| [PMID]: | 23944988 |
| [Au] Autor: | Xi Y; Tan K; Brumwell AN; Chen SC; Kim YH; Kim TJ; Wei Y; Chapman HA |
| [Ad] Endereço: | 1 Pulmonary and Critical Care Division and Department of Medicine, and. |
| [Ti] Título: | Inhibition of epithelial-to-mesenchymal transition and pulmonary fibrosis by methacycline. |
| [So] Source: | Am J Respir Cell Mol Biol;50(1):51-60, 2014 Jan. |
| [Is] ISSN: | 1535-4989 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | A high-throughput small-molecule screen was conducted to identify inhibitors of epithelial-mesenchymal transition (EMT) that could be used as tool compounds to test the importance of EMT signaling in vivo during fibrogenesis. Transforming growth factor (TGF)-ß1-induced fibronectin expression and E-cadherin repression in A549 cells were used as 48-hour endpoints in a cell-based imaging screen. Compounds that directly blocked Smad2/3 phosphorylation were excluded. From 2,100 bioactive compounds, methacycline was identified as an inhibitor of A549 EMT with the half maximal inhibitory concentration (IC50) of roughly 5 µM. In vitro, methacycline inhibited TGF-ß1-induced α-smooth muscle actin, Snail1, and collagen I of primary alveolar epithelial cells . Methacycline inhibited TGF-ß1-induced non-Smad pathways, including c-Jun N-terminal kinase, p38, and Akt activation, but not Smad or ß-catenin transcriptional activity. Methacycline had no effect on baseline c-Jun N-terminal kinase, p38, or Akt activities or lung fibroblast responses to TGF-ß1. In vivo, 100 mg/kg intraperitoneal methacycline delivered daily beginning 10 days after intratracheal bleomycin improved survival at Day 17 (P < 0.01). Bleomycin-induced canonical EMT markers, Snail1, Twist1, collagen I, as well as fibronectin protein and mRNA, were attenuated by methacycline (Day 17). Methacycline did not attenuate inflammatory cell accumulation or alter TGF-ß1-responsive genes in alveolar macrophages. These studies identify a novel inhibitor of EMT as a potent suppressor of fibrogenesis, further supporting the concept that EMT signaling is important to lung fibrosis. The findings also provide support for testing the impact of methacycline or doxycycline, an active analog, on progression of human pulmonary fibrosis. |
| [Mh] Termos MeSH primário: |
Células Epiteliais/efeitos dos fármacos
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Metaciclina/farmacologia
Alvéolos Pulmonares/efeitos dos fármacos
Fibrose Pulmonar/tratamento farmacológico
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| [Mh] Termos MeSH secundário: |
Actinas/metabolismo
Animais
Caderinas/metabolismo
Linhagem Celular
Colágeno Tipo I/metabolismo
Células Epiteliais/metabolismo
Feminino
Seres Humanos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
Macrófagos Alveolares/efeitos dos fármacos
Macrófagos Alveolares/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Proteínas Proto-Oncogênicas c-akt/metabolismo
Alvéolos Pulmonares/metabolismo
Fibrose Pulmonar/metabolismo
Transdução de Sinais/efeitos dos fármacos
Proteínas Smad/metabolismo
Fatores de Transcrição da Família Snail
Fatores de Transcrição/metabolismo
Fator de Crescimento Transformador beta1/metabolismo
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Actins); 0 (Cadherins); 0 (Collagen Type I); 0 (SNAI1 protein, human); 0 (Smad Proteins); 0 (Snai1 protein, mouse); 0 (Snail Family Transcription Factors); 0 (Transcription Factors); 0 (Transforming Growth Factor beta1); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); IR235I7C5P (Methacycline) |
| [Em] Mês de entrada: | 1404 |
| [Cu] Atualização por classe: | 170220 |
[Lr] Data última revisão:
| 170220 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 130816 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1165/rcmb.2013-0099OC |
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