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    The fibrogenic actions of lung fibroblast-derived urokinase: a potential drug target in IPF

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    Author
    Schuliga, M; Jaffar, J; Harris, T; Knight, DA; Westall, G; Stewart, AG
    Date
    2017-01-31
    Source Title
    Scientific Reports
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Stewart, Alastair; Schuliga, Michael; Harris, Trudi
    Affiliation
    Pharmacology and Therapeutics
    University General
    Metadata
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    Document Type
    Journal Article
    Citations
    Schuliga, M., Jaffar, J., Harris, T., Knight, D. A., Westall, G. & Stewart, A. G. (2017). The fibrogenic actions of lung fibroblast-derived urokinase: a potential drug target in IPF. SCIENTIFIC REPORTS, 7 (1), https://doi.org/10.1038/srep41770.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/258093
    DOI
    10.1038/srep41770
    Abstract
    The role of urokinase plasminogen activator (uPA) in idiopathic pulmonary fibrosis (IPF) remains unclear. uPA-generated plasmin has potent fibrogenic actions involving protease activated receptor-1 (PAR-1) and interleukin-6 (IL-6). Here we characterize uPA distribution or levels in lung tissue and sera from IPF patients to establish the mechanism of its fibrogenic actions on lung fibroblasts (LFs). uPA immunoreactivity was detected in regions of fibrosis including fibroblasts of lung tissue from IPF patients (n = 7). Serum uPA levels and activity were also higher in IPF patients (n = 18) than controls (n = 18) (P < 0.05), being negatively correlated with lung function as measured by forced vital capacity (FVC) %predicted (P < 0.05). The culture supernatants of LFs from IPF patients, as compared to controls, showed an increase in plasmin activity after plasminogen incubation (5-15 μg/mL), corresponding with increased levels of uPA and IL-6 (n = 5-6, P < 0.05). Plasminogen-induced increases in plasmin activity and IL-6 levels were attenuated by reducing uPA and/or PAR-1 expression by RNAi. Plasmin(ogen)-induced mitogenesis was also attenuated by targeting uPA, PAR-1 or IL-6. Our data shows uPA is formed in active regions of fibrosis in IPF lung and contributes to LF plasmin generation, IL-6 production and proliferation. Urokinase is a potential target for the treatment of lung fibrosis.

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