title: The fibrogenic actions of lung fibroblast-derived urokinase: a potential drug target in IPF.
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.
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.|School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.|Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Schuliga
authors.affiliation: Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Prahran, Victoria, Australia.
authors.forename: Jade
authors.initials: J
authors.lastname: Jaffar
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Trudi
authors.initials: T
authors.lastname: Harris
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.|Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.|Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Canada.
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Knight
authors.affiliation: Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Prahran, Victoria, Australia.
authors.forename: Glen
authors.initials: G
authors.lastname: Westall
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alastair G
authors.initials: AG
authors.lastname: Stewart
mesh_terms: D000199:Actins / Q000378:metabolism; D015415:Biomarkers; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005341:Fibrinolysin / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D010958:Plasminogen / Q000378:metabolism / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D015415:Biomarkers; D016207:Cytokines; D004791:Enzyme Inhibitors; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator