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Vogelmeier CF, Criner GJ, Martinez FJ, et al., 2017, Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary (vol 53, pg 128, 2017), ARCHIVOS DE BRONCONEUMOLOGIA, Vol: 53, Pages: 411-412, ISSN: 0300-2896
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- Citations: 8
Barnes PJ, 2017, Cellular and molecular mechanisms of asthma and COPD, CLINICAL SCIENCE, Vol: 131, Pages: 1541-1558, ISSN: 0143-5221
Asthma and chronic obstructive pulmonary disease (COPD) both cause airway obstruction and are associated with chronic inflammation of the airways. However, the nature and sites of the inflammation differ between these diseases, resulting in different pathology, clinical manifestations and response to therapy. In this review, the inflammatory and cellular mechanisms of asthma and COPD are compared and the differences in inflammatory cells and profile of inflammatory mediators are highlighted. These differences account for the differences in clinical manifestations of asthma and COPD and their response to therapy. Although asthma and COPD are usually distinct, there are some patients who show an overlap of features, which may be explained by the coincidence of two common diseases or distinct phenotypes of each disease. It is important to better understand the underlying cellular and molecular mechanisms of asthma and COPD in order to develop new treatments in areas of unmet need, such as severe asthma, curative therapy for asthma and effective anti-inflammatory treatments for COPD.
Vogelmeier CF, Criner GJ, Martinez FJ, et al., 2017, Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary (vol 49, 1700214, 2017), EUROPEAN RESPIRATORY JOURNAL, Vol: 49, ISSN: 0903-1936
Di Stefano A, Ricciardolo FLM, Caramori G, et al., 2017, Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression, European Respiratory Journal, Vol: 49, ISSN: 1399-3003
Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12). The bronchial bacterial load of Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was measured by quantitative real-time PCR.TLR4 and NOD1 expression was increased in the bronchial mucosa of patients with severe/very severe stable COPD compared with control subjects. TLR4 bronchial epithelial expression correlated positively with CD4+ and CD8+ cells and airflow obstruction. NOD1 expression correlated with CD8+ cells. The bronchial load of P. aeruginosa was directly correlated, but H. influenzae inversely correlated, with the degree of airflow obstruction. Bacterial load did not correlate with inflammatory cells.Bronchial epithelial overexpression of TLR4 and NOD1 in severe/very severe stable COPD, associated with increased bronchial inflammation and P. aeruginosa bacterial load, may play a role in the pathogenesis of COPD.
Wang Y, Jia M, Yan X, et al., 2017, Increased neutrophil gelatinase-associated lipocalin (NGAL) promotes airway remodelling in chronic obstructive pulmonary disease, CLINICAL SCIENCE, Vol: 131, Pages: 1147-1159, ISSN: 0143-5221
Airway remodelling is an important component of chronic obstructive pulmonary disease (COPD). Neutrophil gelatinase-associated lipocalin (NGAL) from neutrophils may drive COPD epithelial–mesenchymal transition (EMT). NGAL expression was quantified in the lungs of COPD patients and bronchoalveolar lavage fluid (BALF) of ozone-treated mice. Reticular basement membrane (RBM) thickness and E-cadherin and α-smooth muscle actin (α-SMA) expression were determined in mice airways. Effects of cigarette smoke extract (CSE) and inflammatory factors on NGAL expression in human neutrophils as well as the effects of NGAL on airway structural cells was assessed. NGAL was mainly distributed in neutrophils and enhanced in lung tissues of both COPD patients and BALF of ozone-treated mice. We showed decreased E-cadherin and increased α-SMA expression in bronchial epithelium and increased RBM thickness in ozone-treated animals. In vitro, CSE, IL-1β and IL-17 enhanced NGAL mRNA expression in human neutrophils. NGAL, in turn, down-regulated the expression of E-cadherin and up-regulated α-SMA expression in 16HBE cells via the WNT/glycogensynthase kinase-3β (GSK-3β) pathway. Furthermore, NGAL promoted the proliferation and migration of human bronchial smooth muscle cells (HASMCs). The present study suggests that elevated NGAL promotes COPD airway remodelling possibly through altered EMT. NGAL may be a potential target for reversing airway obstruction and remodelling in COPD.
To M, Swallow EB, Akashi K, et al., 2017, Reduced HDAC2 in skeletal muscle of COPD patients, Respiratory Research, Vol: 18, ISSN: 1465-993X
BACKGROUND: Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) is an important predictor of poor prognosis, but the molecular mechanisms of muscle weakness in COPD have not been fully elucidated. The aim of this study was to investigate the role of histone deacetylases(HDAC) in skeletal muscle weakness in COPD. METHODS AND RESULTS: Twelve COPD patients, 8 smokers without COPD (SM) and 4 healthy non-smokers (NS) were recruited to the study. HDAC2 protein expression in quadriceps muscle biopsies of COPD patients (HDAC2/β-actin: 0.59 ± 0.34) was significantly lower than that in SM (1.9 ± 1.1, p = 0.0007) and NS (1.2 ± 0.7, p = 0.029). HDAC2 protein in skeletal muscle was significantly correlated with forced expiratory volume in 1 s % predicted (FEV1 % pred) (rs = 0.53, p = 0.008) and quadriceps maximum voluntary contraction force (MVC) (rs = 0.42, p = 0.029). HDAC5 protein in muscle biopsies of COPD patients (HDAC5/β-actin: 0.44 ± 0.26) was also significantly lower than that in SM (1.29 ± 0.39, p = 0.0001) and NS (0.98 ± 0.43, p = 0.020). HDAC5 protein in muscle was significantly correlated with FEV1 % pred (rs = 0.64, p = 0.0007) but not with MVC (rs = 0.30, p = 0.180). Nuclear factor-kappa B (NF-κB) DNA binding activity in muscle biopsies of COPD patients (10.1 ± 7.4) was significantly higher than that in SM (3.9 ± 7.3, p = 0.020) and NS (1.0 ± 1.2, p = 0.004and significantly correlated with HDAC2 decrease (rs = -0.59, p = 0.003) and HDAC5 (rs = 0.050, p = 0.012). HDAC2 knockdown by RNA interfe
Yanagisawa S, Baker JR, Vuppusetty C, et al., 2017, Decreased phosphatase PTEN amplifies PI3K signaling and enhances pro-inflammatory cytokine release in COPD, American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol: 313, Pages: L230-L239, ISSN: 1522-1504
The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. Our aim was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN expression and activity were measured in the peripheral lung of COPD patients compared to smoking and non-smoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of L-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knock-down by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared to the subjects without COPD (p < 0.001), and positively correlated with the severity of air-flow obstruction (FEV1 % predicted; r = 0.50; p = 0.0012), although no difference was observed in PTEN activity. Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r = -0.41; p = 0.0042). Both in primary bronchial epithelial cells and BEAS-2B cell line, CSE decreased PTEN protein, which was reversed by N-acetylcysteine treatment. PTEN knock-down potentiated Akt phosphorylation and enhanced production of pro-inflammatory cytokines, such as IL-6, CXCL8, CCL2 and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.
Yeo SCM, Fenwick PS, Barnes PJ, et al., 2017, Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid-independent mechanism, British Journal of Pharmacology, Vol: 174, Pages: 2043-2059, ISSN: 1476-5381
Background and PurposeChronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol has exhibited anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aims to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and its pharmacokinetics in vivo.Experimental ApproachPrimary human airway epithelial cells derived from healthy and COPD subjects and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Their effects on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8) were determined and the activation of NF-κB, AP-1, MAPKs and PI3K/Akt/FoxO3A pathways compared to dexamethasone were evaluated. The pharmacokinetic profiles of isorhapontigenin were assessed in Sprague-Dawley rats after respective intravenous and oral administration.Key ResultsIsorhapontigenin exhibited concentration-dependent inhibition of IL-6 and CXCL8 release, with IC50 values at least two-fold lower than resveratrol. These were associated with suppressed NF-κB and AP-1 activation and notably, the PI3K/Akt/FoxO3A pathway that was relatively insensitive to dexamethasone. In vivo, isorhapontigenin was rapidly absorbed with abundant plasma exposure after oral dosing. Its oral bioavailability was approximately 50% higher than resveratrol.Conclusions and ImplicationsIsorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared to resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD.
Yanagisawa S, Papaioannou A, Papaporfyriou A, et al., 2017, Decreased serum sirtuin-1 in chronic obstructive pulmonary disease, Chest, Vol: 152, Pages: 343-352, ISSN: 1931-3543
Background: The protein deacetylase sirtuin-1 (SIRT1) is an anti-aging molecule that is decreased in the lung from patients with chronic obstructive pulmonary disease (COPD). Recently, SIRT1 was reported to be detectable in serum, but serum SIRT1 levels have not yet been reported in patients with COPD.Methods: Serum SIRT1 was measured by Western blotting, and relative ratio of band density in samples against that of a positive control were calculated.Results: Several molecular sizes of SIRT1, including 120kDa (actual size) and fragments (102, 75kDa) were quantified by Western blotting. Among them, only the 120kDa serum SIRT1 (s120S) was significantly decreased in the patients with COPD compared to the control subjects without COPD (s120S ratio in healthy: 0.90±0.34, vs COPD: 0.68±0.24; p=0.014), and was positively correlated with airway obstruction (FEV1/ FVC; r=0.31; p=0.020) and its severity measured by FEV1 % predicted (r=0.29; p=0.029). Serum s120S also showed a positive correlation with body mass index (BMI; r=0.36; p=0.0077) and diffusing capacity of the lung per unit volume (KCO%; r=0.32; p=0.025). It was also significantly decreased with increasing severity of lung emphysema (r=-0.40, p=0.027) and with a clinical history of frequent COPD exacerbations (infrequent: 0.76±0.20 vs frequent: 0.56±0.26; p=0.027). SIRT1 was not detected in supernatant of A549 and primary epithelial cells in normal culture condition.Conclusions: Serum SIRT1 (s120S) was decreased in the patients with COPD, potentially as reflected by the reduced SIRT1 within cells as a result of oxidative stress, and might be a potential biomarkers for certain disease characteristics of COPD.
Horvath I, Barnes PJ, Loukides S, et al., 2017, A European Respiratory Society technical standard: exhaled biomarkers in lung disease, EUROPEAN RESPIRATORY JOURNAL, Vol: 49, ISSN: 0903-1936
Basoglu OK, Pelleg A, Kharitonov SA, et al., 2017, Contrasting effects of ATP and adenosine on capsaicin challenge in asthmatic patients, Pulmonary Pharmacology and Therapeutics, Vol: 45, Pages: 13-18, ISSN: 1094-5539
BackgroundAdenosine 5’-triphosphate (ATP) stimulates pulmonary vagal slow conducting C-fibres and fast conducting Aδ-fibres with rapidly adapting receptors (RARs). Pulmonary C-fibres but not RARs are also sensitive to capsaicin, a potent tussigenic agent in humans. Thus, the aim of this study was to determine the effects of ATP and its metabolite adenosine (given as adenosine 5’-monophosphate, AMP) on capsaicin challenge in asthmatic patients.MethodsCough (quantified as visual analogue scale, VAS), dyspnoea (quantified as Borg score), and FEV1 were quantified following bronchoprovocation using capsaicin, adenosine and ATP in healthy non-smokers (age 40±4y, 6 males), smokers (45±4y, 5 males) and asthmatic patients (37±3y, 5 males); n = 10 in each group.ResultsNone of the healthy non-smokers responded to either AMP or ATP. AMP induced bronchoconstriction in one smoker and eight asthmatics, and ATP in two smokers and all ten asthmatics. The geometric mean of capsaicin causing ≥5 coughs (C5) increased from 134 to 203 μM in non-smokers and from 117 to 287 μM in asthmatics after AMP, whereas it decreased from 203 to 165 μM and 125 to 88 μM, respectively after ATP. AMP decreased C5 from 58 to 29 μM and ATP increased from 33 to 47 μM in smokers. However, due to intergroup variability, these effects of ATP and AMP were not statistically significant (0.125 ≤ p ≤ 0.998). That notwithstanding, in healthy and asthmatic subjects the effects of the ATP showed a tendency to be greater than those of AMP (p < 0.053). Dyspnea, assessed by Borg score, increased after ATP (p < 0.001) and AMP (p < 0.001) only in asthmatic patients. Intensity of cough assessed by VAS increased (p < 0.05) after second capsaicin challenges performed after AMP in all groups, but not after ATP.ConclusionsAsthmatic patients exhibit hypersensitivity to aerosolized AMP and ATP, but aerosolized AMP does not mimic the effects of ATP and
Kobayashi Y, Ito K, Kanda A, et al., 2017, Impaired Dual-Specificity Protein Phosphatase DUSP4 Reduces Corticosteroid Sensitivity, MOLECULAR PHARMACOLOGY, Vol: 91, Pages: 475-+, ISSN: 0026-895X
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.
Vogelmeier CF, Criner GJ, Martinez FJ, et al., 2017, Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease 2017 Report GOLD Executive Summary, RESPIROLOGY, Vol: 22, Pages: 575-601, ISSN: 1323-7799
Vogelmeier CF, Criner GJ, Martinez FJ, et al., 2017, Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary, ARCHIVOS DE BRONCONEUMOLOGIA, Vol: 53, Pages: 128-149, ISSN: 0300-2896
Vogelmeier CF, Criner GJ, Martinez FJ, et al., 2017, Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 557-582, ISSN: 1073-449X
This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 report focuses primarily on the revised and novel parts of the document. The most significant changes include: (1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; (2) for each of the groups A to D, escalation strategies for pharmacologic treatments are proposed; (3) the concept of deescalation of therapy is introduced in the treatment assessment scheme; (4) nonpharmacologic therapies are comprehensively presented; and (5) the importance of comorbid conditions in managing chronic obstructive pulmonary disease is reviewed.
Vogelmeier CF, Criner GJ, Martinez FJ, et al., 2017, Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary, EUROPEAN RESPIRATORY JOURNAL, Vol: 49, ISSN: 0903-1936
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Barnes PJ, 2017, GOLD 2017: A New Report., Chest, Vol: 151, Pages: 245-246
Gross NJ, Barnes PJ, 2017, New Therapies for Asthma and Chronic Obstructive Pulmonary Disease, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 195, Pages: 159-166, ISSN: 1073-449X
Barnes PJ, Hughes M, 2017, Professor Neil Pride OBITUARY, THORAX, Vol: 72, Pages: 292-293, ISSN: 0040-6376
O'Byrne PM, FitzGerald JM, Zhong N, et al., 2017, The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given 'as needed' in mild asthma: study protocols for two randomised controlled trials, Trials, Vol: 18, ISSN: 1745-6215
Background: In many patients with mild asthma, the low frequency of symptoms and the episodic nature ofexacerbations make adherence to regular maintenance treatment difficult. This often leads to over-reliance onshort-acting β2-agonist (SABA) reliever medication and under-treatment of the underlying inflammation, with poorcontrol of asthma symptoms and increased risk of exacerbations. The use of budesonide/formoterol ‘as needed’ inresponse to symptoms may represent an alternative treatment option for patients with mild asthma.Methods/design: The SYmbicort Given as needed in Mild Asthma (SYGMA) programme consists of two 52-week,double-blind, randomised, multicentre, parallel-group, phase 3 trials of patients aged 12 years and older with aclinical diagnosis of asthma for at least 6 months, who would qualify for treatment with regular inhaledcorticosteroids (ICS). SYGMA1 aims to recruit 3750 patients who will be randomised to placebo twice daily (bid)plus as-needed budesonide/formoterol 160/4.5 μg, placebo bid plus as-needed terbutaline 0.4 mg, or budesonide200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the superiority of as-neededbudesonide/formoterol over as-needed terbutaline for asthma control, as measured by well-controlled asthmaweeks; a secondary objective is to establish the noninferiority of as-needed budesonide/formoterol versusmaintenance budesonide plus as-needed terbutaline using the same outcome measure. SYGMA2 aims to recruit4114 patients who will be randomised to placebo bid plus as-needed budesonide/formoterol 160/4.5 μg, orbudesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate thenoninferiority of as-needed budesonide/formoterol over budesonide bid plus as-needed terbutaline as measured bythe annualised severe exacerbation rate. In both studies, use of all blinded study inhalers will be recordedelectronically using Turbuhaler® Usage Monito
Barnes PJ, 2017, Professor Neil B. Pride (1931-2016) IN MEMORIAM, EUROPEAN RESPIRATORY JOURNAL, Vol: 49, ISSN: 0903-1936
Kaliner MA, Barnes PJ, Kunkel GHH, et al., 2017, Preface, Neuropeptides in Respiratory Medicine, Pages: v-vi, ISBN: 9780824791995
"“This outstanding resource offers comprehensive presentations of the latest basic knowledge and the most advanced research on neuropeptides of the respiratory tract covering the structure, receptors, molecular biology, and function of each important neuropeptide and examining how they relate to disease. Demonstrates the utility of immunohistochemistry, autoradiography, molecular biology, smooth muscle contraction, and glandular secretion for the study of neural function both in vitro and in vivo!.
Walton GM, Belchamber KBR, Hughes SM, et al., 2017, Non-Typeable Haemophilus Influenzae Is Associated With Rapid Lung Function Decline And Poor Macrophage And Neutrophil Phagocytosis In Patients With Alpha-1 Anti-Trypsin Deficiency, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Barnes PJ, 2017, Rebuttal From Dr Barnes, CHEST, Vol: 151, Pages: 21-22, ISSN: 0012-3692
Barnes PJ, 2017, Will New Anti-eosinophilic Drugs Be Useful in Asthma Management? No, CHEST, Vol: 151, Pages: 17-20, ISSN: 0012-3692
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Tilman J, Barnes PJ, Donnelly L, 2017, COPD Monocyte-Derived And Tissue Macrophages Are Driven By Gm-Csf Towards A Pro-Inflammatory Phenotype, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Page CP, Barnes PJ, 2017, Pharmacology and Therapeutics of Asthma and COPD Preface, PHARMACOLOGY AND THERAPEUTICS OF ASTHMA AND COPD, Editors: Page, Barnes, Publisher: SPRINGER-VERLAG BERLIN, Pages: VII-VII, ISBN: 978-3-319-52173-2
Belchamber KBR, Barnes PJ, Donnelly L, 2017, Altered Scavenger Receptor Expression In COPD Macrophages After Bacterial Phagocytosis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Baker J, Vuppusetty C, Ito K, et al., 2017, Antagomir Of Microrna-34a Rescues Cellular Senescence In Bronchial Epithelial Cells Of COPD Patients, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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