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Previous issue date: 2017-03-10 / Conselho Nacional de Pesquisa e Desenvolvimento Cient?fico e Tecnol?gico - CNPq / Pulmonary fibrosis is a specific form of interstitial pneumonia characterized by progressive worsening of dyspnea and lung function and associated with a poor prognosis. In addition to the idiopathic cause, pulmonary fibrosis may be caused by drugs such as bleomycin (BLM) - used in lymphomas and germinative tumors treatments. Fructose-1,6-bisphosphate (FBP) is a high energy endogenous glycolytic compound that has antifibrotic, anti-inflammatory and immunomodulatory effects. The aim of this study was to assess the effect of FBP on BLM-induced pulmonary fibrosis model in mice and investigate its effect using a human embryonic lung fibroblast (MRC-5) culture system. C57BL/6 were divided into Control, FBP, BLM and BLM plus FBP. A single dose of bleomycin (7.5 U/kg) was administered intratracheally in mice and survival, body weight, Ashcroft Score and histological analysis (hematoxylin-eosin, Masson?s trichrome and picrosirius) were performed. Pulmonary function and bronchoalveolar lavage fluid (BALF) were also evaluated after a single dose of bleomycin (1.2 U/kg ? intratracheally). Treatment with FBP (500 mg/kg) was given on day 0 intraperitoneally. Fibroblasts (MRC-5 cells) were used to access the effect of FBP in vitro. In vivo, FBP increased survival rate and reduced the body weight loss when BLM and BLM plus FBP were compared (p< 0.05). FBP also prevented the loss of pulmonary function caused by BLM and decreased BALF inflammatory cells. The level of fibrosis and the superficial collagen density were lower in the lungs of animals that received BLM plus FBP as compared to BLM only (p<0.05). In vitro, FBP (0.62 and 1.25 mM) had inhibitory activity on MRC-5 cells and was able to induce senescence in fibroblasts. These results showed that FBP has the potential of reducing the toxic effects of BLM and may provide supportive therapy for conventional methods used for the treatment of cancer. / A fibrose pulmonar ? uma forma espec?fica de pneumonia intersticial caracterizada por piora progressiva da dispneia e da fun??o pulmonar e associada a um mau progn?stico. Al?m da causa idiop?tica, a fibrose pulmonar pode ser causada por drogas como a bleomicina (BLM) - usada no tratamento de linfomas e tumores germinativos. A frutose-1,6-bisfosfato (FBP) ? um composto glicol?tico end?geno de alta energia que possui efeitos antifibr?ticos, anti-inflamat?rios e imunomodulador. O objetivo deste estudo foi avaliar o efeito da FBP sobre um modelo de fibrose pulmonar induzida por BLM em camundongos e investigar seu efeito utilizando um sistema de cultura de fibroblastos de pulm?o embrion?rio humano (MRC-5). Camundongos C57BL/6 foram divididos em grupos Controle, FBP, BLM, BLM + FBP. Foi administrada uma dose ?nica de bleomicina intratraqueal (7,5 U/kg) para avaliar a sobreviv?ncia, o acompanhamento do peso corporal, o escore Ashcroft e a histologia (hematoxilina-eosina, tricr?mio de Masson e picrosirius). Para avaliar a fun??o pulmonar e o lavado broncoalveolar (LBA) foi administrada uma dose ?nica de bleomicina a 1,2 U/kg por via intratraqueal. O tratamento com FBP (500 mg/kg) foi administrado no dia 0 intraperitonealmente. Fibroblastos (c?lulas MRC-5) foram utilizados para acessar o efeito da FBP in vitro. In vivo, a FBP aumentou a taxa de sobreviv?ncia e reduziu a perda de peso corporal quando BLM e BLM mais FBP foram comparados (p <0,05). FBP tamb?m previne a perda de fun??o pulmonar causada por BLM e diminuiu as c?lulas inflamat?rias no LBA. O grau de fibrose e a densidade superficial de col?geno foi menor nos pulm?es de animais que receberam BLM mais FBP comparado com BLM apenas (p <0,05). In vitro, a FBP (0,62 e 1,25 mM) apresentou actividade inibidora em c?lulas MRC-5 e foi capaz de induzir a senesc?ncia em fibroblastos. Estes resultados mostraram que a FBP tem o potencial de reduzir os efeitos t?xicos da bleomicina e pode proporcionar terapia de suporte para m?todos convencionais de pacientes que utilizam essa terapia para o tratamento do c?ncer.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/7483 |
| Date | 10 March 2017 |
| Creators | Jost, Renan Trevisan |
| Contributors | Oliveira, Jarbas Rodrigues de, Melo, Denizar Alberto da Silva |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Medicina e Ci?ncias da Sa?de, PUCRS, Brasil, Escola de Medicina |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| 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 | 7620745074616285884, 600, 600, 600, 600, -224747486637135387, -969369452308786627, -2555911436985713659 |
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