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We present high-resolution (0".4) mid-infrared (mid-IR) polarimetric images and spectra of WL 16, a Herbig Ae star at a distance of 125 pc. WL 16 is surrounded by a protoplanetary disk of $\sim$ 900 AU in diameter, making it one of the most extended Herbig Ae/Be disks as seen in the mid-IR. The star is behind, or embedded in, the $\rho$ Ophiuchus molecular cloud, and obscured by 28 magnitudes of extinction at optical wavelengths by the foreground cloud. Mid-IR polarization of WL 16, mainly arises from aligned elongated dust grains present along the line of sight, suggesting a uniform morphology of polarization vectors with an orientation of 33\degr (East from North) and a polarization fraction of $\sim$ 2.0\%. This orientation is consistent with previous polarimetric surveys in the optical and near-IR bands to probe large-scale magnetic fields in the Ophiuchus star formation region, indicating that the observed mid-IR polarization toward WL 16 is produced by the dichroic absorption of magnetically aligned foreground dust grains by a uniform magnetic field. Using polarizations of WL 16 and Elias 29, a nearby polarization standard star, we constrain the polarization efficiency, \textit{$p_{10.3}/A_{10.3}$}, for the dust grains in the $\rho$ Ophiuchus molecular cloud to be $\sim$ 1.0\% mag$^{-1}$. WL 16 has polycyclic aromatic hydrocarbon (PAH) emission features detected at 8.6, 11.2, 12.0, and 12.7 $\mu$m by our spectroscopic data, and we find an anti-correlation between the PAH surface brightness and the PAH ionization fraction between the NW and SW sides of the disk., Comment: 9 pages, 8 figures, Accepted in MNRAS

Copyright © 2016 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. Methods. Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from nonsmokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. Results. MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. Conclusion MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.

Asthma and COPD remain two diseases of the respiratory tract with unmet medical needs. This review considers the current state of play with respect to what is known about the underlying pathogenesis of these two chronic inflammatory diseases of the lung. The review highlights why they are different conditions requiring different approaches to treatment and provides a backdrop for the subsequent chapters in this volume discussing recent advances in the pharmacology and treatment of asthma and COPD.

Rationale Indoleamine 2,3-dioxygenase (IDO) induces generation of regulatory T cells but suppresses Th17 cells and therefore might attenuate neutrophilic inflammation. The role of IDO in neutrophilic airway diseases such as chronic obstructive pulmonary disease (COPD) remains unknown. We evaluated IDO activity and expression and interleukin (IL)-10 and IL-17A levels in sputum from patients with COPD. Methods IDO activity and cytokine concentrations in sputum supernatants from patients with COPD of varying severity and in smoking and non-smoking control subjects were determined by high-performance liquid chromatography and ELISA, respectively. Results Patients with COPD had reduced sputum IDO activity and expression and IL-10 levels, with increased IL-17A, IL-6 and CXCL8 concentrations and sputum neutrophils. These changes were significantly correlated with disease severity. IDO activity was decreased, but to a lesser extent, in normal smokers compared with non-smoking controls. Conclusions Patients with COPD have a progressive reduction in IDO activity with reversal of the balance between IL-10 and IL-17A, resulting in chronic airway neutrophilic inflammation.

BACKGROUND AND PURPOSE Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids, which has been linked to oxidative stress. Here we show that the long-acting β2-agonist formoterol (FM) reversed corticosteroid insensitivity under oxidative stress via inhibition of phosphoinositide-3-kinase (PI3K) signalling.

Inhaled corticosteroids (ICS) have led to improved asthma control and reduced asthma mortality in the Western world. ICS are effective in combating T-helper type 2-driven inflammation featuring mast cell and eosinophilic airway infiltration. Their effect on innate immunity-driven neutrophilic inflammation is poor and their ability to prevent airway remodeling and accelerated lung decline is controversial. Although ICS remain pivotal drugs in asthma management, research is needed to find drugs complementary to the combination ICS/long-acting β2-agonist in refractory asthma and perhaps a new class of drugs as a first-line treatment in mild to moderate noneosinophilic asthma.

The text that follows reviews and discusses the papers published in the Journal on chronic obstructive pulmonary disease (COPD) during 2011. Whenever relevant, works published earlier or elsewhere are included. The reader is referred to the original papers for further details. We have organized the review according to the following subheadings: Risk Factors, Natural History, Physiology, Disease Mechanisms, Phenotypes and Biomarkers, Comorbidities, Management, and Exacerbations.

Background: Hypoxia inducible factor (HIF)-1 plays an important role in cellular adaptation to hypoxia by activating oxygen-regulated genes such as vascular endothelial growth factor (VEGF) and erythropoietin. Sputum VEGF levels are reported to be decreased in COPD, despite hypoxia. Here we show that patients with COPD fail to induce HIF-1α and VEGF under hypoxic condition because of a reduction in histone deacetylase (HDAC) 7. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with moderate to severe COPD (n = 21), smokers without COPD (n = 12), and nonsmokers (n = 15). PBMCs were exposed to hypoxia (1% oxygen, 5% CO2, and 94% N2) for 24 h, and HIF-1α and HDAC7 protein expression in nuclear extracts were determined by sodium dodecyl sulfate poly acrylamide gel electrophoresis (SDS-PAGE)/Western blotting. Results: HIF-1α was significantly induced by hypoxia in each group when compared with the normoxic condition (12-fold induction in nonsmokers, 24-fold induction in smokers without COPD, fourfold induction in COPD), but induction of HIF-1α under hypoxia was significantly lower in patients with COPD than in nonsmokers and smokers without COPD (P < .05 and P < .01, respectively). VEGF messenger RNA detected by quantitative real-time polymerase chain reaction was correlated with HIF-1α protein in nuclei (r = 0.79, P < .05), and HDAC7 protein expression was correlated with HIF-1α protein in nuclei (r = 0.46, P < .05). HDAC7 knockdown inhibited hypoxia-induced HIF-1α activity in U937 cells, and HIF-1α nuclear translocation and HIF-1α binding to the VEGF promoter in A549 cells. Conclusions: HDAC7 reduction in COPD causes a defect of HIF-1α induction response to hypoxia with impaired VEGF gene expression. This poor cellular adaptation might play a role in the pathogenesis of COPD.

Maintaining an airway clear of inhaled particles, pathogens, and cellular debris is paramount for lung homeostasis. In healthy individuals, the phagocytes of the innate immune system act as sentinels to patrol the airway and ensure sterility. However, in airways diseases, including asthma, COPD, and cystic fibrosis, there is a propensity for bacterial colonization that may contribute to disease worsening. Evidence suggests that this may be due to dysfunctional phagocytosis. In patients with COPD, phagocytosis of several bacterial species and removal of apoptotic cells (efferocytosis) by alveolar macrophages are significantly reduced; however, these cells can remove inert beads normally. Attenuated phagocytosis is also apparent in monocyte-derived macrophages from the same patients, suggesting an inherent defect in these cells. Reduced expression of cell surface recognition receptors has been suggested as one mechanism for these observations; however, the literature is currently contradictory and requires further clarification. In cystic fibrosis, a similar defect is also observed in both airway neutrophils and macrophages, leading to ineffective bacterial uptake and subsequent killing. In asthma and other airways diseases, there are also reports of defective phagocytosis of bacterial pathogens, although the relevance to disease pathophysiology is not understood. Oxidative stress is emerging as a common mechanism that may be altering both macrophage and neutrophil functions that can be reversed by various antioxidant strategies. The identification of this and other mechanisms underlying phagocyte dysfunction may present novel therapeutic opportunities for the treatment of many of these intractable diseases and improve patient morbidity and mortality.

Current asthma management guidelines emphasize the importance of disease control. Although effective drug therapies are available, real-life data indicate that the general level of asthma control is still low. Fixed-dose combinations of inhaled corticosteroids/long-acting beta(2)-agonists (ICS/LABAs) are now increasingly used in the management of asthma. A number of studies have compared the clinical benefits of ICS/LABA fixed combinations with the monocomponents administered using two separate inhalers. We conducted a database search to identify all published studies that have assessed whether fixed-dose combinations achieve greater asthma control compared with administration by separate inhalers. Among fixed combinations, only extrafine beclomethasone/formoterol provided significantly greater asthma control compared with separate inhalers administered as larger aerosol particles. This greater effect may be explained by increased delivery to the small airways by the extrafine formulation.

SummaryBackgroundCombination therapy with inhaled corticosteroids (ICS) and long-acting β2-adrenergic agonists (LABA) is reported to have superior effects on controlling asthma symptoms to ICS alone; however, there is no molecular-based evidence to explain the clinical effects. Here, the effect of the ICS/LABA combination was compared with ICS on glucocorticoid receptor (GR) activation in sputum macrophages.MethodsIn a randomised, double-blind cross-over placebo-controlled 6-visit study, 10 patients with mild asthma were given placebo, formoterol (Oxis® 12 μg), budesonide (Pulmicort® 200 μg :BUD200, or 800 μg :BUD800), or budesonide/formoterol combination (Symbicort®) as a single 100/6 μg (SYM100) or double 200/12 μg (SYM200) dose. Sputum macrophages were separated by plate adhesion from induced sputum. GR binding to the glucocorticoid-response elements on oligonucleotides (GR-GRE binding) was evaluated by ELISA. mRNA expression of MAP-kinase phosphatase (MKP)-1 and IL-8 were measured by quantitative RT-PCR.ResultsGR-GRE binding was significantly increased after treatment with SYM100 (3.5 OD/10 μg protein, median, p

Hydrogen peroxide (H2O2) is detectable in exhaled breath condensate (EBC) and has been proposed to be a surrogate marker of oxidative stress in the airways. In this study we tested whether the breathing pattern during EBC collection influences the concentration of exhaled H2O2.EBC was collected during (1) tidal breathing and (2) breathing with increased tidal volume for 10 min from 16 healthy volunteers. On-line H2O2 measurement was performed by the EcoCheck™ biosensor system. Repeated measurements were also conducted to assess intrasubject reproducibility.Minute ventilation, tidal volume, expiratory flow rate were all increased significantly when subjects were asked to perform breathing with increased tidal volume. In parallel, EBC volume increased (1413±59 vs. 1959±71 μL, p0.001), whereas exhaled H2O2 levels decreased significantly (1400±170 vs. 840±130 nmol/L, p0.001). H2O2 levels did not correlate with any individual breathing parameters (p0.05). Assessment of intersubject variability of H2O2 measurements during the two types of breathing revealed a coefficient of variation of 49 and 54%, respectively. The EBC H2O2 measurement was highly reproducible (888±176 vs. 874±156 nmol/L) as tested during normal breathing.These data demonstrate that the concentration of H2O2 in EBC depends on the ventilatory pattern during sample collection that has to be taken into consideration in all EBC H2O2 assays.

Until the relationship between symptoms, lung function tests, airway inflammation, airway hyper-responsiveness (AHR), exacerbations and remodelling is clarified, regular treatment seems to enable a greater disease control than on-demand therapy in most patients with mild persistent asthma. Current guideline classification based on disease severity remains a cornerstone in asthma management. However, the heterogeneity of asthma, the growing emphasis on subphenotypes, including molecular phenotypes identified by -omics technologies, and their possible implications in terms of different asthma severity, progression and therapeutic response, are changing current asthma treatment mainly based on disease severity classification to a pharmacological strategy more focused on the individual patient.

Peter Barnes first started his career in respiratory research in the late 1970s following studies at the Universities of Oxford and Cambridge. He is currently Professor of Thoracic Medicine at the National Heart and Lung Institute, Head of Respiratory Medicine at Imperial College and Honorary Consultant Physician at the Royal Brompton Hospital. He speaks to Future Medicinal Chemistry about the molecular mechanisms currently under investigation by his group, and discusses his views on the latest therapeutic breakthroughs and the future of respiratory research.

Corticosteroid insensitivity (CI) is a major barrier to treating severe asthma. Despite intensive research, the molecular mechanism of CI remains uncertain. The aim of this study was to determine abnormality in corticosteroid action in severe asthma and to identify the molecular mechanism of the long-acting β(2)-adrenergic agonists (LABAs) formoterol and salmeterol on restoration of corticosteroid sensitivity in severe asthma in vitro. Peripheral blood mononuclear cells (PBMCs) were obtained from 16 subjects with severe corticosteroid-insensitive asthma, 6 subjects with mild corticosteroid-sensitive asthma, and 11 healthy volunteers. Corticosteroid (dexamethasone) sensitivity was determined on tumor necrosis factor-α (TNF-α)-induced interleukin (IL)-8 production. Glucocorticoid receptor (GR) phosphorylation and kinase phosphorylation were evaluated by immunoprecipitation-Western blotting analysis and kinase phosphorylation array in IL-2/IL-4-treated corticosteroid insensitive model in PBMCs. In vitro corticosteroid sensitivity on TNF-α-induced IL-8 production was significantly lower in patients with severe asthma than in healthy volunteers and patients with mild asthma. This CI seen in severe asthma was associated with reduced GR nuclear translocation and with hyperphosphorylation of GR, which were reversed by LABAs. In IL-2/IL-4-treated PBMCs, LABAs inhibited phosphorylation of Jun-NH(2)-terminal kinase and p38 mitogen-activated protein kinase-γ (p38MAPK-γ) as well as GR. In addition, cells with p38MAPK-γ knockdown by RNA interference did not develop CI in the presence of IL-2/IL-4. Furthermore, p38MAPK-γ protein expression was up-regulated in PBMCs from some patients with severe asthma. In conclusion, p38 MAPK-γ activation impairs corticosteroid action and p38 MAPK-γ inhibition by LABAs has potential for the treatment of severe asthma.

Current therapy for asthma is highly effective. β(2)-Adrenergic receptor (β(2)AR) agonists are the most effective bronchodilators and relax airway smooth muscle cells through increased cAMP concentrations and directly opening large conductance Ca(2+) channels. β(2)AR may also activate alternative signaling pathways that may have detrimental effects in asthma. Glucocorticoids are the most effective anti-inflammatory treatments and switch off multiple activated inflammatory genes through recruitment of histone deacetylase-2, activating anti-inflammatory genes, and through increasing mRNA stability of inflammatory genes. There are beneficial molecular interactions between β(2)AR and glucocorticoid-activated pathways. Understanding these signaling pathways may lead to even more effective therapies in the future.

COPD is characterized by chronic airflow limitation and inflammation of the respiratory tract. Several inflammatory biomarkers have been evaluated in COPD but are poorly related to disease severity and progression. Osteoprotegerin (OPG) is a glycoprotein mediator that is expressed in the lung and macrophages, so we have studied its concentration in induced sputum and macrophages of patients with COPD.OPG was measured by enzyme-linked immunosorbent assay in induced sputum of patients with COPD and control subjects.OPG concentrations in induced sputum of patients with COPD (18.7 ± 18.6 ng/mL, n = 39) were significantly higher than those of healthy smokers (8.1 ± 5.6 ng/mL, n = 15), healthy nonsmokers (3.5 ± 3.8 ng/mL, n = 14), or patients with asthma (8.0 ± 5.4 ng/mL, n = 18). Sputum OPG levels in COPD negatively correlated with FEV(1) and positively correlated with residual volume to total lung capacity ratio (RV/TLC) (r = 0.55, P.05), transfer factor of the lung for carbon monoxide (r = -0.53, P.05), and carbon monoxide transfer coefficient (r = -0.61, P.01). By contrast, sputum IL-8 concentrations were related to disease severity but not to RV/TLC or gas diffusion. Airway macrophages and neutrophils were positive for OPG by immunocytochemistry in sputum and peripheral lung tissue. OPG induced matrix metalloproteinase-9 release from sputum macrophages in vitro.Sputum OPG may be a useful biomarker to monitor parenchymal destruction in COPD.

Background The measurement of hydrogen peroxide (H 2 O 2 ) in exhaled breath condensate (EBC) has been proposed as a noninvasive way of monitoring airway inflammation. However, results from individual studies on EBC H 2 O 2 evaluation of asthma are conflicting. The purpose of this study was to explore whether EBC H 2 O 2 is elevated in people with asthma and whether it reflects disease severity and disease control or responds to corticosteroid treatment. Methods Studies were identified by searching PubMed, Embase, Cochrane Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and www.controlled-trials.com for relevant reports published before September 2010. Observational studies comparing levels of EBC H 2 O 2 between patients with asthma who were nonsmokers and healthy subjects were included. Data were independently extracted by two investigators and analyzed using Stata 10.0 software. Results Eight studies (involving 728 participants) were included. EBC H 2 O 2 concentrations were significantly higher in patients with asthma who were nonsmokers compared with healthy subjects, and higher values of EBC H 2 O 2 were observed at each level of asthma, classified either by severity or control level, and the values were negatively correlated with FEV 1 . In addition, EBC H 2 O 2 concentrations were lower in patients with asthma treated with corticosteroids than in patients with asthma not treated with corticosteroids. Conclusions H 2 O 2 might be a promising biomarker for guiding asthma treatment. However, further investigation is needed to establish its role.

Allergic inflammation is due to a complex interplay between several inflammatory cells, including mast cells, basophils, lymphocytes, dendritic cells, eosinophils, and sometimes neutrophils. These cells produce multiple inflammatory mediators, including lipids, purines, cytokines, chemokines, and reactive oxygen species. Allergic inflammation affects target cells, such as epithelial cells, fibroblasts, vascular cells, and airway smooth muscle cells, which become an important source of inflammatory mediators. Sensory nerves are sensitized and activated during allergic inflammation and produce symptoms. Allergic inflammatory responses are orchestrated by several transcription factors, particularly NF-κB and GATA3. Inflammatory genes are also regulated by epigenetic mechanisms, including DNA methylation and histone modifications. There are several endogenous anti-inflammatory mechanisms, including anti-inflammatory lipids and cytokines, which may be defective in allergic disease, thus amplifying and perpetuating the inflammation. Better understanding of the pathophysiology of allergic inflammation has identified new therapeutic targets but developing effective novel therapies has been challenging. Corticosteroids are highly effective with a broad spectrum of anti-inflammatory effects, including epigenetic modulation of the inflammatory response and suppression of GATA3.

Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory disorders of the respiratory tract that are characterized by airflow limitation. They are distinct conditions with different causes, structural changes, and immunopathology. The pathophysiology in asthma and COPD involves not only the proximal large airways, but also the distal small airways, and thus the small airways are an important therapeutic target in the treatment of both diseases. The assessment of diseased distal small airways is challenging. Extensive disease can be present in the small airways with little abnormality in conventional pulmonary function tests. Recent advances in imaging technologies have led to better spatial resolution to assess small airways morphology non-invasively. New physiological tests have been developed to detect disease and response to therapy in regional airways. Improving the efficiency of existing aerosolized therapy to direct drug to the appropriate lung regions may improve clinical efficacy. Approaches to target distal lung regions include developing new drug formulations with smaller aerosol particle size or using inhaler devices that emit aerosolized drug at slow inhalation flows. Large studies are needed to determine whether better distal lung deposition leads to improvements in small airways function that are translated into clinically significant patient outcomes.

Glucocorticoids are the most effective anti-inflammatory therapy for asthma yet are relatively ineffective in chronic obstructive pulmonary disease. Glucocorticoids suppress inflammation via several molecular mechanisms. Glucocorticoids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases, such as asthma, by reversing histone acetylation of activated inflammatory genes through binding of ligand-bound glucocorticoid receptors (GR) to co-activator molecules and recruitment of histone deacetylase-2 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 pro-inflammatory mRNA species. Decreased glucocorticoid responsiveness is found in patients with severe asthma and asthmatics who smoke, as well as in all patients with chronic obstructive pulmonary disease. Several molecular mechanisms of glucocorticoid resistance have now been identified which involve post-translational modifications of GR. Histone deacetylase-2 is markedly reduced in activity and expression as a result of oxidative/nitrative stress so that inflammation becomes 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.

Chronic obstructive pulmonary disease (COPD) is characterised by oxidative stress and increased risk of lung carcinoma. Oxidative stress causes DNA damage which can be repaired by DNA-dependent protein kinase complex.To investigate DNA damage/repair balance and DNA-dependent protein kinase complex in COPD lung and in an animal model of smoking-induced lung damage and to evaluate the effects of oxidative stress on Ku expression and function in human bronchial epithelial cells.Protein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays.8-OH-dG, a marker of oxidant-induced DNA damage, was statistically significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers, while the number of apurinic/apyrimidinic (AP) sites (DNA damage and repair) was increased in smokers compared with non-smokers (p = 0.0012) and patients with COPD (p0.0148). Nuclear expression of Ku86, but not of DNA-PKcs, phospho-DNA-PKcs, Ku70 or γ-H2AFX, was reduced in bronchiolar epithelial cells from patients with COPD compared with normal smokers and non-smokers (p0.039). Loss of Ku86 expression was also observed in a smoking mouse model (p0.012) and prevented by antioxidants. Oxidants reduced (p0.0112) Ku86 expression in human bronchial epithelial cells and Ku86 knock down modified AP sites in response to oxidative stress.Ineffective DNA repair rather than strand breakage per se accounts for the reduced AP sites observed in COPD and this is correlated with a selective decrease of the expression of Ku86 in the bronchiolar epithelium. DNA damage/repair imbalance may contribute to increased risk of lung carcinoma in COPD.

The regulation of human Th17 cell effector function by Treg cells (regulatory T-cells) is poorly understood. In the present study, we report that human Treg (CD4+CD25+) cells inhibit the proliferative response of Th17 cells but not their capacity to secrete IL (interleukin)-17. However, they could inhibit proliferation and cytokine production by Th1 and Th2 cells as determined by IFN-γ (interferon-γ) and IL-5 biosynthesis. Currently, as there is interest in the role of IL-17-producing cells and Treg cells in chronic inflammatory diseases in humans, we investigated the presence of CD4+CD25+ T-cells and IL-17 in inflammation in the human lung. Transcripts for IL-17 were expressed in mononuclear cells and purified T-cells from lung tissue of patients with chronic pulmonary inflammation and, when activated, these cells secrete soluble protein. The T-cell-specific transcription factors RORCv2 (retinoic acid-related orphan receptor Cv2; for Th17) and FOXP3 (forkhead box P3; for Treg cells) were enriched in the T-cell fraction of lung mononuclear cells. Retrospective stratification of the patient cohort into those with COPD (chronic obstructive pulmonary disease) and non-COPD lung disease revealed no difference in the expression of IL-17 and IL-23 receptor between the groups. We observed that CD4+CD25+ T-cells were present in comparable numbers in COPD and non-COPD lung tissue and with no correlation between the presence of CD4+CD25+ T-cells and IL-17-producing cells. These results suggest that IL-17-expressing cells are present in chronically inflamed lung tissue, but there is no evidence to support this is due to the recruitment or expansion of Treg cells.

Research highlights ► Nrf2 anti-oxidant function is impaired when HDAC activity is inhibited. ► HDAC inhibition decreases Nrf2 protein stability. ► HDAC2 is involved in reduced Nrf2 stability and both correlate in COPD samples. ► HDAC inhibition increases Nrf2 acetylation., Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in cellular defence against oxidative stress by inducing the expression of multiple anti-oxidant genes. However, where high levels of oxidative stress are observed, such as chronic obstructive pulmonary disease (COPD), Nrf2 activity is reduced, although the molecular mechanism for this defect is uncertain. Here, we show that down-regulation of histone deacetylase (HDAC) 2 causes Nrf2 instability, resulting in reduced anti-oxidant gene expression and increase sensitivity to oxidative stress. Although Nrf2 protein was clearly stabilized after hydrogen peroxide (H2O2) stimulation in a bronchial epithelial cell line (BEAS2B), Nrf2 stability was decreased and Nrf2 acetylation increased in the presence of an HDAC inhibitor, trichostatin A (TSA). TSA also reduced Nrf2-regulated heme-oxygenase-1 (HO-1) expression in these cells, and this was confirmed in acute cigarette-smoke exposed mice in vivo. HDAC2 knock-down by RNA interference resulted in reduced H2O2-induced Nrf2 protein stability and activity in BEAS2B cells, whereas HDAC1 knockdown had no effect. Furthermore, monocyte-derived macrophages obtained from healthy volunteers (non-smokers and smokers) and COPD patients showed a significant correlation between HDAC2 expression and Nrf2 expression (r = 0.92, p

Educational aims To discuss the similarities and differences in inflammation between COPD and asthma To consider the clinical relevance of these differences To speculate about the therapeutic implications of this basic research

We present multi-wavelength data on the globally infalling molecular cloud/protostellar cluster BYF 73. These include new far-IR spectral line and continuum data from SOFIA's Far Infrared Field-Imaging Line Spectrometer (FIFI-LS), mid-infrared (MIR) observations with the Thermal-Region Camera Spectrograph (T-ReCS) on Gemini-South, and 3 mm continuum data from the Australia Telescope Compact Array (ATCA), plus archival data from Spitzer/IRAC, and Herschel/PACS and SPIRE. The FIFI-LS spectroscopy in [OI]$\lambda63 \mu$m, [OIII]$\lambda88 \mu$m, [OI]$\lambda145 \mu$m, and [CII]$\lambda158 \mu$m highlights different gas environments in and between the dense molecular cloud and HII region. The photo-dissociation region (PDR) between the cloud and HII region is best traced by [OI]$\lambda145 \mu$m and may have density $>$10$^{10}$ m$^{-3}$, but the observed $\lambda145\mu$m/$\lambda63\mu$m and $\lambda63\mu$m/$\lambda158\mu$m line ratios in the densest gas are well outside model values. The HII region is well-traced by [CII], with the $\lambda158\mu$m/$\lambda145\mu$m line ratio indicating a density of 10$^{8.5}$ m$^{-3}$ and a relatively weak ionizing radiation field, 1.5 $\lesssim$ log$(G/G_0)\lesssim$ 2. The T-ReCS data reveal eight protostellar objects in the cloud, of which six appear deeply embedded ($A_V$ $>$ 30$^m$ or more) near the cloud's center. MIR 2 has the most massive core at $\sim$240 M$_{\odot}$, more massive than all the others combined by up to tenfold, with no obvious gas outflow, negligible cooling line emission, and $\sim3-8$% of its 4.7$\times$10$^3$ L$_{\odot}$ luminosity originating from the release of gravitational potential energy. MIR 2's dynamical age may be as little as 7000 yr. This fact, and the cloud's total embedded stellar mass being far less than its gas mass, confirm BYF 73's relatively early stage of evolution., Comment: 6 pages, 5 figures, published in Astrophysical Journal Letters

Patients with chronic obstructive pulmonary disease (COPD) show a poor response to corticosteroids. This has been linked to a reduction of histone deacetylase-2 as a result of oxidative stress and is reversed by theophylline.To determine the role of phosphoinositide-3-kinase-delta (PI3K-δ) on the development of corticosteroid insensitivity in COPD and under oxidative stress, and as a target for theophylline.Corticosteroid sensitivity was determined as the 50% inhibitory concentration of dexamethasone on tumor necrosis factor-α-induced interleukin-8 release in peripheral blood mononuclear cells from patients with COPD (n = 17) and compared with that of nonsmoking (n = 8) and smoking (n = 7) control subjects. The effect of theophylline and a selective PI3K-δ inhibitor (IC87114) on restoration of corticosteroid sensitivity was confirmed in cigarette smoke-exposed mice.Peripheral blood mononuclear cells of COPD (50% inhibitory concentration of dexamethasone: 156.8 ± 32.6 nM) were less corticosteroid sensitive than those of nonsmoking (41.2 ± 10.5 nM; P = 0.018) and smoking control subjects (47.5 ± 19.6 nM; P = 0.031). Corticosteroid insensitivity and reduced histone deacetylase-2 activity after oxidative stress were reversed by a non-selective PI3K inhibitor (LY294002) and low concentrations of theophylline. Theophylline was a potent selective inhibitor of oxidant-activated PI3K-δ, which was up-regulated in peripheral lung tissue of patients with COPD. Furthermore, cells with knock-down of PI3K-δ failed to develop corticosteroid insensitivity with oxidative stress. Both theophylline and IC87114, combined with dexamethasone, inhibited corticosteroid-insensitive lung inflammation in cigarette-smoke-exposed mice in vivo.Inhibition of oxidative stress dependent PI3K-δ activation by a selective inhibitor or theophylline provides a novel approach to reversing corticosteroid insensitivity in COPD.

The upregulation of nitric oxide (NO) by inflammatory cytokines and mediators in central and peripheral airway sites can be monitored easily in exhaled air. It is now possible to estimate the predominant site of increased fraction of exhaled NO (FeNO) and its potential pathologic and physiologic role in various pulmonary diseases. In asthma, increased FeNO reflects eosinophilic-mediated inflammatory pathways moderately well in central and/or peripheral airway sites and implies increased inhaled and systemic corticosteroid responsiveness. Recently, five randomized controlled algorithm asthma trials reported only equivocal benefits of adding measurements of FeNO to usual clinical guideline management including spirometry; however, significant design issues may exist. Overall, FeNO measurement at a single expiratory flow rate of 50 mL/s may be an important adjunct for diagnosis and management in selected cases of asthma. This may supplement standard clinical asthma care guidelines, including spirometry, providing a noninvasive window into predominantly large-airway-presumed eosinophilic inflammation. In COPD, large/central airway maximal NO flux and peripheral/small airway/alveolar NO concentration may be normal and the role of FeNO monitoring is less clear and therefore less established than in asthma. Furthermore, concurrent smoking reduces FeNO. Monitoring FeNO in pulmonary hypertension and cystic fibrosis has opened up a window to the role NO may play in their pathogenesis and possible clinical benefits in the management of these diseases.

Current therapy for asthma with inhaled corticosteroids and long-acting inhaled beta(2)-agonists is highly effective, safe and relatively inexpensive, but for many patients, their disease remains poorly controlled. Most advances in asthma therapy have occurred through improving these drug classes, and a major developmental hurdle is to improve existing drug classes. The major unmet needs include better treatment of severe asthma, and curative therapies for mild to moderate asthma. Many new treatments are specific, targeting a single mediator or receptor, and are unlikely to have a major clinical effect, although they might be effective in specific asthma phenotypes. Drugs with more widespread effects, such as kinase inhibitors, might be more effective but have a greater risk of side effects. New treatments targeting the underlying allergic/immune process would treat concomitant allergic diseases. Improved immunotherapy approaches have the prospect of disease modification, although prospects for a cure are currently remote. The most promising therapeutic developments for asthma are discussed in this review.

Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD.

GOLD ABCD should be used for initial assessment and treatment, but follow-up treatment should focus on treatable traits http://ow.ly/Vm5l30iXYYU

The treatment of asthma has improved greatly during the last two decades, and deaths from the disease have decreased.1 Despite these advances, many asthma patients fail to achieve optimal asthma control as defined by international guidelines.2,3 Severe asthma is associated with high risk of exacerbations and death.4 Definitions of severe asthma vary but, according to European Respiratory Society (ERS)/American Thoracic Society (ATS) and Global Initiative for Asthma (GINA) guidelines, severe asthma is asthma that requires treatment with high doses of inhaled corticosteroids plus a second controller, and/or systemic corticosteroids, to prevent it from becoming uncontrolled, or remains uncontrolled despite this therapy.2,5 In an expert interview, Professor Barnes discusses the latest advances in the management of both mild and severe asthma.

Exposure to household air pollution (HAP) from solid fuel combustion affects almost half of the world population. Adverse respiratory outcomes such as respiratory infections, impaired lung growth and chronic obstructive pulmonary disease have been linked to HAP exposure. Solid fuel smoke is a heterogeneous mixture of various gases and particulates. Cell culture and animal studies with controlled exposure conditions and genetic homogeneity provide important insights into HAP mechanisms. Impaired bacterial phagocytosis in exposed human alveolar macrophages possibly mediates several HAP-related health effects. Lung pathological findings in HAP-exposed individuals demonstrate greater small airways fibrosis and less emphysema compared with cigarette smokers. Field studies using questionnaires, air pollution monitoring and/or biomarkers are needed to better establish human risks. Some, but not all, studies suggest that improving cookstove efficiency or venting emissions may be associated with reduced respiratory symptoms, lung function decline in women and severe pneumonia in children. Current studies focus on fuel switching, stove technology replacements or upgrades and air filter devices. Several governments have initiated major programmes to accelerate the upgrade from solid fuels to clean fuels, particularly liquid petroleum gas, which provides research opportunities for the respiratory health community. [Abstract copyright: Copyright ©ERS 2018.]

We investigate the scale on which the correlation arises between the 843 MHz radio and the 60 micron far-infrared (FIR) emission from star forming regions in the Milky way. The correlation, which exists on the smallest scales investigated (down to ~4 pc), becomes noticeably tight on fields of size 30', corresponding to physical scales of ~20-50 pc. The FIR to radio flux ratio on this scale is consistent with the radio emission being dominated by thermal emission. We also investigate the location dependence of q_mean, a parameter measuring the mean FIR to radio flux ratio, of a sample of star forming regions. We show that q_mean displays a modest dependence on galactic latitude. If this is interpreted as a dependence on the intensity of star formation activity, the result is consistent with studies of the Large Magellanic Cloud (LMC) and other nearby galaxies that show elevated values for q in regions of enhanced star formation., 7 pages, 4 figures, accepted for publication by PASA

Nitric oxide (NO) is increased in the lung periphery of patients with chronic obstructive pulmonary disease (COPD). However, expression of the NO synthase(s) responsible for elevated NO has not been identified in the peripheral lung tissue of patients with COPD of varying severity.Protein and mRNA expression of nitric oxide synthase type I (neuronal NOS [nNOS]), type II (inducible NOS [iNOS]), and type III (endothelial NOS [eNOS]) were quantified by Western blotting and reverse transcription-polymerase chain reaction, respectively, in specimens of surgically resected lung tissue from nonsmoker control subjects, patients with COPD of varying severity, and smokers without COPD, and in a lung epithelial cell line (A549). The effects of nitrative/oxidative stress on NOS expression and activity were also evaluated in vitro in A549 cells. nNOS nitration was quantified by immunoprecipitation and dimerization of nNOS was detected by low-temperature SDS-PAGE/Western blot in the presence of the peroxynitrite generator, 3-morpholinosydnonimine-N-ethylcarbamide (SIN1), in vitro and in vivo.Lung tissue from patients with severe and very severe COPD had graded increases in nNOS (mRNA and protein) compared with nonsmokers and normal smokers. Hydrogen peroxide (H(2)O(2)) and SIN1 as well as the cytokine mixture (IFN-gamma, IL-1beta, and tumor necrosis factor-alpha) increased mRNA expression and activity of nNOS in A549 cells in a concentration-dependent manner compared with nontreated cells. Tyrosine nitration resulted in an increase in nNOS activity in vitro, but did not affect its dimerization.Patients with COPD have a significant increase in nNOS expression and activity that reflects the severity of the disease and may be secondary to oxidative stress.

We report Mopra (ATNF), Anglo-Australian Telescope, and Atacama Submillimeter Telescope Experiment observations of a molecular clump in Carina, BYF73 = G286.21+0.17, which give evidence of large-scale gravitational infall in the dense gas. From the millimetre and far-infrared data, the clump has mass ~ 2 x 10^4 Msun, luminosity ~ 2-3 x 10^4 Lsun, and diameter ~ 0.9 pc. From radiative transfer modelling, we derive a mass infall rate ~ 3.4 x 10^-2 Msun yr-1. If confirmed, this rate for gravitational infall in a molecular core or clump may be the highest yet seen. The near-infrared K-band imaging shows an adjacent compact HII region and IR cluster surrounded by a shell-like photodissociation region showing H2 emission. At the molecular infall peak, the K imaging also reveals a deeply embedded group of stars with associated H2 emission. The combination of these features is very unusual and we suggest they indicate the ongoing formation of a massive star cluster. We discuss the implications of these data for competing theories of massive star formation.

Multiple cytokines play a role in the orchestration of inflammation in inflammatory airway diseases, such as chronic obstructive pulmonary disease, through the recruitment, activation and survival of inflammatory cells. Lymphokines secreted from T cells regulate the pattern of inflammation, whereas proinflammatory cytokines amplify and perpetuate the inflammatory response. Multiple chemokines recruit inflammatory cells from the circulation into the lungs and many growth factors maintain this inflammation and lead to characteristic structural changes in the airways. There are several therapeutic approaches that target cytokine-mediated inflammation in chronic obstructive pulmonary disease, but blocking specific cytokines may not provide clinical benefit, whereas broad-spectrum anti-inflammatory approaches are more likely to be clinically effective.

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field. (c) 2009 Elsevier Ltd. All rights reserved.

There is a pressing requirement to develop new therapies for chronic obstructive pulmonary disease (COPD), as current therapies fail to prevent disease progression or mortality and do not deal with the underlying inflammatory process. The mainstay of current drug therapy is long-acting bronchodilators, but no treatments suppress chronic inflammation in COPD, which is corticosteroid-resistant. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several novel therapeutic targets have been identified, leading to the development of various mediator antagonists, novel broad-spectrum anti-inflammatory treatments and drugs that may reverse the molecular mechanisms of corticosteroid resistance.

BACKGROUND: Increased numbers of activated neutrophils have been reported in the bronchial mucosa of patients with stable chronic obstructive pulmonary disease (COPD), particularly in severe disease. OBJECTIVES: To investigate the expression of neutrophilic chemokines and adhesion molecules in bronchial biopsies from patients with stable COPD of different severity (GOLD stages I-IV) compared with age-matched control subjects, smokers with normal lung function and never smokers. METHODS: The expression of CCL5, CXCL1, 5, 6, 7 and 8, CXCR1, CXCR2, CD11b and CD44 was measured in the bronchial mucosa using immunohistochemistry, confocal immunofluorescence, real-time quantitative polymerase chain reaction (RT-QPCR) and Western blotting (WB). RESULTS: The numbers of CCL5+ epithelial cells and CCL5+ and CXCL7+ immunostained cells were increased in the bronchial submucosa of patients with stable severe COPD compared with control never smokers and smokers with normal lung function. This was also confirmed at the level of mRNA expression. The numbers of CCL5+ cells in the submucosa of patients with COPD were 2-15 times higher than any other chemokines. There was no correlation between the number of these cells and the number of neutrophils in the bronchial submucosa. Compared with control smokers, the percentage of neutrophils co-expressing CD11b and CD44 receptors was significantly increased in the submucosa of patients with COPD. CONCLUSION: The increased expression of CCL5 and CXCL7 in the bronchial mucosa of patients with stable COPD, together with an increased expression of extracellular matrix-binding receptors on neutrophils, may be involved in the pathogenesis of COPD.

Chronic obstructive pulmonary disease (COPD), a disease that encompasses emphysema, chronic obstructive bronchitis and small airway obstruction and that is characterised by largely irreversible airflow obstruction, now affects around 10% of the population over the age of 40 yrs 1. The sixth commonest global cause of death in 1990, currently fourth in developed countries, it is expected rise to third place globally by 2020 2. This increase is linked to the trends of its foremost risk factor, tobacco consumption during the twentieth century, and will track the worldwide smoking trends of this century. Besides smoking cessation and pulmonary rehabilitation, the treatment of COPD has previously consisted of bronchodilators early in the disease and oxygen in the late stages. However, because of the presence of inflammation in COPD, short courses of systemic corticosteroids have been used for decades in the treatment of exacerbations, often along with antibiotics. Their side-effects, however, made them unsuitable for the long-term treatment of stable COPD. In the early 1980s, inhaled formulations of corticosteroids were shown to be highly effective for the treatment of asthma and were readily adopted in COPD with no scientific evidence of their benefit in this indication. This transition from asthma to COPD was so natural to prescribers that a Canadian survey conducted in 1994 found that one-third of patients admitted to hospital for COPD were already using inhaled corticosteroids (ICS) 3, despite the fact that no randomised controlled trials had evaluated their effectiveness in COPD. Today, market research studies estimate that the use of these drugs has increased to the point that they are used by >70% of patients with COPD in the USA and Europe, and are currently given as initial therapy to >50% of patients newly diagnosed with COPD, mostly in combination with a long-acting β-agonist (LABA) 4 …

Peroxynitrite (PN) formed by the reaction of nitric oxide and superoxide is a powerful oxidant/nitrosant. Nitrative stress is implicated in COPD pathogenesis, but PN has not been detected due to a short half-life (1 s) at physiologic condition. Instead, 3-nitrotyrosine has been measured as a footprint of PN release.PN was measured using oxidation of 2',7'-dichlorofluorescein (DCDHF) in exhaled breath condensate (EBC) collected in high pH and sputum cells. The PN scavenging effect was also evaluated by the same system as PN-induced bovine serum albumin (BSA) nitration.The mean (+/- SD) PN levels in EBC of COPD patients (7.9 +/- 3.0 nmol/L; n = 10) were significantly higher than those of healthy volunteers (2.0 +/- 1.1 nmol/L; p0.0001; n = 8) and smokers (2.8 +/- 0.9 nmol/L; p = 0.0017; n = 6). There was a good correlation between PN level and disease severity (FEV(1)) in COPD (p = 0.0016). Fudosteine (FDS), a unique mucolytic antioxidant, showed a stronger scavenging effect of PN than N-acetyl-cysteine on DCDHF oxidation in vitro and in sputum macrophages, and also on PN-induced BSA nitration. FDS (0.1 mmol/L) reduced PN-enhanced interleukin (IL)-1beta-induced IL-8 release and restored corticosteroid sensitivity defected by PN more potently than those induced by H(2)O(2) in A549 airway epithelial cells.This noninvasive PN measurement in EBC may be useful for monitoring airway nitrative stress in COPD. Furthermore, FDS has the potential to inhibit PN-induced events in lung by its scavenging effect.

Summary Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases—including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor κB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-δ inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.