Ian M Adcock

Imperial College London, Londinium, England, United Kingdom

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Publications (426)2108.88 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione-S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD(+)/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications. Copyright © 2015 the American Physiological Society.
    AJP Lung Cellular and Molecular Physiology 06/2015; 308(12):ajplung.00220.2014. DOI:10.1152/ajplung.00220.2014 · 4.04 Impact Factor
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    ABSTRACT: Statins have immunomodulatory properties that may provide beneficial effects in the treatment of COPD. We investigated whether a statin improves the IL-17/IL-10 imbalance in patients with COPD as has previously been demonstrated in patients with asthma. Thirty patients with stable COPD were recruited to a double-blind randomized controlled crossover trial comparing the effect of oral simvastatin 20 mg daily with that of a matched placebo on sputum inflammatory markers and airway inflammation. Each treatment was administered for 4 weeks separated by a 4-week washout period. The primary outcome was Th17 cytokines and indoleamine 2, 3 dioxygenase (IDO) in induced sputum. Secondary outcomes included sputum inflammatory cells, FEV1 and symptoms using the COPD assessment test (CAT). At 4 weeks there was a significant reduction in sputum IL-17A, IL-22, IL-6, and CXCL8 concentrations (mean difference -16.4 pg/ml, p=0.01; -48.6 pg/ml, p<0.001; -45.3 pg/ml, p=0.002 and -190.9 pg/ml, p=0.007, respectively), whereas IL-10 concentrations, IDO mRNA expression (fold change) and IDO activity (kynurenine/tryptophan ratio) were markedly increased during simvastatin treatment compared with placebo treatment periods (mean difference 24.7 pg/ml, p<0.001; 1.02, p<0.001 and 0.47, p<0.001, respectively). The absolute sputum macrophage count, proportion of macrophages and CAT score was reduced after simvastatin compared with placebo (mean difference -0.16 ×106, p=0.004; -14.1%, p<0.001 and -3.2, p=0.02, respectively). Values for other clinical outcomes were similar between the simvastatin and placebo treatments. Simvastatin reversed the IL-17A/IL-10 imbalance in the airways and reduced sputum macrophage but not neutrophil counts in patients with COPD.
    Chest 06/2015; DOI:10.1378/chest.14-3138 · 7.13 Impact Factor
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    ABSTRACT: The primary function of the bronchial epithelium is to act as a defensive barrier aiding the maintenance of normal airway function. Bronchial epithelial cells (BEC) form the interface between the external environment and the internal milieu, making it a major target of inhaled insults. However, BEC can also serve as effectors to initiate and orchestrate immune and inflammatory responses by releasing chemokines and cytokines, which recruit and activate inflammatory cells. They also produce excess reactive oxygen species as a result of an oxidant/antioxidant imbalance that contributes to chronic pulmonary inflammation and lung tissue damage. Accumulated mucus from hyperplastic BEC obstructs the lumen of small airways, whereas impaired cell repair, squamous metaplasia and increased extracellular matrix deposition underlying the epithelium is associated with airway remodelling particularly fibrosis and thickening of the airway wall. These alterations in small airway structure lead to airflow limitation, which is critical in the clinical diagnosis of chronic obstructive pulmonary disease (COPD). In this review, we discuss the abnormal function of BEC within a disturbed immune homeostatic environment consisting of ongoing inflammation, oxidative stress and small airway obstruction. We provide an overview of recent insights into the function of the bronchial epithelium in the pathogenesis of COPD and how this may provide novel therapeutic approaches for a number of chronic lung diseases. © 2015 Asian Pacific Society of Respirology.
    Respirology 04/2015; DOI:10.1111/resp.12542 · 3.50 Impact Factor
  • Iranian journal of allergy, asthma, and immunology 04/2015; · 1.01 Impact Factor
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    ABSTRACT: Innate lymphoid cells (ILCs) are identified as novel population of hematopoietic cells which protect the body by coordinating the innate immune response against a wide range of threats including infections, tissue damages and homeostatic disturbances. ILCs, particularly ILC2 cells, are found throughout the body including the brain. ILCs are morphologically similar to lymphocytes, express and release high levels of T-helper (Th)1, Th2 and Th17 cytokines but do not express classical cell-surface markers that are associated with other immune cell lineages. Three types of ILCs (ILC1, 2 & 3) have been reported depending upon the cytokines produced. ILC1 cells encompass natural killer (NK) cells and interferon (IFN)- releasing cells; ILC2 cells release the Th2 cytokines, IL-5, IL-9 and IL-13 in response to IL-25 and IL-33; and ILC3 cells which release IL-17 and IL-22. ILC2 cells have been implicated in mucosal reactions occurring in animal models of allergic asthma and virus-induced lung disorders resulting in the regulation of airway remodeling and tissue homeostasis. There is evidence for increased ILC2 cell numbers in allergic responses in man but little is known about the role of ILCs in chronic obstructive pulmonary disease (COPD). Further understanding of the characteristics of ILCs such as their origin, location and phenotypes and function would help to clarify the role of these cells in the pathogenesis of various lung diseases. In this review we will focus on the role of ILC2 cells and consider their origin, function, location and possible role in the pathogenesis of the chronic inflammatory disorders such as asthma and COPD.
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    ABSTRACT: Inflammation 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. We 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. Mice 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. Mice 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. Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 03/2015; DOI:10.1016/j.jaci.2015.01.046 · 11.25 Impact Factor
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    ABSTRACT: Respiratory virus infections are commonly associated with COPD exacerbations but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2) but their roles in COPD exacerbations is unknown. We investigated oxidative/nitrosative stress and HDAC2 in COPD exacerbations using experimental rhinovirus infection. 9 subjects with COPD (GOLD stage II), 10 smokers and 11 non-smokers were successfully infected with rhinovirus. Markers of oxidative and nitrosative-stress associated cellular damage, inflammatory mediators and proteases were measured in sputum, and HDAC2 activity measured in sputum and bronchoalveolar macrophages. In an in vitro model monocyte derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 measured. Rhinovirus infection induced significant increases in airways inflammation and markers of oxidative and nitrosative stress in COPD subjects. Oxidative/nitrosative stress markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory makers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity, inhibition of oxidative/nitrosative stress inhibited rhinovirus-induced inflammatory cytokines. Oxidative and nitrosative stress, airways inflammation and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations.
    Chest 03/2015; DOI:10.1378/chest.14-2637 · 7.13 Impact Factor
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    ABSTRACT: The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear. To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli. Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p-ERK1/2 was measured in bronchial mucosa in patients with mild/moderate (n = 17), severe/very severe (n = 16) stable COPD, control smokers (n = 16), control non-smokers (n = 9), in mild asthma (n = 9) and in peripheral airways from COPD patients (n = 15) and control smokers (n = 15). Interleukin (IL)-8 and MAPK mRNA was measured in stimulated 16HBE cells. No significant differences in p-p38 MAPK, p-JNK or p-ERK1/2 expression were seen in bronchial biopsies and peripheral airways between COPD and control subjects. Asthmatics showed increased submucosal p-p38 MAPK expression compared to COPD patients (p < 0.003) and control non-smokers (p < 0.05). Hydrogen peroxide (H2O2), cytomix (tumour necrosis factor-α + IL-1β + interferon-γ) and lipopolysaccharide (LPS) upregulated IL-8 mRNA at 1 or 2 h. p38 MAPKα mRNA was significantly increased after H2O2 and LPS treatment. JNK1 and ERK1 mRNA were unchanged after H2O2, cytomix or LPS treatments. p-p38 MAPK expression is similar in stable COPD and control subjects but increased in the bronchi of mild asthmatics compared to stable COPD patients. p38 MAPK mRNA is increased after bronchial epithelial challenges in vitro. These data together suggest a potential role for this MAPK in Th2 inflammation and possibly during COPD exacerbations. © 2015 S. Karger AG, Basel.
    Respiration 03/2015; 89(4). DOI:10.1159/000375168 · 2.92 Impact Factor
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    ABSTRACT: Abstract Background; Sarcoidosis is a systemic disease of unknown etiology characterized histologically by the observation of non-caseating granulomas and several immunological abnormalities. Sarcoidosis is a multi-organ disorder which involves formation of granulomas in many tissues including the lungs (pulmonary) and others such as skin, bone, heart (extra pulmonary). Associations between human leukocyte antigens (HLA), the encoded cell surface receptor (HLA-DR) and sarcoidosis have been reported in several studies. Several HLA-DR alleles have been described as potential risk factors for sarcoidosis in distinct ethnic groups however evidence for a relationship between HLA-DR alleles and pulmonary and extra-pulmonary sarcoidosis (EPS) is still scarce. Although the etiology of the disease remains unclear, infectious and environmental factors have been postulated. Inflammatory cytokines and chemokines may play important roles in the pathogenesis of sarcoidosis and serum free light chain (FLC) numbers have been implicated in several immunologic disorders. Purpose of the study; The aim of the present study was to investigate HLA associations with serum cytokines and FLC in Iranian patients with pulmonary (n= 86) and EPS (n=46). Results; We found that among the 16 HLA DRB alleles only *7 and *12 were different in sarcoidosis patients. The levels of TNF- and IL-8 in pulmonary sarcoidosis patients were higher than in EPS (P<0.05) whereas the levels of FLC subunits in EPS were higher than in pulmonary sarcoidosis. Conclusion; This data may suggests a link between HLA-DRB *12 and sarcoidosis in Iranian population.
    Journal of Inflammation 03/2015; DOI:10.1186/s12950-015-0066-3 · 2.22 Impact Factor
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    ABSTRACT: Rationale Airway smooth muscle (ASM) mass is increased in asthma and ASM cells from patients with asthma are hyperproliferative and release more IL-6 and CXCL8. The bromo- and extra-terminal (BET) family of proteins (Brd2, Brd3 and Brd4) govern the assembly of histone acetylation-dependent chromatin complexes. We have examined whether they modulate proliferation and cytokine expression in asthmatic ASM cells by studying the effect of BET bromodomain mimics, JQ1/SGCBD01 and I-BET762. Methods ASM cells from healthy individuals, non-severe and severe asthmatics were pre-treated with JQ1/SGCBD01 and I-BET762 prior to stimulation with fetal calf serum (FCS) and transforming growth factor-β (TGF-β). Proliferation was measured by BrdU incorporation. IL-6 and CXCL8 release was measured by ELISA, and mRNA expression was measured by RT-qPCR. Chromatin immunoprecipitation (ChIP) using a specific anti-Brd4 antibody and PCR primers directed against the transcriptional start site of IL-6 and CXCL8 gene promoters was performed. Results Neither JQ1/SGCBD01 nor I-BET762 had any effect on ASM cell viability. JQ1/SGCBD01 and I-BET762 inhibited FCS+TGF-β-induced ASM cell proliferation, IL-6 and CXCL8 release in healthy individuals (≥ 30nM) and in non-severe and severe asthma patients (≥ 100nM), the latter requiring higher concentrations of these mimics. JQ1/SGCBD01 reduced Brd4 binding to IL8 and IL6 promoters induced by FCS+TGF-β. Conclusions Mimics of BET bromodomains inhibit aberrant ASM cell proliferation and inflammation with lesser efficiency in those from asthmatic patients. They may be effective in reducing airway remodelling in asthma. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 02/2015; 290(14). DOI:10.1074/jbc.M114.612671 · 4.60 Impact Factor
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    Mark M Perry, Ian M Adcock, Kian Fan Chung
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    ABSTRACT: Purpose of review: MicroRNAs (miRNAs) modulate gene transcription in response to environmental stressors and other stimuli. A role for miRNAs in inflammation and immunity has been demonstrated and further evidence suggests that miRNAs also play a role in allergic asthma. Recent findings: Studies investigating the differential expression of miRNAs in biological fluids between asthma patients and controls have been published, as have their role in immune cell subsets. Further development of miRNAs in therapy has been addressed. miRNA-146a has been implicated in autoimmunity and allergic inflammation and miRNA-155 in the development of atopy. Targeting of miRNA-1 and miRNA-145 has been used to inhibit lung inflammation in mouse models of asthma. Although these recent findings need to be confirmed, miRNAs may prove to be useful as potential biomarkers of disease. However, their use as therapeutic targets in the lung remains unclear. Summary: There may be a potential role for using circulating miRNAs as biomarkers of disease status or response to therapy. The use of miRNAs as asthma therapy remains to be determined.
    Current Opinion in Allergy and Clinical Immunology 02/2015; doi: 10.1097/ACI.0000000000000147(2). DOI:10.1097/ACI.0000000000000147 · 3.66 Impact Factor
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    ABSTRACT: Recent studies have been established high degree of genetic diversity in solid organ tumors among individuals and even between individual tumor cells. This intratumor and intertumor genetic diversity results in a heterogeneous tumor with unique characteristics which potentially allows effective drug therapy. The goal of pharmacogenomics is to elucidate the genetic network(s) that underlie drug efficacy and drug resistance. Advances in targeted and personalized therapy plays an increasingly important role in many common cancers, notably lung cancer, due to the high incidence, prevalence, mortality and the greater tendency towards drug resistance seen in these patients. Non-small cell lung cancer (NSCLC) is characterized by mutations in the epidermal growth factor receptor (EGFR) and or downstream kinase pathways. This has led to the development of highly selective monoclonal antibodies and EGFR tyrosine kinase inhibitors (EGFR-TKIs) to prevent cancer initiation, proliferation, differentiation, angiogenesis, survival, and invasion. However, resistance to many of these new treatments is induced and further pharmacogenomic analysis has revealed mutations associated with increased or reduced drug efficacy. Combinations of kinase inhibitors or potentially the targeting of cancer stem cells may further increase the success of pharmacogenomics in treating patients with lung cancer. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 02/2015; DOI:10.1016/j.ejphar.2015.02.029 · 2.68 Impact Factor
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    ABSTRACT: The use of flow cytometry in the clinical laboratory has grown substantially in the past decade. Flow cytometric analysis provides a rapid qualitative and quantitative description of multiple characteristics of individual cells. For example, it is possible to detect the cell size and granularity, aspects of DNA and RNA content and the presence of cell surface and nuclear markers which are used to characterize the phenotype of single cells. Flow cytometry has been used for the immunophenotyping of a variety of specimens including whole blood, bone marrow, serous cavity fluids, (cerebrospinal fluid) CSF, urine and all types of body fluids. The technique has also been applied to human bronchoalveolar lavage (BAL) fluid, peritoneal fluids and blood. In this review, we describe the current status of the application of flow cytometry as a diagnostic tool in various lung diseases. We focus on the analysis of BAL cell composition in chronic obstructive lung disease (COPD), asthma, lung cancer, sarcoidosis, tuberculosis and idiopathic eosinophilic pneumonia (IEP).
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    ABSTRACT: The 2nd Cross Company Respiratory Symposium (CCRS), held in Horsham, U.K. in 2012, brought together representatives from across the pharmaceutical industry with expert academics, in the common interest of improving the design and translational predictiveness of in vivo models of respiratory disease. Organized by the respiratory representatives of the European Federation of Pharmaceutical Industries and Federations (EFPIA) group of companies involved in the EU-funded project (U-BIOPRED), the aim of the symposium was to identify state-of-the-art improvements in the utility and design of models of respiratory disease, with a view to improving their translational potential and reducing wasteful animal usage. The respiratory research and development community is responding to the challenge of improving translation in several ways: greater collaboration and open sharing of data, careful selection of the species, complexity and chronicity of the models, improved practices in preclinical research, continued refinement in models of respiratory diseases and their sub-types, greater understanding of the biology underlying human respiratory diseases and their sub-types, and finally greater use of human (and especially disease-relevant) cells, tissues and explants. The present review highlights these initiatives, combining lessons from the symposium and papers published in Clinical Science arising from the symposium, with critiques of the models currently used in the settings of asthma, idiopathic pulmonary fibrosis and COPD. The ultimate hope is that this will contribute to a more rational, efficient and sustainable development of a range of new treatments for respiratory diseases that continue to cause substantial morbidity and mortality across the world.
    Clinical Science 02/2015; 128(4):235-56. DOI:10.1042/CS20140373 · 5.63 Impact Factor
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    ABSTRACT: Inflammation is a central feature of stable chronic obstructive pulmonary disease (COPD) and involves both activation of structural cells of the airways and the lungs and the activation and/or recruitment of infiltrating inflammatory cells. This results in enhanced expression of many pro-inflammatory proteins and reduced expression of some anti-inflammatory mediators. An altered protein expression is generally associated with concomitant changes in gene expression profiles in a cell-specific manner. Increased understanding of the role of transcription factors and of the signaling pathways leading to their activation in stable COPD will provide new targets to enable the development of potential anti-inflammatory drugs. Several new compounds targeting these pathways and/or transcription factors are now in development for the treatment of stable COPD. Furthermore, glucocorticoids drugs already in clinical use act through their own transcription factor, the glucocorticoid receptor, to control the expression of inflammatory and anti-inflammatory genes.
    Annals of the New York Academy of Sciences 01/2015; 13401(1). DOI:10.1111/nyas.12619 · 4.31 Impact Factor
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    ABSTRACT: Necrotizing sarcoid granulomatosis (NSG) is a rare syndrome with unknown etiology. The disease is frequently confused with sarcoidosis and other granulomatous diseases. Diagnosis is made based on typical histologic criteria. No specific laboratory finding can confirm NSG diagnosis. The gender ratio of women to men has been reported as being as high as 4:1 and has a good prognosis.
    01/2015; 4. DOI:10.1016/j.ijmyco.2014.11.044
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    ABSTRACT: Tuberculosis (TB) is one of the most common infections world-wide, and in 2012, an estimated 8.6 million people developed TB and 1.3 million died from the disease (including 320,000 deaths among HIV-positive people). Mycobacterium tuberculosis (MTB) is an intracellular pathogen capable of infecting and surviving within the hosts mononuclear cells, particularly macrophages. This involves sequestration of MTB within organized granulomas. Nontuberculous mycobacteria refers to all the species in the family of mycobacteria that may cause human disease, but does not cause TB. Every year in the world approximately 2 people per 100,000 population develop infections caused by these lesser-known “cousins” of TB and leprosy. In this study, the focus is on a rare case of a patient with chronic granulomatous disease presenting with both MTB and nontuberculous Mycobacteria. As far as this research is concerned, this is the first report of a carrier patient with chronic granulomatous disease combined with MTB and nontuberculous mycobacteria. The presented information may help to improve the diagnosis and open a new light in the investigation of susceptibility of patients to mycobacterium infections.
    01/2015; 4. DOI:10.1016/j.ijmyco.2014.11.045
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    ABSTRACT: Tuberculosis (TB) has previously been linked to acute respiratory distress syndrome (ARDS). Here this study investigates the link between inflammation and TB in ARDS by measuring inflammatory cytokine and chemokine levels in bronchoalveolar lavage (BAL) from 90 patients with TB or ARDS alone and in patients with TB-induced ARDS (ARDS + TB). BAL was collected by fiber-optic bronchoscopy, and the concentrations of interleukin (IL)-6, CXCL8, TNF α and IL-1β were measured by ELISA. CXCL8 levels in BAL were significantly higher in the ARDS + TB group compared with TB and ARDS alone groups. Disease severity in the ARDS + TB group as determined by Murray score correlated with BAL CXCL8 and neutrophils, but not with IL-6, IL-1β and TNF α concentrations. In addition, CXCL8 levels and neutrophils were increased in non-miliary TB versus miliary TB. This difference in CXCL8 was lost in the presence of ARDS. It was concluded from this study that CXCL8 may play an important role in the pathogenesis of this form of ARDS. This further suggests that CXCL8 inhibitors or blockers may be useful to control the onset and/or development of these combined diseases.
    01/2015; 4. DOI:10.1016/j.ijmyco.2014.11.039
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    ABSTRACT: Long noncoding RNAs (lncRNAs) play an important role in the pathogenesis of many human diseases. In this study, we provide the description of genome-wide lncRNA expression in the lung tissue of non-smokers without Chronic obstructive pulmonary disease (COPD), of smokers without COPD and of smokers with COPD. RNA was extracted from human lung tissue and analysed using an Agilent Human lncRNA + mRNA Array v2.0 system. 39,253 distinct lncRNA transcripts were detected in the lung tissues of all subjects. In smokers without COPD 87 lncRNAs were significantly up-regulated and 244 down-regulated compared to non-smokers without COPD with RNA50010|UCSC-9199-1005 and RNA58351| CombinedLit_316_550, the most over- and under-regulated, respectively. In contrast, in COPD patients 120 lncRNAs were over-expressed and 43 under-expressed compared with smokers without COPD with RNA44121|UCSC-2000-3182 and RNA43510|UCSC-1260-3754 being the most over- and under-regulated, respectively. Gene Ontology (GO) and pathway analysis indicated that cigarette smoking was associated with activation of metabolic pathways, whereas COPD transcripts were associated with 'hematopoietic cell lineage', intermediary metabolism and immune system processes. We conclude that the altered expression of lncRNAs might play partial role in pathways implicated in COPD onset and progression such as intermediary metabolism and the immune response.
    Inflammation Research 12/2014; 64(2). DOI:10.1007/s00011-014-0790-9 · 2.14 Impact Factor
  • Kian Fan Chung, Ian M Adcock
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    ABSTRACT: Asthma is a common disease which presents in various clinical forms and levels of severity. The current 'one size fits all' approach to treatment is suboptimal. Using unbiased cluster analysis has identified several asthma phenotypes. Understanding the underlying mechanisms driving these clusters may lead to better patient-orientated medicines. Clustering was initially performed on clinical features only, but the addition of biomarkers that characterize sputum and blood cellular profiles has enabled the prediction of responses to targeted therapies. Clusters of severe asthma include those on high-dose corticosteroid treatment associated with severe airflow obstruction and those with discordance between symptoms and sputum eosinophilia. Sputum eosinophilia can predict therapeutic responses to T-helper type 2 cytokine blockade. Further molecular phenotyping or endotyping of asthma will be necessary to determine new treatment strategies. Low T-helper type 2 expression may be predictive of poor therapeutic response to inhaled corticosteroids, but much less is known about this type of asthma. Phenotype-driven treatment of asthma will be further boosted by the integration of genetic, transcriptomic and proteomic technologies to defining distinct severe asthma phenotypes and biomarkers of therapeutic responses. This will lead towards stratified medicine for asthma.
    Current Opinion in Allergy and Clinical Immunology 12/2014; 15(1). DOI:10.1097/ACI.0000000000000134 · 3.66 Impact Factor

Publication Stats

18k Citations
2,108.88 Total Impact Points

Institutions

  • 1996–2015
    • Imperial College London
      • • Section of Airway Disease
      • • Faculty of Medicine
      • • Division of Cell and Molecular Biology
      Londinium, England, United Kingdom
  • 1993–2014
    • National Heart, Lung, and Blood Institute
      Maryland, United States
    • The Heart Lung Center
      Londinium, England, United Kingdom
  • 2003–2013
    • Universita degli studi di Ferrara
      • Research Center for the Research of Asthma and BPCO
      Ferrara, Emilia-Romagna, Italy
  • 2012
    • Utrecht University
      • Division of Pharmacology
      Utrecht, Utrecht, Netherlands
  • 2011
    • Università degli Studi di Salerno
      • Department of BioMedical and Pharmaceutical Sciences FARMABIOMED
      Fisciano, Campania, Italy
  • 1998–2010
    • Royal Brompton and Harefield NHS Foundation Trust
      Harefield, England, United Kingdom
  • 2008
    • University of Wisconsin–Madison
      • Department of Medicine
      Madison, Wisconsin, United States
  • 2006
    • University Center Rochester
      Рочестер, Minnesota, United States
  • 2005
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2004
    • University of Cologne
      • Division of Cardiology, Pneumology, Angiology and Intensive Care
      Köln, North Rhine-Westphalia, Germany
  • 2001
    • Imperial Valley College
      IPL, California, United States