Journal Article

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

Bell, Joseph A, Yao, Liudi, Fabre, Aurelie, Loxham, Matthew, Vukmirovic, Milica, Davies, Donna E, Jones, Mark G, Thurner, Philipp J, Dean, Lareb SN, Andriotis, Orestis G, Wallis, Timothy, Zhou, Yilu, Brewitz, Lennart, Fletcher, Sophie V, Wang, Yihua, Bhaskar, Atul, Marshall, Benjamin G, Brereton, Christopher J, Tavassoli, Ali, Wang, Siyuan, Schofield, Christopher J, Kaminski, Naftali, Davies, Elizabeth R, Mohammed, Soran, Alzetani, Aiman, Ridley, Robert A, Ewing, Rob M, Conforti, Franco, Richeldi, Luca

2022

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Biomarkers / Cell Biology / Cells, Cultured / Collagen / Collagen - chemistry / Collagen - physiology / Computer software industry / Cross-linking / Enzymes / Epidermal growth factor / Extracellular matrix / Fibroblasts / Fibroblasts - metabolism / Fibrosis / Gene expression / Gene Expression Regulation - physiology / Humans / Hypoxia / Hypoxia-Inducible Factor 1 / Hypoxia-inducible factors / Lung / Mesenchyme / Mixed Function Oxygenases - genetics / Mixed Function Oxygenases - metabolism / Oxidative stress / Oxidative Stress - physiology / Post-translation / Protein expression / Proteins / Pulmonary Fibrosis - metabolism / Pyridinoline / Repressor Proteins - genetics / Repressor Proteins - metabolism / Research Advance / Signal transduction / Structure-function relationships / Transforming Growth Factor beta - genetics / Transforming Growth Factor beta - metabolism / Transforming growth factors