Overexpression of MMP9 in macrophages attenuates pulmonary fibrosis induced by bleomycin

Int J Biochem Cell Biol. 2007;39(12):2324-38. doi: 10.1016/j.biocel.2007.06.022. Epub 2007 Jul 12.


Pulmonary fibrosis is a common response to a variety of lung injuries, characterized by fibroblast/myofibroblast expansion and abnormal accumulation of extracellular matrix. An increased expression of matrix metalloprotease 9 (MMP9) in human and experimental lung fibrosis has been documented, but its role in the fibrotic response is unclear. We studied the effect of MMP9 overexpression in bleomycin-driven lung fibrosis using transgenic mice expressing human MMP9 in alveolar macrophages (hMMP9-TG). At 8 weeks post-bleomycin, the extent of fibrotic lesions and OH-proline content were significantly decreased in the TG mice compared to the WT mice. The decreased fibrosis in hMMP9-TG mice was preceded by a significant reduction of neutrophils and lymphocytes in bronchoalveolar lavage (BAL) at 1 and 4 weeks post-bleomycin, respectively, as well as by significantly less TIMP-1 than the WT mice. From a variety of cytokines/chemokines investigated, we found that BAL levels of insulin-like growth factor binding protein-3 (IGFBP3) as well as the immunoreactive protein in the lungs were significantly lower in hMMP9-TG mice compared with WT mice despite similar levels of gene expression. Using IGFBP-3 substrate zymography we found that BAL from TG mice at 1 week after bleomycin cleaved IGFBP-3. Further, we demonstrated that MMP9 degraded IGFBP-3 into lower molecular mass fragments. These findings suggest that increased activity of MMP9 secreted by alveolar macrophages in the lung microenvironment may have an antifibrotic effect and provide a potential mechanism involving IGFBP3 degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / toxicity*
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Count
  • Cytokines / analysis
  • Cytokines / metabolism
  • Gene Expression
  • Humans
  • Hydroxyproline / metabolism
  • Immunohistochemistry
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism
  • Lung / enzymology
  • Lung / metabolism
  • Lung / pathology
  • Lymphocytes / cytology
  • Macrophages, Alveolar / cytology
  • Macrophages, Alveolar / enzymology*
  • Macrophages, Alveolar / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Neutrophils / cytology
  • Peroxidase / analysis
  • Peroxidase / metabolism
  • Protein Array Analysis
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / enzymology*
  • Pulmonary Fibrosis / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors


  • Cytokines
  • Insulin-Like Growth Factor Binding Protein 3
  • Bleomycin
  • Peroxidase
  • Matrix Metalloproteinase 9
  • Hydroxyproline