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ECM crosslinking enhances fibroblast growth and protects against matrix proteolysis in lung fibrosis

Philp, Christopher J.; Siebeke, Ivonne; Clements, Debbie; Miller, Suzanne; Habgood, Anthony; John, Alison E.; Navaratnam, Vidya; Hubbard, Richard B.; Jenkins, Gisli; Johnson, Simon R.

Authors

Christopher J. Philp christopher.philp@nottingham.ac.uk

Ivonne Siebeke

Anthony Habgood

Vidya Navaratnam vidya.navaratnam@nottingham.ac.uk

RICHARD HUBBARD richard.hubbard@nottingham.ac.uk
Blf/Gsk Professor of Epidemiological Resp Research

GISLI JENKINS gisli.jenkins@nottingham.ac.uk
Professor of Experimental Medicine

SIMON JOHNSON simon.johnson@nottingham.ac.uk
Professor of Respiratory Medicine



Abstract

Idiopathic pulmonary fibrosis (IPF) is characterised by accumulation of extra cellular matrix (ECM) proteins and fibroblast proliferation. ECM cross-linking enzymes have been implicated in fibrotic diseases and we hypothesised that the ECM in IPF is abnormally cross-linked which enhances fibroblast growth and resistance to normal ECM turnover. We used a combination of in vitro ECM preparations and in vivo assays to examine the expression of cross-linking enzymes and the effect of their inhibitors on fibroblast growth and ECM turnover. Lysyl oxidase like 1, 2, 3 and 4 were expressed equally in control and IPF derived fibroblasts. Transglutaminase 2 was more strongly expressed in IPF fibroblasts. Lysyl oxidase like 2, transglutaminase 2 and transglutaminase generated cross-links were strongly expressed in IPF lung tissue. Fibroblasts grown on IPF ECM had higher LOXL3 protein expression and transglutaminase activity compared with those grown on control ECM. IPF derived ECM also enhanced fibroblast adhesion and proliferation compared with control ECM. Inhibition of lysyl oxidase and transglutaminse activity during ECM formation affected ECM structure as visualised by electron microscopy and reduced the enhanced fibroblast adhesion and proliferation of IPF ECM to control levels. Inhibition of transglutaminase, but not lysyl oxidase activity, enhanced the turnover of ECM in vitro. In bleomycin treated mice, during the post-inflammatory fibrotic phase, inhibition of transglutaminases was associated with a reduction in whole lung collagen. Our findings suggest that the ECM in IPF may enhance pathological cross-linking which contributes to increased fibroblast growth, resistance to normal ECM turnover to drive lung fibrosis.

Citation

Philp, C. J., Siebeke, I., Clements, D., Miller, S., Habgood, A., John, A. E., …Johnson, S. R. (2018). ECM crosslinking enhances fibroblast growth and protects against matrix proteolysis in lung fibrosis. American Journal of Respiratory Cell and Molecular Biology, 58(5), 594–603. doi:10.1165/rcmb.2016-0379OC

Journal Article Type Article
Acceptance Date Oct 19, 2017
Online Publication Date Oct 20, 2017
Publication Date May 1, 2018
Deposit Date Nov 8, 2017
Publicly Available Date Nov 8, 2017
Journal American Journal of Respiratory Cell and Molecular Biology
Print ISSN 1044-1549
Electronic ISSN 1535-4989
Publisher American Thoracic Society
Peer Reviewed Peer Reviewed
Volume 58
Issue 5
Pages 594–603
DOI https://doi.org/10.1165/rcmb.2016-0379OC
Keywords IPF; Fibroblast; Extracellular Matrix Cross-linking; Transglutaminase
Public URL http://eprints.nottingham.ac.uk/id/eprint/47990
Publisher URL http://www.atsjournals.org/doi/10.1165/rcmb.2016-0379OC
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information Originally Published in: Christopher J. Philp, Ivonne Siebeke, Debbie Clements, Suzanne Miller, Anthony Habgood, Alison E. John, Vidya Navaratnam, Richard B. Hubbard, Gisli Jenkins, and Simon R. Johnson. Extracellular Matrix Cross-Linking Enhances Fibroblast Growth and Protects against Matrix Proteolysis in Lung Fibrosis. American Journal of Respiratory Cell and Molecular Biology. 2018;Vol. 58, No. 1. DOI: 10.1165/rcmb.2016-0379OC
Copyright © 2018 by the American Thoracic Society
The final publication is available at https://www.atsjournals...0.1165/rcmb.2016-0379OC

Files

IPF cross-linking manuscript.pdf (22.8 Mb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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