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Published ahead of print on April 19, 2007, doi:10.1165/rcmb.2006-0471OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 2, August 2007, 210-221

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Submitted on December 20, 2006
Revised on April 18, 2007

Essential Role of MMP-12 in Fas-induced Lung Fibrosis

Gustavo Matute-Bello1*, Mark M Wurfel2, Janet S Lee3, David R Park2, Charles W Frevert1, David K Madtes4, Steven D Shapiro5, and Thomas R Martin1

1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA; Medical Research Service of the VA Puget Sound Healthcare System, Seattle, WA, USA, 2 Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA, 3 Division of Pulmonary, Allergy and Critical Care, University of Pittsburgh, Pittsburgh, PA, USA, 4 Section of Pulmonary and Critical Care Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 5 Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

* To whom correspondence should be addressed. 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 linking 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 pro-fibrotic genes, including marked upregulation 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. As compared to wild type mice, the mmp12-/- mice showed decreased expression of the pro-fibrotic genes egr1 and cyr61. We conclude that Fas activation in the lungs induces a complex response that includes apoptosis, inflammation and 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.




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