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Frontline Science: Targeted expression of a dominant-negative high mobility group A1 transgene improves outcome in sepsis

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dc.creatorBaron, Rebecca M.spa
dc.creatorKwon, Min?Youngspa
dc.creatorCastano, Ana P.spa
dc.creatorGhanta, Sailajaspa
dc.creatorRiascos?Bernal, Dario F.spa
dc.creatorLópez Guzmán, Silvia
dc.creatorMacias, Alvaro Andresspa
dc.creatorIth, Bonnaspa
dc.creatorSchissel, Scott L.spa
dc.creatorLederer, James A.spa
dc.creatorReeves, Raymondspa
dc.creatorYet, Shaw?Fangspa
dc.creatorLayne, Matthew D.spa
dc.creatorXiaoli, Liuspa
dc.creatorPerrella, Mark A.spa
dc.date.accessioned2020-08-06T16:21:19Z
dc.date.available2020-08-06T16:21:19Z
dc.date.created2018-07-05spa
dc.description.abstractHigh mobility group (HMG) proteins are a family of architectural transcription factors, with HMGA1 playing a role in the regulation of genes involved in promoting systemic inflammatory responses. We speculated that blocking HMGA1?mediated pathways might improve outcomes from sepsis. To investigate HMGA1 further, we developed genetically modified mice expressing a dominant negative (dn) form of HMGA1 targeted to the vasculature. In dnHMGA1 transgenic (Tg) mice, endogenous HMGA1 is present, but its function is decreased due to the mutant transgene. These mice allowed us to specifically study the importance of HMGA1 not only during a purely pro?inflammatory insult of endotoxemia, but also during microbial sepsis induced by implantation of a bacterial?laden fibrin clot into the peritoneum. We found that the dnHMGA1 transgene was only present in Tg and not wild?type (WT) littermate mice, and the mutant transgene was able to interact with transcription factors (such as NF??B), but was not able to bind DNA. Tg mice exhibited a blunted hypotensive response to endotoxemia, and less mortality in microbial sepsis. Moreover, Tg mice had a reduced inflammatory response during sepsis, with decreased macrophage and neutrophil infiltration into tissues, which was associated with reduced expression of monocyte chemotactic protein?1 and macrophage inflammatory protein?2. Collectively, these data suggest that targeted expression of a dnHMGA1 transgene is able to improve outcomes in models of endotoxin exposure and microbial sepsis, in part by modulating the immune response and suggest a novel modifiable pathway to target therapeutics in sepsis.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1002/JLB.4HI0817-333RR
dc.identifier.issnISSN: 0741-5400
dc.identifier.issnEISSN: 1938-3673
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/26325
dc.language.isoengspa
dc.publisherJohn Wiley and Sonsspa
dc.relation.citationEndPage689
dc.relation.citationIssueNo. 4
dc.relation.citationStartPage677
dc.relation.citationTitleJournal of Leukocyte Biology
dc.relation.citationVolumeVol. 104
dc.relation.ispartofJournal of Leukocyte Biology, ISSN: 0741-5400; EISSN: 1938-3673, Vol.104, No.4 (October, 2018); pp.677-689spa
dc.relation.urihttps://jlb.onlinelibrary.wiley.com/doi/abs/10.1002/JLB.4HI0817-333RRspa
dc.rights.accesRightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.accesoRestringido (Acceso a grupos específicos)spa
dc.sourceJournal of Leukocyte Biologyspa
dc.source.instnameinstname:Universidad del Rosario
dc.source.reponamereponame:Repositorio Institucional EdocUR
dc.subject.keywordArchitectural transcription factorspa
dc.subject.keywordChemokinesspa
dc.subject.keywordImmune responsespa
dc.subject.keywordTransgenic Micespa
dc.titleFrontline Science: Targeted expression of a dominant-negative high mobility group A1 transgene improves outcome in sepsisspa
dc.title.TranslatedTitleCiencia de primera línea: la expresión dirigida de un transgén del grupo A1 de alta movilidad dominante-negativo mejora el resultado en la sepsisspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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