48 results found
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, ISSN: 1465-9921
Ramu S, Calvén J, Michaeloudes C, et al., 2020, TLR3/TAK1 signalling regulates rhinovirus-induced interleukin-33 in bronchial smooth muscle cells., ERJ Open Res, Vol: 6, ISSN: 2312-0541
Background: Asthma exacerbations are commonly associated with rhinovirus (RV) infection. Interleukin-33 (IL-33) plays an important role during exacerbation by enhancing Type 2 inflammation. Recently we showed that RV infects bronchial smooth muscle cells (BSMCs) triggering production of interferons and IL-33. Here we compared levels of RV-induced IL-33 in BSMCs from healthy and asthmatic subjects, and explored the involvement of pattern-recognition receptors (PRRs) and downstream signalling pathways in IL-33 expression. Method: BSMCs from healthy and severe and non-severe asthmatic patients were infected with RV1B or stimulated with the PRR agonists poly(I:C) (Toll-like receptor 3 (TLR3)), imiquimod (TLR7) and poly(I:C)/LyoVec (retinoic acid-inducible gene 1 (RIG-I)/melanoma differentiation-associated protein 5 (MDA5)). Knockdown of TLR3, RIG-I and MDA5 was performed, and inhibitors targeting TBK1, nuclear factor-κB (NF-κB) and transforming growth factor (TGF)-β-activated kinase 1 (TAK1) were used. Gene and protein expression were assessed. Results: RV triggered IL-33 gene and protein expression in BSMCs. BSMCs from patients with non-severe asthma showed higher baseline and RV-induced IL-33 gene expression compared to cells from patients with severe asthma and healthy controls. Furthermore, RV-induced IL-33 expression in BSMCs from healthy and asthmatic individuals was attenuated by knockdown of TLR3. Inhibition of TAK1, but not NF-κB or TBK1, limited RV-induced IL-33. The cytokine secretion profile showed higher production of IL-33 in BSMCs from patients with non-severe asthma compared to healthy controls upon RV infection. In addition, BSMCs from patients with non-severe asthma had higher levels of RV-induced IL-8, TNF-α, IL-1β, IL-17A, IL-5 and IL-13. Conclusion: RV infection caused higher levels of IL-33 and increased pro-inflammatory and Type 2 cytokine release in BSMCs from patients with non-severe asthma. RV-induced IL-33 exp
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.
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
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
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
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
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.
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
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
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.
Bhavsar PK, li X, michaeloudes C, et al., 2017, Mesenchymal stem cells alleviate oxidative stress-induced mitochondrial dysfunction in the airways., Journal of Allergy and Clinical Immunology, ISSN: 0091-6749
BACKGROUND: Oxidative stress-induced mitochondrial dysfunction may contribute to inflammation and remodeling in chronic obstructive pulmonary disease (COPD). Mesenchymal stem cells (MSCs) protect against lung damage in animal models of COPD. It is unknown whether these effects occur through attenuating mitochondrial dysfunction in airway cells. OBJECTIVE: To examine the effect of induced-pluripotent stem cell-derived MSCs (iPSC-MSCs) on oxidative stress-induce mitochondrial dysfunction in human airway smooth muscle cells (ASMCs) in vitro and in mouse lungs in vivo. METHODS: ASMCs were co-cultured with iPSC-MSCs in the presence of cigarette smoke medium (CSM), and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) and apoptosis were measured. Conditioned media from iPSC-MSCs and trans-well co-cultures were used to detect any paracrine effects. The effect of systemic injection of iPSC-MSCs on airway inflammation and hyper-responsiveness in ozone-exposed mice was also investigated. RESULTS: Co-culture of iPSC-MSCs with ASMCs attenuated CSM-induced mitochondrial ROS, apoptosis and ΔΨm loss in ASMCs. iPSC-MSC-conditioned media or trans-well co-cultures 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 co-culture and was enhanced by CSM. iPSC-MSCs attenuated ozone-induced mitochondrial dysfunction, airway hyper-responsiveness and inflammation in mouse lungs. CONCLUSION: iPSC-MSCs offered protection against oxidative stress-induced mitochondrial dysfunction in human ASMCs and in mouse lungs, whilst reducing airway inflammation and hyper-responsiveness. These effects are, at least partly, dependent on cell-cell contact that allows for mitochondrial transfer, and paracrine regulation. Therefore, iPSC-MSCs show promise as a therapy for oxidative stress-dependent lung diseases such as COPD.
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
Marwick JA, Tudor C, Khorasani N, et al., 2015, Oxidants Induce a Corticosteroid-Insensitive Phosphorylation of Histone 3 at Serine 10 in Monocytes, PLOS One, Vol: 10, ISSN: 1932-6203
Lo C-Y, Bhavsar PK, Michaeloudes C, et al., 2015, Long-Acting Beta2 Adrenoceptor Agonist Suppresses Fibrocytes In Non- Severe Asthma But Not In Severe Asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Chang P-J, Michaeloudes C, Zhu J, et al., 2015, Impaired Nuclear Translocation of the Glucocorticoid Receptor in Corticosteroid-Insensitive Airway Smooth Muscle in Severe Asthma, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 191, Pages: 54-62, ISSN: 1073-449X
Li X, Michaeloudes C, Zhang Y, et al., 2015, Oxidative Stress-Induced Mitochondria Alteration In Human Airway Smooth Muscle Cells And Mesenchymal Stem Cells, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.