Absence or inhibition of matrix metalloproteinase-8 decreases ventilator-induced lung injury

Am J Respir Cell Mol Biol. 2010 Nov;43(5):555-63. doi: 10.1165/rcmb.2009-0034OC. Epub 2009 Dec 7.


Mechanical ventilation is a life-saving therapy that can also damage the lungs. Ventilator-induced lung injury (VILI) promotes inflammation and up-regulates matrix metalloproteinases (MMPs). Among these enzymes, MMP-8 is involved in the onset of inflammation by processing different immune mediators. To clarify the role of MMP-8 in a model of VILI and their relevance as a therapeutic target, we ventilated wild-type and MMP-8-deficient mice with low or high pressures for 2 hours. There were no significant differences after low-pressure ventilation between wild-type and knockout animals. However, lack of MMP-8 results in better gas exchange, decreased lung edema and permeability, and diminished histological injury after high-pressure ventilation. Mmp8(-/-) mice had a different immune response to injurious ventilation, with decreased neutrophilic infiltration, lower levels of IFN-γ and chemokines (LPS-induced CXC chemokine, macrophage inflammatory protein-2), and significant increases in anti-inflammatory cytokines (IL-4, IL-10) in lung tissue and bronchoalveolar lavage fluid. There were no differences in MMP-2, MMP-9, or tissue inhibitor of metalloproteinase-1 between wild-type and knockout mice. These results were confirmed by showing a similar protective effect in wild-type mice treated with a selective MMP-8 inhibitor. We conclude that MMP-8 promotes acute inflammation after ventilation with high pressures, and its short-term inhibition could be a therapeutic goal to limit VILI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cytokines / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Hydrogen-Ion Concentration / drug effects
  • Lung / enzymology
  • Lung / immunology
  • Lung / pathology
  • Lung / physiopathology
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 8 / deficiency*
  • Matrix Metalloproteinase 8 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Knockout
  • Pulmonary Gas Exchange / drug effects
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Ventilator-Induced Lung Injury / enzymology*
  • Ventilator-Induced Lung Injury / immunology
  • Ventilator-Induced Lung Injury / physiopathology
  • Ventilator-Induced Lung Injury / prevention & control*


  • Biomarkers
  • Cytokines
  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Tissue Inhibitor of Metalloproteinase-1
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9