Epithelial expression of TIMP-1 does not alter sensitivity to bleomycin-induced lung injury in C57BL/6 mice.
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.
Fattman
Cheryl L
CL
University of Pittsburgh, Graduate School of Public Health, Department of Environmental and Occupational Health, Bridgeside Point, 100 Technology Dr., Suite #328, Pittsburgh, PA 15219-3130, USA.
Gambelli
Federica
F
Hoyle
Gary
G
Pitt
Bruce R
BR
Ortiz
Luis A
LA
D000818:Animals; D001761:Bleomycin; D004789:Enzyme Activation; D004848:Epithelium / Q000378:metabolism; D005260:Female; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008668:Metallothionein / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*; D015854:Up-Regulation
D019715:Tissue Inhibitor of Metalloproteinase-1; D001761:Bleomycin; D008668:Metallothionein; D020782:Matrix Metalloproteinases