Membrane-anchored serine protease matriptase is a trigger of pulmonary fibrogenesis

Bardou, Oliver, Menou, Awen, Francois, Charlene, Duitman, Jan Willem, von der Thusen, Jan H., Borie, Raphael, Sales, Katiuchia Uzzun, Mutze, Kathrin, Castier, Yves, Sage, Edouard, Liu, Ligong, Bugge, Thomas H., Fairlie, David P., Konigshoff, Melanie, Crestani, Bruno and Borensztain, Keren S. (2015) Membrane-anchored serine protease matriptase is a trigger of pulmonary fibrogenesis. American Journal of Respiratory and Critical Care Medicine, 193 8: 847-860. doi:10.1164/rccm.201502-0299OC

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Author Bardou, Oliver
Menou, Awen
Francois, Charlene
Duitman, Jan Willem
von der Thusen, Jan H.
Borie, Raphael
Sales, Katiuchia Uzzun
Mutze, Kathrin
Castier, Yves
Sage, Edouard
Liu, Ligong
Bugge, Thomas H.
Fairlie, David P.
Konigshoff, Melanie
Crestani, Bruno
Borensztain, Keren S.
Title Membrane-anchored serine protease matriptase is a trigger of pulmonary fibrogenesis
Journal name American Journal of Respiratory and Critical Care Medicine   Check publisher's open access policy
ISSN 1073-449X
Publication date 2015-11-24
Year available 2015
Sub-type Article (original research)
DOI 10.1164/rccm.201502-0299OC
Open Access Status File (Author Post-print)
Volume 193
Issue 8
Start page 847
End page 860
Total pages 42
Place of publication New York, United States
Publisher American Thoracic Society
Collection year 2016
Language eng
Formatted abstract
Rationale: Idiopathic Pulmonary fibrosis (IPF) is a devastating disease, which remains refractory to current therapies.

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 IPF patients versus controls using qRT-PCR, 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, 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 upregulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by TGF-β. Further, 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 camostat mesilate or by genetic down-regulation, diminished lung injury, collagen production and TGF-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 camostat mesilate, which is already in clinical use for other diseases, may represent potential therapies for IPF.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Created: Wed, 09 Dec 2015, 08:06:31 EST by Susan Allen on behalf of Institute for Molecular Bioscience