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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/L572    most recent 00291.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fattman, C. L. Articles by Ortiz, L. A. Search for Related Content PubMed PubMed Citation Articles by Fattman, C. L. Articles by Ortiz, L. A.

Epithelial expression of TIMP-1 does not alter sensitivity to bleomycin-induced lung injury in C57BL/6 mice

¹Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania; and ²Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky

Submitted 25 July 2007 ; accepted in final form 2 January 2008

Matrix metalloproteinases (MMPs) are mediators of lung injury, and their activity has been associated with the development of pulmonary fibrosis. To understand how MMPs regulate the development of pulmonary fibrosis, we examined MMP expression in two strains of mice with differing sensitivities to the fibrosis-inducing drug bleomycin. After a single intratracheal injection of the drug, bleomycin-sensitive C57BL/6 mice showed increased expression for MMPs (-2, -7, -9, -13) at both 7 and 14 days posttreatment compared with the bleomycin-resistant BALB/c strain. In addition, TIMP-1, an endogenous inhibitor of MMPs, was upregulated in the lungs of C57BL/6 mice but not BALB/c mice. We designed two strategies to decrease MMP expression to potentially decrease sensitivity of C57BL/6 mice: 1) we engineered C57BL/6 mice that overexpressed TIMP-1 in their lungs via surfactant protein C (SP-C) promoter; and 2) we inhibited expression of MMPs independent of TIMP-1 by knocking out metallothionein (MT), a critical zinc binding protein. SP-C-TIMP-1 mice reduced MMP expression in response to bleomycin. However, they were equally sensitive to bleomycin as their wild-type counterparts, displaying similar levels of hydroxyproline in the lung tissue. MT null mice displayed decreased lung activity of MMPs with no change in TIMP-1. Nonetheless, there was no difference between the MT null and wild-type control littermates with regards to any of the lung injury parameters measured. We conclude that although TIMP-1 expression is differentially regulated in fibrosis-sensitive and fibrosis-resistant strains, epithelial overexpression of TIMP-1 does not appear to substantially alter fibrotic lung disease in mice.

matrix metalloproteinase; pulmonary fibrosis; metallothionein