Publications
2499 results found
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
Ali FY, Leaker BR, Nicholson GC, et al., 2017, A Five-Way Crossover Study To Compare Systemic Absorption And Bronchodilator Effect Of Glycopyrrolate After A Single Dose Delivered By Nebulizer (sun-101) Or A Dry Powder Inhaler (seebri) And In Patients With COPD (golden-7), International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
- Author Web Link
- Cite
- Citations: 1
Barnes PJ, 2016, Senescence in COPD and Its Comorbidities, ANNUAL REVIEW OF PHYSIOLOGY, VOL 79, Vol: 79, Pages: 517-539, ISSN: 0066-4278
Carpagnano GE, Foschino-Barbaro MP, Crocetta C, et al., 2016, Validation of the Exhaled Breath Temperature Measure Reference Values in Healthy Subjects, CHEST, Vol: 151, Pages: 855-860, ISSN: 0012-3692
Hakim A, Khan Y, Esteban I, et al., 2016, Effects of a single inhaled budesonide/formoterol dose on glucocorticoid receptor activity in sputum of COPD patients, ERS International Congress 2016, Publisher: European Respiratory Society, Pages: OA3313-OA3313, ISSN: 0903-1936
Barnes PJ, 2016, Glucocorticosteroids., Handb Exp Pharmacol, Vol: 237, Pages: 93-115, ISSN: 0171-2004
Glucocorticosteroids are the most effective anti-inflammatory therapy for asthma but are relatively ineffective in COPD. Glucocorticoids are broad-spectrum anti-inflammatory drugs that suppress inflammation via several molecular mechanisms. Glucocorticoids suppress the multiple inflammatory genes that are activated in asthma by reversing histone acetylation of activated inflammatory genes through binding of ligand-bound glucocorticoid receptors (GR) to coactivator molecules and recruitment of histone deacetylase-2 (HDAC2) to the activated inflammatory gene transcription complex (trans-repression). At higher concentrations of glucocorticoids GR homodimers interact with DNA recognition sites to activate transcription through increased histone acetylation of anti-inflammatory genes and transcription of several genes linked to glucocorticoid side effects (trans-activation). Glucocorticoids also have post-transcriptional effects and decrease stability of some proinflammatory mRNAs. Decreased glucocorticoid responsiveness is found in patients with severe asthma and asthmatics who smoke, as well as in all patients with COPD. Several molecular mechanisms of glucocorticoid resistance have now been identified which involve phosphorylation and other post-translational modifications of GR. HDAC2 is markedly reduced in activity and expression as a result of oxidative/nitrative stress and pi3 kinase-δ inhibition, so that inflammation is resistant to the anti-inflammatory actions of glucocorticoids. Dissociated glucocorticoids and selective GR modulators which show improved trans-repression over trans-activation effects have been developed to reduce side effects, but so far it has been difficult to dissociate anti-inflammatory effects from adverse effects. In patients with glucocorticoid resistance alternative anti-inflammatory treatments are being investigated as well as drugs that may reverse the molecular mechanisms of glucocorticoid resistance.
Baker JR, Vuppusetty C, Colley T, et al., 2016, Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells, Scientific Reports, Vol: 6, ISSN: 2045-2322
Sirtuin-1 (SIRT1) and SIRT6, NAD(+)-dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress. Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD. Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins. Induction of miR-34a expression with H2O2 was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kα activation as well as phosphatase and tensin homolog (PTEN) reduction. Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible. Other sirtuin isoforms were not affected by miR-34a. Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases.
Bewley M, Belchamber K, Chana K, et al., 2016, Differential effects of p38, MAPK, PI3K or Rho kinase inhibitors on bacterial phagocytosis and efferocytosis by macrophages in COPD, PLOS One, Vol: 11, ISSN: 1932-6203
Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD.
Batista C, McIntosh M, Hansel T, et al., 2016, Elevated concentrations of CXCL8 in the nasal mucosal lining fluid of COPD patients as an accessible surrogate measure of bronchial levels, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Biddiscombe M, Meah S, Barnes P, et al., 2016, Drug particle size and lung deposition in COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
- Author Web Link
- Cite
- Citations: 3
Ueda K, Nishimoto Y, Kimura G, et al., 2016, Repeated lipopolysaccharide exposure causes corticosteroid insensitive airway inflammation via activation of phosphoinositide-3-kinase δ pathway, Biochemistry and Biophysics Reports, Vol: 7, Pages: 367-373, ISSN: 2405-5808
Corticosteroid resistance is one of major barriers to effective management of chronic inflammatory respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma. These patients often experience exacerbations with viral and/or bacterial infection, which may cause continuous corticosteroid insensitive inflammation. In this study, we observed that repeated exposure of lipopolysaccharide (LPS) intranasally attenuated the anti-inflammatory effects of the corticosteroid fluticasone propionate (FP) on neutrophils and CXCL1 levels in bronchoalveolar lavage (BAL) fluid in an in vivo murine model. Histone deacetylase-2 (HDAC2) and NF-E2 related factor 2 (Nrf2) levels in lungs after LPS administration for 3 consecutive days were significantly decreased to 38.9±6.3% (mean±SEM) and 77.5±2.7% of the levels seen after only one day of LPS exposure, respectively. In addition, 3 days LPS exposure resulted in an increase of Akt phosphorylation, indicating activation of the phosphoinositide-3-kinase (PI3K) pathway by 4-fold in lungs compared with 1 day of exposure. Furthermore, combination treatment with theophylline and FP significantly decreased the neutrophil accumulation and CXCL1 concentrations in BAL fluid from 22.5±1.8×10 4 cells/mL and 214.6±20.6 pg/mL to 7.9±0.5×10 4 cells/mL and 61.9±13.3 pg/mL, respectively. Combination treatment with IC87114, a selective PI3Kδ inhibitor, and FP also significantly decreased neutrophils and CXCL1 levels from 16.8±0.7×10 4 cells/mL and 182.4±4.6 pg/mL to 5.9±0.3×10 4 cells/mL and 71.4±2.7 pg/mL, respectively. Taken together, repeated exposure of LPS causes corticosteroid-insensitive airway inflammation in vivo, and the corticosteroid-resistance induced by LPS is at least partly mediated through the activation of PI3Kδ, resulting in decreased levels of HDAC2 and Nrf2. These findi
Pelleg A, Schulman ES, Barnes PJ, 2016, Extracellular ATP in Obstructive Airway Diseases., Chest, Vol: 150, Pages: 908-915, ISSN: 0012-3692
In recent years numerous studies have generated data supporting the hypothesis that extracellular adenosine 5'-triphosphate (ATP) plays a major role in obstructive airway diseases. Studies in animal models and human subjects have shown that increased amounts of extracellular ATP are found in the lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma, and that ATP has effects on multiple cell types in the lungs resulting in increased inflammation, induction of bronchoconstriction and cough. These effects of ATP are mediated by cell surface P2 purinergic receptors (P2R) and involve other endogenous inflammatory agents. Recent clinical trials showed promise of treatment with P2X3R antagonists for alleviation of chronic cough. The purpose of this review is to describe these studies and outline some of the remaining questions as well as the potential clinical implications associated with the pharmacologic manipulation of ATP signaling in the lungs.
Maneechotesuwan K, Kasetsinsombat K, Wongkajornsilp A, et al., 2016, Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism., Respiratory Research, Vol: 17, ISSN: 1465-993X
BACKGROUND: Adenosine deaminase (ADA) and osteopontin (OPN) may play opposing roles in the pathogenesis of COPD. Deficiency of ADA results in enhanced adenosine signaling which up-regulates OPN expression. Although statins suppress OPN in cancer cells, little is known about their effects on ADA and OPN in COPD patients. METHODS: We extended a previous randomized double-blind placebo crossover study to investigate the effects of simvastatin (20 mg/day) on sputum ADA and OPN expression and explored the underlying signaling pathways involved by conducting in vitro experiments with cigarette smoke extract (CSE)-treated monocyte-derived macrophages (MDM) from COPD patients and healthy subjects. RESULTS: Simvastatin decreased sputum IL-13, OPN and CD73, while increasing ADA expression, irrespective of inhaled corticosteroid treatment and smoking status in parallel to increased inosine levels. The degree of simvastatin-restored ADA activity was significantly correlated with the magnitude of changes in pre-bronchodilator FEV1. Mechanistic exploration showed that CSE enhanced the expression of IL-13, which induced an increase in OPN and inhibited ADA mRNA accumulation in MDM from COPD patients but not healthy subjects through a STAT6-dependent mechanism. Simvastatin treatment inhibited IL-13 transcription in a dose-dependent manner, and therefore diminished the IL-13-induced increase in OPN and restored IL-13-suppressed ADA. There was no effect of simvastatin on adenosine receptors in CSE-stimulated MDM, indicating that its effects were on the adenosine pathway. CONCLUSION: Simvastatin reversed IL-13-suppressed ADA activity that leads to the down-regulation of adenosine signaling and therefore inhibits OPN expression through the direct inhibition of IL-13-activated STAT6 pathway. Inhibition of IL-13 may reverse the imbalance between ADA and OPN in COPD and therefore may prevent COPD progression.
Usmani OS, 2016, Dilemmas, confusion, and misconceptions related to small airways directed therapy, Chest, Vol: 151, Pages: 1345-1355, ISSN: 1931-3543
Over the last decade, there is increasing evidence that the small airways, i. e. airways <2 mm in internal diameter, contribute significantly to the pathophysiology and clinical expression of asthma and chronic obstructive pulmonary disease (COPD). The increased interest in small airways is, at least in part, a result of innovation in small-particle aerosol formulations that better target the distal lung and also advanced physiological methods of assessing small airway responses. Increasing the precision of drug deposition may improve targeting of specific diseases or receptor locations, decrease airway drug exposure and side effects, and thereby increase the efficiency and effectiveness of inhaled drug delivery. The availability of small-particle aerosols of corticosteroid, bronchodilator or their combination, enables a higher total lung deposition, better peripheral lung penetration, and provides added clinical benefit, compared to large-particle aerosol treatment. However, a number of questions remain unanswered on the pragmatic approach relevant in order for clinicians to consider the role of small airways directed therapy in the day-to-day management of their patients with asthma and COPD. We have thus tried to clarify the dilemmas, confusion, and misconceptions related to small airways directed therapy. To this end, we have systematically reviewed all studies on small-particle aerosol therapy in order to address the dilemmas, confusion, and misconceptions related to small airways directed therapy.
Poletti D, Iannini V, Casolari P, et al., 2016, Nasal inflammation and its response to local glucocorticoid regular treatment in patients with persistent non-allergic rhinitis: a pilot study, Journal of Inflammation, Vol: 13, ISSN: 1476-9255
Background The pathogenesis of non-allergic rhinitis (NAR) is still largely unknown. Furthermore, it is unclear whether there is a correlation between the effect of nasal glucocorticoids on nasal inflammation and on nasal symptoms and quality of life. Methods In this pilot study we recruited 12 healthy subjects and 24 patients with recently diagnosed persistent NAR [12 untreated and 12 under regular treatment with nasal fluticasone furoate (two sprays of 27.5 µg each in each nostril once daily, total daily dose=110 µg) for at least 20 days]. Each subject filled a mini rhinoconjunctivitis quality of life questionnaire (mini RQLQ). Nasal scrapings were obtained from each subject and used to prepare slides for Diff-Quik and immunocytochemical staining for inflammatory and epithelial cells count, MUC5AC expression and the general pro-inflammatory transcription factor nuclear factor B (NF-B) activation. Results The nasal score of the mini RQLQ, the number of nasal inflammatory cells (neutrophils, eosinophils) and the number of goblet cells are significantly higher in untreated patients with persistent NAR compared with control subjects and treated NAR patients. The percentage of MUC5AC+ nasal epithelial cells is significantly increased in untreated patients with persistent NAR compared with the control subjects (41.8±6.4 vs 22.3±4.8, respectively; p=0.0403) without significant differences between control subjects and patients with persistent NAR on regular fluticasone furoate treatment with nasal glucocorticoids (33.9±5.0%; p=0.0604) nor between the 2 groups of persistent NAR subjects (p=0.3260). The number of cytosolic and/or nuclear p65+ nasal epithelial and inflammatory cells was not significantly different between the three groups. Conclusions Patients with persistent untreated NAR, compared with normal control subjects and patients with persistent NAR under regular treatment with nasal fluticasone furoate glucocorticoids by at lea
Antuni JD, Barnes PJ, 2016, Evaluation of Individuals at Risk for COPD: Beyond the Scope of the Global Initiative for Chronic Obstructive Lung Disease, CHRONIC OBSTRUCTIVE PULMONARY DISEASES-JOURNAL OF THE COPD FOUNDATION, Vol: 3, Pages: 653-667, ISSN: 2372-952X
Cosio BG, Shafiek H, Iglesias A, et al., 2016, Oral Low-dose Theophylline on Top of Inhaled Fluticasone-Salmeterol Does Not Reduce Exacerbations in Patients With Severe COPD A Pilot Clinical Trial, CHEST, Vol: 150, Pages: 123-130, ISSN: 0012-3692
- Author Web Link
- Cite
- Citations: 37
Barnes PJ, 2016, Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease, Pharmacological Reviews, Vol: 68, Pages: 788-815, ISSN: 1521-0081
Multiple kinases play a critical role in orchestrating the chronic inflammation and structural changes in the respiratory tract of patients with asthma and chronic obstructive pulmonary disease (COPD). Kinases activate signaling pathways that lead to contraction of airway smooth muscle and release of inflammatory mediators (such as cytokines, chemokines, growth factors) as well as cell migration, activation, and proliferation. For this reason there has been great interest in the development of kinase inhibitors as anti-inflammatory therapies, particular where corticosteroids are less effective, as in severe asthma and COPD. However, it has proven difficult to develop selective kinase inhibitors that are both effective and safe after oral administration and this has led to a search for inhaled kinase inhibitors, which would reduce systemic exposure. Although many kinases have been implicated in inflammation and remodeling of airway disease, very few classes of drug have reached the stage of clinical studies in these diseases. The most promising drugs are p38 MAP kinases, isoenzyme-selective PI3-kinases, Janus-activated kinases, and Syk-kinases, and inhaled formulations of these drugs are now in development. There has also been interest in developing inhibitors that block more than one kinase, because these drugs may be more effective and with less risk of losing efficacy with time. No kinase inhibitors are yet on the market for the treatment of airway diseases, but as kinase inhibitors are improved from other therapeutic areas there is hope that these drugs may eventually prove useful in treating refractory asthma and COPD.
Singh D, Leaker B, Boyce M, et al., 2016, A novel inhaled phosphodiesterase 4 inhibitor (CHF6001) reduces the allergen challenge response in asthmatic patients, Pulmonary Pharmacology & Therapeutics, Vol: 40, Pages: 1-6, ISSN: 1522-9629
CHF6001 is an inhaled phosphodiesterase 4 (PDE4) inhibitor in development for the treatment of obstructive lung diseases. We investigated the efficacy and safety of CHF6001 using the allergen challenge model in a double blind, placebo controlled, 3-way cross-over study. Thirty six atopic asthmatics who were not taking inhaled corticosteroids and who demonstrated a late asthmatic response (LAR) to inhaled allergen at screening were randomised to receive CHF6001 400 μg or 1200 μg or placebo administered once a day using a dry powder inhaler. The three treatment periods were 9 days; allergen challenges were performed on day 9 and induced sputum was obtained after 10 h from challenge. Washout periods between treatments were up to 5 weeks. Both CHF6001 doses significantly attenuated the LAR; the primary endpoint analysis showed that CHF6001 400 μg and 1200 μg caused reductions of 19.7% (p = 0.015) and 28.2% (p < 0.001) respectively of the weighted FEV1 AUC4-10h compared with placebo. The difference between the CHF6001 doses was not statistically significant (p = 0.2). Compared with placebo, CHF 6001 caused greater reduction in sputum eosinophil counts, although these changes were not statistically significant. CHF6001 was well tolerated, with similar numbers of adverse events in each treatment period. This inhaled PDE4 inhibitor has the potential to provide clinical benefits in patients with atopic asthma.
BARNES PJ, 2016, ASTHMA MANAGEMENT - A NEW DIMENSION, JOURNAL OF INTERNATIONAL MEDICAL RESEARCH, Vol: 15, Pages: 397-400, ISSN: 0300-0605
- Author Web Link
- Cite
- Citations: 1
Verbanck S, Ghorbaniasl G, Biddiscombe MF, et al., 2016, Inhaled aerosol distribution in human airways: a scintigraphy-guided study in a 3D printed model, Journal of Aerosol Medicine and Pulmonary Drug Delivery, Vol: 29, Pages: 525-533, ISSN: 1941-2711
Background: While it is generally accepted that inertial impaction will lead to particle loss as aerosol is being carried into the pulmonary airways, most predictive aerosol deposition models adopt the hypothesis that the inhaled particles that remain airborne will distribute according to the gas flow distribution between airways downstream.Methods: Using a 3D printed cast of human airways, we quantified particle deposition and distribution and visualized their inhaled trajectory in the human lung. The human airway cast was exposed to 6 μm monodisperse, radiolabeled aerosol particles at distinct inhaled flow rates and imaged by scintigraphy in two perpendicular planes. In addition, we also imaged the distribution of aerosol beyond the airways into the five lung lobes. The experimental aerosol deposition patterns could be mimicked by computational fluid dynamic (CFD) simulation in the same 3D airway geometry.Results: It was shown that for particles with a diameter of 6 μm inhaled at flows up to 60 L/min, the aerosol distribution over both lungs and the individual five lung lobes roughly followed the corresponding distributions of gas flow. While aerosol deposition was greater in the main bronchi of the left versus right lung, distribution of deposited and suspended particles toward the right lung exceeded that of the left lung. The CFD simulations also predict that for both 3 and 6 μm particles, aerosol distribution between lung units subtending from airways in generation 5 did not match gas distribution between these units and that this effect was driven by inertial impaction.Conclusions: We showed combined imaging experiments and CFD simulations to systematically study aerosol deposition patterns in human airways down to generation 5, where particle deposition could be spatially linked to the airway geometry. As particles are negotiating an increasing number of airways in subsequent branching generations, CFD predicts marked dev
Barbaro MPF, Carpagnano GE, Spanevello A, et al., 2016, Inflammation, oxidative stress and systemic effects in mild chronic obstructive pulmonary disease, INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY, Vol: 20, Pages: 753-763, ISSN: 0394-6320
- Author Web Link
- Cite
- Citations: 59
Nicholson GC, Holloway RA, Leaker BR, et al., 2016, A novel flow cytometric-based method to measure kinase inhibition in sputum from COPD subjects, BMJ Open Respiratory Research, Vol: 3, ISSN: 2052-4439
INTRODUCTION: Janus kinases (JAKs) regulate inflammatory gene expression through phosphorylation of signal transducer and activator of transcription (STAT) proteins. Expression of STAT proteins is increased in chronic obstructive pulmonary disease (COPD), and may be involved in driving chronic inflammation. Oral JAK inhibitors are effective as anti-inflammatory therapy but exhibit dose-limiting adverse effects. Development of inhaled compounds would be enhanced by robust biomarkers that directly reflect the anti-inflammatory and pharmacological activity in the lung. METHODS: A novel flow cytometry assay was developed to measure STAT1 phosphorylation in sputum inflammatory cells. The standard sputum processing method was refined to improve sputum cell viability. The flow cytometric assay was used to assess the reproducibility of the measurement of STAT1 phosphorylation and the in vitro activity of a pan JAK-inhibitor on three separate visits in patients with COPD. RESULTS: Upregulation of STAT1 phosphorylation was measured following in vitro IFNγ stimulation of sputum macrophages (stimulated/unstimulated ratio 1.57; p<0.00001). Upregulation was inhibited following in vitro preincubation with a pan JAK-inhibitor (inhibited+stimulated/unstimulated ratio 0.97). STAT1 phosphorylation activity could only be measured in macrophages. CONCLUSIONS: Sputum from patients with COPD can be used to reproducibly measure phospho-STAT expression in sputum macrophages. The flow cytometry-based method can be used to evaluate kinase inhibitors in vitro and subsequently in ex vivo studies. The assay is particularly useful for the assessment of inhaled compounds where whole blood assays may not be relevant.
Barnes PJ, 2016, Inflammatory mechanisms in patients with chronic obstructive pulmonary disease, Journal of Allergy and Clinical Immunology, Vol: 138, Pages: 16-27, ISSN: 1097-6825
Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important.
Levy ML, Dekhuijzen P, Barnes PJ, et al., 2016, CORRIGENDUM: Inhaler technique: facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT), npj Primary Care Respiratory Medicine, Vol: 26, ISSN: 2055-1010
Levy ML, Dekhuijzen P, Barnes PJ, et al., 2016, Erratum: Inhaler technique: facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT)., npj Primary Care Respiratory Medicine, Vol: 26, Pages: 16028-16028, ISSN: 2055-1010
[This corrects the article DOI: 10.1038/npjpcrm.2016.17.].
Yao X, Wang Y, Adcock I, et al., 2016, Increased neutrophil gelatinase-associated lipocalin (NGAL) promotes airway remodeling in COPD, International Conference of the American Thoracic Society (ATS), Publisher: American Thoracic Society, ISSN: 1535-4970
Usmani OS, Singh D, Spinola M, et al., 2016, The prevalence of small airways disease in adult asthma: A systematic literature review, Respiratory Medicine, Vol: 116, Pages: 19-27, ISSN: 1532-3064
BackgroundSmall airways dysfunction and inflammation contribute significantly to the clinical impact of asthma, yet conventional methods of assessing airways function in the clinic cannot reliably evaluate its presence. However, most recently, promising methods of assessment are being utilised.MethodsWe conducted a systematic literature review, using PubMed, with the aim of determining the prevalence of small airways disease in adult patients with asthma. We ascertained how small airways disease prevalence compared between different studies when measured using distinct techniques of small airways assessment.ResultsFifteen publications were identified determining the prevalence of small airways disease in asthma. Methods of assessments included impulse oscillometry, spirometry, body plethysmography, multiple-breath nitrogen washout, and high-resolution computed tomography. These studies used differing inclusion characteristics and recruited patients with a broad range of asthma severity, yet collectively they reported an overall prevalence of small airways disease of 50 to 60%. Small airways disease was present across all asthma severities, with evidence of distal airway disease even in the absence of proximal airway obstruction.ConclusionsSmall airways disease is highly prevalent in asthma, even in patients with milder disease. Given the clinical impact of small airways disease, its presence should not be underestimated or overlooked as part of the daily management of patients with asthma.
Lee J, Machin M, Russell KE, et al., 2016, Corticosteroid modulation of immunoglobulin expression and B cell function in COPD, Faseb Journal, Vol: 30, Pages: 2014-2026, ISSN: 0892-6638
Purpose: To investigate changes in gene expression that occur in COPD following corticosteroid treatment and identify the mechanisms that regulate these changes. Procedures: Biopsies were taken from COPD patients (GOLD stage I-II) before and after treatment fluticasone propionate (FP)/salmeterol (SM) (Seretide® 50/500, 4 weeks). Gene expression was measured by microarray, confirmed by RT-qPCR. The effect of FP on IgG expression and B-cell proliferation in the presence of oxidative stress was also studied. Findings: FP/SM significantly increased the expression of 180 genes whilst repressing 343 genes. The top 5 down-regulated genes were associated with immunoglobulin production, whereas the immunomodulatory FK506 binding protein (FK506BP) was up-regulated. Genes including IL6, IL8 and the TBET encoding TBX21 were unaffected. FP reduced IgG protein and mRNA expression and proliferation of human B cells through the dephosporylation of ERK1/2 via increased DUSP1 expression. Consistent with in vivo data, oxidative stress did not prevent FP-induced suppression of IgG expression in human B-cells in vitro. Controls: Changes in expression were validated using qPCR and by gene set enrichment analysis in distinct COPD cohorts. Conclusions: FP may reduce the adaptive immune response in COPD and may be more effective in patients with an increased B cell/antibody response indicated by high autoantibody titres.
Barnes PJ, 2016, Asthma mechanisms, Medicine (United Kingdom), Vol: 44, Pages: 265-270, ISSN: 1357-3039
© 2016 Elsevier Ltd. All rights reserved. Asthma is characterized by a chronic allergic inflammatory response in all airways that results in bronchoconstriction, vasodilatation, airway oedema and activation of sensory nerve endings. In asthmatic airways, several inflammatory cells are activated, including mast cells and dendritic cells, and there is infiltration of activated lymphocytes and eosinophils. The predominant lymphocytes in allergic asthma are helper T cells (Th2) and in non-allergic asthma innate lymphoid cells. In severe asthma, Th17 cells may also be involved and linked to neutrophilic inflammation. Structural cells, especially airway epithelial cells and airway smooth muscle cells, can also release inflammatory mediators to drive inflammation. Many (>100) mediators have been implicated in asthma, including lipid mediators, such as cysteinyl leukotrienes, prostaglandin D2, cytokines, particularly T2 cytokines, interleukins 4, 5 and 13, and chemokines that attract inflammatory cells such as Th2 cells and eosinophils into the airways. Chronic inflammation can lead to structural changes, with friability of airway epithelial cells, increased bulk of airway smooth muscle, fibrosis under the epithelium, airway smooth muscle hyperplasia and hypertrophy, increased blood vessels and mucus hyperplasia. Superimposed on the chronic persistent inflammation are acute increases linked to exacerbations and loss of asthma control.
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.