Inflammation and matrix remodeling during repair of ventilator-induced lung injury

Am J Physiol Lung Cell Mol Physiol. 2011 Oct;301(4):L500-9. doi: 10.1152/ajplung.00010.2011. Epub 2011 Jul 8.


High-pressure ventilation triggers different inflammatory and matrix remodeling responses within the lung. Although some of them may cause injury, the involvement of these mediators in repair is largely unknown. To identify mechanisms of repair after ventilator-induced lung injury (VILI), mice were randomly assigned to baseline conditions (no ventilation), injury [90 min of high-pressure ventilation without positive end-expiratory pressure (PEEP)], repair (injury followed by 4 h of low-pressure ventilation with PEEP), and ventilated controls (low-pressure ventilation with PEEP for 90 and 330 min). Histological injury and lung permeability increased during injury, but were partially reverted in the repair group. This was accompanied by a proinflammatory response, together with increases in TNF-α and IFN-γ, which returned to baseline during repair, and a decrease in IL-10. However, macrophage inflammatory protein-2 (MIP-2) and matrix metalloproteinases (MMP)-2 and -9 increased after injury and persisted in being elevated during repair. Mortality in the repair phase was 50%. Survivors showed increased cell proliferation, lower levels of collagen, and higher levels of MIP-2 and MMP-2. Pan-MMP or specific MMP-2 inhibition (but not MIP-2, TNF-α, or IL-4 inhibition) delayed epithelial repair in an in vitro wound model using murine or human alveolar cells cultured in the presence of bronchoalveolar lavage fluid from mice during the repair phase or from patients with acute respiratory distress syndrome, respectively. Similarly, MMP inhibition with doxycycline impaired lung repair after VILI in vivo. In conclusion, VILI can be reverted by normalizing ventilation pressures. An adequate inflammatory response and extracellular matrix remodeling are essential for recovery. MMP-2 could play a key role in epithelial repair after VILI and acute respiratory distress syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Remodeling*
  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chemokine CXCL2 / analysis
  • Chemokine CXCL2 / biosynthesis
  • Collagen / analysis
  • Collagen / biosynthesis
  • Continuous Positive Airway Pressure / adverse effects
  • Doxycycline / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Inflammation / complications
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Interleukin-10 / analysis
  • Interleukin-10 / biosynthesis
  • Lung* / metabolism
  • Lung* / pathology
  • Matrix Metalloproteinase 2 / analysis
  • Matrix Metalloproteinase 2 / biosynthesis
  • Matrix Metalloproteinase 9 / analysis
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Mice, Inbred Strains
  • Respiratory Distress Syndrome / complications
  • Respiratory Distress Syndrome / metabolism*
  • Respiratory Distress Syndrome / pathology
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Ventilator-Induced Lung Injury / complications
  • Ventilator-Induced Lung Injury / metabolism*
  • Ventilator-Induced Lung Injury / pathology
  • Ventilators, Mechanical / adverse effects


  • Chemokine CXCL2
  • Matrix Metalloproteinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Collagen
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Matrix Metalloproteinase 9
  • Doxycycline