title: Resveratrol ameliorates lipopolysaccharide-induced epithelial mesenchymal transition and pulmonary fibrosis through suppression of oxidative stress and transforming growth factor-β1 signaling.
abstract: OBJECTIVE
  Fibrotic changes seem to be responsible for the high mortality rate observed in patients with acute respiratory distress syndrome (ARDS). The present study aimed to determine whether resveratrol, a natural antioxidant polyphenol, had anti-fibrotic effects in the murine model of lipopolysaccharide (LPS)-induced pulmonary fibrosis.
  
  
  METHODS
  Fibrosis was assessed by determination of collagen deposition, hydroxyproline and type I collagen levels in lung tissues. Development of epithelial-mesenchymal transition (EMT) was identified by the loss of E-cadherin accompanying by the acquisition of α-smooth muscle actin (α-SMA). Transforming growth factor (TGF)-β1 content, levels of phosphorylated Smad2/Smad3 and Smad4, malondialdehyde (MDA) content, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, and catalase (CAT) activity in lung tissues were determined.
  
  
  RESULTS
  LPS increased collagen deposition, hydroxyproline and type I collagen contents, and meanwhile induced EMT process, stimulated TGF-β1 production and Smad activation in lung tissues on day 21 to day 28 after LPS administration. In addition, LPS treatment resulted in a rapid induction of oxidative stress as evidenced by increase of MDA and decreases of T-AOC, CAT and SOD activities as early as 7 days after LPS treatment, which was persistent for at least 4 weeks. In contrast, resveratrol treatment attenuated LPS-induced EMT and pulmonary fibrosis, meanwhile it suppressed LPS-induced oxidative stress, TGF-β1 production and activation of Smad signaling pathway.
  
  
  CONCLUSIONS
  Resveratrol may ameliorate LPS-induced EMT and pulmonary fibrosis through suppression of oxidative stress and TGF-β1/Smad signaling pathway. Application of antioxidants may represent a useful adjuvant pharmacologic approach to reduce ARDS-associated pulmonary fibrosis.
authors.affiliation: Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China; Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Yun-Qian
authors.initials: YQ
authors.lastname: Zhang
authors.affiliation: Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Yu-Jian
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China.
authors.forename: Yan-Fei
authors.initials: YF
authors.lastname: Mao
authors.affiliation: Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China.
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Dong
authors.affiliation: Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Second Military Medical University, Shanghai 200433, PR China. Electronic address: xiaoyanzhu@smmu.edu.cn.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China. Electronic address: jianglaimz@126.com.
authors.forename: Lai
authors.initials: L
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D018384:Oxidative Stress / Q000187:drug effects*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D008070:Lipopolysaccharides; D013267:Stilbenes; D053773:Transforming Growth Factor beta1; D008315:Malondialdehyde; D002374:Catalase; D013482:Superoxide Dismutase; D000077185:Resveratrol
keywords: Epithelial mesenchymal transition; Oxidative stress; Pulmonary fibrosis; Resveratrol; TGF-β1