Cigarette smoke-induced alveolar epithelial-mesenchymal transition is mediated by Rac1 activation.
Biochim Biophys Acta
; 1840(6): 1838-49, 2014 Jun.
Article
en En
| MEDLINE
| ID: mdl-24508121
ABSTRACT
BACKGROUND:
Epithelial-mesenchymal transition (EMT) is the major pathophysiological process in lung fibrosis observed in chronic obstructive pulmonary disease (COPD) and lung cancer. Smoking is a risk factor for developing EMT, yet the mechanism remains largely unknown. In this study, we investigated the role of Rac1 in cigarette smoke (CS) induced EMT.METHODS:
EMT was induced in mice and pulmonary epithelial cells by exposure of CS and cigarette smoke extract (CSE) respectively.RESULTS:
Treatment of pulmonary epithelial cells with CSE elevated Rac1 expression associated with increased TGF-ß1 release. Blocking TGF-ß pathway restrained CSE-induced changes in EMT-related markers. Pharmacological inhibition or knockdown of Rac1 decreased the CSE exposure induced TGF-ß1 release and ameliorated CSE-induced EMT. In CS-exposed mice, pharmacological inhibition of Rac1 reduced TGF-ß1 release and prevented aberrations in expression of EMT markers, suggesting that Rac1 is a critical signaling molecule for induction of CS-stimulated EMT. Furthermore, Rac1 inhibition or knockdown abrogated CSE-induced Smad2 and Akt (PKB, protein kinase B) activation in pulmonary epithelial cells. Inhibition of Smad2, PI3K (phosphatidylinositol 3-kinase) or Akt suppressed CSE-induced changes in epithelial and mesenchymal marker expression. CONCLUSIONS AND GENERALSIGNIFICANCE:
Altogether, these data suggest that CS initiates EMT through Rac1/Smad2 and Rac1/PI3K/Akt signaling pathway. Our data provide new insights into the fundamental basis of EMT and suggest a possible new course of therapy for COPD and lung cancer.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Alveolos Pulmonares
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Humo
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Nicotiana
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Neuropéptidos
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Proteína de Unión al GTP rac1
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Transición Epitelial-Mesenquimal
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Biochim Biophys Acta
Año:
2014
Tipo del documento:
Article
País de afiliación:
China