Efeitos centrais e perif??ricos da implanta????o de c??lulas tronco hematopo??ticas associado ao uso de fator estimulador de col??nia de granul??citos na insufici??ncia card??aca experimental

• Author(s): Leon, Elisa Brosina de
• Date: 2016
• Origin: Oasisbr
• Subject(s): Insufici??ncia card??aca; Terapia celular; Col??nia de granul??citos; Tecidos perif??ricos.; CI??NCIAS BIOL??GICAS
• Document Type: Doctoral thesis
• Language: Portuguese

Description

Submitted by Divis??o de Documenta????o/BC Biblioteca Central ([e-mail]) on 2016-12-01T18:44:35Z No. of bitstreams: 1 Tese - Elisa B. Leon.pdf: 1932561 bytes, checksum: 5e6100c77314d1d21141bf03a3e5585b (MD5)

Approved for entry into archive by Divis??o de Documenta????o/BC Biblioteca Central ([e-mail]) on 2016-12-01T18:44:51Z (GMT) No. of bitstreams: 1 Tese - Elisa B. Leon.pdf: 1932561 bytes, checksum: 5e6100c77314d1d21141bf03a3e5585b (MD5)

Approved for entry into archive by Divis??o de Documenta????o/BC Biblioteca Central ([e-mail]) on 2016-12-01T18:45:17Z (GMT) No. of bitstreams: 1 Tese - Elisa B. Leon.pdf: 1932561 bytes, checksum: 5e6100c77314d1d21141bf03a3e5585b (MD5)

Made available in DSpace on 2016-12-01T18:45:17Z (GMT). No. of bitstreams: 1 Tese - Elisa B. Leon.pdf: 1932561 bytes, checksum: 5e6100c77314d1d21141bf03a3e5585b (MD5) Previous issue date: 2013-02-22

CNPq - Conselho Nacional de Desenvolvimento Cient??fico e Tecnol??gico

Background: Immunologic and skeletal muscle morphology changes are associated with functional capacity impairment after myocardial infarction (MI), added central modifications. A better understanding of the hemodynamic and peripheral mechanism involved in heart failure is necessary to develop specific therapeutic strategies, as stem cells (SC) or granulocyte colony-stimulating factor (G-CSF) to slow or prevent muscular atrophy present in this syndrome beyond the deleterious immunologic changes. Aims: Therefore, the purpose of this study was to evaluate the effects of stem cells (SC) or/and granulocyte colony-stimulating factor (G-CSF) administration into heart and peripheral tissues after experimental myocardial infarction induction. Methods: In Balb/C was induced ligation of the left coronary artery. Animals in the control group underwent the surgical procedure without ligation of the artery. One week after the procedure, animals were treated with PBS (IM+PBS), G-CSF (IM+G-CSF) or G-CSF associated with hematopoietic CT (IM+G-CSF+CT). The animals were observed for a period of four weeks and underwent echocardiography, stress testing and collection of tissues (heart, lung, diaphragm, liver and peripheral muscle) for analysis of cytokines and structural changes. Results: The results demonstrate that all the treatments were able to reduce infarct, more evident following administration of G-CSF. Moreover, G-CSF induced response in the worst stress test (smaller total distance and final velocity achieved). Analysis of cytokines skeletal tissue demonstrated increased frequency of high producers of pro-inflammatory cytokines such as TNF-??, IL-6, IL-12, IFN-??, IL-1-?? and IL-4 in mice infarcted, resulting in imbalance in balance anti/pro-inflammatory immune response. The treatments had impaired negative when using G-CSF alone and satisfactory results when combined with the use of SCs. Conclusion: We conclude that using G-CSF alone appears to be responsible for amplifying the inflammatory process in infarcted animals leading to reduced functional capacity of skeletal muscle, which reflects in lower performance in exercise stress testing. In contrast, the use of G-CSF in association with hematopoietic CT appears to have a beneficial effect in modulating the inflammatory response and result in lower deleterious effect on the heart failure syndrome.

Introdu????o: Altera????es imunol??gicas e morfol??gicas na musculatura esquel??tica s??o associadas com piora da capacidade funcional ap??s infarto do mioc??rdio, somado ??s modifica????es centrais. Um melhor entendimento dos mecanismos centrais e perif??ricos envolvidos na insufici??ncia card??aca ?? necess??rio para desenvolvimento de estrat??gias terap??uticas espec??ficas, como a utiliza????o de c??lulas tronco (CT) ou fator estimulador de col??nia de granul??citos (G-CSF) para diminuir ou prevenir atrofia muscular presente nesta s??ndrome, al??m das mudan??as imunol??gicas delet??rias. Objetivo: O objetivo deste estudo foi avaliar os efeitos da administra????o de c??lulas tronco ou/e fator estimulador de col??nia de granul??citos nas modifica????es card??acas e mudan??as teciduais perif??ricas ap??s a indu????o de infarto do mioc??rdio experimental. Metodologia: Em camundongos Balb/C foi induzida a ligadura da art??ria coron??ria esquerda. Os animais do grupo Controle foram submetidos ao procedimento cir??rgico sem a ligadura da art??ria. Uma semana ap??s o procedimento, os animais foram submetidos a tratamento com PBS (IM+PBS), G-CSF (IM+G-CSF) ou G-CSF associado ?? CT hematopo??tica (IM+GCSF+ CT). Os animais foram observados por um per??odo de quatro semanas, sendo ent??o realizada an??lise ecocardiogr??fica, teste de esfor??o e coleta de tecidos (cora????o, pulm??o, diafragma, f??gado e m??sculo perif??rico) para an??lise de citocinas e mudan??as estruturais. Resultados: Os resultados demonstram que todos os tratamentos propostos foram capazes de diminuir a ??rea de infarto, de maneira mais evidente ap??s a administra????o de G-CSF. Por outro lado, o G-CSF induziu a pior resposta no teste de esfor??o (menor distancia total percorrida e velocidade final alcan??ada). A an??lise das citocinas teciduais esquel??ticas demonstrou aumento da frequ??ncia de altos produtores de citocinas pr??-inflamat??rias como TNF-??, IL-6, IL-12, IFN-??, IL1-?? e IL-4 em camundongos infartados, resultando em desequil??brio no balan??o anti/pr??-inflamat??rio da resposta imune. Os tratamentos propostos apresentaram comprometimento negativo durante o uso de G-CSF isolado e resultados satisfat??rios quando associado ao uso das CTs. Conclus??o: Concluiu-se que a utiliza????o de G-CSF sozinho parece ser respons??vel por ampliar o processo inflamat??rio em animais infartados conduzindo a uma diminui????o da capacidade funcional do m??sculo esquel??tico, o qual reflete em desempenho inferior no teste de esfor??o. Em contraste, a utiliza????o de G-CSF, em associa????o com CT hematopoi??ticas parece ter um efeito ben??fico no processo inflamat??rio modulando a resposta e refletindo em menor efeito delet??rio na s??ndrome da insufici??ncia card??aca.