The Stress of Lung Aging: Endoplasmic Reticulum and Senescence Tête-à-Tête

Ngassie, M.L. Koloko; Brandsma, Corry‐Anke; Gosens, Reinoud; Prakash, Y. S.; Burgess, Janette K.

doi:10.1152/physiol.00039.2020

Cited by 8 publications

(7 citation statements)

References 92 publications

(128 reference statements)

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“…Our results using Tg indicate that ER stress reduced CHIR99021-induced Wnt/β-catenin signalling activation. Whereas acute ER stress is important in maintaining cellular homeostasis ( Marciniak, 2019 ), prolonged ER stress responses may result in cellular dysfunction and cell death and is closely linked to other cellular stress responses including oxidative stress, mitochondrial dysfunction and cellular senescence ( Kanaji et al, 2014 ; Koloko Ngassie et al, 2021 ), processes that are increased in lungs from COPD patients. Fibroblasts from COPD patients show disorganized organelle organization and enhanced ER stress ( Weidner et al, 2018 ), which may impact the niche-function of fibroblasts in lung epithelial repair.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke restricts the ability of mesenchymal cells to support lung epithelial organoid formation

Khedoe,

van Schadewijk,

Schwiening

et al. 2023

Front. Cell Dev. Biol.

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Adequate lung epithelial repair relies on supportive interactions within the epithelial niche, including interactions with WNT-responsive fibroblasts. In fibroblasts from patients with chronic obstructive pulmonary disease (COPD) or upon in vitro cigarette smoke exposure, Wnt/β-catenin signalling is distorted, which may affect interactions between epithelial cells and fibroblasts resulting in inadequate lung repair. We hypothesized that cigarette smoke (CS), the main risk factor for COPD, interferes with Wnt/β-catenin signalling in fibroblasts through induction of cellular stress responses, including oxidative- and endoplasmic reticulum (ER) stress, and thereby alters epithelial repair support potential. Therefore, we assessed the effect of CS-exposure and the ER stress inducer Thapsigargin (Tg) on Wnt/β-catenin signalling activation in MRC-5 fibroblasts, and on their ability to support lung epithelial organoid formation. Exposure of MRC-5 cells for 15 min with 5 AU/mL CS extract (CSE), and subsequent 6 h incubation induced oxidative stress (HMOX1). Whereas stimulation with 100 nM Tg increased markers of both the integrated stress response (ISR - GADD34/PPP1R15A, CHOP) and the unfolded protein response (UPR - XBP1spl, GADD34/PPP1R15A, CHOP and HSPA5/BIP), CSE only induced GADD34/PPP1R15A expression. Strikingly, although treatment of MRC-5 cells with the Wnt activator CHIR99021 upregulated the Wnt/β-catenin target gene AXIN2, this response was diminished upon CSE or Tg pre-exposure, which was confirmed using a Wnt-reporter. Furthermore, pre-exposure of MRC-5 cells to CSE or Tg, restricted their ability to support organoid formation upon co-culture with murine pulmonary EpCam+ cells in Matrigel at day 14. This restriction was alleviated by pre-treatment with CHIR99021. We conclude that exposure of MRC-5 cells to CSE increases oxidative stress, GADD34/PPP1R15A expression and impairs their ability to support organoid formation. This inhibitory effect may be restored by activating the Wnt/β-catenin signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Cigarette smoke restricts the ability of mesenchymal cells to support lung epithelial organoid formation

Khedoe,

van Schadewijk,

Schwiening

et al. 2023

Front. Cell Dev. Biol.

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“…Although the underlying mechanisms of cell senescence remain ambiguous, a recent study indicates that ERS caused by impaired homeostasis is an essential cause of aging and age-related diseases [ 66 ]. ERS was found to be one of the causes of epithelial dysfunction in pulmonary fibrosis [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis

et al. 2023

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“…Aging is associated with a gradual loss of pulmonary function because of aggravated cell aging, reduced regeneration ability, and damaged natural host defense [ 35 ]. Under physiological conditions, aging can result in lung elasticity loss and enlarge the alveolar spaces among the old population, a phenomenon called 'senile emphysema', and during COPD, peripheral airway fibrosis and alveolar wall destruction are observed [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway

Liu

Li²,

Zheng³

et al. 2022

J Inflamm

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Backgrounds Chronic obstructive pulmonary disease (COPD) is a major health issue resulting in significant mortality worldwide. Due to the high heterogeneity and unclear pathogenesis, the management and therapy of COPD are still challenging until now. Elevated serum uric acid(SUA) levels seem to be associated with the inflammatory level in patients with COPD. However, the underlying mechanism is not yet clearly established. In the current research, we aim to elucidate the effect of high SUA levels on airway inflammation among COPD patients. Methods Through bioinformatic analysis, the common potential key genes were determined in both COPD and hyperuricemia (HUA) patients. A total of 68 COPD patients aged 50—75-year were included in the study, and their clinical parameters, including baseline characteristics, lung function test, as well as blood chemistry test were recorded. These parameters were then compared between the COPD patients with and without HUA. Hematoxylin & Eosin (HE), immunofluorescence (IF), and Masson trichrome staining were performed to demonstrate the pathological changes in the lung tissues. Furthermore, we isolated extracellular vesicles (EVs) from plasma, sputum, and bronchoalveolar lavage fluid (BALF) samples and detected the expression of inflammatory factor (Interleukin-6 (IL-6), IL-8 and COPD related proteases (antitrypsin and elastase) between two groups. Additionally, we treated the human bronchial epithelial (HBE) cells with cigarette smoke extract (CSE), and EVs were derived from the plasma in vitro experiments. The critical pathway involving the relationship between COPD and HUA was eventually validated based on the results of RNA sequencing (RNA-seq) and western blot (WB). Results In the study, the COPD patients co-existing with HUA were found to have more loss of pulmonary function compared with those COPD patients without HUA. The lung tissue samples of patients who had co-existing COPD and HUA indicated greater inflammatory cell infiltration, more severe airway destruction and even fibrosis. Furthermore, the high SUA level could exacerbate the progress of airway inflammation in COPD through the transfer of EVs. In vitro experiments, we determined that EVs isolated from plasma, sputum, and BALF played pivotal roles in the CSE-induced inflammation of HBE. The EVs in HUA patients might exacerbate both systemic inflammation and airway inflammatory response via the senescence-related pathway. Conclusion The pulmonary function and clinical indicators of COPD patients with HUA were worse than those without HUA, which may be caused by the increased airway inflammatory response through the EVs in the patient's peripheral blood. Moreover, it might mediate the EVs via senescence-related pathways in COPD patients with HUA.

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The Stress of Lung Aging: Endoplasmic Reticulum and Senescence Tête-à-Tête

Cited by 8 publications

References 92 publications

Cigarette smoke restricts the ability of mesenchymal cells to support lung epithelial organoid formation

Cigarette smoke restricts the ability of mesenchymal cells to support lung epithelial organoid formation

EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis

Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway

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