Published ahead of print on April 19, 2007, doi:10.1165/rcmb.2006-0471OC
American Journal of Respiratory Cell and Molecular Biology. Vol. 37, pp. 210-221, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-0471OC
Essential Role of MMP-12 in Fas-Induced Lung Fibrosis
Gustavo Matute-Bello,
Mark M. Wurfel,
Janet S. Lee,
David R. Park,
Charles W. Frevert,
David K. Madtes,
Steven D. Shapiro and
Thomas R. Martin
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington; Medical Research Service of the VA Puget Sound Healthcare System; Section of Pulmonary and Critical Care Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington; and Division of Pulmonary, Allergy and Critical Care, and Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Correspondence and requests for reprints should be addressed to Gustavo Matute-Bello, UW Medicine/South Lake Union Campus, 815 Mercer Street, Seattle, WA 98109. E-mail: matuteb{at}u.washington.edu
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.
Key Words: apoptosis • inflammation • MMP-12 • Fas • CYR61/CCN1
| CLINICAL RELEVANCE
This study provides novel information suggesting that macrophage activation drives the lung fibrotic response to Fas activation, and that matrix metalloproteinase-12, a metalloelastase previously associated with emphysema, is essential for Fas-induced fibroproliferation.
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