دورية أكاديمية
Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis.
| العنوان: | Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis. |
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| المؤلفون: | Brereton CJ; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom., Yao L; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom., Davies ER; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom.; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom., Zhou Y; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom., Vukmirovic M; Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, United States.; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada., Bell JA; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom., Wang S; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom., Ridley RA; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom., Dean LSN; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom., Andriotis OG; Institute of Lightweight Design and Structural Biomechanics, TU Wien, Vienna, Austria., Conforti F; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom., Brewitz L; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, Oxford, United Kingdom., Mohammed S; School of Chemistry, University of Southampton, Southampton, United Kingdom., Wallis T; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom., Tavassoli A; School of Chemistry, University of Southampton, Southampton, United Kingdom., Ewing RM; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom., Alzetani A; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom.; University Hospital Southampton, Southampton, United Kingdom., Marshall BG; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom.; University Hospital Southampton, Southampton, United Kingdom., Fletcher SV; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom.; University Hospital Southampton, Southampton, United Kingdom., Thurner PJ; Institute of Lightweight Design and Structural Biomechanics, TU Wien, Vienna, Austria., Fabre A; Department of Histopathology, St. Vincent's University Hospital & UCD School of Medicine, University College Dublin, Dublin, Ireland., Kaminski N; Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, United States., Richeldi L; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom.; Unità Operativa Complessa di Pneumologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy., Bhaskar A; Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, United Kingdom., Schofield CJ; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, Oxford, United Kingdom., Loxham M; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom., Davies DE; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom., Wang Y; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom.; Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom., Jones MG; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom.; Institute for Life Sciences, University of Southampton, Southampton, United Kingdom. |
| المصدر: | ELife [Elife] 2022 Feb 21; Vol. 11. Date of Electronic Publication: 2022 Feb 21. |
| 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: | Collagen/*physiology , Pulmonary Fibrosis/*metabolism, Biomarkers ; Cells, Cultured ; Collagen/chemistry ; Fibroblasts/metabolism ; Gene Expression Regulation/physiology ; Humans ; Hypoxia-Inducible Factor 1 ; Mixed Function Oxygenases/genetics ; Mixed Function Oxygenases/metabolism ; Oxidative Stress/physiology ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism |
| مستخلص: | Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we provide evidence that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of the oxygen status (pseudohypoxia). Whilst TGFβ increased the rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting pyridinoline cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knockdown of Factor Inhibiting HIF (FIH), which modulates HIF activity, or oxidative stress caused pseudohypoxic HIF activation in the normal fibroblasts. By contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF-mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of human lung fibrosis mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen structure-function in fibrosis. Competing Interests: CB, LY, ED, YZ, MV, JB, SW, RR, LD, OA, FC, LB, SM, TW, AT, RE, AA, BM, SF, PT, AF, NK, LR, AB, CS, ML, DD, YW, MJ No competing interests declared (© 2022, Brereton et al.) |
| التعليقات: | Comment in: Elife. 2022 Feb 21;11:. (PMID: 35188461) |
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| معلومات مُعتمدة: | 100638/Z/12/Z United Kingdom WT_ Wellcome Trust; BB/PO11365/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; UL1 TR001863 United States TR NCATS NIH HHS; 16466 United Kingdom CRUK_ Cancer Research UK; United Kingdom DH_ Department of Health; MR/S025480/1 United Kingdom MRC_ Medical Research Council; MRF_MRF-091-0003-RG-CONFO United Kingdom MRF MRF; United Kingdom WT_ Wellcome Trust |
| فهرسة مساهمة: | Keywords: Collagen; Lung; cell biology; fibrosis; human |
| سلسلة جزيئية: | GEO GSE135893; GSE40839; GSE73854; GSE169500 |
| المشرفين على المادة: | 0 (Biomarkers) 0 (Hypoxia-Inducible Factor 1) 0 (Repressor Proteins) 0 (Transforming Growth Factor beta) 9007-34-5 (Collagen) EC 1.- (Mixed Function Oxygenases) EC 1.14.11.- (HIF1AN protein, human) |
| تواريخ الأحداث: | Date Created: 20220221 Date Completed: 20220316 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC8860444 |
| DOI: | 10.7554/eLife.69348 |
| PMID: | 35188460 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2050-084X |
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| DOI: | 10.7554/eLife.69348 |