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Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary...
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Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Metabolism".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 19604

Special Issue Editors

Prof. Dr. Irene Heijink

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Guest Editor
Dept of Pathology and Medical Biology, Dept. of Pulmonology, Experimental Pulmonology and Inflammation Research, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
Interests: respiratory system; cell and molecular biology; mucosal immunology; asthma; COPD; regenerative medicine
Dr. Simon D. Pouwels

E-Mail Website
Guest Editor
University Medical Center Groningen, Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University of Groningen, 9713 GZ Groningen, The Netherlands
Interests: COPD; DAMPs; innate immune system; cigarette smoke; biomarkers; cell death; RAGE
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

COPD is a severe and debilitating lung disease that is associated with high morbodity and mortality. Currently, no curative treatments are available. In order to identify novel therapeutic targets, it is important to understand the molecular and cellular mechanisms underlying the pathogenesis of COPD.

The primary focus of this Special Issue is to explore the metabolic alterations and cellular stress responses upon exposure to noxious particles in healthy and diseased lungs and how these contribute to the development of Accumulating evidence points towards the crucial role of cellular stress and alterations in the metabolic processes of structural and innate immune cells. Chronic inhalation of toxic gases and particles, including cigarette smoke, exhaust fumes, fine dust, and micro- and nanoplastics induces oxidative stress and cellular damage in the lungs. In combination with genetic susceptiblity and/or epigenetic modifications, this can ultimately lead to metabolic reprogramming in lung tissue as well as systemic changes leading to metalobic abnormalities. At the cellular level, COPD lungs display mitochondrial dysfunction, DNA damage, impaired proteasomal activity, and ER stress. This is associated with metabolic reprogramming, cell damage and death, and subsequent release of damage-associated molecular patterns (DAMPs), triggering immune and remodelling processes and systemic manifestations. We aim for the submission of review and research atricles that cover the latest findings in the field of metabolic alterations and cellular stress responses in COPD, including the effects of cigarette smoke and environmental pollutants; oxidative stress responses; mitochondrial dysfunction; mitophagy; the role of novel cell death modalities such as ferroptosis, necroptosis, NETosis, DAMP release; and systemic metabolic alterations.

Prof. Dr. Irene Heijink
Dr. Simon D. Pouwels
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • COPD
  • oxidative stress
  • metabolic alterations
  • mitochondrial dysfunction
  • proteasomal abnormalities and ER stress
  • cell death modalities
  • NETosis
  • DAMPs
  • DNA damage
  • autophagy/mitophagy

Published Papers (7 papers)

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Research

Jump to: Review

32 pages, 6075 KiB  
Article
Smoking-Associated Exposure of Human Primary Bronchial Epithelial Cells to Aldehydes: Impact on Molecular Mechanisms Controlling Mitochondrial Content and Function
by Christy B. M. Tulen, Evert Duistermaat, Johannes W. J. M. Cremers, Walther N. M. Klerx, Paul H. B. Fokkens, Naömi Weibolt, Nico Kloosterboer, Mieke A. Dentener, Eric R. Gremmer, Phyllis J. J. Jessen, Evi J. C. Koene, Lou Maas, Antoon Opperhuizen, Frederik-Jan van Schooten, Yvonne C. M. Staal and Alexander H. V. Remels
Cells 2022, 11(21), 3481; https://doi.org/10.3390/cells11213481 - 03 Nov 2022
Cited by 3 | Viewed by 1694
Abstract
Chronic obstructive pulmonary disease (COPD) is a devastating lung disease primarily caused by exposure to cigarette smoke (CS). During the pyrolysis and combustion of tobacco, reactive aldehydes such as acetaldehyde, acrolein, and formaldehyde are formed, which are known to be involved in respiratory [...] Read more.
Chronic obstructive pulmonary disease (COPD) is a devastating lung disease primarily caused by exposure to cigarette smoke (CS). During the pyrolysis and combustion of tobacco, reactive aldehydes such as acetaldehyde, acrolein, and formaldehyde are formed, which are known to be involved in respiratory toxicity. Although CS-induced mitochondrial dysfunction has been implicated in the pathophysiology of COPD, the role of aldehydes therein is incompletely understood. To investigate this, we used a physiologically relevant in vitro exposure model of differentiated human primary bronchial epithelial cells (PBEC) exposed to CS (one cigarette) or a mixture of acetaldehyde, acrolein, and formaldehyde (at relevant concentrations of one cigarette) or air, in a continuous flow system using a puff-like exposure protocol. Exposure of PBEC to CS resulted in elevated IL-8 cytokine and mRNA levels, increased abundance of constituents associated with autophagy, decreased protein levels of molecules associated with the mitophagy machinery, and alterations in the abundance of regulators of mitochondrial biogenesis. Furthermore, decreased transcript levels of basal epithelial cell marker KRT5 were reported after CS exposure. Only parts of these changes were replicated in PBEC upon exposure to a combination of acetaldehyde, acrolein, and formaldehyde. More specifically, aldehydes decreased MAP1LC3A mRNA (autophagy) and BNIP3 protein (mitophagy) and increased ESRRA protein (mitochondrial biogenesis). These data suggest that other compounds in addition to aldehydes in CS contribute to CS-induced dysregulation of constituents controlling mitochondrial content and function in airway epithelial cells. Full article
(This article belongs to the Special Issue Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease)
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18 pages, 2049 KiB  
Article
From Differential DNA Methylation in COPD to Mitochondria: Regulation of AHRR Expression Affects Airway Epithelial Response to Cigarette Smoke
by Qing Chen, Kingsley Okechukwu Nwozor, Maarten van den Berge, Dirk-Jan Slebos, Alen Faiz, Marnix R. Jonker, H. Marike Boezen, Irene H. Heijink and Maaike de Vries
Cells 2022, 11(21), 3423; https://doi.org/10.3390/cells11213423 - 29 Oct 2022
Cited by 4 | Viewed by 1807
Abstract
Cigarette smoking causes hypomethylation of the gene Aryl Hydrocarbon Receptor Repressor (AHRR), which regulates detoxification and oxidative stress-responses. We investigated whether AHRR DNA methylation is related to chronic obstructive pulmonary disease (COPD) and studied its function in airway epithelial cells (AECs). [...] Read more.
Cigarette smoking causes hypomethylation of the gene Aryl Hydrocarbon Receptor Repressor (AHRR), which regulates detoxification and oxidative stress-responses. We investigated whether AHRR DNA methylation is related to chronic obstructive pulmonary disease (COPD) and studied its function in airway epithelial cells (AECs). The association with COPD was assessed in blood from never and current smokers with/without COPD, and in AECs from ex-smoking non-COPD controls and GOLD stage II-IV COPD patients cultured with/without cigarette smoke extract (CSE). The effect of CRISPR/Cas9-induced AHRR knockout on proliferation, CSE-induced mitochondrial membrane potential and apoptosis/necrosis in human bronchial epithelial 16HBE cells was studied. In blood, DNA methylation of AHRR at cg05575921 and cg21161138 was lower in smoking COPD subjects than smoking controls. In vitro, AHRR DNA methylation at these CpG-sites was lower in COPD-derived than control-derived AECs only upon CSE exposure. Upon AHRR knockout, we found a lower proliferation rate at baseline, stronger CSE-induced decrease in mitochondrial membrane potential, and higher CSE-induced late apoptosis/necroptosis. Together, our results show lower DNA methylation of AHRR upon smoking in COPD patients compared to non-COPD controls. Our data suggest that higher airway epithelial AHRR expression may lead to impaired cigarette smoke-induced mitochondrial dysfunction and apoptosis/necroptosis, potentially promoting unprogrammed/immunogenic cell death. Full article
(This article belongs to the Special Issue Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease)
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20 pages, 3466 KiB  
Article
Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue: In Vivo and In Vitro Studies
by Lei Wang, Lieke E. J. van Iersel, Charlotte E. Pelgrim, Jingyi Lu, Ingrid van Ark, Thea Leusink-Muis, Harry R. Gosker, Ramon C. J. Langen, Annemie M. W. J. Schols, Josep M. Argilés, Ardy van Helvoort, Aletta D. Kraneveld, Johan Garssen, Paul A. J. Henricks, Gert Folkerts and Saskia Braber
Cells 2022, 11(18), 2893; https://doi.org/10.3390/cells11182893 - 16 Sep 2022
Cited by 7 | Viewed by 3771
Abstract
Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro [...] Read more.
Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis. Full article
(This article belongs to the Special Issue Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease)
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27 pages, 3578 KiB  
Article
Cigarette Smoke Extract Disturbs Mitochondria-Regulated Airway Epithelial Cell Responses to Pneumococci
by Mahyar Aghapour, Christy B. M. Tulen, Mohsen Abdi Sarabi, Sönke Weinert, Mathias Müsken, Borna Relja, Frederik-Jan van Schooten, Andreas Jeron, Rüdiger Braun-Dullaeus, Alexander H. Remels and Dunja Bruder
Cells 2022, 11(11), 1771; https://doi.org/10.3390/cells11111771 - 28 May 2022
Cited by 2 | Viewed by 2845
Abstract
Mitochondrial functionality is crucial for the execution of physiologic functions of metabolically active cells in the respiratory tract including airway epithelial cells (AECs). Cigarette smoke is known to impair mitochondrial function in AECs. However, the potential contribution of mitochondrial dysfunction in AECs to [...] Read more.
Mitochondrial functionality is crucial for the execution of physiologic functions of metabolically active cells in the respiratory tract including airway epithelial cells (AECs). Cigarette smoke is known to impair mitochondrial function in AECs. However, the potential contribution of mitochondrial dysfunction in AECs to airway infection and airway epithelial barrier dysfunction is unknown. In this study, we used an in vitro model based on AECs exposed to cigarette smoke extract (CSE) followed by an infection with Streptococcus pneumoniae (Sp). The levels of oxidative stress as an indicator of mitochondrial stress were quantified upon CSE and Sp treatment. In addition, expression of proteins associated with mitophagy, mitochondrial content, and biogenesis as well as mitochondrial fission and fusion was quantified. Transcriptional AEC profiling was performed to identify the potential changes in innate immune pathways and correlate them with indices of mitochondrial function. We observed that CSE exposure substantially altered mitochondrial function in AECs by suppressing mitochondrial complex protein levels, reducing mitochondrial membrane potential and increasing mitochondrial stress and mitophagy. Moreover, CSE-induced mitochondrial dysfunction correlated with reduced enrichment of genes involved in apical junctions and innate immune responses to Sp, particularly type I interferon responses. Together, our results demonstrated that CSE-induced mitochondrial dysfunction may contribute to impaired innate immune responses to Sp. Full article
(This article belongs to the Special Issue Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease)
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Review

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19 pages, 2501 KiB  
Review
Targeting Lung–Gut Axis for Regulating Pollution Particle–Mediated Inflammation and Metabolic Disorders
by Tzu-Yu Cheng, Chih-Cheng Chang, Ching-Shan Luo, Kuan-Yuan Chen, Yun-Kai Yeh, Jing-Quan Zheng and Sheng-Ming Wu
Cells 2023, 12(6), 901; https://doi.org/10.3390/cells12060901 - 15 Mar 2023
Cited by 4 | Viewed by 2479
Abstract
Cigarette smoking (CS) or ambient particulate matter (PM) exposure is a risk factor for metabolic disorders, such as insulin resistance (IR), increased plasma triglycerides, hyperglycemia, and diabetes mellitus (DM); it can also cause gut microbiota dysbiosis. In smokers with metabolic disorders, CS cessation [...] Read more.
Cigarette smoking (CS) or ambient particulate matter (PM) exposure is a risk factor for metabolic disorders, such as insulin resistance (IR), increased plasma triglycerides, hyperglycemia, and diabetes mellitus (DM); it can also cause gut microbiota dysbiosis. In smokers with metabolic disorders, CS cessation decreases the risks of serious pulmonary events, inflammation, and metabolic disorder. This review included recent studies examining the mechanisms underlying the effects of CS and PM on gut microbiota dysbiosis and metabolic disorder development; one of the potential mechanisms is the disruption of the lung–gut axis, leading to gut microbiota dysbiosis, intestinal dysfunction, systemic inflammation, and metabolic disease. Short-chain fatty acids (SCFAs) are the primary metabolites of gut bacteria, which are derived from the fermentation of dietary fibers. They activate G-protein-coupled receptor (GPCR) signaling, suppress histone deacetylase (HDAC) activity, and inhibit inflammation, facilitating the maintenance of gut health and biofunction. The aforementioned gut microbiota dysbiosis reduces SCFA levels. Treatment targeting SCFA/GPCR signaling may alleviate air pollution–associated inflammation and metabolic disorders, which involve lung–gut axis disruption. Full article
(This article belongs to the Special Issue Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease)
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28 pages, 1354 KiB  
Review
The Tobacco Smoke Component, Acrolein, as a Major Culprit in Lung Diseases and Respiratory Cancers: Molecular Mechanisms of Acrolein Cytotoxic Activity
by Pawel Hikisz and Damian Jacenik
Cells 2023, 12(6), 879; https://doi.org/10.3390/cells12060879 - 11 Mar 2023
Cited by 18 | Viewed by 4059
Abstract
Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant that seriously threatens human health and life. Due to its high reactivity, cytotoxicity and genotoxicity, acrolein is involved in the development of several diseases, including multiple sclerosis, neurodegenerative diseases such as Alzheimer’s [...] Read more.
Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant that seriously threatens human health and life. Due to its high reactivity, cytotoxicity and genotoxicity, acrolein is involved in the development of several diseases, including multiple sclerosis, neurodegenerative diseases such as Alzheimer’s disease, cardiovascular and respiratory diseases, diabetes mellitus and even the development of cancer. Traditional tobacco smokers and e-cigarette users are particularly exposed to the harmful effects of acrolein. High concentrations of acrolein have been found in both mainstream and side-stream tobacco smoke. Acrolein is considered one of cigarette smoke’s most toxic and harmful components. Chronic exposure to acrolein through cigarette smoke has been linked to the development of asthma, acute lung injury, chronic obstructive pulmonary disease (COPD) and even respiratory cancers. This review addresses the current state of knowledge on the pathological molecular mechanisms of acrolein in the induction, course and development of lung diseases and cancers in smokers. Full article
(This article belongs to the Special Issue Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease)
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22 pages, 766 KiB  
Review
Disruption of the Molecular Regulation of Mitochondrial Metabolism in Airway and Lung Epithelial Cells by Cigarette Smoke: Are Aldehydes the Culprit?
by Christy B. M. Tulen, Antoon Opperhuizen, Frederik-Jan van Schooten and Alexander H. V. Remels
Cells 2023, 12(2), 299; https://doi.org/10.3390/cells12020299 - 12 Jan 2023
Cited by 3 | Viewed by 1887
Abstract
Chronic obstructive pulmonary disease (COPD) is a devastating lung disease for which cigarette smoking is the main risk factor. Acetaldehyde, acrolein, and formaldehyde are short-chain aldehydes known to be formed during pyrolysis and combustion of tobacco and have been linked to respiratory toxicity. [...] Read more.
Chronic obstructive pulmonary disease (COPD) is a devastating lung disease for which cigarette smoking is the main risk factor. Acetaldehyde, acrolein, and formaldehyde are short-chain aldehydes known to be formed during pyrolysis and combustion of tobacco and have been linked to respiratory toxicity. Mitochondrial dysfunction is suggested to be mechanistically and causally involved in the pathogenesis of smoking-associated lung diseases such as COPD. Cigarette smoke (CS) has been shown to impair the molecular regulation of mitochondrial metabolism and content in epithelial cells of the airways and lungs. Although it is unknown which specific chemicals present in CS are responsible for this, it has been suggested that aldehydes may be involved. Therefore, it has been proposed by the World Health Organization to regulate aldehydes in commercially-available cigarettes. In this review, we comprehensively describe and discuss the impact of acetaldehyde, acrolein, and formaldehyde on mitochondrial function and content and the molecular pathways controlling this (biogenesis versus mitophagy) in epithelial cells of the airways and lungs. In addition, potential therapeutic applications targeting (aldehyde-induced) mitochondrial dysfunction, as well as regulatory implications, and the necessary required future studies to provide scientific support for this regulation, have been covered in this review. Full article
(This article belongs to the Special Issue Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease)
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