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Previous issue date: 2017-03-24 / Mesenchymal stem cells (MSC) were first identified by Friedenstein and Petrakova (1966), who isolated these progenitor cells from rat bone marrow and found that these cells are able to differentiate into connective tissue lineage including bone, adipose tissue, cartilage and muscle. MSCs have emerged in recent years as therapeutic tools based on four important features: differentiation potential, capacity to modulate immune responses, pro-angiogenic and repair promoting capacities, and low immunogenicity, the latter feature may allow allogeneic treatments. Based on their immunomodulatory properties and paracrine effects through trophic factors with anti-fibrotic, anti-apoptotic or pro-angiogenic properties, MSCs are considered a promising instrument for cell therapy, in particular for inflammatory diseases. MSCs regulate the function of a broad range of immune cells, and are activated by inflammatory mediators released from activated immune cells. The mechanisms involved in the immunoregulatory activity of MSCs are still under investigation. Therefore, MSCs become a potential treatment alternative for sepsis and for acute lung infection, which may lead to the interruption of the sequence in the pathogenesis and cause mortality reduction of both pathologies. The principal objective of this study was to evaluate the therapeutic and immunomodulatory effect of MSCs in the treatment of sepsis and acute lung injury and search for their possible mechanisms of action. Our results demonstrated for the first time that the reduction of inflammation in sepsis caused by treatment with MSCs is directly involved in the inhibition of the pathway of mitogen-activated proteins (MAPKs) and that MSCs were unable to modulate the expression of toll-like receptors. During acute lung injury (ALI), the immunomodulation caused by the treatment and the decrease of the oxidative stress that consequently led to a decrease in the formation of extracellular neutrophil network (NETs), leading to an increase in the survival of animals with LPA. The promising results obtained in these studies are encouraging and suggest that MSCs might be a therapeutic option to treat sepsis and acute lung infection in patients in the future. / As c?lulas-tronco mesenquimais (MSC) foram identificadas primeiramente por Friedenstein e Petrakova (1966), que isolaram estas c?lulas progenitoras a partir da medula ?ssea de rato e observaram serem capazes de se diferenciarem em linhagem de tecido conectivo, incluindo osso, tecido adiposo, cartilagem e m?sculo. As MSCs surgiram nos ?ltimos anos como ferramentas terap?uticas baseadas em quatro caracter?sticas importantes: potencial de diferencia??o, capacidade para modular a resposta imune, capacidades pr?-angiog?nicas promovendo regenera??o tecidual, e baixa imunogenicidade, sendo que esta ?ltima caracter?stica pode permitir tratamentos alog?nicos. Com base nas suas propriedades imunomoduladoras e efeitos par?crinos atrav?s de fatores tr?ficos com propriedades anti-fibr?ticas, anti-apopt?ticas ou pr?-angiog?nicas, as MSCs s?o consideradas um instrumento promissor para a terapia celular, em particular para doen?as inflamat?rias. As MSCs regulam as fun??es de uma ampla gama de c?lulas imunes, e s?o ativadas por mediadores inflamat?rios liberados de c?lulas imunes ativadas. Os mecanismos envolvidos na atividade imunorreguladora de MSCs est?o ainda sob investiga??o. Desta forma, as c?lulas-tronco mesequimais se tornam uma potencial alternativa de tratamento para a sepse e para infec??o pulmonar aguda, podendo levar a interrup??o do curso da patog?nese, e provocar a redu??o da mortalidade de ambas patologias. O principal objetivo deste trabalho foi avaliar o efeito terap?utico e imunomodulador de c?lulas-tronco mesenquimais no tratamento da sepse e da les?o pulmonar aguda e buscar os seus poss?veis mecanismos de a??o. Nossos resultados demonstraram pela primeira vez, que a redu??o da inflama??o na sepse provocada pelo tratamento com c?lulas-tronco mesenquimais est? diretamente envolvido a inibi??o da via das prote?nas ativadas por mit?genos (MAPKs) e que as MSCs foram incapazes de modular a express?o de receptores do tipo toll. Durante a les?o pulmonar aguda (LPA) ficou evidente a imunomodula??o provocada pelo tratamento e a diminui??o do estresse oxidativo que consequentemente ocasionou a uma diminui??o da forma??o das redes extracelulares de neutr?filos (NETs), levando a um aumento na sobrevida dos animais com LPA. Os resultados promissores obtidos neste estudo s?o encorajadores e sugerem que as MSCs podem ser uma op??o terap?utica para tratar a sepse e a les?o pulmonar aguda em pacientes no futuro.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/7532 |
| Date | 24 March 2017 |
| Creators | Pedrazza, Leonardo |
| Contributors | Oliveira, Jarbas Rodrigues de |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biologia Celular e Molecular, PUCRS, Brasil, Faculdade de Bioci?ncias |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 3463594373552466096, 600, 600, 600, 4699616958383316066, -1634559385931244697 |
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