1. Pivotal role of matrix metalloproteinase 13 in extracellular matrix turnover in idiopathic pulmonary fibrosis.
- Author
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Nkyimbeng T, Ruppert C, Shiomi T, Dahal B, Lang G, Seeger W, Okada Y, D'Armiento J, and Günther A
- Subjects
- Adult, Animals, Bleomycin pharmacology, Case-Control Studies, Collagen metabolism, Extracellular Matrix drug effects, Humans, Hydroxyproline metabolism, Idiopathic Pulmonary Fibrosis chemically induced, Idiopathic Pulmonary Fibrosis metabolism, Lung drug effects, Lung enzymology, Lung pathology, Matrix Metalloproteinase 1 genetics, Matrix Metalloproteinase 1 metabolism, Matrix Metalloproteinase 13 deficiency, Matrix Metalloproteinase 13 genetics, Mice, Middle Aged, Proteolysis drug effects, Tissue Donors, Tissue Inhibitor of Metalloproteinases metabolism, Up-Regulation drug effects, Extracellular Matrix metabolism, Idiopathic Pulmonary Fibrosis enzymology, Idiopathic Pulmonary Fibrosis pathology, Matrix Metalloproteinase 13 metabolism
- Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by excessive deposition of extracellular matrix (ECM)., Objectives: We investigated the regulation of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lung fibrosis., Methods: MMP and TIMP expression, collagenolytic activity and collagen content was assessed in IPF (n=16) versus donor (n=6) lung homogenates and accomplished by in-situ-zymography for gelatinolytic and collagenolytic activities, combined with MMP antigen detection. Role of MMP13 was assessed employing the bleomycin model of lung fibrosis in MMP-13(-/-) versus wild-type mice., Measurements and Main Results: In IPF, MMPs-1, 2, 7, 9 and 13, but not MMP-8, were significantly upregulated, whereas none of the TIMPs (1-4) were significantly altered. Collagen content was slightly increased and collagenolytic activity was most prominent in the airways and co-localized with MMP-13. We observed an exaggerated early inflammatory response and an augmented lung fibrosis in bleomycin-challenged MMP-13(-/-) versus wild-type mice, with elevated lung collagen content 28d after bleomycin challenge in the MMP-13(-/-) mice., Conclusions: Our data suggest that i) collagen deposition in IPF lungs is not primarily due to excessive TIMP production, but rather due to overwhelming ECM production in face of an overall increased, but spatially imbalanced collagenolytic activity, ii) preferential distribution of collagenolytic activity, largely MMP-13, in the airways offers an explanation for the development of honeycomb cysts and iii) despite an overall increase in inflammatory cell content the presence of MMP-13 seems to limit the overall extent of ECM deposition in lung fibrosis.
- Published
- 2013
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