Mechanical stress induces lung fibrosis by epithelial-mesenchymal transition

Crit Care Med. 2012 Feb;40(2):510-7. doi: 10.1097/CCM.0b013e31822f09d7.


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 groups: healthy controls; hydrochloric acid aspiration alone; vehicle control solution followed 24 hrs later by mechanical ventilation (peak inspiratory pressure 22 cm H(2)O and positive end-expiratory pressure 2 cm H(2)O 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopsy, Needle
  • Blotting, Western
  • Cells, Cultured
  • Disease Models, Animal
  • Electrophoresis, Gel, Two-Dimensional
  • Epithelial-Mesenchymal Transition / physiology*
  • Immunohistochemistry
  • 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*