Mechanisms of neutrophil recruitment in a model of hepatic ischemia and reperfusion injury
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Universidade Federal de Minas Gerais
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Tese de doutorado
Título alternativo
Mecanismos de recrutamento de neutrófilos em modelo de lesão hepática induzida por isquemia e reperfusão
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Membros da banca
Steyner de França Côrtes
Fernando de Queiroz Cunha
Philippe Van den Steen
Danielle da Glória de Souza
Fernando de Queiroz Cunha
Philippe Van den Steen
Danielle da Glória de Souza
Resumo
Ischemia 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.
Abstract
Assunto
Fisiologia, Doença hepática induzida por substâncias e drogas, Quimiocinas, Glicosaminoglicanos, Metaloproteases, Neutrófilos
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Hepatic IRI, Chemokines, Glycosaminoglycans, Metalloproteinases, Neutrophil-mediated liver injury
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