| Defibrotide interferes with several steps of the coagulation-inflammation cycle and exhibits therapeutic potential to treat severe malaria. | |
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MedLine Citation:
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PMID: 22116094 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), a mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities and has been successfully used to treat comatose children with veno-occlusive disease. DF was investigated here as a drug to treat cerebral malaria. METHODS AND RESULTS: DF blocks tissue factor expression by ECs incubated with parasitized red blood cells and attenuates prothrombinase activity, platelet aggregation, and complement activation. In contrast, it does not affect nitric oxide bioavailability. We also demonstrated that Plasmodium falciparum glycosylphosphatidylinositol (Pf-GPI) induces tissue factor expression in ECs and cytokine production by dendritic cells. Notably, dendritic cells, known to modulate coagulation and inflammation systemically, were identified as a novel target for DF. Accordingly, DF inhibits Toll-like receptor ligand-dependent dendritic cells activation by a mechanism that is blocked by adenosine receptor antagonist (8-p-sulfophenyltheophylline) but not reproduced by synthetic poly-A, -C, -T, and -G. These results imply that aptameric sequences and adenosine receptor mediate dendritic cells responses to the drug. DF also prevents rosetting formation, red blood cells invasion by P. falciparum and 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. CONCLUSION: Therapeutic use of DF in malaria is proposed. |
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Authors:
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Ivo M B Francischetti; Carlo J Oliveira; Graciela R Ostera; Stephanie B Yager; Françoise Debierre-Grockiego; Vanessa Carregaro; Giovanna Jaramillo-Gutierrez; Jen C C Hume; Lubin Jiang; Samuel E Moretz; Christina K Lin; José M C Ribeiro; Carole A Long; Brandi K Vickers; Ralph T Schwarz; Karl B Seydel; Massimo Iacobelli; Hans C Ackerman; Prakash Srinivasan; Regis B Gomes; Xunde Wang; Robson Q Monteiro; Michail Kotsyfakis; Anderson Sá-Nunes; Michael Waisberg |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2011-11-23 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 32 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-02-20 Completed Date: 2012-04-13 Revised Date: 2013-04-15 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 786-98 Citation Subset: IM |
Affiliation:
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Section of Vector Biology, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ifrancischetti@niaid.nih.gov |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Inflammatory Agents / pharmacology* Anticoagulants / pharmacology* Antimalarials / pharmacology* Blood Coagulation / drug effects* Cells, Cultured Complement Activation / drug effects Cytokines / blood Dendritic Cells / drug effects, immunology, parasitology Disease Models, Animal Dose-Response Relationship, Drug Endothelial Cells / drug effects*, immunology, metabolism, parasitology Female Glycosylphosphatidylinositols / metabolism Hemoglobins / metabolism Humans Inflammation Mediators / blood Malaria, Cerebral / blood, drug therapy*, immunology, parasitology Mice Mice, Inbred BALB C Mice, Inbred C57BL Nitric Oxide / metabolism Plasmodium berghei / drug effects*, pathogenicity Plasmodium falciparum / drug effects*, growth & development, metabolism, pathogenicity Platelet Aggregation / drug effects Polydeoxyribonucleotides / pharmacology* Receptors, Purinergic P1 / drug effects, metabolism Severity of Illness Index Thromboplastin / metabolism Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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Z01 AI000810-11/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents; 0/Anticoagulants; 0/Antimalarials; 0/Cytokines; 0/Glycosylphosphatidylinositols; 0/Hemoglobins; 0/Inflammation Mediators; 0/Polydeoxyribonucleotides; 0/Receptors, Purinergic P1; 10102-43-9/Nitric Oxide; 83712-60-1/defibrotide; 9035-58-9/Thromboplastin |
| Comments/Corrections | |
Comment In:
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Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):541-4
[PMID:
22345588
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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