Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function

Yu, Guoying; Τzouvelekis, Αrgyris; Wang, Rong; Herazo-Maya, José D.; Ibarra, Gabriel; Srivastava, Anup; Werneck-de-Castro, João Pedro; DeIuliis, Giuseppe; Ahangari, Farida; Woolard, Tony; Aurelien, Nachelle; Drigo, Rafael Arrojo e; Gan, Ye; Graham, Morven; Liu, Xinran; Homer, Robert J.; Scanlan, Thomas S.; Mannam, Praveen; Lee, Patty J; Herzog, Erica L.; Bianco, Antonio C.; Kaminski, Naftali

doi:10.1038/nm.4447

Cited by 266 publications

(282 citation statements)

References 65 publications

(82 reference statements)

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“…In this study, the expression of PGC‐1α was increased in IPF‐LFs and senescence‐induced Ctrl‐LFs. However, Yu et al recently reported that levels of PGC‐1α protein were decreased in lung homogenates of IPF patients (even though levels of its mRNA were increased). The PGC‐1α detected in lung lysates by immunoblotting was comparable in size to the PGC‐1α1 isoform, which has a predicted MW of 92 kDa, with lower MW forms not described or shown.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Schuliga

Pechkovsky

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et al. 2018

J Cellular Molecular Medi

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Increasing evidence highlights that senescence plays an important role in idiopathic pulmonary fibrosis (IPF). This study delineates the specific contribution of mitochondria and the superoxide they form to the senescent phenotype of lung fibroblasts from IPF patients (IPF‐LFs). Primary cultures of IPF‐LFs exhibited an intensified DNA damage response (DDR) and were more senescent than age‐matched fibroblasts from control donors (Ctrl‐LFs). Furthermore, IPF‐LFs exhibited mitochondrial dysfunction, exemplified by increases in mitochondrial superoxide, DNA, stress and activation of mTORC1. The DNA damaging agent etoposide elicited a DDR and augmented senescence in Ctrl‐LFs, which were accompanied by disturbances in mitochondrial homoeostasis including heightened superoxide production. However, etoposide had no effect on IPF‐LFs. Mitochondrial perturbation by rotenone involving sharp increases in superoxide production also evoked a DDR and senescence in Ctrl‐LFs, but not IPF‐LFs. Inhibition of mTORC1, antioxidant treatment and a mitochondrial targeting antioxidant decelerated IPF‐LF senescence and/or attenuated pharmacologically induced Ctrl‐LF senescence. In conclusion, increased superoxide production by dysfunctional mitochondria reinforces lung fibroblast senescence via prolongation of the DDR. As part of an auto‐amplifying loop, mTORC1 is activated, altering mitochondrial homoeostasis and increasing superoxide production. Deeper understanding the mechanisms by which mitochondria contribute to fibroblast senescence in IPF has potentially important therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Schuliga

Pechkovsky

Read

et al. 2018

J Cellular Molecular Medi

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“…3B). PGC1α is a transcriptional co-activator responsible for regulating genes required for mitochondrial biogenesis and cell energy expenditure, and is protective in experimental lung fibrosis (Yu et al, 2018). ARHGAP12 and ARHGAP29 are small Rho-binding subfamily members whose function has recently been highlighted as being critical for YAP/TAZ inactivation (Meng et al, 2018), major regulators of fibroblast activation in fibrosis (Liu et al, 2015).…”

Section: Hdac Inhibition Blocks Gene Expression Changes Associated Wimentioning

confidence: 99%

“…To investigate whether TGFβ-mediated repression of anti-fibrotic genes precedes TGFβ-mediated upregulation of pro-fibrotic genes, we examined the effect of TGFβ on select genes identified in Figs 3B and 4A over time. For anti-fibrotic genes, we selected PGC1α, ARHGAP12 and DACH1 due to their reported anti-fibrotic effect in fibrosis and fibroblasts (Lynch et al, 2018;Peng et al, 2017;Sandner and Stasch, 2017;Yu et al, 2018) in addition to their robust upregulation in the presence of pracinostat (Fig. 3B).…”

Section: Hdac Inhibition Blocks Gene Expression Changes Associated Wimentioning

confidence: 99%

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Jones

Haak

Caporarello

et al. 2019

Journal of Cell Science

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Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβmediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene PPARGC1A (PGC1α) in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose siRNA-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together, these results provide novel mechanistic insight into the essential role HDACs play in TGFβmediated fibroblast activation via targeted gene repression.

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“…Microarray Analysis: Geo2R (53) was used to analyse GSE47460 generated by the lung genome research consortium (54).…”

Section: Uk Biobankmentioning

confidence: 99%

The circadian clock protein REVERBα inhibits pulmonary fibrosis development

Cunningham¹,

Meijer²,

Nazgiewicz³

et al. 2019

Preprint

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Pulmonary inflammatory responses lie under circadian control; however the importance of circadian mechanisms in fibrosis is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the poorly described transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of two human cohorts. In the UK Biobank circadian strain markers (sleep length, chronotype and shift work) are associated with pulmonary fibrosis making them novel risk factors. In a separate cohort REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, suggesting targeting REVERBα could be a viable therapeutic approach.SignificanceThe circadian clock plays an essential role in energy metabolism, and inflammation. In contrast the importance of the clock in the pathogenesis of fibrosis remains poorly explored. This study describes a striking alteration in circadian biology during pulmonary fibrosis where the relatively arrhythmic alveolar structures gain circadian but desynchronous rhythmicity due to infiltration by fibroblasts. Disruption of the clock in these cells, which are not widely implicated in circadian pathophysiology, results in a pro-fibrotic phenotype. Translation of these findings in humans revealed previously unrecognised important circadian risk factors for pulmonary fibrosis (sleep length, chronotype and shift work). In addition, targeting REVERBα repressed collagen secretion from human fibrotic lung tissue making this protein a promising therapeutic target.

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Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function

Cited by 266 publications

References 65 publications

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

The circadian clock protein REVERBα inhibits pulmonary fibrosis development

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