81 results found
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, 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
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
Bhavsar PK, 2018, Role of humoral defense in severe asthma, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1369-1371, ISSN: 1073-449X
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
Mullegama R, Pavlidis S, Chung KF, et al., 2017, CLINICAL AND TRANSCRIPTOMIC PROFILES OF SEVERE ASTHMATICS WITH HIGH OR LOW EXPRESSION OF THE GLUCOCORTICOID RECEPTOR AND IMPORTIN-7, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A40-A41, ISSN: 0040-6376
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.
Shaikh N, Johnson M, Hall D, et al., 2017, Intracellular interactions of umeclidinium and vilanterol in human airway smooth muscle, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 12, Pages: 1903-1913, ISSN: 1176-9106
Background: Intracellular mechanisms of action of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a long-acting β2-adrenoceptor (β2R) agonist, were investigated in target cells: human airway smooth-muscle cells (ASMCs).Materials and methods: ASMCs from tracheas of healthy lung-transplant donors were treated with VI, UMEC, UMEC and VI combined, or control compounds (salmeterol, propranolol, ICI 118.551, or methacholine [MCh]). Cyclic adenosine monophosphate (cAMP) was measured using an enzyme-linked immunosorbent assay, intracellular free calcium ([Ca2+]i) using a fluorescence assay, and regulator of G-protein signaling 2 (RGS2) messenger RNA using real-time quantitative polymerase chain reaction.Results: VI and salmeterol (10–12–10–6 M) induced cAMP production from ASMCs in a concentration-dependent manner, which was greater for VI at all concentrations. β2R antagonism by propranolol or ICI 118.551 (10–12–10–4 M) resulted in concentration-dependent inhibition of VI-induced cAMP production, and ICI 118.551 was more potent. MCh (5×10–6 M, 30 minutes) attenuated VI-induced cAMP production (P<0.05), whereas pretreatment with UMEC (10–8 M, 1 hour) restored the magnitude of VI-induced cAMP production. ASMC stimulation with MCh (10–11–5×10–6 M) resulted in a concentration-dependent increase in [Ca2+]i, which was attenuated with UMEC pretreatment. Reduction of MCh-induced [Ca2+]i release was greater with UMEC + VI versus UMEC. UMEC enhanced VI-induced RGS2 messenger RNA expression.Conclusion: These data indicate that UMEC reverses cholinergic inhibition of VI-induced cAMP production, and is a more potent muscarinic receptor antagonist when in combination with VI versus either alone.
Bhavsar PK, Sehra G, Johnson M, et al., 2017, Pharmacological characterization Of Maba, Gsk961081 on human airway smooth muscle cells, 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
Shaikh N, Johnson M, Riley J, et al., 2016, Effects Of Vilanterol And Umeclidinium Alone And In Combination In Human Airway Smooth Muscle Cells, International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X
Zhang Q, Cox M, Liang Z, et al., 2016, Airway microbiota in severe asthma and relationship to asthma severity and phenotypes, PLOS One, Vol: 11, ISSN: 1932-6203
Background: The lower airways harbor a community of bacterial species which is altered in asthma. Objectives: We examined whether the lower airway microbiota were related to measures of asthma severityMethods: We prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed. Results: We obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P=2.8x10-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR=2.26; 95% CI=1.94-2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR=2.15; 95%CI=1.89-2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia.Conclusions: Sputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.
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
Colley T, Mercado N, Kunori Y, et al., 2015, Defective sirtuin-1 increases IL-4 expression through acetylation of GATA-3 in patients with severe asthma., Journal of Allergy and Clinical Immunology, Vol: 137, Pages: 1595-1597.e7, ISSN: 1097-6825
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
Khorasani N, Baker J, Johnson M, et al., 2015, Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 10, Pages: 283-291, ISSN: 1176-9106
Background: Corticosteroids (CS) have limited efficacy in the treatment of chronic obstructivepulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation isincreased in lung macrophages of COPD. We investigated whether p38 MAPK inhibitioncan modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patientswith COPD.Methods: PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed tolipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10-10–10-6 M),with dexamethasone (10-10–10-6 M), or with both. Phosphorylated glucocorticoid receptor (GR)was measured by Western blot.Results: Baseline (P,0.01) and LPS-induced (P,0.05) CXCL8 release was greater in PBMCsfrom COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone(10-6 M) was reduced, and baseline and LPS-induced p38 MAPK activation increasedin PBMCs of COPD. GW856553 (10-9 and 10-10 M) synergistically increased the inhibitoryeffect of dexamethasone (10-8 and 10-6 M) on LPS-induced CXCL8 release in COPD. Similarresults were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activatedphosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibitionof p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.Conclusion: p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.
Shaikh N, Hall DA, Chung K, et al., 2015, Response Of Human Airway Smooth Muscle Cells To Vilanterol And Umeclidinium, Components Of A New Once-Daily Combination Bronchodilator, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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
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
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
Lo C-Y, Michaeloudes C, Bhavsar PK, et al., 2014, Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma, Journal of Allergy and Clinical Immunology, Vol: 135, Pages: 1186-1195.e6, ISSN: 1097-6825
BackgroundPatients with severe asthma are less responsive to corticosteroid therapy and show increased airway remodeling. The mesenchymal progenitors, fibrocytes, may be involved in the remodeling of asthmatic airways. We propose that fibrocytes in severe asthma are different from those in nonsevere asthma.ObjectivesTo examine the survival, myofibroblastic differentiation, and C-C chemokine receptor 7 (CCR7) expression in blood fibrocytes from patients with severe and nonsevere asthma and study the effect of corticosteroids on fibrocyte function.MethodsThe nonadherent non–T-cell fraction of blood mononuclear cells was isolated from healthy subjects and patients with nonsevere and severe asthma. Total and differentiating fibrocytes were identified by their expression of CD45, collagen I, and α-smooth muscle actin using flow cytometry. The expression of CCR7 and of the glucocorticoid receptor was measured by using flow cytometry.ResultsIncreased numbers of circulating fibrocytes, with greater myofibroblastic differentiation potential, were observed in patients with severe asthma. Dexamethasone induced apoptosis, leading to reduction in the number of cultured fibrocytes and total nonadherent non-T cells from healthy subjects and patients with nonsevere asthma but not from patients with severe asthma. Dexamethasone reduced CCR7 expression in fibrocytes from patients with nonsevere asthma but not from patients with severe asthma. Glucocorticoid receptor expression was attenuated in fibrocytes from patients with severe asthma.ConclusionsPatients with severe asthma have elevated numbers of circulating fibrocytes that show enhanced myofibroblastic differentiation and that are less responsive to the effects of corticosteroids.
Saito J, Mackay A, Rossios C, et al., 2014, Hydrogen sulfide (H2S) in sputum and serum as a novel biomarker of COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Saito J, Mackay A, Rossios C, et al., 2014, Hydrogen sulfide (H2S) in sputum and serum as a novel biomarker of COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Liang Z, Zhang Q, Thomas CMR, et al., 2014, Impaired macrophage phagocytosis of bacteria in severe asthma, RESPIRATORY RESEARCH, Vol: 15
Michaeloudes C, Mercado N, Clarke C, et al., 2014, Bromodomain and Extraterminal Proteins Suppress NF-E2-Related Factor 2-Mediated Antioxidant Gene Expression., J Immunol
Saito J, Gibeon D, Macedo P, et al., 2014, Domiciliary diurnal variation of exhaled nitric oxide fraction for asthma control, EUROPEAN RESPIRATORY JOURNAL, Vol: 43, Pages: 474-484, ISSN: 0903-1936
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