Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis

eLife

Joseph A Bell¹  Robert A Ridley²  Donna E Davies²  Orestis G Andriotis³  Lennart Brewitz⁴  Atul Bhaskar⁴  Liudi Yao⁴  Philipp J Thurner⁴  Milica Vukmirovic⁴  Ali Tavassoli⁴  Aiman Alzetani⁴  Mark G Jones⁵  Elizabeth R Davies⁶  Matthew Loxham⁶  Soran Mohammed⁶  Siyuan Wang⁶  Yilu Zhou⁷  Sophie V Fletcher⁷  Luca Richeldi⁷  Franco Conforti⁷  Rob M Ewing⁷  Christopher J Brereton⁷  Timothy Wallis⁷  Aurelie Fabre⁸  Benjamin G Marshall⁹  Yihua Wang^1,10  Christopher J Schofield^1,11  Naftali Kaminski^1,11  Lareb SN Dean^1,12 

[1] Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom;Institute for Life Sciences, University of Southampton, Southampton, United Kingdom;Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada;NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom;University Hospital Southampton, Southampton, United Kingdom;Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom;Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, Oxford, United Kingdom;Institute of Lightweight Design and Structural Biomechanics, TU Wien, Vienna, Austria;NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom;School of Chemistry, University of Southampton, Southampton, United Kingdom;Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, United States;

关键词: fibrosis;    Collagen;    Lung;   

DOI  :  10.7554/eLife.69348

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown