Papel do receptor MET na viabilidade de neutrófilos em modelos de inflamação aguda

• Ano de defesa: 2017
• Autor(a) principal: Julia Dias da Silva
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; ICB - INSTITUTO DE CIÊNCIAS BIOLOGICAS; Programa de Pós-Graduação em Biologia Celular; UFMG
• Palavras-chave em Português: Biologia Celular; Proteínas proto-oncogênicas c-met; Inflamação; Neutrófilos
• Link de acesso: http://hdl.handle.net/1843/35391

Inflammation is a salutary host reaction to infectious or sterile tissue damage and has the crucial purpose of restoring tissue homeostasis. However, an unresolved inflammation can lead to tissue damage and give rise to chronic inflammatory diseases associated to loss of organs function. Thus, it is now evident that the resolution of inflammation is the main process that occurs during an acute inflammatory response associated to return to homeostasis. Met is a proto-oncogene involved in the intracellular signaling pathway for cell growth, proliferation and survival. It codify the hepatocyte growth factor receptor (HGFR or Met) present on the membrane of different cell types is important in cell proliferation, survival and migration. However, its participation in the resolution of inflammation has not been studied. Here, we evaluated the role of MET in neutrophil survival using two models of inflammation in mice: the pleurisy induced by LPS and gout. Firstly, mice were challenged with 250 ng/cavity of LPS. Six hour after LPS challenge the mice was treated with the MET inhibitor, PF-04217903. Cells were recovered from the pleural cavity 4 hours after treatment with the drug. Treatment with PF-04217903 decreased the number of neutrophils in the pleural cavity without affecting the number of mononuclear cells. This decrease in the number of neutrophils was accompanied by an increase in number of apoptotic neutrophils and efferocytosis. The second model used was the acute gout induced by crystals of monosodium urate (MSU). The mice were injected with 100 μg MSU at the tibiofemoral joint. Initially, we verified that the kinetics of MET expression in neutrophils paralleled with the accumulation of these cells in the joint cavity. The treatment of mice with PF-04217903, at the peak of inflammation, also reduced the number of neutrophil associated with increased apoptotic neutrophil in articular cavity. In addition, we demonstrated that the inhibition of MET was able to reduce the threshold of hypernociception. We also evaluated the effect of PF-04217903 on survival of human neutrophils in vitro. PF-04217903 induced apoptosis in human neutrophil. Thus, these results demonstrated that MET has a important role in the maintenance of neutrophil survival and that inhibition of the activity of this receptor can induce neutrophil apoptosis, contributing to the resolution of acute inflammatory response.