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Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis

Pardo, A and Gibson, K and Cisneros, J and Richards, TJ and Yang, Y and Becerril, C and Yousem, S and Herrera, I and Ruiz, V and Selman, M and Kaminski, N (2005) Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. PLoS Medicine, 2 (9). 0891 - 0903. ISSN 1549-1277

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Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung. Methods and Findings: Using oligonucleotide arrays, we identified osteopontin as one of the genes that significantly distinguishes IPF from normal lungs. Osteopontin was localized to alveolar epithelial cells in IPF lungs and was also significantly elevated in bronchoalveolar lavage from IPF patients. To study the fibrosis-relevant effects of osteopontin we stimulated primary human lung fibroblasts and alveolar epithelial cells (A549) with recombinant osteopontin. Osteopontin induced a significant increase of migration and proliferation in both fibroblasts and epithelial cells. Epithelial growth was inhibited by the pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) and antibody to CD44, while fibroproliferation was inhibited by GRGDS and antibody to avb3 integrin. Fibroblast and epithelial cell migration were inhibited by GRGDS, anti-CD44, and anti- αvβ3. In fibroblasts, osteopontin up-regulated tissue inhibitor of metalloprotease-1 and type I collagen, and down-regulated matrix metalloprotease-1 (MMP-1) expression, while in A549 cells it caused up-regulation of MMP-7. In human IPF lungs, osteopontin colocalized with MMP-7 in alveolar epithelial cells, and application of weakest link statistical models to microarray data suggested a significant interaction between osteopontin and MMP-7. Conclusions: Our results provide a potential mechanism by which osteopontin secreted from the alveolar epithelium may exert a profibrotic effect in IPF lungs and highlight osteopontin as a potential target for therapeutic intervention in this incurable disease. © 2005 Pardo et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Pardo, A
Gibson, Kkfg@pitt.eduKFG
Cisneros, J
Richards, TJ
Yang, Y
Becerril, C
Yousem, Syousem@pitt.eduYOUSEM
Herrera, I
Ruiz, V
Selman, M
Kaminski, N
ContributionContributors NameEmailPitt UsernameORCID
Date: 7 October 2005
Date Type: Publication
Journal or Publication Title: PLoS Medicine
Volume: 2
Number: 9
Page Range: 0891 - 0903
DOI or Unique Handle: 10.1371/journal.pmed.0020251
Schools and Programs: School of Medicine > Critical Care Medicine
Refereed: Yes
ISSN: 1549-1277
PubMed ID: 16128620
Date Deposited: 11 Jul 2012 17:51
Last Modified: 22 Jun 2021 16:55


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