title: Cigarette smoke-induced alveolar epithelial-mesenchymal transition is mediated by Rac1 activation.
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-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.
  
  
  CONCLUSIONS
  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.
authors: The Second Affiliated Hospital, Medical College of Zhejiang University, Hangzhou 310009, China; Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Hui-juan
authors: HJ
authors: Shen
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Yan-hong
authors: YH
authors: Sun
authors: Pharmacy College of Zhejiang Chinese Medical University, Hangzhou 310053, China.
authors: Shui-juan
authors: SJ
authors: Zhang
authors: The Second Affiliated Hospital, Medical College of Zhejiang University, Hangzhou 310009, China; Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Jun-xia
authors: JX
authors: Jiang
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Xin-wei
authors: XW
authors: Dong
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Yong-liang
authors: YL
authors: Jia
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Jian
authors: J
authors: Shen
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Yan
authors: Y
authors: Guan
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Lin-hui
authors: LH
authors: Zhang
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Fen-fen
authors: FF
authors: Li
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Xi-xi
authors: XX
authors: Lin
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China.
authors: Xi-mei
authors: XM
authors: Wu
authors: Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Medical College of Zhejiang University, Hangzhou 310058, China; Laboratory Animal Center of Zhejiang University, Hangzhou 310058, China. Electronic address: xieqm@zju.edu.cn.
authors: Qiang-min
authors: QM
authors: Xie
authors: The Second Affiliated Hospital, Medical College of Zhejiang University, Hangzhou 310009, China. Electronic address: yanxiaofeng0804@sina.com.
authors: Xiao-feng
authors: XF
authors: Yan
mesh_terms: D000818:Animals; D058750:Epithelial-Mesenchymal Transition; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011650:Pulmonary Alveoli / Q000473:pathology*; D051899:Smad2 Protein / Q000502:physiology; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000096:biosynthesis; D020830:rac1 GTP-Binding Protein / Q000502:physiology*
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D012906:Smoke; D053773:Transforming Growth Factor beta1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein
keywords: Cigarette smoke extract; Epithelial–mesenchymal transition; Pulmonary fibrosis; Rac1; TGF-β1