1. Membrane-anchored serine protease matriptase is a trigger of pulmonary fibrogenesis
- Author
-
Ligong Liu, Thomas H. Bugge, David P. Fairlie, JanWillem Duitman, Awen Menou, Kathrin Mutze, Katiuchia Uzzun Sales, Keren Borensztajn, Bruno Crestani, Olivier Bardou, Yves Castier, Jan H. von der Thüsen, Raphael Borie, Charlene Francois, Melanie Königshoff, Edouard Sage, AII - Amsterdam institute for Infection and Immunity, CCA -Cancer Center Amsterdam, Laboratory Genetic Metabolic Diseases, Other departments, Center of Experimental and Molecular Medicine, and Pathology
- Subjects
Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Blotting, Western ,Critical Care and Intensive Care Medicine ,Idiopathic Pulmonary Fibrosis ,Matriptase ,Camostat Mesilate ,Fibroblast ,Protease-activated Receptor-2 ,Polymerase Chain Reaction ,Mice ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,Western blot ,SDG 3 - Good Health and Well-being ,Pulmonary fibrosis ,medicine ,Animals ,Humans ,Lung ,Protease-activated receptor 2 ,Serine protease ,biology ,medicine.diagnostic_test ,business.industry ,Serine Endopeptidases ,Middle Aged ,respiratory system ,medicine.disease ,Molecular biology ,ENZIMAS ,respiratory tract diseases ,Mice, Inbred C57BL ,Blot ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Female ,Serine Proteases ,business - 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-beta. 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-b 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.
- Published
- 2016