- Title
- The fibrogenic actions of lung fibroblast-derived urokinase: a potential drug target in IPF
- Creator
- Schuliga, Michael; Jaffar, Jade; Harris, Trudi; Knight, Darryl A.; Westall, Glen; Stewart, Alastair G.
- Relation
- NHMRC.1022048 | NHMRC|1023185 | NHMRC|1059665 http://purl.org/au-research/grants/nhmrc/1059665
- Relation
- Scientific Reports Vol. 7, no. 41770
- Publisher Link
- http://dx.doi.org/10.1038/srep41770
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2017
- Description
- 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.
- Subject
- mechanisms of disease; preclinical research; urokinase plasminogen activator (uPA); idiopathic pulmonary fibrosis (IPF)
- Identifier
- http://hdl.handle.net/1959.13/1352859
- Identifier
- uon:30970
- Identifier
- ISSN:2045-2322
- Rights
- This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Language
- eng
- Full Text
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