TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment?

Am J Physiol Lung Cell Mol Physiol. 2000 Sep;279(3):L562-74. doi: 10.1152/ajplung.2000.279.3.L562.


Fibroblast proliferation and extracellular matrix accumulation characterize idiopathic pulmonary fibrosis (IPF). We evaluated the presence of tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4; collagenase-1, -2, and -3; gelatinases A and B; and membrane type 1 matrix metalloproteinase (MMP) in 12 IPF and 6 control lungs. TIMP-1 was found in interstitial macrophages and TIMP-2 in fibroblast foci. TIMP-3 revealed an intense staining mainly decorating the elastic lamina in vessels. TIMP-4 was expressed in IPF lungs by epithelial and plasma cells. TIMP-2 colocalized with Ki67 in fibroblasts, whereas TIMP-3 colocalized with p27 in inflammatory and epithelial cells. Collagenase-1 was localized in macrophages and alveolar epithelial cells, collagenase-2 was localized in a few neutrophils, and collagenase-3 was not detected. MMP-9 was found in neutrophils and subepithelial myofibroblasts. Myofibroblast expression of MMP-9 was corroborated in vitro by RT-PCR. MMP-2 was noticed in myofibroblasts, some of them close to areas of basement membrane disruption, and membrane type 1 MMP was noticed in interstitial macrophages. These findings suggest that in IPF there is higher expression of TIMPs compared with collagenases, supporting the hypothesis that a nondegrading fibrillar collagen microenvironment is prevailing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Collagenases / metabolism
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Ki-67 Antigen / metabolism*
  • Lung / metabolism*
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism
  • Middle Aged
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Pulmonary Fibrosis / metabolism*
  • RNA, Messenger / metabolism
  • Tissue Distribution
  • Tissue Inhibitor of Metalloproteinases / genetics
  • Tissue Inhibitor of Metalloproteinases / metabolism*


  • Ki-67 Antigen
  • Proliferating Cell Nuclear Antigen
  • Protein Isoforms
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinases
  • p27 antigen
  • Collagenases
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9