Targeting Hypoxia-Inducible Factor-1α/Pyruvate Dehydrogenase Kinase 1 Axis by Dichloroacetate Suppresses Bleomycin-induced Pulmonary Fibrosis

Abstract

Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin-induced pulmonary fibrotic progression was evaluated in two independent, fibroblast-specific, promoter-driven, hypoxia-inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate-treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor-β-induced myofibroblast differentiation through HIF-1α, whereas overexpression of the critical HIF-1α-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1α. Inhibition of the HIF-1α/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1α/PDK1-mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis.

Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis

“…Unlike what happened with AEC2s in bleomycin injured aged mice, IPF AEC2s showed lower glycolysis-related genes. The role of HIF1a in lung fibrosis has been reported in fibroblast (Goodwin et al, 2018), macrophages (Philip et al, 2017), as well as in IPF lung tissue (Kusko et al, 2016). We observed that HIF1A expression is decreased in IPF AEC2s.…”

Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation

“…We generated Col1a1-CreER-CFIm25 fl/fl mice by crossing CFIm25 fl/fl mice with Col1a1-CreER mice, thus allowing us to knock out CFIm25 expression in Col1a1-expressing cells, including fibroblasts, in an inducible manner. Although the Col1a1-CreER mice are reported to have high Cre activity in osteoblasts and odontoblasts, other studies have used these mice to successfully knock out genes in lung fibroblasts (14). Four-to five-week-old mice were treated with tamoxifen for five consecutive days to induce Cre expression.…”

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

“…In our study, we also found that all control groups showed no abnormalities, while WT‐BLM mice showed significant fibrotic responses in the lung; these were accompanied by decreased endothelial markers VE‐cadherin and CD31 but increased mesenchymal cell marker α‐smooth muscle actin (α‐SMA), indicating EndoMT. Recent studies have demonstrated that myofibroblasts are the cells ultimately responsible for the severe organ fibrotic process such as in pulmonary fibrosis . Activated myofibroblasts can originate from various cell sources including endothelial cells that have acquired a mesenchymal phenotype through EndoMT …”

“…Recent studies have demonstrated that myofibroblasts are the cells ultimately responsible for the severe organ fibrotic process such as in pulmonary fibrosis. [23][24][25] Activated myofibroblasts can originate from various cell sources including endothelial cells that have acquired a mesenchymal phenotype through EndoMT. 26,27 Emerging evidence has shown that diverse mediators such as TGF-β1, TNF-α, IL-1β, β-catenin, Akt/NF-κB, snail, and so on, tightly control the process of EndoMT in fibrotic diseases.…”