Impaired AMPK Activity Drives Age-Associated Acute Lung Injury after Hemorrhage

Southern, Brian D.; Scheraga, Rachel G.; Olman, Mitchell A.

doi:10.1165/rcmb.2017-0023ed

Cited by 7 publications

(4 citation statements)

References 24 publications

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“…Rosiglitazone, a PPARγ activator, has antifibrotic effects both in vivo29 and in vitro 30. Rosiglitazone acts through PPARγ dependent and independent mechanisms, including through adenosine monophosphate-activated protein kinase activation,31 a known activator of PPARGC1A gene transcription,32 and exerts beneficial effects in experimental lung fibrosis33 and ageing 34. Rosiglitazone reduced both fibrotic ( ACTA2 , p=0.007) and senescent features (p=0.1 for both CDKN2A and GLB1 ) while simultaneously elevating PPARGC1A transcripts in IPF fibroblasts (p=0.014) (figure 6B,C).…”

Section: Resultsmentioning

confidence: 99%

PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state

Caporarello

Meridew

Jones

et al. 2019

Thorax

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Idiopathic pulmonary fibrosis (IPF) is a fatal ageing-related disease linked to mitochondrial dysfunction. The present study aimed to determine whether peroxisome proliferator activated receptor gamma co-activator 1-alpha (PPARGC1A, encoding PGC1α), a master regulator of mitochondrial biogenesis, is diminished in IPF and controls pathologic fibroblast activation. Primary human IPF, control lung fibroblasts and fibroblasts sorted from bleomycin-injured mice were used to evaluate the expression and function of PGC1α. In vitro PGC1α manipulation was performed by small interfering RNA knockdown or overexpression. Fibroblast activation was assessed by quantitative PCR, Western blotting, matrix deposition, secreted cytokine array, immunofluorescence and traction force microscopy. Mitochondrial function was assessed by Seahorse analyzer and mitochondria mass and number by flow cytometry, mitochondrial DNA quantification and transmission electron microscopy (TEM). We found that PGC1α levels are stably repressed in IPF fibroblasts. After bleomycin injury in young mice, PGC1α expression drops transiently but then increases prior to fibrosis resolution. In contrast, PGC1α expression fails to recover in aged mice with persistent fibrosis. PGC1α knockdown alone in normal human lung fibroblasts reduces mitochondrial mass and function while enhancing contractile and matrix synthetic fibroblast activation, senescence-related gene expression and soluble profibrotic and prosenescence signalling. Re-expression of PGC1α in IPF fibroblasts ameliorates all of these pathological cellular functions. Pharmacological treatment of IPF fibroblasts with rosiglitazone, but not thyroid hormone, elevated PGC1α expression and attenuated fibroblast activation. The sustained repression of PGC1α and beneficial effects of its rescue in IPF fibroblasts identifies PGC1α as an important regulator of the fibroblast’s pathological state in IPF.

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Section: Resultsmentioning

confidence: 99%

PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state

Caporarello

Meridew

Jones

et al. 2019

Thorax

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“…Increasing evidence has revealed that AMPK protects against fibrosis in the heart ( Zhang et al, 2011 ), liver ( Yang et al, 2015 ), lung ( King et al, 2012 ), kidney ( Cavaglieri et al, 2015 ), and skin ( Takata et al, 2014 ). In this respect, loss or reduction of AMPK has been implicated in diabetes mellitus, obesity and aging ( Burkewitz et al, 2014 ; Southern et al, 2017 ; Rana et al, 2020 ). To explore the possible role of AMPK in silicosis, we investigated the expression of AMPK and mTOR.…”

Section: Discussionmentioning

confidence: 99%

Metformin Attenuates Silica-Induced Pulmonary Fibrosis by Activating Autophagy via the AMPK-mTOR Signaling Pathway

Pang

et al. 2021

Front. Pharmacol.

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Long-term exposure to crystalline silica particles leads to silicosis characterized by persistent inflammation and progressive fibrosis in the lung. So far, there is no specific treatment to cure the disease other than supportive care. In this study, we examined the effects of metformin, a prescribed drug for type || diabetes on silicosis and explored the possible mechanisms in an established rat silicosis model in vivo, and an in vitro co-cultured model containing human macrophages cells (THP-1) and human bronchial epithelial cells (HBEC). Our results showed that metformin significantly alleviated the inflammation and fibrosis of lung tissues of rats exposed to silica particles. Metformin significantly reduced silica particle-induced inflammatory cytokines including transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in rat lung tissue and HBEC culture supernatant. The protein levels of Vimentin and α-smooth muscle actin (α-SMA) were significantly decreased by metfomin while expression level of E-cadherin (E-Cad) increased. Besides, metformin increased the expression levels of phosphorylated adenosine 5′-monophosphate (AMP)-activated protein kinase (p-AMPK), microtubule-associated protein (MAP) light chain 3B (LC3B) and Beclin1 proteins, and reduced levels of phosphorylated mammalian target of rapamycin (p-mTOR) and p62 proteins in vivo and in vitro. These results suggest that metformin could inhibit silica-induced pulmonary fibrosis by activating autophagy through the AMPK-mTOR pathway.

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“…( Zheng et al, 2019 ; Wen et al, 2021 ). Further studies proved that the activation of Nrf2 induced by LBP is mediated by AMPK ( Southern et al, 2017 ; Zheng et al, 2019 ).…”

Section: Lung-protective Mechanisms Of Plant Polysaccharidesmentioning

confidence: 96%

Plant polysaccharides with anti-lung injury effects as a potential therapeutic strategy for COVID-19

Huang

Zhang²,

Duan³

et al. 2022

Front. Pharmacol.

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When coronavirus disease 2019 (COVID-19) develops into the severe phase, lung injury, acute respiratory distress syndrome, and/or respiratory failure could develop within a few days. As a result of pulmonary tissue injury, pathomorphological changes usually present endothelial dysfunction, inflammatory cell infiltration of the lung interstitium, defective gas exchange, and wall leakage. Consequently, COVID-19 may progress to tremendous lung injury, ongoing lung failure, and death. Exploring the treatment drugs has important implications. Recently, the application of traditional Chinese medicine had better performance in reducing fatalities, relieving symptoms, and curtailing hospitalization. Through constant research and study, plant polysaccharides may emerge as a crucial resource against lung injury with high potency and low side effects. However, the absence of a comprehensive understanding of lung-protective mechanisms impedes further investigation of polysaccharides. In the present article, a comprehensive review of research into plant polysaccharides in the past 5 years was performed. In total, 30 types of polysaccharides from 19 kinds of plants have shown lung-protective effects through the pathological processes of inflammation, oxidative stress, apoptosis, autophagy, epithelial–mesenchymal transition, and immunomodulation by mediating mucin and aquaporins, macrophage, endoplasmic reticulum stress, neutrophil, TGF-β1 pathways, Nrf2 pathway, and other mechanisms. Moreover, the deficiencies of the current studies and the future research direction are also tentatively discussed. This research provides a comprehensive perspective for better understanding the mechanism and development of polysaccharides against lung injury for the treatment of COVID-19.

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Impaired AMPK Activity Drives Age-Associated Acute Lung Injury after Hemorrhage

Cited by 7 publications

References 24 publications

PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state

PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state

Metformin Attenuates Silica-Induced Pulmonary Fibrosis by Activating Autophagy via the AMPK-mTOR Signaling Pathway

Plant polysaccharides with anti-lung injury effects as a potential therapeutic strategy for COVID-19

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