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Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis

Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis
Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis
Matrix stiffening with downstream activation of mechanosensitive pathways is strongly implicated in progressive fibrosis, however pathologic changes in extracellular matrix (ECM) that initiate mechano-homeostasis dysregulation are not defined in human disease. By integrated multiscale biomechanical and biological analyses of idiopathic pulmonary fibrosis lung tissue we identify that increased tissue stiffness is a function of dysregulated post-translational collagen cross-linking rather than any collagen concentration increase whilst at the nanometre-scale collagen fibrils are structurally and functionally abnormal with increased stiffness, reduced swelling ratio, and reduced diameter. In ex vivo and animal models of lung fibrosis, dual inhibition of lysyl oxidase-like (LOXL) 2 and LOXL3 was sufficient to normalise collagen fibrillogenesis, reduce tissue stiffness, and improve lung function in vivo. Thus, in human fibrosis altered collagen architecture is a key determinant of abnormal ECM structure-function, and inhibition of pyridinoline cross-linking can maintain mechano-homeostasis to limit the self-sustaining effects of ECM on progressive fibrosis.
2050-084X
Jones, Mark
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Andriotis, Orestis
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Roberts, James
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Lunn, Kerry
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Tear, Victoria
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Cao, Lucy
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Ask, Kjetil
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Smart, D.E.
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Bonfanti, Alessandra
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Johnson, Peter
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Alzetani, Aiman
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Conforti, Franco
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Doherty, R.
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Lai, Chester
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Johnson, Benjamin
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Bourdakos, Konstantinos
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Marshall, Benjamin
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Jogai, Sanjay
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Brereton, Christopher, J
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Chee, Serena, Jamie Tzu Wen
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Ottensmeier, Christian
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Sime, Patricia J.
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Gauldie, Jack
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Kolb, Martin
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Mahajan, Sumeet
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Fabre, A.
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Jarolimek, Wolfgang
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Richeldi, Luca
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O'Reilly, Katherine M.A.
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Monk, Phillip
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Thurner, Philipp
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Davies, Donna
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Jones, Mark
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Andriotis, Orestis
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Roberts, James
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Lunn, Kerry
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Tear, Victoria
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Cao, Lucy
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Ask, Kjetil
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Smart, D.E.
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Bonfanti, Alessandra
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Johnson, Peter
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Alzetani, Aiman
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Conforti, Franco
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Doherty, R.
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Lai, Chester
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Johnson, Benjamin
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Bourdakos, Konstantinos
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Fletcher, Sophie
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Marshall, Benjamin
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Jogai, Sanjay
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Brereton, Christopher, J
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Chee, Serena, Jamie Tzu Wen
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Ottensmeier, Christian
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Sime, Patricia J.
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Gauldie, Jack
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Kolb, Martin
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Mahajan, Sumeet
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Fabre, A.
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Bhaskar, Atul
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Jarolimek, Wolfgang
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Richeldi, Luca
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O'Reilly, Katherine M.A.
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Monk, Phillip
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Thurner, Philipp
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Davies, Donna
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Jones, Mark, Andriotis, Orestis, Roberts, James, Lunn, Kerry, Tear, Victoria, Cao, Lucy, Ask, Kjetil, Smart, D.E., Bonfanti, Alessandra, Johnson, Peter, Alzetani, Aiman, Conforti, Franco, Doherty, R., Lai, Chester, Johnson, Benjamin, Bourdakos, Konstantinos, Fletcher, Sophie, Marshall, Benjamin, Jogai, Sanjay, Brereton, Christopher, J, Chee, Serena, Jamie Tzu Wen, Ottensmeier, Christian, Sime, Patricia J., Gauldie, Jack, Kolb, Martin, Mahajan, Sumeet, Fabre, A., Bhaskar, Atul, Jarolimek, Wolfgang, Richeldi, Luca, O'Reilly, Katherine M.A., Monk, Phillip, Thurner, Philipp and Davies, Donna (2018) Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis. eLife, 7 (e36354). (doi:10.7554/eLife.36354).

Record type: Article

Abstract

Matrix stiffening with downstream activation of mechanosensitive pathways is strongly implicated in progressive fibrosis, however pathologic changes in extracellular matrix (ECM) that initiate mechano-homeostasis dysregulation are not defined in human disease. By integrated multiscale biomechanical and biological analyses of idiopathic pulmonary fibrosis lung tissue we identify that increased tissue stiffness is a function of dysregulated post-translational collagen cross-linking rather than any collagen concentration increase whilst at the nanometre-scale collagen fibrils are structurally and functionally abnormal with increased stiffness, reduced swelling ratio, and reduced diameter. In ex vivo and animal models of lung fibrosis, dual inhibition of lysyl oxidase-like (LOXL) 2 and LOXL3 was sufficient to normalise collagen fibrillogenesis, reduce tissue stiffness, and improve lung function in vivo. Thus, in human fibrosis altered collagen architecture is a key determinant of abnormal ECM structure-function, and inhibition of pyridinoline cross-linking can maintain mechano-homeostasis to limit the self-sustaining effects of ECM on progressive fibrosis.

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CollageninIPFElife - Accepted Manuscript
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Accepted/In Press date: 7 June 2018
e-pub ahead of print date: 3 July 2018

Identifiers

Local EPrints ID: 421521
URI: https://eprints.soton.ac.uk/id/eprint/421521
ISSN: 2050-084X
PURE UUID: ea5e31df-99df-4038-a7de-e280c85a29df
ORCID for Sumeet Mahajan: ORCID iD orcid.org/0000-0001-8923-6666
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991

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Date deposited: 14 Jun 2018 16:30
Last modified: 24 May 2019 00:40

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Contributors

Author: Mark Jones
Author: Orestis Andriotis
Author: James Roberts
Author: Kerry Lunn
Author: Victoria Tear
Author: Lucy Cao
Author: Kjetil Ask
Author: D.E. Smart
Author: Alessandra Bonfanti
Author: Peter Johnson
Author: Aiman Alzetani
Author: Franco Conforti
Author: R. Doherty
Author: Chester Lai
Author: Benjamin Johnson
Author: Konstantinos Bourdakos
Author: Sophie Fletcher
Author: Sanjay Jogai
Author: Christopher, J Brereton
Author: Serena, Jamie Tzu Wen Chee
Author: Patricia J. Sime
Author: Jack Gauldie
Author: Martin Kolb
Author: Sumeet Mahajan ORCID iD
Author: A. Fabre
Author: Atul Bhaskar
Author: Wolfgang Jarolimek
Author: Luca Richeldi
Author: Katherine M.A. O'Reilly
Author: Phillip Monk
Author: Philipp Thurner
Author: Donna Davies ORCID iD

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