Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by fibroblast expansion and extracellular matrix accumulation. However, the mechanisms involved in matrix remodeling have not been elucidated. In this study, the authors aimed to evaluate the expression of the tissue inhibitors of matrix metalloproteinases (TIMPs) in human fibroblasts and whole tissues from IPF and normal lungs. They also determined the role of mitogen-activated protein kinase (MAPK) in TIMP3 expression. TIMP1, TIMP2, and TIMP3 were highly expressed in lung fibroblasts. Transforming growth factor (TGF)-beta1, a profibrotic mediator, induced strong up-regulation of TIMP3 at the mRNA and protein levels. The authors examined whether the MAPK pathway was involved in TGF-beta1-induced TIMP3 expression. TGF-beta1 induced the phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2. Biochemical blockade of p38 by SB203580, but not of the ERK MAPK pathway, inhibited the effect of this factor. The effect was also blocked by the tyrosine kinase inhibitor genistein and by antagonizing TGF-beta1 receptor type I (activin-linked kinase [ALK5]). In IPF tissues TIMP3 gene expression was significantly increased and the protein was localized to fibroblastic foci and extracellular matrix. Our findings suggest that TGF-beta1-induced TIMP3 may be an important mediator in lung fibrogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cells, Cultured
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Endothelial Cells / pathology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Enzyme Inhibitors / pharmacology
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Fibroblasts / physiology
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Genistein / pharmacology
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Humans
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Imidazoles / pharmacology
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Interferon-gamma / pharmacology
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Pulmonary Fibrosis / metabolism*
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Pulmonary Fibrosis / pathology
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Pulmonary Fibrosis / physiopathology
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Pyridines / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Tissue Inhibitor of Metalloproteinase-3 / genetics
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Tissue Inhibitor of Metalloproteinase-3 / metabolism*
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Transforming Growth Factor beta / physiology*
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Transforming Growth Factor beta1
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Up-Regulation / drug effects*
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Up-Regulation / physiology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Enzyme Inhibitors
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Imidazoles
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Pyridines
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RNA, Messenger
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TGFB1 protein, human
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Tissue Inhibitor of Metalloproteinase-1
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Tissue Inhibitor of Metalloproteinase-3
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Interferon-gamma
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Genistein
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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SB 203580