دورية أكاديمية
Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis.
| العنوان: | Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis. |
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| المؤلفون: | Jones MG; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Andriotis OG; Institute for Lightweight Design and Structural Biomechanics, TU Wien, Getreidemarkt, Austria., Roberts JJ; Synairgen Research Ltd, Southampton, United Kingdom., Lunn K; Synairgen Research Ltd, Southampton, United Kingdom., Tear VJ; Synairgen Research Ltd, Southampton, United Kingdom., Cao L; Pharmaxis Ltd, Frenchs Forest, Australia., Ask K; Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St. Joe's Hamilton, Hamilton, Canada., Smart DE; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Bonfanti A; Aeronautics, Astronautics and Computational Engineering, Faculty of Engineering and the Environment, University of Southampton, Southampton, United Kingdom., Johnson P; Department of Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom., Alzetani A; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; University Hospital Southampton, Southampton, United Kingdom., Conforti F; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Doherty R; Biomedical Imaging Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Lai CY; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Johnson B; CRUK and NIHR Experimental Cancer Medicine Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Bourdakos KN; Department of Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom., Fletcher SV; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; University Hospital Southampton, Southampton, United Kingdom., Marshall BG; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; University Hospital Southampton, Southampton, United Kingdom., Jogai S; University Hospital Southampton, Southampton, United Kingdom., Brereton CJ; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Chee SJ; University Hospital Southampton, Southampton, United Kingdom.; CRUK and NIHR Experimental Cancer Medicine Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Ottensmeier CH; CRUK and NIHR Experimental Cancer Medicine Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom., Sime P; Division of Pulmonary and Critical Care Medicine, University of Rochester School of Medicine and Dentistry, Rochester, United States., Gauldie J; Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St. Joe's Hamilton, Hamilton, Canada., Kolb M; Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St. Joe's Hamilton, Hamilton, Canada., Mahajan S; Department of Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom., Fabre A; Department of Histopathology, St. Vincent's University Hospital & UCD School of Medicine, University College Dublin, Dublin, Ireland., Bhaskar A; Aeronautics, Astronautics and Computational Engineering, Faculty of Engineering and the Environment, University of Southampton, Southampton, United Kingdom., Jarolimek W; Pharmaxis Ltd, Frenchs Forest, Australia., Richeldi L; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy., O'Reilly KM; Mater Misericordiae University Hospital, Dublin, Ireland.; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland., Monk PD; Synairgen Research Ltd, Southampton, United Kingdom., Thurner PJ; Institute for Lightweight Design and Structural Biomechanics, TU Wien, Getreidemarkt, Austria., Davies DE; NIHR Southampton Biomedical Research Centre, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom. |
| المصدر: | ELife [Elife] 2018 Jul 03; Vol. 7. Date of Electronic Publication: 2018 Jul 03. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012- |
| مواضيع طبية MeSH: | Amino Acid Oxidoreductases/*antagonists & inhibitors , Collagen/*chemistry , Enzyme Inhibitors/*pharmacology , Extracellular Matrix/*chemistry , Pulmonary Fibrosis/*drug therapy , Reticulin/*chemistry, Amino Acid Oxidoreductases/genetics ; Amino Acid Oxidoreductases/metabolism ; Amino Acids/chemistry ; Animals ; Biomechanical Phenomena ; Case-Control Studies ; Collagen/metabolism ; Collagen/ultrastructure ; Cross-Linking Reagents/chemistry ; Disease Models, Animal ; Extracellular Matrix/metabolism ; Extracellular Matrix/ultrastructure ; Female ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Gene Expression ; Homeostasis/genetics ; Humans ; Lung/metabolism ; Lung/pathology ; Mechanotransduction, Cellular ; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase/antagonists & inhibitors ; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase/genetics ; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase/metabolism ; Protein-Lysine 6-Oxidase ; Pulmonary Fibrosis/genetics ; Pulmonary Fibrosis/metabolism ; Pulmonary Fibrosis/pathology ; Rats ; Rats, Sprague-Dawley ; Reticulin/metabolism ; Reticulin/ultrastructure ; Structure-Activity Relationship ; Transforming Growth Factor beta1/antagonists & inhibitors ; Transforming Growth Factor beta1/pharmacology |
| مستخلص: | 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. Competing Interests: MJ, OA, KA, DS, AB, PJ, AA, FC, RD, CL, BJ, KB, SF, BM, SJ, CB, SC, CO, PS, JG, MK, SM, AF, AB, LR, KO, PT No competing interests declared, JR As a current employee of Synairgen Research Ltd, J.J.W.R has share options in the company. KL As a current employee of Synairgen Research Ltd, K.L has share options in the company. VT As a current employee of Synairgen Research Ltd, V.J.T has share options in the company. LC As a former or current employee of Pharmaxis Pharmaceuticals Ltd, L.C. has an equity stake in the company. WJ As a current employee of Pharmaxis Pharmaceuticals Ltd, W.J. has an equity stake in the company. PM As a current employee of Synairgen Research Ltd, P.D.M has share options and is a share-holder in the company. DD D.E.D is co-founder of, share-holder in and consultant to Synairgen Research Ltd. (© 2018, Jones et al.) |
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| معلومات مُعتمدة: | 100638/Z/12/Z United Kingdom WT_ Wellcome Trust; G0900453 United Kingdom MRC_ Medical Research Council; MRF_MRF-091-0003-RG-CONFO United Kingdom MRF MRF; United Kingdom WT_ Wellcome Trust; MOP-136950 Canada CIHR; G0800766 United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Keywords: biomechanics; collagen; extracellular matrix; fibrosis; human; human biology; lung; lysyl oxidase; medicine; mouse |
| المشرفين على المادة: | 0 (Amino Acids) 0 (Cross-Linking Reagents) 0 (Enzyme Inhibitors) 0 (Reticulin) 0 (TGFB1 protein, human) 0 (Transforming Growth Factor beta1) 63800-01-1 (pyridinoline) 9007-34-5 (Collagen) EC 1.14.11.4 (PLOD2 protein, human) EC 1.14.11.4 (Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase) EC 1.4.- (Amino Acid Oxidoreductases) EC 1.4.3.- (LOXL2 protein, human) EC 1.4.3.- (LOXL3 protein, human) EC 1.4.3.- (LOXL4 protein, human) EC 1.4.3.13 (Protein-Lysine 6-Oxidase) |
| تواريخ الأحداث: | Date Created: 20180704 Date Completed: 20190318 Latest Revision: 20220720 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC6029847 |
| DOI: | 10.7554/eLife.36354 |
| PMID: | 29966587 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2050-084X |
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| DOI: | 10.7554/eLife.36354 |