Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice

Am J Respir Cell Mol Biol. 2005 Sep;33(3):271-9. doi: 10.1165/rcmb.2005-0111OC. Epub 2005 Jun 9.


Bleomycin-induced lung injury triggers a profound and durable increase in tissue inhibitor of metalloproteinase (TIMP)-1 expression, suggesting a potential role for this antiproteinase in the regulation of lung inflammation and fibrosis. TIMP-1 protein induction is spatially restricted to areas of lung injury as determined by immunohistochemistry. Using TIMP-1 null mutation mice, we demonstrate that TIMP-1 deficiency amplifies acute lung injury as determined by exaggerated pulmonary neutrophilia, hemorrhage, and vascular permeability compared with wild-type littermates after bleomycin exposure. The augmented pulmonary neutrophilia observed in TIMP-1-deficient animals was not found in similarly treated TIMP-2-deficient mice. Using TIMP-1 bone marrow (BM) chimeric mice, we observed that the TIMP-1-deficient phenotype was abolished in wild-type recipients of TIMP-1-deficient BM but not in TIMP-1-deficient recipients of wild-type BM. Acute lung injury in TIMP-1-deficient mice was accompanied by exaggerated gelatinase-B activity in the alveolar compartment. TIMP-1 deficiency did not alter neutrophil chemotactic factor accumulation in the injured lung nor neutrophil migration in response to chemotactic stimuli in vivo or in vitro. Moreover, TIMP-1 deficiency did not modify collagen accumulation after bleomycin injury. Our results provide direct evidence that TIMP-1 contributes significantly to the regulation of acute lung injury, functioning to limit inflammation and lung permeability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic
  • Bleomycin
  • Capillary Permeability / immunology
  • Chemotaxis, Leukocyte / immunology
  • Gene Expression / immunology
  • Hemorrhage / immunology
  • Hemorrhage / mortality
  • Hemorrhage / physiopathology
  • Lipopolysaccharides
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neutrophils / cytology
  • Neutrophils / immunology
  • Pulmonary Alveoli / enzymology
  • Pulmonary Alveoli / immunology
  • Pulmonary Alveoli / pathology
  • Pulmonary Fibrosis / immunology
  • Pulmonary Fibrosis / mortality
  • Pulmonary Fibrosis / physiopathology
  • Respiratory Distress Syndrome / immunology*
  • Respiratory Distress Syndrome / mortality
  • Respiratory Distress Syndrome / physiopathology*
  • Specific Pathogen-Free Organisms
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*
  • Tissue Inhibitor of Metalloproteinase-1 / immunology*
  • Weight Loss


  • Antibiotics, Antineoplastic
  • Lipopolysaccharides
  • Tissue Inhibitor of Metalloproteinase-1
  • Bleomycin
  • Matrix Metalloproteinase 9