ:AV0Z60220518
Keywords : anticoagulants * blood coagulation * endothelium * microcirculation * vascular biology * malaria * defibrotide * inflammation
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 6.338, year: 2012

The therapeutic use of defibrotide (DF) in malaria is proposed. DF blocks the induction of endothelial tissue factor-mediated coagulation by parasitized red blood cells. At a concentration achievable in vivo, DF suppresses Toll-like receptors 4 and 2 agonist-driven proinflammatory cytokine production by dendritic cells (DCs). We demonstrate that DF directly decreases platelet aggregation and blocks the alternative complement pathway further proposing that DF may act through adenosine receptors. Accordingly, we observe that DF-exposed DCs produce prostaglandin E2 and have enhanced lipopolysaccharide-induced IL-10 secretion. DF blocks parasite invasion of red blood cells and rosetting and the agglutination of parasitized red blood cells. Finally, DF abolishes oocysts development in Anopheles gambiae; in a murine model of cerebral malaria, DF affected parasitemia, decreased IFN-γ levels, and ameliorated clinical score (day 5) with a trend for increased survival.
Permanent Link: http://hdl.handle.net/11104/0208512