Yun-Qian Zhang1, Yu-Jian Liu2, Yan-Fei Mao3, Wen-Wen Dong3, Xiao-Yan Zhu4, Lai Jiang5. 1. 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. 2. Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Second Military Medical University, Shanghai 200433, PR China. 3. Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China. 4. 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. 5. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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: Lei Sun; Elissa M Hult; Timothy T Cornell; Kevin K Kim; Thomas P Shanley; Carol A Wilke; Manisha Agarwal; Stephen J Gurczynski; Bethany B Moore; Mary K Dahmer Journal: Am J Physiol Lung Cell Mol Physiol Date: 2019-03-06 Impact factor: 5.464