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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2012.tde-18092012-111519
Document
Author
Full name
Camila Leindecker Stumm
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2012
Supervisor
Committee
Negro, Sonia Jancar (President)
Arruda, Luisa Karla de Paula
Capelozzi, Vera Luiza
Oliveira Junior, Itamar Souza de
Sato, Maria Notomi
Title in Portuguese
Papel anti-fibrótico de PGE2 e BMP-7 na asma alérgica experimental.
Keywords in Portuguese
Asma
Asma alérgica
Fibroblastos
Hipersensibilidade
Inflamação
Abstract in Portuguese
A asma alérgica é uma doença inflamatória crônica das vias aéreas que envolve ativação de fibroblastos pulmonares. Esta ativação é induzida por TGF-b e este processo é regulado por moléculas anti-fibróticas. Nosso objetivo foi elucidar mecanismos envolvidos na fibrose das vias aéreas em um modelo de asma. Na primeira parte, investigamos o eixo síntese/resposta da PGE2. A PGE2 e seu análogo forskolina inibiram síntese de colágeno I e proliferação de fibroblastos. Estas células apresentaram perda tempo-dependente na capacidade de sintetizar PGE2 sob estímulo com IL-1b, e menor expressão de COX-2 e mPGEs-1. Na segunda parte, estudamos a relação TGF-b1/BMP-7 na fibrose das vias aéreas. Há predomínio da molécula pró-fibrótica TGF-b1 sobre a molécula anti-fibrótica BMP-7 nos pulmões de animais asmáticos. Em fibroblastos, a BMP-7 inibe a síntese de colágeno tipo I induzida pelo TGF-b1 e as vias de SMAD-2, SMAD-3 e p38. O tratamento dos animais com BMP-7 causou diminuição significativa da fibrose. Os resultados implicam estes mecanismos na fibrose das vias aéreas na asma.
Title in English
Anti-fibrotic role of PGE2 and BMP-7 in experimental allergic asthma.
Keywords in English
Allergic Asthma
Asthma
Fibroblasts
Hypersensitivity
Inflammation
Abstract in English
Allergic asthma is a chronic inflammatory disease of the airways that involves activation of lung fibroblasts. This activation is induced by TGF-b and this process is regulated by anti-fibrotic molecules. Our goal was to elucidate mechanisms involved in airway fibrosis in an animal model of asthma. In the first part, we investigated the PGE2 synthesis/response axis. PGE2 and its analog forskolin inhibited collagen I synthesis and proliferation of fibroblasts. These cells showed a time-dependent loss in the ability to synthesize PGE2 under IL-1b stimulation, and downregulated COX-2 and mPGEs-1. In the second part, we studied the ratio TGF-b1/BMP-7 in airway fibrosis. There is predominance of the pro-fibrotic TGF-b1 over the anti-fibrotic BMP-7 in the lungs of asthmatic animals. In fibroblasts, BMP-7 inhibits TGF-b1-induced type I collagen synthesis and the SMAD-2, SMAD-3 and p38 pathways. Treatment of the animals with BMP-7 caused significant decrease in fibrosis. The results implicate these mechanisms in airway fibrosis in asthma.
 
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Publishing Date
2012-10-23
 
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