title: Pivotal role of matrix metalloproteinase 13 in extracellular matrix turnover in idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by excessive deposition of extracellular matrix (ECM).
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: University of Giessen & Marburg Lung Center (UGMLC), Giessen, Germany ; Department of Medicine, Division of Molecular Medicine, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Takwi
authors.initials: T
authors.lastname: Nkyimbeng
authors.forename: Clemens
authors.initials: C
authors.lastname: Ruppert
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shiomi
authors.forename: Bhola
authors.initials: B
authors.lastname: Dahal
authors.forename: György
authors.initials: G
authors.lastname: Lang
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
mesh_terms: D000328:Adult; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D016022:Case-Control Studies; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D059748:Proteolysis / Q000187:drug effects; D014019:Tissue Donors; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D001761:Bleomycin; D003094:Collagen; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1; D006909:Hydroxyproline
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