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dc.contributor.authorKeshari, Ravi Shankar
dc.contributor.authorSilasi, Robert
dc.contributor.authorPopescu, Narcis Ioan
dc.contributor.authorPatel, Maulin Mukeshchandra
dc.contributor.authorChaaban, Hala
dc.contributor.authorLupu, Cristina
dc.contributor.authorCoggeshall, K. Mark
dc.contributor.authorMollnes, Tom Eirik
dc.contributor.authorDeMarco, Steven J.
dc.contributor.authorLupu, Florea
dc.date.accessioned2018-06-29T12:32:26Z
dc.date.available2018-06-29T12:32:26Z
dc.date.issued2017-07-18
dc.description.abstractBacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of Escherichia coli sepsis. RA101295 strongly inhibited E. coli-induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9. RA101295 reduced the E. coli-induced “oxidative burst,” as well as leukocyte activation, without affecting host phagocytosis of E. coli. RA101295 treatment reduced plasma LPS content in E. coli-challenged baboons, implying reduced complement-mediated bacteriolysis, whereas treated animals showed slightly improved bacterial clearance during the bacteremic stage compared with controls. Treatment with RA101295 also improved consumptive coagulopathy and preserved endothelial anticoagulant and vascular barrier functions. RA101295 abolished sepsis-induced surges in proinflammatory cytokines and attenuated systemic circulatory and febrile responses, likely reflecting decreased systemic levels of LPS and C5a. Overall, RA101295 treatment was associated with significant organ protection and markedly reduced mortality compared with nontreated controls (four of five animals survived in a 100% lethal model). We therefore conclude that inhibition of C5 cleavage during the bacteremic stage of sepsis could be an important therapeutic approach to prevent sepsis-induced inflammation, consumptive coagulopathy, and subsequent organ failure and death.en_US
dc.description.sponsorshipNIH Grants (GM097747,GM116184, GM121601, U19AI062629, and P30GM114731) Ra Pharmaceuticalsen_US
dc.descriptionSource at <a href=https://doi.org/10.1073/pnas.1706818114> https://doi.org/10.1073/pnas.1706818114</a>.en_US
dc.identifier.citationKeshari, R.S., Silasi, R., Popescu, N.I., Patel, M.M., Chaaban, H., Lupu, C., ... Lupu, F. (2017). Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis. Proceedings of the National Academy of Sciences of the United States of America, 114(31), E6390-E6399. https://doi.org/10.1073/pnas.1706818114en_US
dc.identifier.cristinIDFRIDAID 1514364
dc.identifier.doi10.1073/pnas.1706818114
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttps://hdl.handle.net/10037/13062
dc.language.isoengen_US
dc.publisherNational Academy of Sciencesen_US
dc.relation.journalProceedings of the National Academy of Sciences of the United States of America
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/BIOTEK2021/244390/Norway/A novel treatment regimen for inflammatory diseases: Targeting the interaction between the complement system and CD14//en_US
dc.relationThis article contains supporting information online at http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1706818114/-/DCSupplementalen
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750en_US
dc.subjectVDP::Medical disciplines: 700::Clinical medical disciplines: 750en_US
dc.subjectcomplementen_US
dc.subjectcoagulationen_US
dc.subjectsepsisen_US
dc.subjectEscherichia colien_US
dc.subjectorgan failureen_US
dc.titleInhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsisen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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