Showing papers by "Peter J. Barnes published in 2014"
TL;DR: The pulmonary inflammation may enhance the development and growth of lung cancer and the peripheral inflammation extends into the circulation, resulting in systemic inflammation with the same inflammatory proteins.
350 citations
TL;DR: Persistence of bacteria in the lower airways may result partly from a reduced phagocytic capacity of macrophages for bacteria, which may contribute to increased exacerbations, airway colonization and persistence of inflammation.
Abstract: Background: Bacteria are frequently cultured from sputum samples of severe asthma patients suggesting a defect in bacterial clearance from the airway. We measured the capacity of macrophages from patients with asthma to phagocytose bacteria. Methods: Phagocytosis of fluorescently-labelled polystyrene beads, Haemophilus influenzae or Staphylococcus aureus by broncholaveolar lavage alveolar macrophages (AM) and by monocyte-derived macrophages (MDM) from non-asthmatics, mild-moderate and severe asthmatic patients was assessed using fluorimetry. Results: There were no differences in phagocytosis of polystyrene beads by AMs or MDMs from any of the subject groups. There was reduced phagocytosis of Haemophilus influenzae and Staphylococcus aureus in MDMs from patients with severe asthma compared to non-severe asthma (p < 0.05 and p < 0.01, respectively) and healthy subjects (p < 0.01and p < 0.001, respectively). Phagocytosis of Haemophilus influenzae and Staphylococcus aureus by AM was also reduced in severe asthma compared to normal subjects (p < 0.05). Dexamethasone and formoterol did not suppress phagocytosis of bacteria by MDMs from any of the groups. Conclusions: Persistence of bacteria in the lower airways may result partly from a reduced phagocytic capacity of macrophages for bacteria. This may contribute to increased exacerbations, airway colonization and persistence of inflammation.
91 citations
TL;DR: Oxidative stress enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by Brd4 inhibition and provides a potential novel anti-inflammatory target.
Abstract: Background
Chronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-κB). Histone acetylation plays a critical role in chronic inflammation and bromodomain and extra terminal (BET) proteins act as “readers” of acetylated histones. Therefore, we examined the role of BET proteins in particular Brd2 and Brd4 and their inhibitors (JQ1 and PFI-1) in oxidative stress- enhanced inflammation in human bronchial epithelial cells.
90 citations
TL;DR: Investigation of passive smoking-dependent molecular abnormalities in alveolar macrophages in children with uncontrolled severe asthma found that passive smoking impairs HDAC2 function via PI3K signaling activation, which could contribute to corticosteroid-insensitive inflammation inChildren with severe asthma.
88 citations
TL;DR: In this paper, the activation of innate immunity and inflammasome pathways in the bronchial mucosa and bronchoalveolar lavage (BAL) of patients with stable COPD of different severity and control healthy smokers and non-smokers was investigated.
Abstract: Background In models of COPD, environmental stressors induce innate immune responses, inflammasome activation and inflammation. However, the interaction between these responses and their role in driving pulmonary inflammation in stable COPD is unknown. Objectives To investigate the activation of innate immunity and inflammasome pathways in the bronchial mucosa and bronchoalveolar lavage (BAL) of patients with stable COPD of different severity and control healthy smokers and non-smokers. Methods Innate immune mediators (interleukin (IL)-6, IL-7, IL-10, IL-27, IL-37, thymic stromal lymphopoietin (TSLP), interferon γ and their receptors, STAT1 and pSTAT1) and inflammasome components (NLRP3, NALP7, caspase 1, IL-1β and its receptors, IL-18, IL-33, ST2) were measured in the bronchial mucosa using immunohistochemistry. IL-6, soluble IL-6R, sgp130, IL-7, IL-27, HMGB1, IL-33, IL-37 and soluble ST2 were measured in BAL using ELISA. Results In bronchial biopsies IL-27+ and pSTAT1+ cells are increased in patients with severe COPD compared with control healthy smokers. IL-7+ cells are increased in patients with COPD and control smokers compared with control non-smokers. In severe stable COPD IL-7R+, IL-27R+ and TSLPR+ cells are increased in comparison with both control groups. The NALP3 inflammasome is not activated in patients with stable COPD compared with control subjects. The inflammasome inhibitory molecules NALP7 and IL-37 are increased in patients with COPD compared with control smokers. IL-6 levels are increased in BAL from patients with stable COPD compared with control smokers with normal lung function whereas IL-1β and IL-18 were similar across all groups. Conclusions Increased expression of IL-27, IL-37 and NALP7 in the bronchial mucosa may be involved in progression of stable COPD.
88 citations
TL;DR: In this article, the authors investigated the acute and chronic effects of ozone exposure-induced oxidative stress-related inflammation mechanics in mouse lung and found that ozone exposure was associated with increased levels of chemokines and cytokines in all ozone-exposed groups, indicating the presence of a persistent inflammatory environment in the lung.
Abstract: Ozone is an oxidizing environmental pollutant that contributes significantly to respiratory health. Exposure to increased levels of ozone has been associated with worsening of symptoms of patients with asthma and COPD (chronic obstructive pulmonary disease). In the present study, we investigated the acute and chronic effects of ozone exposure-induced oxidative stress-related inflammation mechanics in mouse lung. In particular, we investigated the oxidative stress-induced effects on HDAC2 (histone deacetylase 2) modification and activation of the Nrf2 (nuclear factor erythroid-related factor 2) and HIF-1α (hypoxia-inducible factor-1α) signalling pathways. Male C57BL/6 mice were exposed to ozone (3 p.p.m.) for 3 h a day, twice a week for a period of 1, 3 or 6 weeks. Control mice were exposed to normal air. After the last exposure, mice were killed for BAL (bronchoalveolar lavage) fluid and lung tissue collection. BAL total cell counts were elevated at all of the time points studied. This was associated with increased levels of chemokines and cytokines in all ozone-exposed groups, indicating the presence of a persistent inflammatory environment in the lung. Increased inflammation and L m (mean linear intercept) scores were observed in chronic exposed mice, indicating emphysematous changes were present in lungs of chronic exposed mice. The antioxidative stress response was active (indicated by increased Nrf2 activity and protein) after 1 week of ozone exposure, but this ability was lost after 3 and 6 weeks of ozone exposure. The transcription factor HIF-1α was elevated in 3- and 6-week ozone-exposed mice and this was associated with increased gene expression levels of several HIF-1α target genes including Hdac2 (histone deacetylase 2), Vegf (vascular endothelial growth factor), Keap1 (kelch-like ECH-associated protein 1) and Mif (macrophage migration inhibitory factor). HDAC2 protein was found to be phosphorylated and carbonylated in nuclear and cytoplasm fractions, respectively, and was associated with a decrease in DNA-binding activity and protein expression of HDAC2. Decreased HDAC2 activity, most likely a direct result of protein modification, in combination with the loss of the antioxidative stress response and activation of the HIF-1α pathway, contribute to the inflammatory response and emphysema observed in ozone-exposed mice.
63 citations
TL;DR: Airway and systemic inflammation, as measured by fibrinogen, is greater in stable COPD patients with PPMs detected using the culture-independent qPCR technique, and appears to have a total pathogen-load threshold and appears attributable to Haemophilus influenzae.
Abstract: Background: There has been increasing interest in the use of newer, culture-independent techniques to study the airway microbiome of COPD patients. We investigated the relationships between the three common potentially pathogenic microorganisms (PPMs) Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis, as detected by quantitative PCR (qPCR), and inflammation and health status in stable patients in the London COPD cohort. Methods: We prospectively collected sputum, serum and plasma samples for analysis of airway bacterial presence and load, and airway and systemic inflammation from 99 stable COPD patients between January 2011 and October 2012. Health status was measured with St George’s Respiratory Questionnaire and COPD Assessment Test. Results: Airway inflammation and plasma fibrinogen, but not C-reactive protein, were greater in samples with PPM detection (p 0.05). Samples with high total bacterial loads had significantly higher airway inflammation than both samples without PPM detection and those with lower loads. Haemophilus influenzae presence was associated with significantly higher levels of airway but not systemic inflammation for all given pathogen loads (p 0.05). Conclusions: Airway and systemic inflammation, as measured by fibrinogen, is greater in stable COPD patients with PPMs detected using the culture-independent qPCR technique. The airway, but not systemic inflammatory response, appears to have a total pathogen-load threshold and appears attributable to Haemophilus influenzae. However, discordance between inflammation and health status was observed.
61 citations
TL;DR: CCL11 is a potentially useful biomarker for the diagnosis and assessment of asthma severity and control, especially in sputum, and is crucial in eosinophil chemoattraction and activation in asthma pathogenesis.
Abstract: Objective: Asthma is an inflammatory airway disease characterized by airway eosinophilia, in which CCL11 (eotaxin) plays a crucial role. The aim of study is to determine the elevation of CCL11 levels in bronchoalveolar lavage fluid (BALF), blood, exhaled breath condensate (EBC) and sputum in asthma patients and to identify which medium yields the most significant change in CCL11 level. Methods: The databases of PubMed, Embase and Cochrane Centre Register of Controlled Trials were systematically searched from inception to September 2013. Controlled clinical trials that focused on CCL11 concentrations in asthma patients and controls, and their correlations with other asthma indicators were obtained. Data were analysed using Stata 12.0. Results: Thirty studies were included in this investigation. CCL11 levels in blood, EBC and sputum were significantly higher in asthma patients than in healthy subjects. Sputum CCL11 concentrations were significantly elevated in unstable asthma patients versus stable ...
58 citations
TL;DR: BET proteins, particularly Brd2 and Brd4, may play a key role in the regulation of Nrf2-dependent antioxidant gene transcription and are hence an important target for augmenting antioxidant responses in oxidative stress–mediated diseases.
Abstract: Oxidative stress, a pathogenetic factor in many conditions including chronic obstructive pulmonary disease (COPD) arises due to accumulation of reactive oxygen species (ROS) and defective antioxidant defences in the lungs. The latter is due, at least in part, to impaired activation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor involved in the activation of antioxidant and cytoprotective genes. The bromodomain and extra-terminal (BET) proteins, Brd2, Brd3, Brd4 and BrdT, bind to acetylated lysine residues on histone or non-histone proteins recruiting transcriptional regulators and thus activating or repressing gene transcription. We investigated whether BET proteins modulate the regulation of Nrf2-dependent gene expression in primary human airway smooth muscle cells (ASMCs) and the human monocytic cell line, THP-1. Inhibition of BET protein bromodomains using the inhibitor JQ1+, or attenuation of Brd2 and Brd4 expression using siRNA led to activation of Nrf2-dependent transcription and expression of the antioxidant proteins heme oxygenase (HO)-1, NADPH quinone oxidoreductase 1 (NQO1) and glutamate-cysteine ligase catalytic subunit (GCLC). Also, JQ1+ prevented hydrogen peroxide (H2O2)-induced intracellular ROS production. By co-immunoprecipitation, BET proteins were found to be complexed with Nrf2, whilst chromatin-immunoprecipitation studies indicated recruitment of Brd2 and Brd4 to Nrf2-binding sites on the promoters of HO-1 and NQO1. BET proteins, particularly Brd2 and Brd4, may play a key role in the regulation of Nrf2-dependent antioxidant gene transcription and are hence an important target for augmenting antioxidant responses in oxidative stress-mediated diseases.
53 citations
TL;DR: This study identifies a specific macrophages phenotype in the lungs of patients with COPD who are glucocorticosteroid insensitive with a density of 1.036 to 1.048 g/mL but do not correspond to the current concept of macrophage phenotypes.
Abstract: Background In patients with chronic obstructive pulmonary disease (COPD), pulmonary macrophages increase in number, release increased levels of inflammatory mediators, and respond poorly to glucocorticosteroids. Whether this is due to a change in macrophage phenotype or localized activation is unknown. Objective We sought to investigate whether macrophages from patients with COPD are a distinct phenotype. Methods Macrophage populations were isolated from human lung tissue from nonsmokers, smokers, and patients with COPD by using Percoll density gradients. Five macrophage populations were isolated on the basis of density (1.011-1.023, 1.023-1.036, 1.036-1.048, 1.048-1.061, and 1.061-1.073 g/mL), and cell-surface expression of CD14, CD16, CD163, CD40, and CD206 was assessed by using flow cytometry. Release of active matrix metalloproteinase 9, TNF-α, CXCL8, and IL-10 was measured by using ELISA. Results The 2 least dense fractions were more than 90% apoptotic/necrotic, with the remaining fractions greater than 70% viable. Macrophages from nonsmokers and smokers were CD163 + , CD206 + , CD14 + , and CD40 − , whereas macrophages from patients with COPD were less defined, showing significantly lower expression of all receptors. There were no differences in receptor expression associated with density. Macrophages from patients with COPD of a density of 1.036 to 1.048 g/mL released higher levels of active matrix metalloproteinase 9 compared with cells from nonsmokers, with no difference between the remaining fractions. This population of macrophages from patients with COPD was less responsive to budesonide compared with those from nonsmokers and smokers when stimulated with LPS. Glucocorticosteroid insensitivity was selective for proinflammatory cytokines because budesonide inhibition of LPS-stimulated IL-10 release was similar for all macrophages. Conclusions This study identifies a specific macrophage phenotype in the lungs of patients with COPD who are glucocorticosteroid insensitive with a density of 1.036 to 1.048 g/mL but do not correspond to the current concept of macrophage phenotypes.
49 citations
TL;DR: TNF-α delays human eosinophil apoptosis via TNF-receptor 1 and the resulting changes in longevity depend on yin-yang balance between activation of NF-κB and AP-1.
Abstract: Eosinophils play a central role in asthma. The present study was performed to investigate the effect of tumour necrosis factor-α (TNF-α) on longevity of isolated human eosinophils. In contrast to Fas, TNF-α inhibited eosinophil apoptosis as evidenced by a combination of flow cytometry, DNA fragmentation assay and morphological analyses. The effect of TNF-α on eosinophil apoptosis was reversed by a TNF-α neutralising antibody. The anti-apoptotic effect of TNF-α was not due to autocrine release of known survival-prolonging cytokines interleukins 3 and 5 or granulocyte-macrophage-colony-stimulating factor as their neutralisation did not affect the effect of TNF-α. The anti-apoptotic signal was mediated mainly by the TNF-receptor 1. TNF-α induced phosphorylation and degradation of IκB and an increase in NF-κB DNA-binding activity. The survival-prolonging effect of TNF-α was reversed by inhibitors of NF-κB pyrrolidinedithiocarbamate and gliotoxin and by an inhibitor of IκB kinase, BMS-345541. TNF-α induced also an increase in AP-1 DNA-binding activity and the antiapoptotic effect of TNF-α was potentiated by inhibitors of AP-1, SR 11302 and tanshinone IIA and by an inhibitor of c-jun-N-terminal kinase, SP600125, which is an upstream kinase activating AP-1. Our results thus suggest that TNF-α delays human eosinophil apoptosis via TNF-receptor 1 and the resulting changes in longevity depend on yin-yang balance between activation of NF-κB and AP-1.
TL;DR: Sputum MPO Levels were increased in stable COPD patients when compared with normal controls, and this increase was especially pronounced during exacerbations as compared with MPO levels during the stable state.
Abstract: Airway inflammation, especially neutrophilic airway inflammation, is a cardinal pathophysiologic feature in chronic obstructive pulmonary disease (COPD) patients. The ideal biomarkers characterizing the inflammation might have important potential clinical applications in disease assessment and therapeutic intervention. Sputum myeloperoxidase (MPO) is recognized as a marker of neutrophil activity. The purpose of this meta-analysis is to determine whether sputum MPO levels could reflect disease status or be regulated by regular medications for COPD. Studies were identified by searching PubMed, Embase, the Cochrane Database, CINAHL and http://www.controlled-trials.com
for relevant reports published before September 2012. Observational studies comparing sputum MPO in COPD patients and healthy subjects or asthmatics, or within the COPD group, and studies comparing sputum MPO before and after treatment were all included. Data were independently extracted by two investigators and analyzed using STATA 10.0 software. A total of 24 studies were included in the meta-analysis. Sputum MPO levels were increased in stable COPD patients when compared with normal controls, and this increase was especially pronounced during exacerbations as compared with MPO levels during the stable state. Theophylline treatment was able to reduce MPO levels in COPD patients, while glucocorticoid treatment failed to achieve the same result. Sputum MPO might be a promising biomarker for guiding COPD management; however, further investigations are needed to confirm this.
TL;DR: The bronchial production of NO can be determined by measuring ΔA UC-NO50-200, whereas AUC-NO200 measures its peripheral concentration, and this approach is simple, quick, and does not require sophisticated equipment or mathematical models.
TL;DR: Observations suggest that TB and sarcoidosis may not only share the same etiology, but may even be different aspects of one disease.
Abstract: Sarcoidosis is a granulomatous inflammatory disease that is induced by unknown antigen(s) in a genetically susceptible host. Although the direct link between Mycobacterium tuberculosis (MTB) infection and sarcoidosis can be excluded on the basis of current knowledge, non-infectious mechanisms may explain the causative role of mycobacterial antigens. Ever since sarcoidosis was first described, its relationship with tuberculosis (TB) has been under-investigated. Whereas some researchers consider sarcoidosis and TB as two examples of the same disease process, others have rejected mycobacteria as playing any causative role in sarcoidosis. Whether they are linked causally or not, clinical evidence makes a differential diagnosis between the two conditions very challenging, particularly in countries with high burden of TB. The present study analyzes the relationship between sarcoidosis and TB and its implications in clinical practice. The coincidence of TB and sarcoidosis and the higher incidence of mycobacterial DNA in biological samples of sarcoid patients have been reported by many authors. In addition, new evidence of a similarity in MTB phenotype in sarcoidosis is provided. Overall, these observations suggest that TB and sarcoidosis may not only share the same etiology, but may even be different aspects of one disease.
TL;DR: In this paper, the anti-oxidant capacity is crucial defence against environmental or endogenous oxidative stress and cellular senescence, and novel therapeutics that enhance Nrf2 signalling are an attractive approach to treat these diseases.
Abstract: Background
Anti-oxidant capacity is crucial defence against environmental or endogenous oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that plays a key defensive role against oxidative and cytotoxic stress and cellular senescence. However, Nrf2 signalling is impaired in several aging-related diseases, such as chronic pulmonary obstructive disease (COPD), cancer, and neurodegenerative diseases. Thus, novel therapeutics that enhance Nrf2 signalling are an attractive approach to treat these diseases.
TL;DR: Cessation of smoking in patients with COPD causes a transient improvement in FEV1 and decreases the presence of micronodules, offering an opportunity for concomitant therapy during smoking cessation to augment these effects.
TL;DR: Oral MEM 1414, a novel PDE4 inhibitor, significantly reduces the late response following inhaled allergen challenge and was associated with a typical adverse event profile of PDE 4 inhibitors, namely nausea and vomiting although these were mild side effects.
Abstract: Inhaled allergen challenge is a standard method to study airway responses to inflammatory provocation and evaluate the therapeutic potential of novel anti-inflammatory compounds in asthma. MEM 1414 is a novel oral PDE4 inhibitor with high affinity and selectivity creating the potential for an improved side effect profile vs non-selective PDE inhibitors. We evaluated the tolerability and effect of MEM 1414 on airway responses in mild asthmatics. A randomised double blind placebo controlled cross over study in two centres, in which sixteen steroid naive atopic asthmatics were challenged with inhaled allergen. Subjects were dosed with MEM 1414 (600 mg) or placebo, twice daily orally for 7 days. Allergen challenge was performed on day 6 (2 hours post-dose), and methacholine responsiveness was measured 24 hours post allergen (day 7). Biomarkers of drug effects using ex vivo LPS stimulation of whole blood production of interleukin (IL)-6 and leukotriene (LT)-B4 and fractional exhaled nitric oxide (FeNO) were measured on day 6 (0, 2 and 8 hours post-dose). Plasma pharmacokinetics were measured on days 1, 6 and 7. The primary endpoint was the effect on late asthmatic response to allergen. Treatment with MEM 1414 abrogated the late phase response with a mean difference in FEV1 (LAR 3–10 hours) of 104 ml (25%) vs placebo (p < 0.005), with no effect on the early response. Biomarker responses were also attenuated with MEM 1414 treatment with reductions in LPS-stimulated whole blood assays for TNFα at 8 hours (p < 0.03) and LTB4 at 24 hours (p = 0.0808) with no change in the IL-6 response. The MEM 1414 treatment phase was associated with higher incidence of nausea (6/16 MEM 1414 vs 2/16 placebo) and vomiting (3/16 vs 0/16 placebo). Oral MEM 1414, a novel PDE4 inhibitor, significantly reduces the late response following inhaled allergen challenge. MEM 1414 also inhibited whole blood assays of cytokine production from inflammatory cells. MEM 1414 was associated with a typical adverse event profile of PDE4 inhibitors, namely nausea and vomiting although these were mild side effects. Current controlled trials ISRCTN48047493
.
TL;DR: BAL CXCL8 levels were significantly higher in patients with ARDS induced by TB and could suggest an important role of CxCL8 in the pathogenesis of this form of ARDS, which suggests that C XCL8 inhibitors or blockers may be useful to control the onset and/or development of these combined diseases.
Abstract: Tuberculosis (TB) is a rare but known cause of acute respiratory distress syndrome (ARDS). The role of inflammatory cytokines in the progression of ARDS in TB patients is unknown. In this study we investigated the possible link between the levels of inflammatory cytokines in bronchoalveolar lavage (BAL) in patients with TB or ARDS alone or in patients with TB-induced ARDS (ARDS + TB). 90 patients were studied: 30 with TB alone, 30 with ARDS alone and 30 with ARDS + TB. BAL was collected by fiberoptic bronchoscopy and the concentrations of interleukin(IL)-6, CXCL8, TNF-α and IL-1β and the amounts of total protein were measured by ELISA and bicinchoninic acid assay (BCA) methods respectively. The correlation between disease severity measured by Murray scores, SOFA and APACHE II analysis and BAL mediators and cells was also determined. CXCL8 levels in BAL were significantly higher in the ARDS + TB group compared to 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. BAL CXCL8 levels were significantly higher in patients with ARDS induced by TB and could suggest an important role of CXCL8 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.
TL;DR: The results suggest that in the airways of chronic asthma patients there is an imbalance between increased numbers of CD4+IL-17+ cells and Th2 cells and decreased number ofCD4+Foxp3+TGF-β+.
Abstract: Asthma is a chronic inflammatory disorder of the airways with the proven role of Th2 cells in its pathogenesis. The role and characteristic of different subsets of CD4+ cells is much less known. The aim of the study was to analyze the incidence of different subsets of CD4+ T cells, in particular different subsets of CD4+ cells with the co-expression of different cytokines. Twenty five stable asthmatic and twelve age-matched control subjects were recruited to the study. Bronchoscopy and bronchoalveolar lavage (BAL) were performed in all study subjects. CD4+ T cells were isolated from BAL fluid by positive magnetic selection. After stimulation simultaneous expression of TGF-β, FoxP3, CD25, IFN-γ, IL-4, TNF-α (set 1); IL-10, FoxP3, CD25, IFN-γ, IL-4, MIP-1β (set 2); IL-17A, IL-8, IFN-γ, IL-4, MIP-1β (set 3) were measured by flow cytometry. The percentage of CD4+ cells co-expressing Foxp3 and TGF-β (CD4+Foxp3+TGF-β+ cells) was significantly lower (P = 0.03), whereas the percentage of CD4+IL-17+ cells (P = 0.008), CD4+IL-17+ IFN-γ+ cells (P = 0.047) and CD4+IL-4+ cells (P = 0.01) were significantly increased in asthmatics compared with that seen in healthy subjects. A significantly higher percentage of CD4+Foxp3+ cells from asthma patients expressed IFN-γ (P = 0.01), IL-4 (P = 0.004) and CD25 (P = 0.04), whereas the percentage of CD4+IL-10+ cells expressing Foxp3 was significantly decreased in asthmatics (P = 0.03). FEV1% predicted correlated negatively with the percentage of CD4+IL-17+ cells (r = -0.33; P = 0.046) and positively with CD4+Foxp3+TGF-β+ cells (r = 0.43; P = 0.01). Our results suggest that in the airways of chronic asthma patients there is an imbalance between increased numbers of CD4+IL-17+ cells and Th2 cells and decreased number of CD4+Foxp3+TGF-β+.
TL;DR: Serum levels of H2S positively correlate with the decline in lung function in chronic obstructive pulmonary disease (COPD) and were significantly lower in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III patients compared with those in GOLD I.
Abstract: To the Editor:
Hydrogen sulfide (H2S) has emerged as a new and important endogenous regulator of inflammation in recent years [1] and may also protect from emphysema induced by cigarette smoke exposure [2]. We have also recently shown that H2S can inhibit airway smooth muscle cell proliferation and inflammatory mediator release in vitro [3]. Serum levels of H2S positively correlate with the decline in lung function in chronic obstructive pulmonary disease (COPD) and were significantly lower in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III patients compared with those in GOLD I [4]. Existing therapies for COPD, such as corticosteroids or long-acting anticholinergic agents, may reduce the exacerbation rate but do not significantly slow disease progression. A previous study has shown that theophylline alone had no impact on serum H2S levels and is of limited value in the management of stable COPD [5]. Interestingly, sputum H2S measured in patients with asthma correlated with sputum neutrophil counts and the degree of airflow obstruction measured by forced expiratory volume in 1 s (FEV1) % predicted [6]. Moreover, combination therapy of an inhaled glucocorticoid with low-dose theophylline has been shown to attenuate airway inflammation in patients with COPD and reverse glucocorticoid resistance [7]. We therefore investigated whether the combination of inhaled corticosteroid and low-dose theophylline, as opposed to …
TL;DR: The focus of the exercise was definitely the future, the importance of the past as the basis of all change was emphasised by the presence of the former Executive Director who attended in an observer role to recall the history of the ERS and previous decisions.
Abstract: The European Respiratory Society (ERS), in order to serve better its members and achieve its mission objectives (table 1) [1], organised a Strategy Meeting to plan its core strategic priorities for the period 2013–2018, taking into account changes occurring both within the society and within the respiratory field in Europe and beyond. This meeting was held on July 3 and 4, 2013 in Lausanne, Switzerland to formulate future directions. We took into account the Executive Summary of the 2006–2007 Strategy Meeting [2] summarising the ERS pillars (fig. 1) and the recently published ERS Presidential plans as an operational guide [3–5].
View this table:
Table 1– Objectives and means of action of the European Respiratory Society (ERS)
Figure 1–
The three pillars of the European Respiratory Society.
The Strategy Meeting involved the ERS Leadership represented by the members of the Steering Committee (fig. 2). It was prepared by an ad hoc meeting preceding the event, involving the Past President and the Secretary General Elect (the officers designated to act as chair and moderator), as well as the Executive Director and the Head of the Executive Office. This was used as the starting point to develop the strategic meeting agenda. Participants were encouraged to express their opinions freely and to think “outside the box” in order to bring fresh ideas to the table. Whilst the focus of the exercise was definitely the future, the importance of the past as the basis of all change was emphasised by the presence of the former Executive Director who attended in an observer role to recall the history of the ERS and previous decisions.
Figure 2–
The European Respiratory Society Strategy Meeting in Lausanne, Switzerland.
Operational minutes discussions were first drafted to allow an accurate summary of the decisions taken, which were then approved by the Steering and Executive Committees following ERS regulations. As it was felt that …
TL;DR: The European Respiratory Society has been quick to respond to changing health priorities, and to raise awareness of respiratory medicine in the media and attract the attention of policy makers in Europe.
Abstract: The lungs are essential organs for life. However, lung diseases (including at least 10 major conditions and many more rare and orphan diseases) cause pain and suffering for millions and are among the leading causes of mortality worldwide. There are many risk factors for respiratory disease, which can start from a very early age, although many are avoidable and their effects treatable.
As a society, over the years, the European Respiratory Society (ERS) has been quick to respond to changing health priorities, and to raise awareness of respiratory medicine in the media and attract the attention of policy makers in Europe. In 2013, the society launched a new edition of The European Lung White Book [1], which draws on the latest data from the World …
Journal Article•
TL;DR: CHF6001, a novel PDE4 inhibitor, optimized for inhaled delivery to improve efficacy and tolerability, significantly reduces LAR after allergen challenge, particularly with respect to gastrointestinal side effects.
Abstract: The anti-inflammatory effect of CHF6001, a novel phosphodiesterase-4 (PDE4) inhibitor delivered via a dry powder inhaler, was evaluated in asthmatics on the airway response to allergen challenge (AC).
METHODS: Thirty-six steroid-naive asthmatics with dual response to AC were enrolled in a randomized, double-blind, placebo-controlled, 3-way crossover trial. They received daily treatment with CHF6001 low dose (400 µg), high dose (1200 µg) or placebo for 9 days. On Day 9 subjects underwent AC and pharmacokinetic evaluation.
RESULTS: Both doses of CHF6001 significantly attenuated the late asthmatic response (LAR): the weighted FEV1 AUC4-10h was reduced by 20% (p=0.014) and 30% (p<0.01) respectively with low and high dose compared with placebo. The maximum FEV1 fall during LAR was reduced by 16% (p=0.027) and 24% (p<0.01) with low and high dose, respectively. There was no effect on the early asthmatic response (0-2h post AC). Exposure to CHF6001 increased dose proportionally with peak plasma levels at 2 h post-dose and elimination half-lives of approximately 24 h. Systemic exposure to metabolites was low compared to the parent compound, suggesting limited formation in vivo . There were no gastrointestinal adverse events, except dyspepsia in one patient after both CHF6001 400 µg and placebo.
CONCLUSIONS: CHF6001, a novel PDE4 inhibitor, optimized for inhaled delivery to improve efficacy and tolerability, significantly reduces LAR after allergen challenge. Both doses of CHF6001 were safe and well tolerated, particularly with respect to gastrointestinal side effects.
Journal Article•
TL;DR: The results suggest that the anti-inflammatory effects of SFN occur independently of Nrf2 in human airway epithelial cells and macrophages.
Abstract: Sulforaphane (SFN) is a naturally occurring compound, found in cruciferous vegetables. SFN is a potent activator of the endogenous anti-oxidant transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Due to its anti-oxidant and anti-inflammatory properties SFN has been identified as a potential treatment for a number of diseases including chronic obstructive pulmonary (COPD). We confirmed that SFN activates of the Nrf2 pathway and induces the expression of haemoxygenase (HO)-1 and NAD(P)H:Quinone Oxireductase (NQO)-1. SFN suppressed interleukin (IL)-1b-induced and IL-1b plus oxidative stress (hydrogen peroxide, H 2 O 2 )-induced CXCL8 expression in a concentration-dependent manner in human bronchial epithelial and monocyte cell lines. Nrf2 siRNA significantly reduced the ability of SFN to enhance Nrf2-mediated induction of HO-1 and NQO-1 without any effect on the ability of SFN to suppress IL-1b- and IL-1b+H 2 O 2 -induced CXCL8 expression in these cells. Our results suggest that the anti-inflammatory effects of SFN occur independently of Nrf2 in human airway epithelial cells and macrophages. Figure legend. Nrf2 knockdown using siRNA abrogates the ability of sulpforophane to induce Nrf2 activation (A & B) and that of the downstream target NQO-1 (c & d) in BEAS-2B cells. Nrf2 knockdown does not have a significant effect on the ability of sulforophane to suppress IL-1b-induced CXCL8 release in BEAS-2B or U937 cells (e & f).
TL;DR: This poster focuses on the parts of the lungs that are affected by chronic obstructive pulmonary disease and the use of corticosteroids and injections to correct these problems.
Journal Article•
TL;DR: It is concluded 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.
Abstract: Background : Long noncoding RNAs (lncRNAs) play an important role in a variety of pathological processes. We describe the expression of lncRNAs and mRNAs in non-smokers, smokers without COPD and smokers with COPD using microarray analysis. Methodology : RNA was extracted from lung tissue and analysed using an Agilent Human lncRNA + mRNA Array v2.0 system. Gene Ontology(GO) and pathway analysis was performed and mapped genes to the Kyoto Encyclopedia of Genes and Genomes database. Results: 39,253 distinct lncRNA transcripts were detected in the lung tissues of non-smokers, smokers without COPD and smokers with COPD. 87 lncRNAs were significantly up-regulated and 244 down-regulated in smokers without COPD compared to non-smokers with RNA50010︱UCSC-9199-1005 (fold-change: 13.02297) and RNA58351|CombinedLit_316_550 (fold-change: 12.609704)the mostover- and under-regulated. In contrast, 120 lncRNAs were overexpressed and 43 underexpressed in COPD patients compared with smokers without COPD with RNA44121︱UCSC-2000-3182 (fold-change: 8.721127) and RNA43510︱UCSC-1260-3754 (fold-change: 5.527549) being the mostover- and under-regulated. GO and pathway analysis indicated that cigarette smoking was associated with metabolic pathways, and COPD transcripts were associated with 9hematopoietic cell lineage9, intermediary metabolism and immune system processes. Conclusions: Our study is the first to determine the genome-wide expression of lncRNAs in lung tissues. The results show that smoking and the presence of COPD alters the expression of lncRNAs in lung tissues and that these lncRNAs play important roles in pathways implicated in disease onset and progression such as intermediary metabolism and the immune system.