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

American Journal of Physiology. Lung Cellular and Molecular Physiology
Cheryl L FattmanLuis A Ortiz

Abstract

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 tiss...Continue Reading

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Citations

Dec 17, 2009·The American Journal of Pathology·Sean E GillWilliam C Parks
Dec 5, 2012·Laboratory Investigation; a Journal of Technical Methods and Pathology·Takayoshi SumiokaShizuya Saika
Dec 4, 2013·Fibrogenesis & Tissue Repair·Louise WalkinPeter J Margetts
Sep 19, 2018·International Journal of Molecular Sciences·Luis G Vazquez-de-LaraRoberto Berra-Romani

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