Publications
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Wiegman C, Fedele L, Koufaki M-I, et al., 2023, To game or not to game-that is the question: Evaluation of newly developed gamification elements in MSc pharmacology modules, Pharmacology Annual Meeting, Publisher: WILEY, Pages: 556-556, ISSN: 0007-1188
Burke-Gaffney A, Koufaki M-I, Wiegman CH, et al., 2021, Who cares wins: Teaching MSc students challenges of drug development through gamification, Publisher: WILEY, Pages: 5006-5006, ISSN: 0007-1188
Tiotiu A, Badi Y, Abubakr-Waziri H, et al., 2021, Sputum transcriptomic analysis of air pollutant signatures: link to asthma severity and phenotype, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Adcock I, Main M, Rothaul A, et al., 2021, The pan janus kinase (JAK) inhibitor KN-002 suppresses inflammatory mediator release from severe asthma bronchial epithelial cells, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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.
Lowe J, Adcock I, Wiegman C, 2020, Oxidative stress and mitochondrial dysfunction in a novel in vivo exacerbation model of severe asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Wiegman CH, Li F, Ryffel B, et al., 2020, Oxidative Stress in Ozone-Induced Chronic Lung Inflammation and Emphysema: A Facet of Chronic Obstructive Pulmonary Disease, Frontiers in Immunology, Vol: 11
Prihandoko R, Kaur D, Wiegman CH, et al., 2020, Pathophysiological regulation of lung function by the free fatty acid receptor FFA4, Science Translational Medicine, Vol: 12, Pages: 1-13, ISSN: 1946-6234
Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein-coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated at least in part by the release of the prostaglandin E2 (PGE2) that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke-induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.
Östling J, van Geest M, Schofield JPR, et al., 2019, IL-17-high asthma with features of a psoriasis immunophenotype, Journal of Allergy and Clinical Immunology, Vol: 144, Pages: 1198-1213, ISSN: 0091-6749
BACKGROUND: The role of interleukin-17 immunity is well established in inflammatory diseases like psoriasis and inflammatory bowel disease but not in asthma where further study is required. OBJECTIVE: To undertake a deep-phenotyping study of asthmatics with up-regulated interleukin-17 immunity. METHODS: Whole genome transcriptomic analysis was performed using epithelial brushings, bronchial biopsies (91 asthmatics patients and 46 healthy controls) and whole blood samples (n=498) from the U-BIOPRED cohort. Gene signatures induced in vitro by interleukin-17 and interleukin-13 in bronchial epithelial cells were used to identify patients with interleukin-17-high and interleukin-13-high phenotypes of asthma. RESULTS: 22 out of 91 patients were identified with interleukin-17 and 9 patients with interleukin-13 gene signatures. The interleukin-17-high asthmatics were characterised by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis, the differentially expressed genes in interleukin-17-high patients were shared with those reported as altered in psoriasis lesions, and included genes regulating epithelial barrier function and defence mechanisms, such as interleukin-1β, interleukin-6, interleukin-8, and beta-defensin. CONCLUSION: The interleukin-17-high asthma phenotype, characterized by bronchial epithelial dysfunction, upregulated anti-microbial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway which should be considered as a biomarker for this phenotype in further studies, including clinical trials targeting interleukin-17.
Schofield JPR, Burg D, Nicholas B, et al., 2019, Stratification of asthma phenotypes by airway proteomic signatures, Journal of Allergy and Clinical Immunology, Vol: 144, Pages: 70-82, ISSN: 0091-6749
BACKGROUND: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy to predict treatment responses and a need for better understanding of the underlying mechanisms. OBJECTIVE: Identify molecular sub-phenotypes of asthma defined by proteomic signatures for improved stratification. METHODS: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyse the proteomes of sputum supernatants from 246 participants (206 asthmatics) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. RESULTS: Analysis of the sputum proteome resulted in 10 clusters, proteotypes, based on similarity in proteomics features, representing discrete molecular sub-phenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined three of these as highly eosinophilic, three as highly neutrophilic, and two as highly atopic with relatively low granulocytic inflammation. For each of these three phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. CONCLUSION: This study provides further stratification of asthma currently classified by quantifying granulocytic inflammation and gives additional insight into their underlying mechanisms which could become targets for novel therapies.
Perotin J-M, Schofield JPR, Wilson SJ, et al., 2019, Epithelial dysregulation in obese severe asthmatics with gastro-oesophageal reflux, European Respiratory Journal, Vol: 53, ISSN: 0903-1936
De Meulder B, Lefaudeux D, Bansal AT, et al., 2018, A computational framework for complex disease stratification from multiple large-scale datasets, BMC Systems Biology, Vol: 12, ISSN: 1752-0509
BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.
Michaudel C, Maillet I, Fauconnier L, et al., 2018, Interleukin-1 alpha mediates ozone-induced myeloid differentiation factor-88-dependent epithelial tissue injury and inflammation, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
Air pollution associated with ozone exposure represents a major inducer of respiratory disease in man. In mice, a single ozone exposure causes lung injury with disruption of the respiratory barrier and inflammation. We investigated the role of interleukin-1 (IL-1)-associated cytokines upon a single ozone exposure (1 ppm for 1 h) using IL-1α-, IL-1β-, and IL-18-deficient mice or an anti-IL-1α neutralizing antibody underlying the rapid epithelial cell death. Here, we demonstrate the release of the alarmin IL-1α after ozone exposure and that the acute respiratory barrier injury and inflammation and airway hyperreactivity are IL-1α-dependent. IL-1α signaling via IL-1R1 depends on the adaptor protein myeloid differentiation factor-88 (MyD88). Importantly, epithelial cell signaling is critical, since deletion of MyD88 in lung type I alveolar epithelial cells reduced ozone-induced inflammation. In addition, intratracheal injection of recombinant rmIL-1α in MyD88acid mice led to reduction of inflammation in comparison with wild type mice treated with rmIL-1α. Therefore, a major part of inflammation is mediated by IL-1α signaling in epithelial cells. In conclusion, the alarmin IL-1α released upon ozone-induced tissue damage and inflammation is mediated by MyD88 signaling in epithelial cells. Therefore, IL-1α may represent a therapeutic target to attenuate ozone-induced lung inflammation and hyperreactivity.
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.
Rossios C, Pavlidis S, Hoda U, et al., 2017, Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 560-570, ISSN: 1097-6825
BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13-induced TH2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammati
Chung KF, Seiffert J, Chen S, et al., 2017, Inactivation, clearance, and functional effects of lung-instilled short and long silver nanowires in rats, ACS Nano, Vol: 11, Pages: 2652-2664, ISSN: 1936-086X
There is a potential for silver nanowires (AgNWs) to be inhaled, but there is little information on their health effects and their chemical transformation inside the lungs in vivo. We studied the effects of short (S-AgNWs; 1.5 μm) and long (L-AgNWs; 10 μm) nanowires instilled into the lungs of Sprague–Dawley rats. S- and L-AgNWs were phagocytosed and degraded by macrophages; there was no frustrated phagocytosis. Interestingly, both AgNWs were internalized in alveolar epithelial cells, with precipitation of Ag2S on their surface as secondary Ag2S nanoparticles. Quantitative serial block face three-dimensional scanning electron microscopy showed a small, but significant, reduction of NW lengths inside alveolar epithelial cells. AgNWs were also present in the lung subpleural space where L-AgNWs exposure resulted in more Ag+ve macrophages situated within the pleura and subpleural alveoli, compared with the S-AgNWs exposure. For both AgNWs, there was lung inflammation at day 1, disappearing by day 21, but in bronchoalveolar lavage fluid (BALF), L-AgNWs caused a delayed neutrophilic and macrophagic inflammation, while S-AgNWs caused only acute transient neutrophilia. Surfactant protein D (SP-D) levels in BALF increased after S- and L-AgNWs exposure at day 7. L-AgNWs induced MIP-1α and S-AgNWs induced IL-18 at day 1. Large airway bronchial responsiveness to acetylcholine increased following L-AgNWs, but not S-AgNWs, exposure. The attenuated response to AgNW instillation may be due to silver inactivation after precipitation of Ag2S with limited dissolution. Our findings have important consequences for the safety of silver-based technologies to human health.
Shim JM, Lee JS, Russell KE, et al., 2017, BET proteins are a key component of immunoglobulin gene expression, Epigenomics, Vol: 9, Pages: 393-406, ISSN: 1750-192X
Aims:Bromo and extraterminal domain (BET) proteins have been shown to regulate gene expression including inflammatory genes. Methods:In order to investigate the role of the BET proteins in immunoglobulin production we treated the human B cell line CLNH11.4 and primary human B cells and ozone exposed mice with BET inhibitors (JQ1 or IBET151). Results:Both proliferation and IgG production were reduced by JQ1 in a concentration-dependent manner. JQ1 significantly reduced immunoglobulin gene transcription. In vivo treatment of ozone-exposed mice with the BET inhibitor IBET151 similarly inhibited ozone induced immunoglobulin production. JQ1 did not reduce the protein levels of Brd4 or Oct2 per se but reduced the ability of Brd4 and Oct2 to co-immunoprecipitate and of Oct2 to bind to immunoglobulin gene promoters.Conclusions:Our results indicate that BET proteins including Brd4 play a crucial role regulation B cell specific gene expression and immunoglobulin production.
Lefaudeux D, De Meulder B, Loza MJ, et al., 2016, U-BIOPRED clinical adult asthma clusters linked to a subset of sputum -omics, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1797-1807, ISSN: 1097-6825
Jones B, Donovan C, Liu G, et al., 2016, Animal models of COPD: What do they tell us?, Respirology, Vol: 22, Pages: 21-32, ISSN: 1440-1843
COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD.
Hogema F, Dai R, Li X, et al., 2016, High-fat diet in mice leads to amplified ozone-induced airway hyperresponsiveness (AHR), mitochondrial dysfunction and insulin resistance, European Respitory Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Pavlidis S, Adcock I, Chung F, et al., 2016, Enrichment of the Janus kinase (JAK) activation signature in severe asthma sputum: Correlation with IL-13 expression, European Respiratory Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Ojo OO, Wiegman C, Chung K, et al., 2016, Necroptosis signalling in lung epithelial cells modulates mitochondrial function and reactive oxygen species generation in healthy and asthmatic airway smooth muscle (ASM) cells, International Conference of the American Thoracic Society (ATS), Publisher: American Thoracic Society, ISSN: 1535-4970
Bradley SJ, Wiegman CH, Iglesias MM, et al., 2016, Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 4524-4529, ISSN: 1091-6490
G protein-coupled receptors (GPCRs) are known to initiate a plethora of signaling pathways in vitro. However, it is unclear which of these pathways are engaged to mediate physiological responses. Here, we examine the distinct roles of Gq/11-dependent signaling and receptor phosphorylation-dependent signaling in bronchial airway contraction and lung function regulated through the M3-muscarinic acetylcholine receptor (M3-mAChR). By using a genetically engineered mouse expressing a G protein-biased M3-mAChR mutant, we reveal the first evidence, to our knowledge, of a role for M3-mAChR phosphorylation in bronchial smooth muscle contraction in health and in a disease state with relevance to human asthma. Furthermore, this mouse model can be used to distinguish the physiological responses that are regulated by M3-mAChR phosphorylation (which include control of lung function) from those responses that are downstream of G protein signaling. In this way, we present an approach by which to predict the physiological/therapeutic outcome of M3-mAChR–biased ligands with important implications for drug discovery.
Russell KE, Chung KF, Clarke CJ, et al., 2016, The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD., PLOS One, Vol: 11, ISSN: 1932-6203
INTRODUCTION: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. METHODS: Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. RESULTS: MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. CONCLUSION: MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.
Gao W, Yuan C, Zhang J, et al., 2015, Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury., Clinical Science, Vol: 129, Pages: 1011-1023, ISSN: 0143-5221
COPD (chronic obstructive pulmonary disease) is associated with sustained inflammation, excessive injury, and accelerated lung aging. Human Klotho (KL) is an anti-aging protein that protects cells against inflammation and damage. In the present study, we quantified KL expression in the lungs of COPD patients and in an ozone-induced mouse model of COPD, and investigated the mechanisms that control KL expression and function in the airways. KL distribution and levels in human and mouse airways were measured by immunohistochemistry and Western blotting. The effect of CSE (cigarette smoke extract) on KL expression was detected in human bronchial epithelial cells. Moreover, the effect of KL on CSE-mediated inflammation and hydrogen peroxide-induced cellular injury/apoptosis was determined using siRNAs. KL expression was decreased in the lungs of smokers and further reduced in patients with COPD. Similarly, 6 weeks of exposure to ozone decreased KL levels in airway epithelial cells. CSE and TNFα (tumour necrosis factor α) decreased KL expression and release from airway epithelial cells, which was associated with enhanced pro-inflammatory cytokine expression. Moreover, KL depletion increased cell sensitivity to cigarette smoke-induced inflammation and oxidative stress-induced cell damage. These effects involved the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and Nrf2 (nuclear factor erythroid 2-related factor 2) pathways. Reduced KL expression in COPD airway epithelial cells was associated with increased oxidative stress, inflammation and apoptosis. These data provide new insights into the mechanisms associated with the accelerated lung aging in COPD development.
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
Russell K, Pavlidis S, Wiegman C, et al., 2015, Mapping a mouse model of severe asthma to human asthma using gene set variation analysis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wiegman C, Adcock I, Rothaul A, et al., 2015, In-vitro evaluation of a new potent, selective pan-Janus kinase (JAK) inhibitor VR588, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Wiegman CH, Adcock IM, Rothaul A, et al., 2015, ACTIVITY OF THE NOVEL AND SELECTIVE PANJANUS KINASE (JAK) INHIBITOR VR588 IN A MURINE POLYINOSINIC: POLYCYTIDILIC ACID (POLY(I:C)) MODEL OF VIRAL LUNG INFLAMMATION, 20th ISAM Congress, Publisher: Mary Ann Liebert, Pages: A23-A23, ISSN: 1941-2711
Rationale: VR588 is a potent, selective pan-JAK inhibitor. Viralinfection is regarded as an important trigger of airway inflammation.This study investigates VR588 by the inhaled and oral routes in amurine model of viral lung inflammationMethods: Male BALB/c mice were administered Poly(I:C) 1 mg/mlintranasally (i.n) 1 hour after VR588 administration and again 16 hourslater. VR588 was given (i.n 1.5, 7.5, 15 mg/kg and p.o 15 mg/kg; n¼6per group). Lung tissue and bronchoalveolar lavage fluid (BALF) washarvested 40 hours after the initial Poly(I:C) challenge. Inflammatorycell count from BALF (FACS analysis), JAK-STAT activation(pSTAT1, 3 & 5) (ELISA) and BAL inflammatory cytokines (Lumineximmunoassay) were measured. Fluticasone propionate (FP) (i.n 1.5 mg/kg) and tofacitinib (T) (p.o 15 mg/kg) were positive controls.Results: Poly(I:C) increased total BAL cell count which was reducedin a dose-related manner by i.n VR588; oral VR588 was ineffective. Poly(I:C)-elevated BAL cytokines (eotaxin, MIP-1a & b, IP-10, KC, TNF-aand MCP-1) were all reduced by i.n VR588. pSTAT1 and pSTAT5 (butnot pSTAT3) were increased by Poly(I:C) and subsequently attenuatedby VR588. Intranasal VR588 activity was typically greater than that seenfor oral and at least as great as that with FP or T.Conclusions: VR588 attenuation of Poly(I:C) induced inflammatorycell accumulation, cytokines and STAT phosphorylation supportsits possible use in the treatment of viral induced airway inflammation.
Wiegman CH, Adcock IM, Rothaul A, et al., 2015, IN VITRO EVALUATION OF A NEW POTENT, SELECTIVE PAN-JANUS KINASE (JAK) INHIBITOR VR588, 20th ISAM Congress, Publisher: Mary Ann Liebert, Pages: A23-A23, ISSN: 1941-2711
Rationale: VR588 is promising pan-JAK inhibitor suited to inhalationdelivery. These studies were designed to characterise the invitrokinase inhibition profile of VR588 and to determine its selectivityversus non-JAK kinases.Methods: Kinase activity was assessed in a non-cell (Z’Lyte Florescence assay) and in cell based assays using stimulation of humanwhole blood (IL-2 stimulated INFc production and JAK1/JAK3and pSTATa/b activation and IL-6 stimulated pSTAT3 to assessJAK1, JAK2 and Tyk2 activity). Selectivity of VR588 (1 mM) againsta panel of 93 human kinases was also assessed.Results: VR588 potently inhibited JAK 1, 2, 3 and Tyk2 kinases(IC50 4.2, 0.7, 2.1 & 6 nM respectively) in the non-cell based assay andshowed poor inhibitory activity against non –JAK kinases FLT3,PDGFB, JNK2 and Syk (IC50 247, 2350,4000, 8900 nM respectively).JAK inhibition was confirmed in the cell based assays with inhibition ofIL-2 stimulated INFc, IL-2 stimulated pSTATa/b & IL-6 stimulatedpSTAT3 demonstrating IC50 values of 209, 29 & 62 nM respectively.Selectivity versus human kinases revealed no relevant off- target effects.Conclusions: VR588 represents a potent, selective and balancedpan-JAK inhibitor, suggesting VR588 may have utility as a treatmentfor asthma and COPD.
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