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).
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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- Faculties (pre 2018 reorg) > Faculty of Medicine (pre 2018 reorg) > Medical Education (pre 2018 reorg)
- Faculties (pre 2018 reorg) > Faculty of Engineering and the Environment (pre 2018 reorg) > Aeronautics, Astronautics & Comp. Eng (pre 2018 reorg) > Computational Engineering & Design Group (pre 2018 reorg)
Current Faculties > Faculty of Engineering and Physical Sciences > School of Engineering > Aeronautical and Astronautical Engineering > Aeronautics, Astronautics & Comp. Eng (pre 2018 reorg) > Computational Engineering & Design Group (pre 2018 reorg)
Aeronautical and Astronautical Engineering > Aeronautics, Astronautics & Comp. Eng (pre 2018 reorg) > Computational Engineering & Design Group (pre 2018 reorg) - Faculties (pre 2018 reorg) > Faculty of Natural and Environmental Sciences (pre 2018 reorg) > Chemistry (pre 2018 reorg)
Current Faculties > Faculty of Engineering and Physical Sciences > School of Chemistry > Chemistry (pre 2018 reorg)
School of Chemistry > Chemistry (pre 2018 reorg) - Faculties (pre 2018 reorg) > Faculty of Natural and Environmental Sciences (pre 2018 reorg) > Institute for Life Sciences (pre 2018 reorg)
Current Faculties > Faculty of Environmental and Life Sciences > Institute for Life Sciences > Institute for Life Sciences (pre 2018 reorg)
Institute for Life Sciences > Institute for Life Sciences (pre 2018 reorg) - Faculties (pre 2018 reorg) > Faculty of Engineering and the Environment (pre 2018 reorg) > Aeronautics, Astronautics & Comp. Eng (pre 2018 reorg)
Current Faculties > Faculty of Engineering and Physical Sciences > School of Engineering > Aeronautical and Astronautical Engineering > Aeronautics, Astronautics & Comp. Eng (pre 2018 reorg)
Aeronautical and Astronautical Engineering > Aeronautics, Astronautics & Comp. Eng (pre 2018 reorg) - Faculties (pre 2018 reorg) > Faculty of Medicine (pre 2018 reorg) > Clinical & Experimental Sciences (pre 2018 reorg)
Current Faculties > Faculty of Medicine > Clinical and Experimental Sciences > Clinical & Experimental Sciences (pre 2018 reorg)
Clinical and Experimental Sciences > Clinical & Experimental Sciences (pre 2018 reorg) - Faculties (pre 2018 reorg) > Faculty of Engineering and the Environment (pre 2018 reorg) > Southampton Marine & Maritime Institute (pre 2018 reorg)
- Faculties (pre 2018 reorg) > Faculty of Medicine (pre 2018 reorg) > Cancer Sciences (pre 2018 reorg)
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