TY - JOUR
T1 - Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis
AU - Yamashita, Cory M.
AU - Dolgonos, Lior
AU - Zemans, Rachel L.
AU - Young, Scott K.
AU - Robertson, Jennifer
AU - Briones, Natalie
AU - Suzuki, Tomoko
AU - Campbell, Megan N.
AU - Gauldie, Jack
AU - Radisky, Derek C.
AU - Riches, David W.H.
AU - Yu, Guoying
AU - Kaminski, Naftali
AU - McCulloch, Christopher A.G.
AU - Downey, Gregory P.
N1 - Funding Information:
Supported by grants from the National Institutes of Health ( HL090669 to G.P.D., CA122086 and CA128660 to D.C.R., HL0894932 to N.K., and HL68628 to D.W.H.R.) and the Canadian Institutes of Health Research ( MOP 84254 to C.A.G.M.), by funds from the Harold and Mary Zirin Chair in Pulmonary Biology at National Jewish Health (G.P.D.), and by funding from the Schulich School of Medicine and Dentistry Resident Research Career Program (C.M.Y.).
PY - 2011/10
Y1 - 2011/10
N2 - Idiopathic pulmonary fibrosis (IPF) may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 (MMP-3) in the pathogenesis of IPF through i) determination of MMP-3 expression in patients with IPF, ii) in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii) in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in IPF, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and pulmonary fibrosis. Conversely, MMP-3-null mice were protected against bleomycin-induced pulmonary fibrosis. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the β-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.
AB - Idiopathic pulmonary fibrosis (IPF) may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 (MMP-3) in the pathogenesis of IPF through i) determination of MMP-3 expression in patients with IPF, ii) in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii) in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in IPF, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and pulmonary fibrosis. Conversely, MMP-3-null mice were protected against bleomycin-induced pulmonary fibrosis. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the β-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.
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U2 - 10.1016/j.ajpath.2011.06.041
DO - 10.1016/j.ajpath.2011.06.041
M3 - Article
C2 - 21871427
AN - SCOPUS:80053272507
SN - 0002-9440
VL - 179
SP - 1733
EP - 1745
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -