Publications
103 results found
Li X, Michaeloudes C, Zhang Y, et al., 2017, 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
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.
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
Rationale: Patients with severe asthma (SA) are less responsive to the beneficial effects of corticosteroid (CS) therapy, and relative CS insensitivity has been shown in airway smooth muscle cells (ASMC) from patients with SA.Objectives: We investigated whether there was a defect in the actions of the glucocorticoid receptor (GR) underlying the ability of CS to suppress the inflammatory response in ASMC of patients with SA. ASMC from healthy subjects (n = 10) and subjects with severe (n = 8) and nonsevere asthma (N-SA; n = 8) were cultured from endobronchial biopsies.Measurements and Main Results: GR expression in ASMC from SA and N-SA was reduced compared with that from healthy subjects by 49% (P < 0.01). Although baseline levels of nuclear GR were similar, GR nuclear translocation induced by dexamethasone (10−7 M) in SA was 60% of that measured in either healthy subjects or subjects with N-SA. Tumor necrosis factor (TNF)-α induced greater nuclear factor (NF)-κB (p65) mRNA expression in ASMC from subjects with SA (5.6- vs. 2.0-fold; P < 0.01), whereas baseline and TNF-α–induced nuclear translocation and dexamethasone-mediated suppression of p65 expression were similar between groups. Dexamethasone, although not modulating TNF-α–induced p65 nuclear translocation, attenuated p65 recruitment to the CCL11 promoter in the healthy and N-SA groups, but this suppressive effect was impaired in subjects with SA.Conclusions: Decreased GR expression with impaired nuclear translocation in ASMC, associated with reduced dexamethasone-mediated attenuation of p65 recruitment to NF-κB–dependent gene promoters, may underlie CS insensitivity of severe asthma.
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
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
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
- Author Web Link
- Cite
- Citations: 1
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 AJ, Rossios C, et al., 2014, Sputum-to-serum hydrogen sulfide ratio in COPD, THORAX, Vol: 69, Pages: 903-909, ISSN: 0040-6376
- Author Web Link
- Cite
- Citations: 20
Saito J, Mackay A, Rossios C, et al., 2014, Hydrogen sulfide (H<sub>2</sub>S) 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 (H<sub>2</sub>S) 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
- Author Web Link
- Open Access Link
- Cite
- Citations: 74
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
- Author Web Link
- Cite
- Citations: 25
Tupper LL, Bausman D, Chowdhury M, et al., 2014, Development of a Professional Services Management Training Program A Case Study, TRANSPORTATION RESEARCH RECORD, Pages: 29-34, ISSN: 0361-1981
Gibeon D, Zhu J, Sogbesan A, et al., 2014, Lipid-laden bronchoalveolar macrophages in asthma and chronic cough, RESPIRATORY MEDICINE, Vol: 108, Pages: 71-77, ISSN: 0954-6111
- Author Web Link
- Cite
- Citations: 19
Li F, Wiegman C, Seiffert JM, et al., 2013, Effects of N-acetylcysteine in ozone-induced chronic obstructive pulmonary disease model, PLOS One, Vol: 8, ISSN: 1932-6203
Saito J, Zhang Q, Hui C, et al., 2013, ENDOGENOUS HYDROGEN SULFIDE IN SERUM AND SPUTUM AS NOVEL BIOMARKER OF ASTHMA, RESPIROLOGY, Vol: 18, Pages: 36-36, ISSN: 1323-7799
Saito J, Gibeon D, Macedo P, et al., 2013, Domiciliary diurnal variation of fractional exhaled nitric oxide (FeNO) to monitor asthma control, EUROPEAN RESPIRATORY JOURNAL, Vol: 42, ISSN: 0903-1936
Binia A, Van Stiphout N, Liang L, et al., 2013, A Polymorphism Affecting MYB Binding within the Promoter of the <i>PDCD4</i> Gene is Associated with Severe Asthma in Children, HUMAN MUTATION, Vol: 34, Pages: 1131-1139, ISSN: 1059-7794
- Author Web Link
- Cite
- Citations: 14
Gow AM, Chung KF, Gibeon D, et al., 2013, Obesity associated severe asthma represents a distinct clinical phenotype – Analysis of the British Thoracic Society Difficult Asthma Registry patient cohort according to body mass index, CHEST Journal
Pennino D, Bhavsar PK, Effner R, et al., 2013, IL-22 suppresses IFN-γ-mediated lung inflammation in asthmatic patients, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 131, Pages: 562-570, ISSN: 0091-6749
- Author Web Link
- Open Access Link
- Cite
- Citations: 59
Saito J, Zhang Q, Hui C, et al., 2013, Successful desensitization to rosuvastatin in a patient with a history of anaphylaxis to multiple statins, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 131, Pages: 234-U340, ISSN: 0091-6749
- Author Web Link
- Cite
- Citations: 1
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.