52 results found
Michaeloudes C, Abubakar-Waziri H, Lakhdar R, et al., 2021, Molecular mechanisms of oxidative stress in asthma, Molecular Aspects of Medicine, Pages: 101026-101026, ISSN: 0098-2997
The lungs are exposed to reactive oxygen species oxygen (ROS) produced as a result of inhalation of oxygen, as well as smoke and other air pollutants. Cell metabolism and the NADPH oxidases (Nox) generate low levels of intracellular ROS that act as signal transduction mediators by inducing oxidative modifications of histones, enzymes and transcription factors. Redox signalling is also regulated by localised production and sensing of ROS in mitochondria, the endoplasmic reticulum (ER) and inside the nucleus. Intracellular ROS are maintained at low levels through the action of a battery of enzymatic and non-enzymatic antioxidants. Asthma is a heterogeneous airway inflammatory disease with different immune endotypes; these include atopic or non-atopic Th2 type immune response associated with eosinophilia, or a non-Th2 response associated with neutrophilia. Airway remodelling and hyperresponsiveness accompany the inflammatory response in asthma. Over-production of ROS resulting from infiltrating immune cells, particularly eosinophils and neutrophils, and a concomitant impairment of antioxidant responses lead to development of oxidative stress in asthma. Oxidative stress is augmented in severe asthma and during exacerbations, as well as by air pollution and obesity, and causes oxidative damage of tissues promoting airway inflammation and hyperresponsiveness. Furthermore, deregulated Nox activity, mitochondrial dysfunction, ER stress and/or oxidative DNA damage, resulting from exposure to irritants, inflammatory mediators or obesity, may lead to redox-dependent changes in cell signalling. ROS play a central role in airway epithelium-mediated sensing, development of innate and adaptive immune responses, and airway remodelling and hyperresponsiveness. Nonetheless, antioxidant compounds have proven clinically ineffective as therapeutic agents for asthma, partly due to issues with stability and in vivo metabolism of these compounds. The compartmentalised nature of ROS product
Chen R, Michaeloudes C, Liang Y, et al., 2021, ORMDL3 regulates cigarette smoke-induced endoplasmic reticulum stress in airway smooth muscle cells., J Allergy Clin Immunol
BACKGROUND: Orosomucoid 1-like protein 3 (ORMDL3), a transmembrane protein localized in the endoplasmic reticulum (ER), has been genetically associated with chronic obstructive pulmonary disease (COPD), in addition to childhood-onset asthma. However, the functional role of ORMDL3 in the pathogenesis of COPD is still unknown. OBJECTIVE: Because cigarette smoke is the major risk factor for COPD, we aimed to investigate the role of ORMDL3 in cigarette smoke-induced human airway smooth muscle cell (HASMC) injury. METHODS: The mRNA and protein expression of ORMDL3 was examined in HASMCs from nonsmokers and smokers without or with COPD. Knockdown of ORMDL3 in primary healthy HASMCs was performed using small interfering RNA before exposure to cigarette smoke medium (CSM) for 24 hours. Inflammatory, proliferative/apoptotic, ER stress, and mitochondrial markers were evaluated. RESULTS: Elevation of ORMDL3 mRNA and protein expression was observed in HASMCs of smokers without or with COPD. CSM caused significant upregulation of ORMDL3 expression in healthy nonsmokers. ORMDL3 knockdown regulated CSM-induced inflammation, cell proliferation, and apoptosis. Silencing ORMDL3 led to reduction of CSM-induced ER stress via inhibition of unfolded protein response pathways such as activating transcription factor 6 and protein kinase RNA-like ER kinase. ORMDL3 was also involved in CSM-induced mitochondrial dysfunction via the mitochondrial fission process. CONCLUSIONS: We report the induction of ORMDL3 in HASMCs after cigarette smoke exposure. ORMDL3 may mediate cigarette smoke-induced activation of unfolded protein response pathways during airway smooth muscle cell injury.
Michaeloudes C, Li X, Mak JCW, et al., 2021, Study of Mesenchymal Stem Cell-Mediated Mitochondrial Transfer in In Vitro Models of Oxidant-Mediated Airway Epithelial and Smooth Muscle Cell Injury., Methods Mol Biol, Vol: 2269, Pages: 93-105
Mesenchymal stem cells (MSCs) have emerged as an attractive candidate for cell-based therapy. In the past decade, many animal and pilot clinical studies have demonstrated that MSCs are therapeutically beneficial for the treatment of obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, due to the scarcity of adult human MSCs, human-induced pluripotent stem cells mesenchymal stem cells (iPSCs) are now increasingly used as a source of MSCs. iPSCs are derived by reprogramming somatic cells from a wide variety of tissues such as skin biopsies and then differentiating them into iPSC-MSCs. One of the mechanisms through which MSCs exert their protective effects is mitochondrial transfer. Specifically, transfer of mitochondria from iPSC-MSCs to lung cells was shown to protect lung cells against oxidative stress-induced mitochondrial dysfunction and apoptosis and to reduce lung injury and inflammation in in vivo models of lung disease. In this chapter, we detail our methods to visualize and quantify iPSC-MSC-mediated mitochondrial transfer and to study its effects on oxidant-induced airway epithelial and smooth muscle cell models of acute airway cell injury.
Haji G, Wiegman C, Michaeloudes C, et al., 2020, Mitochondrial dysfunction in airways and quadriceps muscle of patients with Chronic Obstructive Pulmonary Disease, Respiratory Research, Vol: 21, ISSN: 1465-9921
BackgroundMitochondrial damage and dysfunction have been reported in airway and quadriceps muscle cells of patients with chronic obstructive pulmonary disease (COPD). We determined the concomitance of mitochondrial dysfunction in these cells in COPD.MethodsBronchial biopsies were obtained from never- and ex-smoker volunteers and COPD patients (GOLD Grade 2) and quadriceps muscle biopsies from the same volunteers in addition to COPD patients at GOLD Grade 3/4 for measurement of mitochondrial function.ResultsDecreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mtROS) and decreased superoxide dismutase 2 (SOD2) levels were observed in mitochondria isolated from bronchial biopsies from Grade 2 patients compared to healthy never- and ex-smokers. There was a significant correlation between ΔΨm and FEV1 (% predicted), transfer factor of the lung for carbon monoxide (TLCOC % predicted), 6-min walk test and maximum oxygen consumption. In addition, ΔΨm was also associated with decreased expression levels of electron transport chain (ETC) complex proteins I and II. In quadriceps muscle of Grade 2 COPD patients, a significant increase in total ROS and mtROS was observed without changes in ΔΨm, SOD2 or ETC complex protein expression. However, quadriceps muscle of GOLD Grade 3/4 COPD patients showed an increased mtROS and decreased SOD2 and ETC complex proteins I, II, III and V expression.ConclusionsMitochondrial dysfunction in the airways, but not in quadriceps muscle, is associated with airflow obstruction and exercise capacity in Grade 2 COPD. Oxidative stress-induced mitochondrial dysfunction in the quadriceps may result from similar disease processes occurring in the lungs.
Michaeloudes C, Seiffert J, Chen S, et al., 2020, Effect of silver nanospheres and nanowires on human airway smooth muscle cells: role of sulfidation, Nanoscale Advances, Vol: 2, Pages: 5635-5647, ISSN: 2516-0230
Background: The toxicity of inhaled silver nanoparticles on contractile and pro-inflammatory airway smooth muscle cells (ASMCs) that control airway calibre is unknown. We explored the oxidative activities and sulfidation processes of the toxic-inflammatory response. Method: Silver nanospheres (AgNSs) of 20 nm and 50 nm diameter and silver nanowires (AgNWs), short S-AgNWs, 1.5 μm and long L-AgNWs, 10 μm, both 72 nm in diameter were manufactured. We measured their effects on cell proliferation, mitochondrial reactive oxygen species (ROS) release and membrane potential, and also performed electron microscopic studies. Main results and findings: The greatest effects were observed for the smallest particles with the highest specific surface area and greatest solubility that were avidly internalised. ASMCs exposed to 20 nm AgNSs (25 μg mL−1) for 72 hours exhibited a significant decrease in DNA incorporation (−72.4%; p < 0.05), whereas neither the 50 nm AgNSs nor the s-AgNWs altered DNA synthesis or viability. There was a small reduction in ASMC proliferation for the smaller AgNS, although Ag+ at 25 μL mL−1 reduced DNA synthesis by 93.3% (p < 0.001). Mitochondrial potential was reduced by both Ag+ (25 μg mL−1) by 47.1% and 20 nm Ag NSs (25 μg mL−1) by 40.1% (*both at p < 0.05), but was not affected by 50 nm AgNSs and the AgNWs. None of the samples showed a change in ROS toxicity. However, malondialdehyde release, associated with greater total ROS, was observed for all AgNPs, to an extent following the geometric size (20 nm AgNS: 213%, p < 0.01; 50 nm AgNS: 179.5%, p < 0.01 and L-AgNWs by 156.2%, p < 0.05). The antioxidant, N-acetylcysteine, prevented the reduction in mitochondrial potential caused by 20 nm AgNSs. The smaller nanostructures were internalised and dissolved within the ASMCs with the formation of non-reactive silver sulphide (Ag2S) on their surface, but with very little uptake of L-AgNWs. When A
Ramu S, Calven J, Michaeloudes C, et al., 2020, TLR3/TAK1 signalling regulates rhinovirus-induced interleukin-33 in bronchial smooth muscle cells, ERJ OPEN RESEARCH, Vol: 6
Michaeloudes C, Bhavsar PK, Mumby S, et al., 2020, Role of metabolic reprogramming in pulmonary innate immunity and Its impact on lung diseases, Journal of Innate Immunity, Vol: 12, Pages: 1-16, ISSN: 1662-811X
Lung innate immunity is the first line of defence against inhaled allergens, pathogens and environmental pollutants. Cellular metabolism plays a key role in innate immunity. Catabolic pathways, including glycolysis and fatty acid oxidation (FAO), are interconnected with biosynthetic and redox pathways. Innate immune cell activation and differentiation trigger extensive metabolic changes that are required to support their function. Pro-inflammatory polarisation of macrophages and activation of dendritic cells, mast cells and neutrophils are associated with increased glycolysis and a shift towards the pentose phosphate pathway and fatty acid synthesis. These changes provide the macromolecules required for proliferation and inflammatory mediator production and reactive oxygen species for anti-microbial effects. Conversely, anti-inflammatory macrophages use primarily FAO and oxidative phosphorylation to ensure efficient energy production and redox balance required for prolonged survival. Deregulation of metabolic reprogramming in lung diseases, such as asthma and chronic obstructive pulmonary disease, may contribute to impaired innate immune cell function. Understanding how innate immune cell metabolism is altered in lung disease may lead to identification of new therapeutic targets. This is important as drugs targeting a number of metabolic pathways are already in clinical development for the treatment of other diseases such as cancer.
dela Cruz A, Garcia JF, Michaeloudes C, et al., 2019, PARACRINE-MEDIATED TRANSFER OF MITOCHONDRIA BETWEEN AIRWAY SMOOTH MUSCLE CELLS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A67-A67, ISSN: 0040-6376
Garcia JF, Xu B, Hui C, et al., 2019, REGULATION OF MITOCHONDRIAL TRANSFER BETWEEN AIRWAY SMOOTH MUSCLE CELLS (ASMCS): RELEVANCE TO COPD, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A48-A49, ISSN: 0040-6376
Garcia JF, Mak J, Xu B, et al., 2019, Regulation of mitochondrial transfer between airway smooth muscle cells: relevance to COPD, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Michaeloudes C, Garcia JF, Xu B, et al., 2019, Altered mitochondrial function in proliferating airway smooth muscle cells, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Stock CJW, Michaeloudes C, Leoni P, et al., 2019, Bromodomain and extra-terminal (BET) protein inhibition restores redox balance and inhibits myofibroblast activation, BioMed Research International, Vol: 2019, ISSN: 2314-6133
Background and Objective. Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor-β (TGF-β) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts. Methods. In TGF-β-stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by α-smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation. Results and Conclusions. Affymetrix gene array analysis revealed increased NOX4 and reduced SOD2 expression in SSc and IPF fibroblasts. SOD2 silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF-β increased NOX4 and inhibited SOD2 expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF-β-mediated NOX4/SOD2 imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the NOX4 promoter and drive TGF-β-induced NOX4 expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.
Tsang J, Xu B, Xie J, et al., 2019, Effect of Corticosteroids on Metabolic Gene Expression in Airway Smooth Muscle Cells, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Garcia JF, Michaeloudes C, Xu B, et al., 2019, Mechanisms of Mitochondrial Transfer in Health and Disease, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bhavsar PK, li X, michaeloudes C, et al., 2018, Mesenchymal stem cells alleviate oxidative stress-induced mitochondrial dysfunction in the airways., Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1634-1645.e5, ISSN: 0091-6749
BackgroundOxidative stress–induced mitochondrial dysfunction can contribute to inflammation and remodeling in patients with chronic obstructive pulmonary disease (COPD). Mesenchymal stem cells protect against lung damage in animal models of COPD. It is unknown whether these effects occur through attenuating mitochondrial dysfunction in airway cells.ObjectiveWe sought to examine the effect of induced pluripotent stem cell–derived mesenchymal stem cells (iPSC-MSCs) on oxidative stress–induce mitochondrial dysfunction in human airway smooth muscle cells (ASMCs) in vitro and in mouse lungs in vivo.MethodsASMCs were cocultured with iPSC-MSCs in the presence of cigarette smoke medium (CSM), and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), and apoptosis were measured. Conditioned medium from iPSC-MSCs and transwell cocultures were used to detect any paracrine effects. The effect of systemic injection of iPSC-MSCs on airway inflammation and hyperresponsiveness in ozone-exposed mice was also investigated.ResultsCoculture of iPSC-MSCs with ASMCs attenuated CSM-induced mitochondrial ROS, apoptosis, and ΔΨm loss in ASMCs. iPSC-MSC–conditioned medium or transwell cocultures with iPSC-MSCs reduced CSM-induced mitochondrial ROS but not ΔΨm or apoptosis in ASMCs. Mitochondrial transfer from iPSC-MSCs to ASMCs was observed after direct coculture and was enhanced by CSM. iPSC-MSCs attenuated ozone-induced mitochondrial dysfunction, airway hyperresponsiveness, and inflammation in mouse lungs.ConclusioniPSC-MSCs offered protection against oxidative stress–induced mitochondrial dysfunction in human ASMCs and in mouse lungs while reducing airway inflammation and hyperresponsiveness. These effects are, at least in part, dependent on cell-cell contact, which allows for mitochondrial transfer, and paracrine regulation. Therefore iPSC-MSCs show promise as a therapy for oxidative stress&
Perry MM, Lavender P, Scott Kuo C-H, et al., 2018, DNA methylation modules in airway smooth muscle are associated with asthma severity, European Respiratory Journal, Vol: 51, ISSN: 0903-1936
Abnormal DNA methylation patterns distinguish airway smooth muscle cell function in asthma and asthma severity.
Dhesi SS, Chung KF, Michaeloudes C, et al., 2017, THE EFFECT OF LONG ACTING BETA-AGONISTS ON GLUCOCORTICOID RECEPTOR AND IMPORTIN-7 NUCLEAR TRANSLOCATION IN AIRWAY SMOOTH MUSCLE CELLS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A55-A55, ISSN: 0040-6376
Michaeloudes C, Kuo C-H, Haji G, et al., 2017, Metabolic re-patterning in COPD airway smooth muscle cells., European Respiratory Journal, Vol: 50, ISSN: 0903-1936
Chronic obstructive pulmonary disease (COPD) airways are characterised by thickening of airway smooth muscle, partly due to airway smooth muscle cell (ASMC) hyperplasia. Metabolic reprogramming involving increased glycolysis and glutamine catabolism supports the biosynthetic and redox balance required for cellular growth. We examined whether COPD ASMCs show a distinct metabolic phenotype that may contribute to increased growth.We performed an exploratory intracellular metabolic profile analysis of ASMCs from healthy nonsmokers, healthy smokers and COPD patients, under unstimulated or growth conditions of transforming growth factor (TGF)-β and fetal bovine serum (FBS).COPD ASMCs showed impaired energy balance and accumulation of the glycolytic product lactate, glutamine, fatty acids and amino acids compared to controls in unstimulated and growth conditions. Fatty acid oxidation capacity was reduced under unstimulated conditions. TGF-β/FBS-stimulated COPD ASMCs showed restoration of fatty acid oxidation capacity, upregulation of the pentose phosphate pathway product ribose-5-phosphate and of nucleotide biosynthesis intermediates, and increased levels of the glutamine catabolite glutamate. In addition, TGF-β/FBS-stimulated COPD ASMCs showed a higher reduced-to-oxidised glutathione ratio and lower mitochondrial oxidant levels. Inhibition of glycolysis and glutamine depletion attenuated TGF-β/FBS-stimulated growth of COPD ASMCs.Changes in glycolysis, glutamine and fatty acid metabolism may lead to increased biosynthesis and redox balance, supporting COPD ASMC growth.
Lo C-Y, Michaeloudes C, Bhavsar PK, et al., 2017, Reduced suppressive effect of beta(2)-adrenoceptor agonist on fibrocyte function in severe asthma, RESPIRATORY RESEARCH, Vol: 18, ISSN: 1465-993X
BackgroundPatients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function.MethodsNon-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I+/CD45+ cells) and differentiating fibrocytes (α-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of β2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram.ResultsSalmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface β2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased β2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation.ConclusionsFibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.
Michaeloudes C, Bhavsar PK, Mumby S, et al., 2017, Dealing with Stress: Defective Metabolic Adaptation in Chronic Obstructive Pulmonary Disease Pathogenesis, Annals of the American Thoracic Society, Vol: 14, Pages: S374-S382, ISSN: 2329-6933
The mitochondrion is the main site of energy production and ahub of key signaling pathways. It is also central in stress-adaptiveresponse due to its dynamic morphology and ability to interactwith other organelles. In response to stress, mitochondria fuseinto networks to increase bioenergetic efficiency and protectagainst oxidative damage. Mitochondrial damage triggerssegregation of damaged mitochondria from the mitochondrialnetwork through fission and their proteolytic degradation bymitophagy. Post-translational modifications of themitochondrial proteome and nuclear cross-talk lead toreprogramming of metabolic gene expression to maintain energyproduction and redox balance. Chronic obstructive pulmonarydisease (COPD) is caused by chronic exposure to oxidativestress arising from inhaled irritants, such as cigarette smoke.Impaired mitochondrial structure and function, due tooxidative stress–induced damage, may play a key role incausing COPD. Deregulated metabolic adaptation maycontribute to the development and persistence of mitochondrialdysfunction in COPD. We discuss the evidence for deregulatedmetabolic adaptation and highlight important areas forinvestigation that will allow the identification of moleculartargets for protecting the COPD lung from the effects ofdysfunctional mitochondria.
Michaeloudes C, Mumby S, Chung KF, et al., 2017, Bromodomain And Extra-Terminal (BET) proteins regulate metabolic and redox function in COPD airway smooth muscle cells, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Michaeloudes C, Mumby S, Chung KF, et al., 2017, Bromodomain and extra-terminal (bet) proteins regulate the oxidant-antioxidant balance in airway smooth muscle cells from patients with COPD, International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X
Rasiah MG, Michaeloudes C, Svermova T, et al., 2016, PLASMA SYNDECAN-1 LEVEL AS A PREDICTIVE MARKER OF VASOPLEGIA ASSOCIATED WITH SURGERY REQUIRING CARDIOPULMONARY BYPASS AND POSSIBLE INVOLVEMENT OF OXIDATIVE STRESS, British Thoracic Society Winter Meeting 2016, Publisher: BMJ PUBLISHING GROUP, Pages: A9-A9, ISSN: 0040-6376
Calven J, Akbarshahi H, Ramu S, et al., 2016, Rhinovirus-induced IL-33 expression in asthmatic airway smooth muscle cells is TLR3-dependent and involves activation of TAK1, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Michaeloudes C, Kuo C-H, Adcock IM, et al., 2016, Altered redox and metabolic status in airway smooth muscle cells of patients with COPD, International Conference of the American Thoracic Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X
Stock C, Hubank M, Michaeloudes C, et al., 2016, Microarray Analysis Maps Global Effects of Epigenetic Bromodomain Inhibitor JQ1 on Gene Expression in Transforming Growth Factor-β-Stimulated Adult Lung Fibroblasts, British Society for Rheumatology, British Health Professionals in Rheumatology and the British Society for Paediatric and Adolescent Rheumatology Annual Meeting 2015, Publisher: Oxford University Press (OUP), Pages: 164-165, ISSN: 1462-0332
Li X, Michaeloudes C, Zhang Y, et al., 2016, Induced-Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Attenuate Cigarette Smoke-Induced Mitochondrial Dysfunction And Apoptosis In Airway Smooth Muscle Cells, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Michaeloudes C, Kirkham P, Adcock IM, et al., 2015, Mitochondrial reactive oxygen species and glycolysis in airway smooth muscle cell proliferation in COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wiegman CH, Michaeloudes C, Haji G, et al., 2015, Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 769-780, ISSN: 1097-6825
BackgroundInflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology.ObjectiveWe sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells.MethodsMice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ.ResultsMice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release.ConclusionsMitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammat
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