title: Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a devastating disease that remains refractory to current therapies.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 1 Inserm UMR1152, Medical School Xavier Bichat, Paris, France.|2 Université Paris Diderot, Sorbonne Paris Cité, Département Hospitalo-universitaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bardou
authors.affiliation: 1 Inserm UMR1152, Medical School Xavier Bichat, Paris, France.|2 Université Paris Diderot, Sorbonne Paris Cité, Département Hospitalo-universitaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France.
authors.forename: Awen
authors.initials: A
authors.lastname: Menou
authors.affiliation: 1 Inserm UMR1152, Medical School Xavier Bichat, Paris, France.|2 Université Paris Diderot, Sorbonne Paris Cité, Département Hospitalo-universitaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: François
authors.affiliation: 3 Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Duitman
authors.affiliation: 4 Department of Pathology, Erasmus Medical Centre, Rotterdam, the Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: von der Thüsen
authors.affiliation: 2 Université Paris Diderot, Sorbonne Paris Cité, Département Hospitalo-universitaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France.|5 Assistance Publique-Hôpitaux de Paris, Department of Pulmonology A, Competence Center for Rare Lung Diseases, Bichat-Claude Bernard University Hospital, Paris, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Borie
authors.affiliation: 6 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.|7 Department of Cell and Molecular Biology, Ribeirão Preto School of Medicine, University of São Paulo Ribeirão Preto, São Paulo, Brazil.
authors.forename: Katiuchia Uzzun
authors.initials: KU
authors.lastname: Sales
authors.affiliation: 8 Member of the German Center of Lung Research, Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mutze
authors.affiliation: 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.
authors.forename: Yves
authors.initials: Y
authors.lastname: Castier
authors.affiliation: 10 Department of Thoracic Surgery and Lung Transplantation, Hôpital Foch, Suresnes, France; and.
authors.forename: Edouard
authors.initials: E
authors.lastname: Sage
authors.affiliation: 11 Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.affiliation: 6 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.affiliation: 11 Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: 8 Member of the German Center of Lung Research, Comprehensive Pneumology Center, University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: 1 Inserm UMR1152, Medical School Xavier Bichat, Paris, France.|2 Université Paris Diderot, Sorbonne Paris Cité, Département Hospitalo-universitaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France.|5 Assistance Publique-Hôpitaux de Paris, Department of Pulmonology A, Competence Center for Rare Lung Diseases, Bichat-Claude Bernard University Hospital, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.affiliation: 1 Inserm UMR1152, Medical School Xavier Bichat, Paris, France.|2 Université Paris Diderot, Sorbonne Paris Cité, Département Hospitalo-universitaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France.
authors.forename: Keren S
authors.initials: KS
authors.lastname: Borensztajn
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000378:metabolism*; D057057:Serine Proteases / Q000378:metabolism
chemical_list: D057057:Serine Proteases; D012697:Serine Endopeptidases; C485595:matriptase
keywords: camostat mesilate; fibroblast; idiopathic pulmonary fibrosis; matriptase; protease-activated receptor-2