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Please use this identifier to cite or link to this item: http://hdl.handle.net/1843/35937
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dc.contributor.advisor1Mauro Martins Teixeirapt_BR
dc.contributor.advisor1Latteshttp://lattes.cnpq.br/1316412551645220pt_BR
dc.contributor.advisor2Paul Proostpt_BR
dc.contributor.advisor-co1Pedro Elias Marquespt_BR
dc.contributor.advisor-co2Anneleen Mortierpt_BR
dc.contributor.referee1Steyner de França Côrtespt_BR
dc.contributor.referee2Fernando de Queiroz Cunhapt_BR
dc.contributor.referee3Philippe Van den Steenpt_BR
dc.contributor.referee4Danielle da Glória de Souzapt_BR
dc.creatorThiago Henrique Caldeira de Oliveirapt_BR
dc.creator.Latteshttp://lattes.cnpq.br/6622834023494045pt_BR
dc.date.accessioned2021-05-10T18:42:54Z-
dc.date.available2021-05-10T18:42:54Z-
dc.date.issued2017-08-24-
dc.identifier.urihttp://hdl.handle.net/1843/35937-
dc.description.resumoIschemia and reperfusion injury (IRI) may facilitate graft rejection is the main cause of morbidity and mortality after liver transplantation. During IRI, an intense inflammatory process occurs in the liver. Hepatic inflammation is initiated by the ischemic period but occurs mainly during the reperfusion time, and is characterized by marked neutrophil recruitment to the liver. The role of neutrophils as the main amplifiers of liver injury has been recognized in many publications. However, the mechanisms involved in neutrophil recruitment during liver IRI are not well known. Additionally, the molecules necessary for this type of migration are poorly defined. Here, we investigated different pathways used by neutrophils to infiltrate the liver and cause damage during inflammation induced by a model of liver IRI. We showed that IR induced significant liver injury, as observed by high levels of hepatic transaminases, neutrophil recruitment and tissue damage. We used intravital microscopy to show that neutrophil behavior changes during liver injury. During IRI, the number of neutrophils increased between 6h and 24h of reperfusion, whereas the distance traveled, velocity, neutrophil size, cluster formation and neutrophil shape reached maximum 6h after reperfusion. Neutrophil migration correlated with liver injury and was dependent on the chemokine receptors CXCR1/2, since mice treated with Reparixin had reduced liver injury and inflammation. In vivo imaging also revealed that Reparixin decreased neutrophil infiltration, migration and displacement. Moreover, neutrophils had smaller size and less elongated shape, indicating reduced activation. Moreover, we documented that MMP-9 expressed by neutrophils is likely to be a key factor in cell transmigration and activation. The lack of Mmp-9 led to protection against liver IRI, as observed by reduced levels of transaminases, cytokines and histological evaluation. Interestingly, we documented that MMP-9 seems to control neutrophil degranulation. We showed that lack of Mmp-9 impaired neutrophil release of others enzymes, including myeloperoxidase (MPO), elastase and neutrophil gelatinase B-associated lipocalin (NGAL). Finally, we also demonstrated that disruption of the interaction between glycosaminoglycans (GAG) and chemokines protected mice against liver IRI. Mice treated with a peptide containing the 30 C-terminal amino acids of CXCL9 (MIG 30) showed reduced liver injury and inflammation. We conclude that pharmacological manipulation or gene deletion of one of these pathways hold promise as strategies to treat IR and improve overall graft success in liver transplantation.pt_BR
dc.description.sponsorshipCNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológicopt_BR
dc.description.sponsorshipFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Geraispt_BR
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superiorpt_BR
dc.languageengpt_BR
dc.publisherUniversidade Federal de Minas Geraispt_BR
dc.publisher.countryBrasilpt_BR
dc.publisher.departmentICB - INSTITUTO DE CIÊNCIAS BIOLOGICASpt_BR
dc.publisher.programPrograma de Pós-Graduação em Ciências Biológicas - Fisiologia e Farmacologiapt_BR
dc.publisher.initialsUFMGpt_BR
dc.rightsAcesso Abertopt_BR
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/pt/*
dc.subjectHepatic IRIpt_BR
dc.subjectChemokinespt_BR
dc.subjectGlycosaminoglycanspt_BR
dc.subjectMetalloproteinasespt_BR
dc.subjectNeutrophil-mediated liver injurypt_BR
dc.subject.otherFisiologiapt_BR
dc.subject.otherDoença hepática induzida por substâncias e drogaspt_BR
dc.subject.otherQuimiocinaspt_BR
dc.subject.otherGlicosaminoglicanospt_BR
dc.subject.otherMetaloproteasespt_BR
dc.subject.otherNeutrófilospt_BR
dc.titleMechanisms of neutrophil recruitment in a model of hepatic ischemia and reperfusion injurypt_BR
dc.title.alternativeMecanismos de recrutamento de neutrófilos em modelo de lesão hepática induzida por isquemia e reperfusãopt_BR
dc.typeTesept_BR
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