Impaired lung repair during neutropenia can be reverted by matrix metalloproteinase-9

Thorax. 2018 Apr;73(4):321-330. doi: 10.1136/thoraxjnl-2017-210105. Epub 2017 Sep 25.


Background: Neutrophils may cause tissue disruption during migration and by releasing cytotoxic molecules. However, the benefits of neutrophil depletion observed in experimental models of lung injury do not correspond with the poor outcome of neutropenic patients.

Methods: To clarify the role of neutrophils during repair, mice with ventilator induced lung injury (VILI) were rendered neutropenic after damage, and followed for 48 hours of spontaneous breathing. Lungs were harvested and inflammatory mediators and matrix metalloproteinases measured. Bronchoalveolar lavage fluid (BALF) from ventilated patients with acute respiratory distress syndrome, with or without neutropenia, was collected, the same mediators measured and their effects in an ex vivo model of alveolar repair studied. Finally, neutropenic mice were treated after VILI with exogenous matrix metalloproteinase-9 (MMP-9).

Results: Lungs from neutropenic animals showed delayed repair and displayed higher levels of tumour necrosis factor α, interferon γ and macrophage inflammatory protein 2, and absence of MMP-9. BALF from ventilated neutropenic patients with acute respiratory distress syndrome showed similar results. BALFs from neutropenic patients yielded a delayed closure rate of epithelial wounds ex vivo, which was improved by removal of collagen or addition of exogenous MMP-9. Lastly, treatment of neutropenic mice with exogenous MMP-9 after VILI reduced tissue damage without modifying cytokine concentrations.

Conclusion: Release of MMP-9 from neutrophils is required for adequate matrix processing and lung repair.

Keywords: ARDS; Neutrophil Biology; immunodeficiency; lung proteases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Bronchoalveolar Lavage Fluid / cytology
  • Chemokine CXCL2 / metabolism
  • Disease Models, Animal
  • Humans
  • Interferon-gamma / metabolism
  • Matrix Metalloproteinase 9 / biosynthesis*
  • Mice
  • Neutropenia / metabolism*
  • Neutropenia / pathology
  • Neutrophils / metabolism*
  • Respiratory Distress Syndrome / enzymology
  • Respiratory Distress Syndrome / metabolism*
  • Respiratory Distress Syndrome / pathology
  • Tumor Necrosis Factor-alpha / metabolism
  • Ventilator-Induced Lung Injury / enzymology
  • Ventilator-Induced Lung Injury / metabolism*
  • Ventilator-Induced Lung Injury / pathology
  • Ventilator-Induced Lung Injury / prevention & control


  • Biomarkers
  • Chemokine CXCL2
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Matrix Metalloproteinase 9