Cigarette smoke-induced alveolar epithelial–mesenchymal transition is mediated by Rac1 activation

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 o...

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Vydáno v:Biochimica et biophysica acta Ročník 1840; číslo 6; s. 1838 - 1849
Hlavní autoři: Shen, Hui-juan, Sun, Yan-hong, Zhang, Shui-juan, Jiang, Jun-xia, Dong, Xin-wei, Jia, Yong-liang, Shen, Jian, Guan, Yan, Zhang, Lin-hui, Li, Fen-fen, Lin, Xi-xi, Wu, Xi-mei, Xie, Qiang-min, Yan, Xiao-feng
Médium: Journal Article
Jazyk:angličtina
Vydáno: Netherlands 01.06.2014
Témata:
Animals
cigarettes
epithelial cells
Epithelial-Mesenchymal Transition
epithelium
fibrosis
lung neoplasms
Mice
Mice, Inbred C57BL
Neuropeptides - physiology
Nicotiana - adverse effects
non-specific serine/threonine protein kinase
phosphatidylinositol 3-kinase
Phosphatidylinositol 3-Kinases - physiology
Proto-Oncogene Proteins c-akt - physiology
Pulmonary Alveoli - pathology
rac1 GTP-Binding Protein - physiology
risk factors
signal transduction
Smad2 Protein - physiology
Smoke - adverse effects
therapeutics
transforming growth factor beta 1
Transforming Growth Factor beta1 - analysis
Transforming Growth Factor beta1 - biosynthesis
Epithelial–mesenchymal transition
TGF-β1
Pulmonary fibrosis
Rac1
Cigarette smoke extract
ISSN:0304-4165, 0006-3002
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Shrnutí: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. EMT was induced in mice and pulmonary epithelial cells by exposure of CS and cigarette smoke extract (CSE) respectively. Treatment of pulmonary epithelial cells with CSE elevated Rac1 expression associated with increased TGF-β1 release. Blocking TGF-β pathway restrained CSE-induced changes in EMT-related markers. Pharmacological inhibition or knockdown of Rac1 decreased the CSE exposure induced TGF-β1 release and ameliorated CSE-induced EMT. In CS-exposed mice, pharmacological inhibition of Rac1 reduced TGF-β1 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. 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.
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ISSN:0304-4165
0006-3002
DOI:10.1016/j.bbagen.2014.01.033