Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis
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, th...
| 主要な著者: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| フォーマット: | Journal article |
| 言語: | English |
| 出版事項: |
eLife
2022
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| _version_ | 1826311067487174656 |
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| author | Brereton, CJ Yao, L Davies, ER Zhou, Y Vukmirovic, M Bell, JA Wang, S Ridley, RA Dean, LSN Andriotis, OG Conforti, F Brewitz, L Mohammed, S Wallis, T Tavassoli, A Ewing, RM Alzetani, A Marshall, BG Fletcher, SV Thurner, PJ Fabre, A Kaminski, N Richeldi, L Bhaskar, A Schofield, CJ Loxham, M Davies, DE Wang, Y Jones, MG |
| author_facet | Brereton, CJ Yao, L Davies, ER Zhou, Y Vukmirovic, M Bell, JA Wang, S Ridley, RA Dean, LSN Andriotis, OG Conforti, F Brewitz, L Mohammed, S Wallis, T Tavassoli, A Ewing, RM Alzetani, A Marshall, BG Fletcher, SV Thurner, PJ Fabre, A Kaminski, N Richeldi, L Bhaskar, A Schofield, CJ Loxham, M Davies, DE Wang, Y Jones, MG |
| author_sort | Brereton, CJ |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T08:02:53Z |
| format | Journal article |
| id | oxford-uuid:f0a4dc04-30ed-43f2-a554-9ed1e8877fc8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:02:53Z |
| publishDate | 2022 |
| publisher | eLife |
| record_format | dspace |
| spelling | oxford-uuid:f0a4dc04-30ed-43f2-a554-9ed1e8877fc82023-10-05T10:12:03ZPseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f0a4dc04-30ed-43f2-a554-9ed1e8877fc8EnglishSymplectic ElementseLife2022Brereton, CJYao, LDavies, ERZhou, YVukmirovic, MBell, JAWang, SRidley, RADean, LSNAndriotis, OGConforti, FBrewitz, LMohammed, SWallis, TTavassoli, AEwing, RMAlzetani, AMarshall, BGFletcher, SVThurner, PJFabre, AKaminski, NRicheldi, LBhaskar, ASchofield, CJLoxham, MDavies, DEWang, YJones, MGExtracellular 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. |
| spellingShingle | Brereton, CJ Yao, L Davies, ER Zhou, Y Vukmirovic, M Bell, JA Wang, S Ridley, RA Dean, LSN Andriotis, OG Conforti, F Brewitz, L Mohammed, S Wallis, T Tavassoli, A Ewing, RM Alzetani, A Marshall, BG Fletcher, SV Thurner, PJ Fabre, A Kaminski, N Richeldi, L Bhaskar, A Schofield, CJ Loxham, M Davies, DE Wang, Y Jones, MG Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis |
| title | Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis |
| title_full | Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis |
| title_fullStr | Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis |
| title_full_unstemmed | Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis |
| title_short | Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis |
| title_sort | pseudohypoxic hif pathway activation dysregulates collagen structure function in human lung fibrosis |
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