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MMP-12 Mediates Fibrosis after Lung Injury in Mice

¹ Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington; ² VA Puget Sound HealthCare System, Seattle, Washington; and ³ Division of Pulmonary, Allergy and Critical Care, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Gustavo Matute-Bello, M.D., UW Medicine/South Lake Union Campus, 815 Mercer Street, Box 358050, Seattle, WA 98109. E-mail: matuteb{at}u.washington.edu

Acute lung injury (ALI) is characterized by an early inflammatory response, and a late fibroproliferative phase. Activation of the Fas receptor is associated with ALI followed by fibrosis. The goal of this study was to determine the mechanisms that link Fas activation with fibrosis in the lungs. We treated mice with three daily intratracheal instillations of a Fas-activating monoclonal antibody (Jo2) 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, and increased total lung collagen on Day 21. Gene expression profiling performed on Days 2, 4 and 7 showed sequential activation of specific clusters of pro-fibrotic genes, including marked up-regulation of matrix metalloproteinase 12 (MMP-12). Mice with targeted deletion of MMP-12 were protected from Fas-induced pulmonary fibrosis, despite the fact that the inflammatory responses in the lungs of mmp12^–/– mice were similar to those of wild-type mice. Comparison of gene expression in mmp12^–/– and wild-type mice studied on Day 7 revealed that the pro-fibrotic genes egr1 and cyr61 were underexpressed in the mmp12^–/– mice. We conclude that MMP-12 is essential for the fibrotic response after Fas activation in the lungs. The data suggest that MMP-12 activity is required for expression of egr1 and cyr61, and that egr1 and cyr61 are required for the fibroproliferative response to Fas activation in the lungs.

FOOTNOTES

Funded in part by: NIH-HL083044, NIH-HL70840 (G.M.-B.) and the Department of Veterans Affairs.

Conflict of Interest Statement: G.M.-B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.M.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.S.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.W.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.S. has served on several Advisory Boards receiving nominal fees below the ATS threshold. He also serves as Editor of the AJRCMB, for which he is compensated by ATS. T.R.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form November 11, 2007; accepted in final form November 16, 2007)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Matute-Bello, G. Articles by Martin, T. R. PubMed Articles by Matute-Bello, G. Articles by Martin, T. R.