Mechanical stress induces lung fibrosis by epithelial–mesenchymal transition

OBJECTIVES:Many mechanically ventilated patients with acute respiratory distress syndrome develop pulmonary fibrosis. Stresses induced by mechanical ventilation may explain the development of fibrosis by a number of mechanisms (e.g., damage the alveolar epithelium, biotrauma). The objective of this...

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Published in:	Critical care medicine Vol. 40; no. 2; pp. 510 - 517
Main Authors:	Cabrera-Benítez, Nuria E, Parotto, Matteo, Post, Martin, Han, Bing, Spieth, Peter M, Cheng, Wei-Erh, Valladares, Francisco, Villar, Jesús, Liu, Mingayo, Sato, Masaaki, Zhang, Haibo, Slutsky, Arthur S
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD by the Society of Critical Care Medicine and Lippincott Williams & Wilkins 01-02-2012 Lippincott Williams & Wilkins
Subjects:	Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Biological and medical sciences Biopsy, Needle Blotting, Western Cells, Cultured Disease Models, Animal Electrophoresis, Gel, Two-Dimensional Emergency and intensive respiratory care Epithelial-Mesenchymal Transition - physiology Immunohistochemistry Intensive care medicine Medical sciences Mice Mice, Inbred C57BL Positive-Pressure Respiration - adverse effects Positive-Pressure Respiration - methods Pulmonary Fibrosis - etiology Pulmonary Fibrosis - pathology Random Allocation Reference Values Respiratory Mechanics Reverse Transcriptase Polymerase Chain Reaction Sensitivity and Specificity Severity of Illness Index Stress, Mechanical Ventilator-Induced Lung Injury - etiology Ventilator-Induced Lung Injury - pathology Lung disease Ventilator Intensive care Pulmonary fibrosis Respiratory disease Mechanical stress Transition Extracellular matrix Epithelium ventilator-induced lung injury acute lung injury Resuscitation
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Summary:	OBJECTIVES:Many mechanically ventilated patients with acute respiratory distress syndrome develop pulmonary fibrosis. Stresses induced by mechanical ventilation may explain the development of fibrosis by a number of mechanisms (e.g., damage the alveolar epithelium, biotrauma). The objective of this study was t test the hypothesis that mechanical ventilation plays an important role in the pathogenesis of lung fibrosis. METHODS:C57BL/6 mice were randomized into four groupshealthy controls; hydrochloric acid aspiration alone; vehicle control solution followed 24 hrs later by mechanical ventilation (peak inspiratory pressure 22 cm H2O and positive end-expiratory pressure 2 cm H2O for 2 hrs); and acid aspiration followed 24 hrs later by mechanical ventilation. The animals were monitored for up to 15 days after acid aspiration. To explore the direct effects of mechanical stress on lung fibrotic formation, human lung epithelial cells (BEAS-2B) were exposed to mechanical stretch for up to 48 hrs. MEASUREMENT AND MAIN RESULTS:Impaired lung mechanics after mechanical ventilation was associated with increased lung hydroxyproline content, and increased expression of transforming growth factor-β, β-catenin, and mesenchymal markers (α-smooth muscle actin and vimentin) at both the gene and protein levels. Expression of epithelial markers including cytokeratin-8, E-cadherin, and prosurfactant protein B decreased. Lung histology demonstrated fibrosis formation and potential epithelia–mesenchymal transition. In vitro direct mechanical stretch of BEAS-2B cells resulted in similar fibrotic and epithelia–mesenchymal transition formation. CONCLUSIONS:Mechanical stress induces lung fibrosis, and epithelia–mesenchymal transition may play an important role in mediating the ventilator-induced lung fibrosis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 NEC and MP contributed equally to the work
ISSN:	0090-3493 1530-0293
DOI:	10.1097/CCM.0b013e31822f09d7