Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria
Identifieur interne : 000A77 ( Main/Exploration ); précédent : 000A76; suivant : 000A78Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria
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Abstract
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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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria</title><author><name sortKey="Francischetti, Ivo M B" uniqKey="Francischetti I">Ivo M. B. Francischetti</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Oliveira, Carlo J" uniqKey="Oliveira C">Carlo J. Oliveira</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Instituto de Ciencias Biológicas e Naturais, Universidade Federal do Triangulo Mineiro</s1><s2>Uberaba</s2><s3>BRA</s3><sZ>2 aut.</sZ></inist:fA14><country>Brésil</country><wicri:noRegion>Uberaba</wicri:noRegion></affiliation></author><author><name sortKey="Ostera, Graciela R" uniqKey="Ostera G">Graciela R. Ostera</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Yager, Stephanie B" uniqKey="Yager S">Stephanie B. Yager</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>11 aut.</sZ><sZ>14 aut.</sZ><sZ>25 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Debierre Grockiego, Francoise" uniqKey="Debierre Grockiego F">Françoise Debierre-Grockiego</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Institute for Virology, Laboratory of Parasitology, Philipps-University</s1><s2>Marburg</s2><s3>DEU</s3><sZ>5 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Giessen</region><settlement type="city">Marbourg</settlement></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Parasite Immunology, Vaccinology and Anti-infectious Biotherapy</s1><s2>Tours</s2><s3>FRA</s3><sZ>5 aut.</sZ></inist:fA14><country>France</country><placeName><region type="région">Région Centre</region><settlement type="city">Tours</settlement></placeName></affiliation></author><author><name sortKey="Carregaro, Vanessa" uniqKey="Carregaro V">Vanessa Carregaro</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="06"><s1>Departamento de Farmacologia and Departamento de Imunologia , Universidade de São Paulo</s1><s2>Ribeirao Preto</s2><s3>BRA</s3><sZ>6 aut.</sZ></inist:fA14><country>Brésil</country><placeName><settlement type="city">São Paulo</settlement><region type="state">État de São Paulo</region></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Jaramillo Gutierrez, Giovanna" uniqKey="Jaramillo Gutierrez G">Giovanna Jaramillo-Gutierrez</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Hume, Jen C C" uniqKey="Hume J">Jen C. C Hume</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="07"><s1>Seattle Biomedical Research Institute</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de Washington</region></placeName></affiliation></author><author><name>LUBIN JIANG</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Moretz, Samuel E" uniqKey="Moretz S">Samuel E. Moretz</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Lin, Christina K" uniqKey="Lin C">Christina K. Lin</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>11 aut.</sZ><sZ>14 aut.</sZ><sZ>25 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Ribeiro, Jose M C" uniqKey="Ribeiro J">José M. C. Ribeiro</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Long, Carole A" uniqKey="Long C">Carole A. Long</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Vickers, Brandi K" uniqKey="Vickers B">Brandi K. Vickers</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>11 aut.</sZ><sZ>14 aut.</sZ><sZ>25 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Schwarz, Ralph T" uniqKey="Schwarz R">Ralph T. Schwarz</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Institute for Virology, Laboratory of Parasitology, Philipps-University</s1><s2>Marburg</s2><s3>DEU</s3><sZ>5 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Giessen</region><settlement type="city">Marbourg</settlement></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Unit of Structural and Functional Glycobiology , Universite Lille Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>15 aut.</sZ></inist:fA14><country>France</country><placeName><region type="région">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Seydel, Karl B" uniqKey="Seydel K">Karl B. Seydel</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="09"><s1>Department of Medicine, College of Osteopathic Medicine, Michigan State University</s1><s2>East Lansing, MI</s2><s3>USA</s3><sZ>16 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Michigan</region></placeName></affiliation></author><author><name sortKey="Iacobelli, Massimo" uniqKey="Iacobelli M">Massimo Iacobelli</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Gentium SpA, villa Guardia</s1><s2>Como</s2><s3>ITA</s3><sZ>17 aut.</sZ></inist:fA14><country>Italie</country><wicri:noRegion>Como</wicri:noRegion></affiliation></author><author><name sortKey="Ackerman, Hans C" uniqKey="Ackerman H">Hans C. Ackerman</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Srinivasan, Prakash" uniqKey="Srinivasan P">Prakash Srinivasan</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Gomes, Regis B" uniqKey="Gomes R">Regis B. Gomes</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name>XUNDE WANG</name><affiliation wicri:level="2"><inist:fA14 i1="11"><s1>Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>21 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Monteiro, Robson Q" uniqKey="Monteiro R">Robson Q. Monteiro</name><affiliation wicri:level="3"><inist:fA14 i1="12"><s1>Instituto de Bioquimica Medica, Universidade Federal do Rio de Janeiro</s1><s2>Rio de Janeiro</s2><s3>BRA</s3><sZ>22 aut.</sZ></inist:fA14><country>Brésil</country><placeName><settlement type="city">Rio de Janeiro</settlement><region type="state">État de Rio de Janeiro</region></placeName></affiliation></author><author><name sortKey="Kotsyfakis, Michail" uniqKey="Kotsyfakis M">Michail Kotsyfakis</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="13"><s1>Institute of Parasitology, Biology Centre of the Academy of Sciences of Czech Republic</s1><s2>Ceske Budejovice</s2><s3>CZE</s3><sZ>23 aut.</sZ></inist:fA14><country>République tchèque</country><wicri:noRegion>Ceske Budejovice</wicri:noRegion></affiliation></author><author><name sortKey="Sa Nunes, Anderson" uniqKey="Sa Nunes A">Anderson Sa-Nunes</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="14"><s1>Departamento de Imunologia, Instituto de Ciencias Biomédicas, Universidade de São Paulo</s1><s2>São Paulo</s2><s3>BRA</s3><sZ>24 aut.</sZ></inist:fA14><country>Brésil</country><placeName><settlement type="city">São Paulo</settlement><region type="state">État de São Paulo</region></placeName><orgName type="university">Université de São Paulo</orgName></affiliation></author><author><name sortKey="Waisberg, Michael" uniqKey="Waisberg M">Michael Waisberg</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>11 aut.</sZ><sZ>14 aut.</sZ><sZ>25 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="inist">12-0108818</idno><date when="2012">2012</date><idno type="stanalyst">PASCAL 12-0108818 INIST</idno><idno type="RBID">Pascal:12-0108818</idno><idno type="wicri:Area/Main/Corpus">000C96</idno><idno type="wicri:Area/Main/Curation">001C00</idno><idno type="wicri:Area/Main/Exploration">000A77</idno></publicationStmt><seriesStmt><idno type="ISSN">1079-5642</idno><title level="j" type="abbreviated">Arterioscler. thromb. vasc. biol.</title><title level="j" type="main">Arteriosclerosis, thrombosis, and vascular biology</title></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Anticoagulant</term><term>Atherosclerosis</term><term>Blood coagulation</term><term>Cardiovascular disease</term><term>Defibrotide</term><term>Endothelium</term><term>Fibrinolytic</term><term>Inflammation</term><term>Malaria</term><term>Microcirculation</term><term>Treatment</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Paludisme</term><term>Pathologie de l'appareil circulatoire</term><term>Athérosclérose</term><term>Défibrotide</term><term>Inflammation</term><term>Traitement</term><term>Anticoagulant</term><term>Coagulation sanguine</term><term>Endothélium</term><term>Microcirculation</term><term>Fibrinolytique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>1079-5642</s0></fA01><fA02 i1="01"><s0>ATVBFA</s0></fA02><fA03 i2="1"><s0>Arterioscler. thromb. vasc. biol.</s0></fA03><fA05><s2>32</s2></fA05><fA06><s2>3</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria</s1></fA08><fA11 i1="01" i2="1"><s1>FRANCISCHETTI (Ivo M. B.)</s1></fA11><fA11 i1="02" i2="1"><s1>OLIVEIRA (Carlo J.)</s1></fA11><fA11 i1="03" i2="1"><s1>OSTERA (Graciela R.)</s1></fA11><fA11 i1="04" i2="1"><s1>YAGER (Stephanie B.)</s1></fA11><fA11 i1="05" i2="1"><s1>DEBIERRE-GROCKIEGO (Françoise)</s1></fA11><fA11 i1="06" i2="1"><s1>CARREGARO (Vanessa)</s1></fA11><fA11 i1="07" i2="1"><s1>JARAMILLO-GUTIERREZ (Giovanna)</s1></fA11><fA11 i1="08" i2="1"><s1>HUME (Jen C. C)</s1></fA11><fA11 i1="09" i2="1"><s1>LUBIN JIANG</s1></fA11><fA11 i1="10" i2="1"><s1>MORETZ (Samuel E.)</s1></fA11><fA11 i1="11" i2="1"><s1>LIN (Christina K.)</s1></fA11><fA11 i1="12" i2="1"><s1>RIBEIRO (José M. C.)</s1></fA11><fA11 i1="13" i2="1"><s1>LONG (Carole A.)</s1></fA11><fA11 i1="14" i2="1"><s1>VICKERS (Brandi K.)</s1></fA11><fA11 i1="15" i2="1"><s1>SCHWARZ (Ralph T.)</s1></fA11><fA11 i1="16" i2="1"><s1>SEYDEL (Karl B.)</s1></fA11><fA11 i1="17" i2="1"><s1>IACOBELLI (Massimo)</s1></fA11><fA11 i1="18" i2="1"><s1>ACKERMAN (Hans C.)</s1></fA11><fA11 i1="19" i2="1"><s1>SRINIVASAN (Prakash)</s1></fA11><fA11 i1="20" i2="1"><s1>GOMES (Regis B.)</s1></fA11><fA11 i1="21" i2="1"><s1>XUNDE WANG</s1></fA11><fA11 i1="22" i2="1"><s1>MONTEIRO (Robson Q.)</s1></fA11><fA11 i1="23" i2="1"><s1>KOTSYFAKIS (Michail)</s1></fA11><fA11 i1="24" i2="1"><s1>SA-NUNES (Anderson)</s1></fA11><fA11 i1="25" i2="1"><s1>WAISBERG (Michael)</s1></fA11><fA14 i1="01"><s1>Laboratory of Malaria and Vector Research , National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ><sZ>16 aut.</sZ><sZ>18 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>23 aut.</sZ><sZ>24 aut.</sZ></fA14><fA14 i1="02"><s1>Instituto de Ciencias Biológicas e Naturais, Universidade Federal do Triangulo Mineiro</s1><s2>Uberaba</s2><s3>BRA</s3><sZ>2 aut.</sZ></fA14><fA14 i1="03"><s1>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>11 aut.</sZ><sZ>14 aut.</sZ><sZ>25 aut.</sZ></fA14><fA14 i1="04"><s1>Institute for Virology, Laboratory of Parasitology, Philipps-University</s1><s2>Marburg</s2><s3>DEU</s3><sZ>5 aut.</sZ><sZ>15 aut.</sZ></fA14><fA14 i1="05"><s1>Parasite Immunology, Vaccinology and Anti-infectious Biotherapy</s1><s2>Tours</s2><s3>FRA</s3><sZ>5 aut.</sZ></fA14><fA14 i1="06"><s1>Departamento de Farmacologia and Departamento de Imunologia , Universidade de São Paulo</s1><s2>Ribeirao Preto</s2><s3>BRA</s3><sZ>6 aut.</sZ></fA14><fA14 i1="07"><s1>Seattle Biomedical Research Institute</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>8 aut.</sZ></fA14><fA14 i1="08"><s1>Unit of Structural and Functional Glycobiology , Universite Lille Nord de France</s1><s2>Lille</s2><s3>FRA</s3><sZ>15 aut.</sZ></fA14><fA14 i1="09"><s1>Department of Medicine, College of Osteopathic Medicine, Michigan State University</s1><s2>East Lansing, MI</s2><s3>USA</s3><sZ>16 aut.</sZ></fA14><fA14 i1="10"><s1>Gentium SpA, villa Guardia</s1><s2>Como</s2><s3>ITA</s3><sZ>17 aut.</sZ></fA14><fA14 i1="11"><s1>Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>21 aut.</sZ></fA14><fA14 i1="12"><s1>Instituto de Bioquimica Medica, Universidade Federal do Rio de Janeiro</s1><s2>Rio de Janeiro</s2><s3>BRA</s3><sZ>22 aut.</sZ></fA14><fA14 i1="13"><s1>Institute of Parasitology, Biology Centre of the Academy of Sciences of Czech Republic</s1><s2>Ceske Budejovice</s2><s3>CZE</s3><sZ>23 aut.</sZ></fA14><fA14 i1="14"><s1>Departamento de Imunologia, Instituto de Ciencias Biomédicas, Universidade de São Paulo</s1><s2>São Paulo</s2><s3>BRA</s3><sZ>24 aut.</sZ></fA14><fA20><s1>786-798</s1></fA20><fA21><s1>2012</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>19104</s2><s5>354000508687940320</s5></fA43><fA44><s0>0000</s0><s1>© 2012 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>50 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>12-0108818</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Arteriosclerosis, thrombosis, and vascular biology</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>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.</s0></fC01><fC02 i1="01" i2="X"><s0>002B12B01</s0></fC02><fC02 i1="02" i2="X"><s0>002B12B03</s0></fC02><fC02 i1="03" i2="X"><s0>002B02F04</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Paludisme</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Malaria</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Paludismo</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Pathologie de l'appareil circulatoire</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Cardiovascular disease</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Aparato circulatorio patología</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Athérosclérose</s0><s2>NM</s2><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Atherosclerosis</s0><s2>NM</s2><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Ateroesclerosis</s0><s2>NM</s2><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Défibrotide</s0><s2>NK</s2><s2>FR</s2><s5>09</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Defibrotide</s0><s2>NK</s2><s2>FR</s2><s5>09</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Defibrotida</s0><s2>NK</s2><s2>FR</s2><s5>09</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Inflammation</s0><s5>10</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Inflammation</s0><s5>10</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Inflamación</s0><s5>10</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Traitement</s0><s5>11</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Treatment</s0><s5>11</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Tratamiento</s0><s5>11</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Anticoagulant</s0><s5>12</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Anticoagulant</s0><s5>12</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Anticoagulante</s0><s5>12</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Coagulation sanguine</s0><s5>13</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Blood coagulation</s0><s5>13</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Coagulación sanguínea</s0><s5>13</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Endothélium</s0><s5>14</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Endothelium</s0><s5>14</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Endotelio</s0><s5>14</s5></fC03><fC03 i1="10" i2="X" l="FRE"><s0>Microcirculation</s0><s5>15</s5></fC03><fC03 i1="10" i2="X" l="ENG"><s0>Microcirculation</s0><s5>15</s5></fC03><fC03 i1="10" i2="X" l="SPA"><s0>Microcirculación</s0><s5>15</s5></fC03><fC03 i1="11" i2="X" l="FRE"><s0>Fibrinolytique</s0><s5>78</s5></fC03><fC03 i1="11" i2="X" l="ENG"><s0>Fibrinolytic</s0><s5>78</s5></fC03><fC03 i1="11" i2="X" l="SPA"><s0>Fibrinolítico</s0><s5>78</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Protozoose</s0></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Protozoal disease</s0></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Protozoosis</s0></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Parasitose</s0></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Parasitosis</s0></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Parasitosis</s0></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Infection</s0></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Infection</s0></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Infección</s0></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Pathologie des vaisseaux sanguins</s0><s5>37</s5></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Vascular disease</s0><s5>37</s5></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Vaso sanguíneo patología</s0><s5>37</s5></fC07><fN21><s1>079</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist></record>Pour manipuler ce document sous Unix (Dilib)
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