Olivier Bardou1,2, Awen Menou1,2, Charlène François1,2, Jan Willem Duitman3, Jan H von der Thüsen4, Raphaël Borie2,5, Katiuchia Uzzun Sales6,7, Kathrin Mutze8, Yves Castier9, Edouard Sage10, Ligong Liu11, Thomas H Bugge6, David P Fairlie11, Mélanie Königshoff8, Bruno Crestani1,2,5, Keren S Borensztajn1,2. 1. 1 Inserm UMR1152, Medical School Xavier Bichat, Paris, France. 2. 2 Université Paris Diderot, Sorbonne Paris Cité, Département Hospitalo-universitaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France. 3. 3 Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands. 4. 4 Department of Pathology, Erasmus Medical Centre, Rotterdam, the Netherlands. 5. 5 Assistance Publique-Hôpitaux de Paris, Department of Pulmonology A, Competence Center for Rare Lung Diseases, Bichat-Claude Bernard University Hospital, Paris, France. 6. 6 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland. 7. 7 Department of Cell and Molecular Biology, Ribeirão Preto School of Medicine, University of São Paulo Ribeirão Preto, São Paulo, Brazil. 8. 8 Member of the German Center of Lung Research, Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Germany. 9. 9 Assistance Publique-Hôpitaux de Paris, Department of Vascular and Thoracic Surgery, Bichat-Claude Bernard University Hospital, Denis Diderot University and Medical School Paris VII, France. 10. 10 Department of Thoracic Surgery and Lung Transplantation, Hôpital Foch, Suresnes, France; and. 11. 11 Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Abstract
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that remains refractory to current therapies. OBJECTIVES: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. METHODS: Matriptase expression was assessed in tissue specimens from patients with IPF versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. Matriptase-induced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate (CM), or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. MEASUREMENTS AND MAIN RESULTS: Matriptase expression and activity were up-regulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-β. Furthermore, matriptase elicited signaling via protease-activated receptor-2 (PAR-2), and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic down-regulation, diminished lung injury, collagen production, and transforming growth factor-β expression and signaling. CONCLUSIONS: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for IPF.
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that remains refractory to current therapies. OBJECTIVES: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. METHODS:Matriptase expression was assessed in tissue specimens from patients with IPF versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. Matriptase-induced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate (CM), or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. MEASUREMENTS AND MAIN RESULTS:Matriptase expression and activity were up-regulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-β. Furthermore, matriptase elicited signaling via protease-activated receptor-2 (PAR-2), and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic down-regulation, diminished lung injury, collagen production, and transforming growth factor-β expression and signaling. CONCLUSIONS: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for IPF.
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