Essential role of MMP-12 in fas-induced lung fibrosis

  • Matute-Bello G
  • Wurfel M
  • Lee J
 et al. 
  • 34

    Readers

    Mendeley users who have this article in their library.
  • 81

    Citations

    Citations of this article.

Abstract

Acute lung injury (ALI) is characterized by an early inflammatory response followed by a late fibroproliferative phase, and by an increase in the bronchoalveolar lavage fluid (BALF) concentrations of bioactive soluble FasL (sFasL). Activation of Fas (CD95) has been associated with the development of lung fibrosis in mice. The goal of this study was to determine the mechanisms that link Fas activation with the development of fibrosis in the lungs. We treated mice with three daily intratracheal instillations of a Fas-activating monoclonal antibody (Jo2) or a control IgG, and studied the animals at sequential times. Mice treated with Jo2 had increased caspase-3 activation in alveolar wall cells on Days 2, 4, and 7; an inflammatory response peaking on Day 7, and increased total lung collagen on Day 21. Gene expression profiling performed on Days 2, 4, and 7 showed sequential activation of co-regulated profibrotic genes, including marked up-regulation of matrix metalloproteinase 12 (MMP-12). Targeted deletion of MMP-12 protected mice from Fas-induced pulmonary fibrosis, even though the inflammatory responses in the lungs were similar to those of wild-type mice. Compared with wild-type mice, the mmp12(-/-) mice showed decreased expression of the profibrotic genes egr1 and cyr61. We conclude that Fas activation in the lungs induces a complex response that includes apoptosis, inflammation, and eventually fibrosis, and that MMP-12 is essential for the fibrotic phenotype. We speculate that MMP-12 activity is required for activation of the profibrotic genes egr1 and cyr61.

Author-supplied keywords

  • Apoptosis
  • CYR61/CCN1
  • Fas
  • Inflammation
  • MMP-12

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Get full text

Authors

  • Gustavo Matute-Bello

  • Mark M. Wurfel

  • Janet S. Lee

  • David R. Park

  • Charles W. Frevert

  • David K. Madtes

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free