Lumican Regulates Ventilation-Induced Epithelial-Mesenchymal Transition Through Extracelluar Signal-Regulated Kinase Pathway

Li, Lifu; Chu, Pao‐Hsien; Hung, Cheng-Yiu; Kao, Winston Whei‐Yang; Lin, Meng-Chih; Liu, Yung-Yang; Yang, Cheng‐Ta

doi:10.1378/chest.12-2058

Cited by 25 publications

(22 citation statements)

References 34 publications

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“…Type I collagen is more prevalent in the late‐phase of ALI, whereas type III collagen fibre, which is relatively more flexible and susceptible to breakdown, predominates in the early stage of ALI . Furthermore, mechanical forces can modify the gene expression and structural remodelling of ECM through increased transpulmonary pressure, heterogeneous distribution of ventilation, increased tissue stretch, reduced pulmonary lymphatic drainage and direct secretion of various growth factors, including TGF‐β1 . We demonstrated that high tidal volume MV increased oxidative stress, collagen accumulation and increase of collagen 1a gene expression.…”

Section: Discussionmentioning

confidence: 79%

“…This transition features the loss of epithelial markers (E‐cadherin and aquaporin‐5) and apical–basal polarity as well as cytoskeletal rearrangement, transition to a spindle‐shaped morphology and the acquisition of mesenchymal markers (α‐smooth muscle actin (α‐SMA) and N‐cadherin) . Furthermore, MV can induce EMT and thus initiate and propagate VILI‐associated lung fibrosis . The Src protein tyrosine kinase is expressed by leucocytes, alveolar epithelial cells, endothelial cells and fibroblasts in the lung.…”

Section: Introductionmentioning

confidence: 99%

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Nintedanib reduces ventilation‐augmented bleomycin‐induced epithelial–mesenchymal transition and lung fibrosis through suppression of the Src pathway

Kao

Liu

et al. 2017

J Cellular Molecular Medi

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Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)‐β1‐induced epithelial–mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear. In this study, we suggested hypothesized that nintedanib can suppress MV‐augmented bleomycin‐induced EMT and pulmonary fibrosis by inhibiting the Src pathway. Five days after administrating bleomycin to mimic acute lung injury (ALI), C57BL/6 mice, either wild‐type or Src‐deficient were exposed to low tidal volume (VT) (6 ml/kg) or high VT (30 ml/kg) MV with room air for 5 hrs. Oral nintedanib was administered once daily in doses of 30, 60 and 100 mg/kg for 5 days before MV. Non‐ventilated mice were used as control groups. Following bleomycin exposure in wild‐type mice, high VT MV induced substantial increases in microvascular permeability, TGF‐β1, malondialdehyde, Masson's trichrome staining, collagen 1a1 gene expression, EMT (identified by colocalization of increased staining of α‐smooth muscle actin and decreased staining of E‐cadherin) and alveolar epithelial apoptosis (P < 0.05). Oral nintedanib, which simulated genetic downregulation of Src signalling using Src‐deficient mice, dampened the MV‐augmented profibrotic mediators, EMT profile, epithelial apoptotic cell death and pathologic fibrotic scores (P < 0.05). Our data indicate that nintedanib reduces high VT MV‐augmented EMT and pulmonary fibrosis after bleomycin‐induced ALI, partly by inhibiting the Src pathway.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Nintedanib reduces ventilation‐augmented bleomycin‐induced epithelial–mesenchymal transition and lung fibrosis through suppression of the Src pathway

Kao

Liu

et al. 2017

J Cellular Molecular Medi

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“…Imbalance between oxidant production and antioxidant protection results in accumulation of ROS oxidants may contribute to the development of pulmonary fibrosis due to their effects on the production of TGF-β (Li et al 2013), suggesting that using antioxidants may be helpful in the prevention, and perhaps the treatment of fibrosis in VILI.…”

Section: Discussionmentioning

confidence: 99%

N-Acetylcysteine Inhibits Ventilation-Induced Collagen Accumulation in the Rat Lung

Chen

Guan

Quinn

et al. 2015

Tohoku J. Exp. Med.

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Mechanical ventilation is the most important life supportive therapy for patients with acute respiratory distress syndrome (ARDS). However, increasing evidence from clinical studies suggests that mechanical ventilation can cause lung fibrosis, which may significantly contribute to morbidity and mortality. Recent studies also found fibroproliferation occurred in early stage of ARDS with poor outcome. We have hypothesized that mechanical ventilation-induced lung injury may be a major contributor to lung fibrosis, and antioxidant could be a potential therapeutic agent for the treatment to mechanic ventilation induced fibroproliferation. We therefore used Sprague-Dawley rats that were ventilated with large tidal volume (20 ml/kg) or low tidal volume (7 ml/kg). We analyzed the time course of collagen level in the lung and the effect of N-acetylcysteine (NAC), a thiol antioxidant, on mechanical ventilation-induced collagen accumulation. In addition, normal human lung fibroblasts (NHLF) were exposed to mechanical stretch, which mimics ventilator-induced lung inflation, to evaluate the collagen secretion in culture medium. We found that ventilation-induced collagen accumulation occurred even after 2-hour ventilation. Pretreatment with NAC (140 mg/kg) inhibited collagen accumulation in lungs of rats ventilated with large tidal volume. Moreover, mechanical stretch caused the accumulation of collagen in the culture medium of NHLF, the magnitude of which was decreased with the pretreatment with NAC (1 mM). These results indicate that mechanical ventilation can induce collagen accumulation within 2 hours. NAC alleviated the collagen accumulation induced by mechanical ventilation with high tidal volume. Therefore, NAC can be considered as a good candidate in preventing ventilation-induced lung fibrosis.

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“… 3 A large proportion of data implicates that epithelial cells undergoing the process of epithelial-mesenchymal transition (EMT) is one source of fibroblasts. 4 , 5 During EMT, epithelial cells gradually lose their epithelial characteristics and transform into a mesenchymal-like cell phenotype, which begins to synthesize the components of ECM, such as collagen I and fibronectin. Among the extracellular cytokines that activate EMT, transforming growth factor β (TGF-β) is known to be the main inducer.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-29b Mediates Lung Mesenchymal-Epithelial Transition and Prevents Lung Fibrosis in the Silicosis Model

Sun

Lian

et al. 2019

Molecular Therapy - Nucleic Acids

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Lung epithelial-mesenchymal transition (EMT) plays an important role in silicosis fibrosis. The reverse process of EMT is mesenchymal-epithelial transition (MET), which is viewed as an anti-EMT therapy and is a good target toward fibrosis. MicroRNAs (miRNAs) have emerged as potent regulators of EMT and MET programs, and, hence, we tested the miRNA expression using microarray assay and investigated their roles in silica-induced EMT in lung epithelial cells. We found that miRNA-29b (miR-29b) was dynamically downregulated by silica and influenced the promotion of MET in RLE-6TN cells. Furthermore, delivery of miR-29b to mice significantly inhibited silica-induced EMT, prevented lung fibrosis, and improved lung function. Together, our results clearly demonstrated that miR-29b acted as a novel negative regulator of silicosis fibrosis-inhibited lung fibrosis, probably by promoting MET and by suppressing EMT in the lung. These findings may represent a new potential therapeutic target for treating silicosis fibrosis.

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Lumican Regulates Ventilation-Induced Epithelial-Mesenchymal Transition Through Extracelluar Signal-Regulated Kinase Pathway

Cited by 25 publications

References 34 publications

Nintedanib reduces ventilation‐augmented bleomycin‐induced epithelial–mesenchymal transition and lung fibrosis through suppression of the Src pathway

Nintedanib reduces ventilation‐augmented bleomycin‐induced epithelial–mesenchymal transition and lung fibrosis through suppression of the Src pathway

N-Acetylcysteine Inhibits Ventilation-Induced Collagen Accumulation in the Rat Lung

MicroRNA-29b Mediates Lung Mesenchymal-Epithelial Transition and Prevents Lung Fibrosis in the Silicosis Model

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